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THE INTERNATIONAL JOURNAL OF

CLINICAL PRACTICE I JCP

FEBRUARY 2011 VOLUME 65 SPECIAL ISSUE

ISSN 1368-5031 (print) ISSN 1742-1241 (online)

ATTD 2010 Yearbook Advanced Technologies and Treatments for Diabetes

Endorsed by the International Conference on ATTD organized by Kenes International

SPECIAL ISSUE

www.IJCP.org

issn 1368-5031 (Print) issn 1742-1241 (Online)

EDITOR-IN-CHIEF Graham Jackson, MD, FESC, FRCP, FACC, Consultant Cardiologist, Cardiothoracic Centre, Guy’s and St Thomas’ Hospital, London, UK

ASSOCIATE EDITORS AND EDITORIAL DEPARTMENTS Rheumatology Karen Costenbader, MD, MPH, Rheumatology and Immunology, Brigham and Women’s Hospital, Boston, MA, USA Cardiovascular Disease Prevention and Metabolic Diseases Anthony Wierzbicki, FACA, FACB, Senior Lecturer in Chemical Pathology, St. Thomas’ Hospital, London, UK Primary Care & Cardiovascular Medicine Rubin Minhas, General Practitioner and Honorary Senior Lecturer with the Faculty of Science, Technology and Medical Studies, University of Kent, Kent, UK Endocrine and Metabolic Diseases Serge Jabbour, MD, Associate Professor of Clinical Medicine, Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College/Thomas Jefferson University, Philadelphia, PA, USA Urology Matt Rosenberg, MD, Medical Director, Mid-Michigan Health Centers, Allegiance Health Systems, Jackson, Michigan, USA Psychiatry Leslie Citrome, MD, MPH, Professor of Psychiatry at the New York University School of Medicine, NY, USA

Neurology & Geriatrics Jagdish Sharma, FRCP, Sherwood Forest NHS Trust and Nottingham University, UK Oncology Mark Harries, MA, PhD, MRCP, Consultant in Medical Oncology, Guy’s Hospital, London, UK Infectious Disease Richard Stein, Department of Molecular Biology, Princeton University, NJ, USA Diabetes George Thomson, PhD, Professor of Diabetes and Endocrinology, Sherwood Forest Hospitals NHS Trust and Sheffield Hallam University, UK Respiratory Medicine Renaud Louis, Professor of Respiratory Medicine, CHU Sart-Tilman, Liege, Belgium Gastroenterology Peter Irving, Consultant Gastroenterologist, Guy’s and St Thomas’ Hospitals, London, UK

EDITORIAL BOARD Harold Bays, Louisville, KY, USA John Betteridge, London, UK Jako Burgers, Nijmegen, The Netherlands John Chambers, London, UK Roger Chapman, Oxford, UK Christopher Chapple, Sheffield, UK Andrew Coatesworth, York, UK Simon Chowdhury, London, UK Gary Das, Woldingham, UK Prokar Dasgupta, London, UK Hans-Christoph Diener, Essen, Germany Edzard Ernst, Devon, UK Ian Fentiman, London, UK Albert Ferro, London, UK Jonathan Foulds, New Brunswick, NJ, USA Robin Gauld, Dunedin, New Zealand Brian Gazzard, London, UK Paul Giangrande, Oxford, UK Barry Goldstein, Rahway, NJ, USA

Irwin Goldstein, Milton, MA, USA Robin Graham-Brown, Leicester, UK Rodney Grahame, London, UK Peter Harper, London, UK Donald Harrison, Cincinnati, OH, USA Ted Johnson, Decatur, GA, USA Martin Jourdan, London, UK George Kassianos, Wokingham, UK Vik Khullar, London, UK Michael Kirby, Baldock, UK Andrew J. Larner, Liverpool, UK Gregory Lip, Birmingham, UK Colin Michie, London, UK Martin Miner, Providence, RI, USA Mark Nelson, London, UK Bertram Pitt, Ann Arbor, MI, USA Stephen Powis, London, UK Basant Puri, London, UK John P Reckless, Bath, UK

Editorial office:

Publisher Chris Graf John Wiley & Sons Inc. Wiley-Blackwell 155 Cremone Street Melbourne, VIC 3121 Australia Tel þ61 418 513 4444 cgraf @wiley.com

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Enquiries for Advertising: Neil Chesher Tel þ44 (0)1865 476 383 Commercial sales: Tobias Trinkl Tel þ49 30 4703 1468 Reprints: Liz Day Tel þ44 (0)1865 476 355

John Rees, London, UK Paul Ross, London, UK Grannum Sant, Cambridge, MA, USA Naveed Sattar, Glasgow, UK H Ralph Schumacher Jr, Philadelphia, PA, USA Patrick Serruys, Rotterdam, The Netherlands Chris Simms, Halifax, Nova Scotia, Canada James Spicer, Sutton, UK David R Staskin, Boston, MA, USA John Stevenson, London, UK Manouche Tavakoli, St. Andrews, UK David Taylor, London, UK Diethelm Tscho¨pe, Bad Oeynhausen, Germany Michael Weinblatt, Boston, MA, USA Claus Wendt, Mannheim, Germany John Wilding, Liverpool, UK Internationally referenced:

• MEDLINE/PubMed • EMBASE (Excerpta Medica) • ISI, Current Contents Impact Factor: 2.245 (ranked 31/132 in ISI JCR )

THE INTERNATIONAL JOURNAL OF

CLINICAL PRACTICE I JCP

FEBRUARY 2011 VOLUME 65 SPECIAL ISSUE

ATTD 2010 Yearbook Advanced Technologies and Treatments for Diabetes

Endorsed by the International Conference on ATTD organized by Kenes International

February 2011 | Volume 65 | Special Issue

ATTD 2010 Yearbook Preface

iii

Advanced Technologies and Treatments for Diabetes Self-monitoring of blood glucose

1

S. K. Garg, I. B. Hirsch

Continuous glucose monitoring in 2010

10

T. Battelino, B. W. Bode

Insulin pumps

16

J. Pickup

Closing the loop

20

E. Dassau, E. Atlas, M. Phillip

New insulins and insulin therapy

26

T. Danne, J. Bolinder

New way of insulin delivery

31

L. Heinemann

Information technology in the service of diabetes prevention and treatment

47

N. Kaufman

Technology and pregnancy

55

J. Nudell, A. Slade, L. Jovanovicˇ, M. Hod

Immune intervention for type 1 diabetes mellitus

61

J. S. Skyler

Exercise and diabetes

71

H. Zisser, P. Gong, C. M. Kelley, J. S. Seidman, M. C. Riddell

Diabetes technology and treatments in the paediatric age group

76

S. Shalitin, H. Peter Chase

Diabetes technology and the human factor A. Liberman, B. Buckingham, M. Phillip

83

Preface The first ATTD 2009 Yearbook presented in February 2010 in Basel was an attempt to create a recognisable appearance to the rapidly developing field of advanced technology and treatment of diabetes, packed with condensed information covering the best research and knowledge as appreciated by the associate editors and the editors. Looking from the distance of a year, the ATTD 2009 Yearbook was a success! It found its way into the hands of clinicians, diabetes educators, researchers in academic institutions, medical departments in international corporations as well as many people interested in diabetes. Its availability on the ATTD webpage and recently in PubMed facilitated access to practically anyone interested in the field. Work on the present ATTD 2010 Yearbook was therefore seasoned with additional responsibility to match the quality and warm acceptance of the first one. Hundreds of papers published between July 2009 and June 2010 were stimulating and made the endeavour worthwhile. The associate editors’ mission was to choose articles that have the most important contribution for the understanding the mechanisms, for the way of thinking, for changing the existing concepts of the clinicians in the specific field that may lead to changing of their way of treating their patients. They were asked to relate also to papers which are more of basic science but which are arising hope for new treatments, even if still quite preliminary. It is not only to highlight them but also to assist the reader to understand why these articles are important and how it can influence the future outlook. The volume is broadened by two new chapters: ‘Diabetes technology and treatment in the paediatric age group’ and ‘Diabetes technology and the human factor’ in addition to the overviews on new drugs and means of delivery, glucose measurement and sensing, the help of information technology, immunomodulation, and type 2 diabetes, diabetes in pregnancy, and closed-loop delivery. Short summaries of selected original papers with comments from the associate editors and editors again bring an expert insight to every specific topic. The reader might notice that in some cases the same paper is

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), iii

discussed in various chapters by different associate editors, highlighting different aspects of the research and its contribution. It is our sincere wish that the ATTD 2010 Yearbook will facilitate the transfer of scientific knowledge and original research to the medical community that strives to assist people with diabetes in their daily struggle to manage the disease. We believe it will foster active communication among all partners in the field of diabetes, from the routine clinical environment, academic institutions, the industry and most importantly – people with diabetes. Finally, we hope the ATTD 2010 Yearbook will help in uniting the tremendous efforts of all partners in finding best solutions to improve life with diabetes and to dream about a life without it.

Conflicts of interest MP’s institution received research grant support, with receipt of travel and accommodation expenses in some cases, from Medtronic and Dexcom. MP is a consultant for Animas, Medtronic and Bayer; and is a member of Scientific advisory boards for CGM3 Ltd., D-Medical and Physical Logic. TB’s institution received research grant support, with receipt of travel and accommodation expenses in some cases, from Abbott, Medtronic, Novo Nordisk and Diamyd. TB is on the speaker’s bureaux of Eli Lilly, Novo Nordisk, Bayer and Medtronic; and is a member of scientific advisory boards for Bayer, Life Scan and Medtronic.

Moshe Phillip The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petah Tikva 49202, Israel Tel: +972-3-9253731 Fax: +972-3-9253836 Email: mosheph@post.tau.ac.il. Tadej Battelino University Children’s Hospital, Dept of Pediatric & Adolescent Endocrinology, Faculty of Medicine, University of Ljubljana, Vrazov trg 1, 1525 Ljubljana, Slovenia Tel: +386 1 522 3584 Fax: +386 1 522 9357 Email: tadej.battelino@mf.uni-lj.si

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Advanced Technologies and Treatments for Diabetes

Self Monitoring Self-monitoring of blood glucose S. K. Garg,1 I. B. Hirsch2 1

University of Colorado Health Science Center, Aurora, CO, USA University of Washington Medical Center, Seattle, WA, USA

2

Many would argue that the introduction of modern-day diabetes management started 30 years ago with the introduction of self-monitoring of blood glucose (SMBG) at home. While that may be true, it is interesting that many of today’s fundamental questions have yet to be answered. Furthermore, the technology itself continues to change, to improve and to better exist with our non-diabetes technology. For example, the first SMBG ‘apps’ are available now for smartphones (iPhone), and we can expect the phones themselves to participate more directly with SMBG and diabetes management. Still, both researchers (and payors) continue to ask some fundamental questions. 1. 2. 3. 4. 5. 6.

What is the efficacy of SMBG for patients not requiring insulin therapy? What is the optimum frequency of SMBG for patients who do require insulin therapy? What is the role of software to assist in data management for SMBG (for both patients and clinicians)? What is the cost effectiveness of SMBG for all of the different patient populations with diabetes? What is the ideal chemistry which results in the least amount of interfering substances with SMBG? What is an acceptable accuracy for SMBG both at home and in the hospital? The accuracy question is more important than ever since all continuous glucose monitoring (CGM) for now are calibrated with SMBG results. 7. What is the best strategy for teaching patients how best to use their SMBG data? 8. What is the best way to integrate SMBG with insulin pump therapy? 9. What is the role of SMBG with today’s CGM devices? 10. What will the role of SMBG be 5–10 years from now with future CGM devices?

Correspondence to: Satish K. Garg, University of Colorado Health Science Center, Aurora, CO, USA Tel.: +1-303-724-6713 Fax: +1-303-724-6784 Email: satish.garg@ucdenver.edu Disclosures: SG received honoraria for Advisory board or for giving talks for Roche Diagnostics, DexCom and Sanofi-Aventis in the last year. SG has also received research funding from Medtronic/Minimed for Close-Loop studies through the University of Colorado. IH received consulting fees from Roche, Bayer, Johnson & Johnson and Abbott Diabetes Care. SG has also received research funding from Novo Nordisk, Sanofi-Aventis and Mannkind Corporation. Endorsed by the International Conference on ATTD organized by Kenes International.

These are just some of the questions which need more thought and study as we move into 2011. In this chapter we have selected papers that appeared in the PubMed on this topic and chose those we thought were most influential in this area. We have then addressed many of these topics although answers are far from clear for many of them. Although SMBG is not ‘new’ technology, much research needs to be completed before we fully understand this tool’s full impact, particularly as CGM becomes more popular.

The prevalence of selfmonitoring of blood glucose and costs of glucometer strips in a nationwide cohort R. L. S. Kjome,1 A. G. Granas,2 K. Nerhus,3 T. H. Roraas,3 S. Sandberg3,4 1 Section for General Practice, University of Bergen, Bergen, Norway, 2Centre for Pharmacy, Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway, 3Norwegian Centre for Quality Improvement of Primary Care Laboratories, University of Bergen, Bergen, Norway, and

4

Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway Diabetes Technol Ther 2010; 12: 701–5

Background: Nationwide data were used to determine the prevalence of SMBG in Norway and to estimate the frequency and cost of SMBG and the use of different glucometers among patients with diabetes. Methods: This retrospective study was based on data of glucometer strips sales to non-institutionalised persons in Norway. The data included demographic details, type and cost of strips, and the number ⁄ time ⁄ place of packages dispensed. Additionally, details

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about insulin and oral antidiabetes medication sales were obtained from the Norwegian Prescription Database. Results: A total of 96,999 persons (2%) purchased strips. Approximately 70% of diabetes patients practised SMBG, and less than 50% of patients performed daily SMBG. An average patient used 1.7 strips per day, and younger patients purchased more strips than older patients. Most patients used only one type of strips, but the number of strips purchased increased with the number of different strips. Conclusions: In total 2% of all non-institutionalised population and an estimated 70% of patients using diabetes medication

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purchased SMBG strips. This, together with the fact that over 50% of the patients measure less than once per day, calls for more tight monitoring of diabetes patients. • Comment: This is an important nationwide (Norway) study that addresses the importance of SMBG in patients with diabetes. Even though more than 70% of patients with diabetes bought SMBG strips, there were still more than half of the patients that monitored their glucose less than once per day. The overall cost for SMBG strips for diabetes management only accounted for 8% of the total cost (446 euros ⁄ person). Unfortunately, this study does not address the relationship of utilisation of SMBG strips and the complications and long-term health outcomes of patients with diabetes. Such studies using national databases may be able to answer in the future the important question of cost–benefit of SMBG in insulin-requiring or non-insulin-taking patients with diabetes.

Evolution of data management tools for managing selfmonitoring of blood glucose results: a survey of iPhone applications A. Rao, P. Hou, T. Golnik, J. Flaherty, S. Vu AgaMatrix Inc., Salem, NH, USA J Diabetes Sci Technol 2010; 4: 949–57 Background: Feedback from the healthcare provider based on SMBG can help achieve target glycaemic control. Electronic SMBG data management and sharing tools for the PC and smart phones may help in reducing the effort to manage SMBG data. Methods: Software and top-ranking applications (apps) for the iPhone platform were reviewed for useful features, and patients with diabetes were observed as they recorded and relayed sample SMBG results to their hypothetical healthcare provider using three apps. Results: The WaveSense Diabetes Manager allowed the participants to complete preselected SMBG data entry and relay tasks faster than other apps. The survey revealed patient behaviour patterns that would be useful in future app development. Conclusions: Being able to record, analyse and obtain feedback on the SMBG data using an iPhone ⁄ iTouch app might potentially benefit patients. Trends in SMBG data management and the possibility of having interoperability of SMBG and smart phones may open up new avenues of diabetes management. • Comment: This study uses WaveSense Diabetes Manager applications on iPhone.

The results of the study are reported as primarily potential as no application of these data has been applied in clinical practice. However, the use of such technology might allow more effective use of SMBG and its interpretation with a possible impact on glucose control and long-term health outcomes. The only problem with this study is that, if iPhone application is used as a standalone entity along with a blood glucose (BG) meter as part of the iPhone, it is likely that regulatory agencies [Food and Drug Administration (FDA) and European Medicines Agency] may consider the iPhone as a new device and thus require Pre-Market Approval applications, which is a very lengthy process for approval of the devices.

ROSSO-in-praxi: a selfmonitoring of blood glucose structured 12-week lifestyle intervention significantly improves glucometabolic control of patients with type 2 diabetes mellitus K. Kempf1, J. Kruse2, S. Martin1 1 West-German Centre of Diabetes and Health, Sana Hospital Gerresheim, Sana Clinics Du¨sseldorf GmbH, Du¨sseldorf, Germany, and 2 Department of Psychosomatic Medicine and Psychotherapy, Justus-Liebig-University Gießen, Gießen, Germany Diabetes Technol Ther 2010; 12: 547–53 Background: Lifestyle changes with healthy diet and physical activity should be the basis for each therapy in patients with type 2 diabetes. The only tool to visualise immediate effects of these changes is SMBG. The aim of the 12-week lifestyle intervention ROSSO-inpraxi was to evaluate the impact of an SMBG-structured motivation and education programme on metabolic and health parameters in diabetes patients not treated with insulin. Methods: Participants (n = 405) generated a seven-point SMBG diurnal profile every 4 weeks, including actual weight, waist circumference and steps per day. At baseline and the end of the study, HbA1c, blood pressure, cholesterol levels, lifestyle changes and well-being were assessed. Results: In total 327 participants (81%) completed the programme and significantly improved their quality of diet and physical activity, accompanied by an increase of > 2300 steps ⁄ day. Patients significantly reduced body mass index, waist circumference, BG, blood pressure, low-density lipo-

protein cholesterol and HbA1c (all p < 0.001), accompanied by increased physical and mental health and reduced depression measurements. Weight loss was significantly associated with overall improvements of metabolic and health parameters. Conclusions: The evaluated SMBG-structured lifestyle intervention is applicable to motivate individuals with type 2 diabetes for lifestyle changes. Integration of this highly motivational low-cost intervention in patients without insulin therapy could strengthen patient empowerment and change lifestyle with improved general health. • Comment: This is a prospective non-randomised controlled trial where patients were followed for 12 weeks. The subjects were asked to do seven-point BG profiles every 4 weeks along with lifestyle intervention. The results clearly indicate that when lifestyle interventions are properly implemented they result in significant improvement of A1c and other glucose, metabolic and health parameters in patients with diabetes. We are not sure if the structured SMBG (seven-point glucose profile) done in this study reflects the improvement in A1c by 0.3%. This modest drop in A1c could easily have been related to the lifestyle modification rather than to the structured SMBG.

The value of episodic, intensive blood glucose monitoring in non-insulin-treated persons with type 2 diabetes: design of the Structured Testing Program (STeP) study, a clusterrandomised, clinical trial W. Polonsky,1 L. Fisher,2 C. Schikman,3 D. Hinnen,4 C. Parkin,5 Z. Jelsovsky,6 L. Amstutz,7 M. Schweitzer,7 R. Wagner7 1 University of California, San Diego, and Behavioral Diabetes Institute, San Diego, CA, USA, 2University of California, San Francisco, CA, USA, 3North Shore University Health System, Skokie, IL, USA, 4Mid America Diabetes Associates, Wichita, KS, USA, 5Health Management Resources Inc., Carmel, IN, USA, 6Biostat International Inc., Tampa, FL, USA, and 7 Roche Diagnostics, Indianapolis, IN, USA BMC Fam Pract 2010; 11: 37 Background: The Structured Testing Program is a 12-month, cluster-randomised, multicentre clinical trial that will try to evaluate whether poorly controlled (HbA1c ‡ 7.5%), non-insulin-treated type 2 diabetes mellitus patients benefit from an integrated physician ⁄ patient intervention using structured SMBG in US primary care practices.

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Methods: A total of 504 patients will be enrolled from 34 clinics, and will be randomly assigned to an active control group that receives enhanced usual care or to an enhanced usual care group plus structured SMBG. Differences in timing and degree of treatment intensification, cost effectiveness, changes in patient self-management behaviours, and quality of life over time will be assessed. Change in HbA1c and other variables over time will be evaluated, and results will be available in 2010. Conclusions: The intervention and trial design emphasise appropriate and collaborative use of SMBG by both patients and physicians, with assessment of the broader impact of intervention on multiple dependent variables. • Comment: This is a randomised control trial sponsored by Roche Diagnostics. The cluster randomisation was done by the practices and the active control group received enhanced usual care plus the structured SMBG. This paper only highlights the design of the study; however, the data were presented at the American Diabetes Association Conference (ADA) in Orlando, FL, 2010. The conclusion of the abstract presented at the ADA showed significantly better A1c improvement in the active control group that was maintained up to 1 year. We shall have to wait for the full paper to be published for further comments.

Evaluation of self-monitoring of blood glucose in non-insulintreated diabetic patients by randomised controlled trials: little bang for the buck M. B. Davidson Charles Drew University, Los Angeles, CA, USA Rev Recent Clin Trials 2010; 5: 138–42 Background: There are still controversial data about the benefit of SMBG in non-insulin-treated type 2 diabetes patients. Only randomised controlled trials can provide the answer. Methods: A meta-analysis on 14 randomised controlled trials where SMBG was performed was done. Results: Nine studies showed no benefit in lowering HbA1c levels. In four of five positive ones, the SMBG group received more intensive education and ⁄ or treatment than the control group. In the one in which patients in both groups were followed similarly, over 500 patients were required to produce a sta-

tistically significant difference of 0.2% favouring SMBG. Conclusions: There is scant evidence that SMBG in non-insulin-treated type 2 diabetes patients is effective in improving glycaemic control. • Comment: The controversy on the role of SMBG in type 2 diabetes continues especially in patients not requiring insulin therapy. In this paper Mayer Davidson did a meta-analysis on 14 randomised controlled trials where SMBG was performed. There was an improvement of only 0.2% in A1c values in favour of SMBG and the clinical significance of that remains debatable. Davidson believes that SMBG is very expensive and may not be useful for non-insulin-requiring patients with type 2 diabetes. It is hoped that there will be a study done one day which will answer this question once and for all rather than continuing to debate based on meta-analysis.

Self-monitoring of blood glucose in type 2 diabetes: systematic review C. Clar,1 K. Barnard,2 E. Cummins,3 P. Royle,4 N. Waugh5 Aberdeen Health Technology Assessment Group 1 Systematic Reviews, Berlin, Germany, 2University of Southampton, Southampton, UK, 3 McMaster Development Consultants, Glasgow, UK, 4University of Aberdeen, Aberdeen, UK, and 5Department of Public Health, Medical School Buildings, Foresterhill, Aberdeen, UK Health Technol Assess 2010; 14: 1–140 Background: A meta-analysis was done to examine whether SMBG is worthwhile in terms of glycaemic control, quality of life and cost per quality-adjusted life year (QALY) in adult patients with type 2 diabetes who were not treated with insulin or who were on basal insulin in combination with oral agents. Methods: A literature search included English language systematic reviews published since 1996 and meta-analyses of randomised controlled trials along with review of qualitative and economic studies. Databases included the Cochrane Library, MEDLINE, EMBASE, PsycINFO, Web of Science (limited to meeting abstracts) and websites. The intervention was SMBG with a meter and test strips. Data were analysed by outcome and subgroups. The following analyses were carried out: SMBG compared to self-monitoring of urine glucose; SMBG vs. no SMBG; more intensive SMBG vs. less intensive SMBG; and more intensive SMBG vs. no SMBG. Results: The review identified 30 randomised controlled trials. Ten trials comparing

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SMBG with no SMBG showed a reduction in HbA1c of 0.21%, which may not be considered clinically significant. A similar difference was shown where SMBG with education was compared with SMBG without education or feedback. Randomised controlled trials showed no consistent effect on hypoglycaemic episodes and no impact on medication changes. Costs of SMBG per year varied considerably. Diabetes Glycaemic Education and Monitoring analysis concluded that SMBG was not cost effective. Qualitative studies revealed that there was a lack of education in how to interpret and use the data from SMBG, with common failure to act on the results. Conclusions: SMBG is of limited clinical effectiveness in improving glycaemic control in type 2 diabetes patients treated with oral agents or diet alone, and is therefore unlikely to be cost effective. SMBG may lead to improved glycaemic control only in the context of appropriate education for patients and healthcare professionals on how to respond to the data (lifestyle and treatment adjustment). • Comment: Here is another meta-analysis similar to the one presented above which further highlights that the cost–benefit ratio goes against SMBG. Similar to the previous study, this meta-analysis also showed a favourable drop in A1c of 0.21% in the SMBG group in the randomised, controlled trial. However, the authors continue to discuss whether this modest reduction in A1c justifies the cost increase to patients with diabetes. One wonders if a better return for the money might come from lifestyle modifications and other medical management in patients with type 2 diabetes not requiring insulin therapy.

System accuracy evaluation of 27 blood glucose monitoring systems according to DIN EN ISO 15197 G. Freckmann,1 A. Baumstark,1 N. Jendrike,1 E. Zschornack,1 S. Kocher,2 J. Tshiananga,2 F. Heister,2 C. Haug1 1 Institute for Diabetes-Technology at the University of Ulm, Ulm, Germany, and 2Institute for Medical Informatics and Biostatistics, Basel, Switzerland Diabetes Technol Ther 2010; 12: 221–31 Background: Blood glucose monitoring systems with a Conformite´ Europe´enne (CE) label should meet the standard DIN EN ISO 15197: 2003: ‡ 95% of the BG results shall fall within ±15 mg ⁄ dl of the reference method at BG concentrations < 75 mg ⁄ dl and within ±20% at BG concentrations ‡ 75 mg ⁄ dl. This

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study evaluated if BG monitoring systems with a CE label fulfil these minimum accuracy requirements. Methods: Twenty-seven BG monitoring systems from 18 manufacturers were evaluated for system accuracy according to DIN EN ISO 15197: 2003. Twenty-four systems were compared with the glucose oxidase reaction (YSI 2300 glucose analyser, YSI Life Sciences, Yellow Springs, OH, USA) and three systems with the hexokinase reaction (Hitachi 917, Roche Diagnostics, Mannheim, Germany). Results: Sixteen of the 27 BG monitoring systems fulfilled the minimum accuracy requirements of the standard, i.e. ‡ 95% of their results showed the minimum acceptable accuracy. Overall, the mean percentage of results showing the minimum acceptable accuracy was 95.2% ± 5.2%, ranging from 80.0% to 100.0%. Conclusions: More than 40% of the evaluated BG monitoring systems did not fulfil the minimal accuracy requirements of DIN EN ISO 15197: 2003 with the risk of false treatment decisions by the diabetes patient and subsequent possible severe health injury. Thus, manufacturers should effectively check the quality of BG meters and test strips. • Comment: This is an important study that compares 27 different BG monitoring systems. The study concludes that more than 40% of the BG monitoring systems did not fulfil the ISO 15197: 2003 minimum criteria of ±20% of the BG concentrations more than 75 mg ⁄ dl. This is more important than ever as we calibrate continuous glucose monitoring systems with SMBG systems. Any error in calibration will result in a much larger mean absolute relative difference on the continuous glucose monitoring system. This is why the FDA is requesting all the meter companies to improve the accuracy of their meters to ±10%.

Cost effectiveness of selfmonitoring of blood glucose in patients with type 2 diabetes mellitus managed without insulin C. Cameron,1 D. Coyle,2 E. Ur3,5,6, S. Klarenbach4–6 1 Canadian Optimal Medication Prescribing and Utilization Service, 2Canadian Agency for Drugs and Technologies in Health, Ottawa, ON, Department of Epidemiology and Community Medicine, 3University of Ottawa, Ottawa, ON, Division of Endocrinology, 4St Paul’s Hospital and Vancouver General Hospital, University of British Columbia, Vancouver, BC,

Department of Medicine, 5University of Alberta, Calgary, AB, and 6Canadian Optimal Medication Prescribing and Utilization Service Expert Review Committee CMAJ 2010 12; 182: 28–34 Background: This study tried to determine the cost effectiveness of SMBG for patients with type 2 diabetes not using insulin. Methods: A cost effectiveness analysis of the SMBG in adult patients with type 2 diabetes not taking insulin was performed using the UK Prospective Diabetes Study (UKPDS) model to forecast diabetes-related complications, corresponding QALYs and costs. Clinical data were obtained from a systematic review comparing self-monitoring with no self-monitoring. Results: Based on a clinically modest reduction in HbA1c of 0.25% (estimated from the systematic review), the UKPDS model predicted that SMBG performed ‡ 7 times ⁄ week reduced the lifetime incidence of diabetes-related complications compared with no SMBG, albeit at a higher cost. Conclusions: For most patients with type 2 diabetes not using insulin, use of BG test strips for frequent SMBG ‡7 times ⁄ week is unlikely to represent efficient use of finite healthcare resources, although periodic testing of once or twice a week may be cost effective. • Comment: Here is another study from Canada looking into cost effectiveness of SMBG in non-insulin-requiring patients with type 2 diabetes. A similar but modest reduction in A1c of 0.25% was reported in subjects using SMBG seven or more times per week. The authors conclude that SMBG is unlikely to represent efficient use of finite healthcare resources. There needs to be a proper study done for a longer duration addressing the cost–benefit ratio of SMBG.

Inpatient glucose control: a glycaemic survey of 126 US hospitals C. B. Cook,1 G. L. Kongable,2 D. J. Potter,2 V. J. Abad,2 D. E. Leija,2 M. Anderson 3 1 Mayo Clinic College of Medicine, Scottsdale, AZ, USA, 2The Epsilon Group Virginia, LLC, Charlottesville, VA, USA, and 3Medical Automation Systems, Charlottesville, VA, USA J Hosp Med 2009; 4 (9): E7–E14 Background: There is a significant value of treating inpatient hyperglycaemia. However, little is known about glucose control in US hospitals. Methods: The Remote Automated Laboratory System-Plus was used to extract inpatient

point-of-care bedside glucose (POC-BG) tests from 126 hospitals between January and December 2007. Patient-day-weighted mean POC-BG and hypoglycaemia ⁄ hyperglycaemia rates were calculated for intensive care unit (ICU) and non-ICU areas, and the relationship of POC-BG levels and hospital characteristics was determined. Results: A total of 12,559,305 POC-BG measurements were analysed (23.4% from the ICU and 76.6% from the non-ICU). Patientday-weighted mean POC-BG was similar for ICU and for non-ICU (165 mg ⁄ dl and 166 mg ⁄ dl, respectively). Prevalence of hospital hyperglycaemia (> 180 mg ⁄ dl) was 46.0% and 31.7% and for hypoglycaemia (< 70 mg ⁄ dl) 10.1% and 3.5% for ICU and for non-ICU, respectively. Larger hospitals (‡ 400 beds) had significantly lower patientday-weighted mean POC-BG per patient day than smaller hospitals (< 200 beds, p < 0.001). Rural hospitals had higher POCBG levels than urban and academic hospitals (p < 0.05), and hospitals in the West had the lowest values. Conclusions: POC-BG data can support hospital efforts to monitor the status of inpatient glycaemic control. Hospital hyperglycaemia was found to be common, whereas hypoglycaemia prevalence was low, and POCBG levels varied by hospital characteristics. • Comment: This is an interesting study that addresses remote automated lab systems to evaluate inpatient POC-BG tests. The results were strikingly different in rural hospitals compared to academic or urban hospitals. Rural hospitals had much higher POC-BG levels than academic institutes. Such a system could possibly guide remote facilities electronically with better inpatient diabetes management. We are sure that in the future we will see many such applications available to many institutes worldwide.

Evaluation of a simple policy for pre- and post-prandial blood glucose self-monitoring in people with type 2 diabetes not on insulin K. Bonomo, A. De Salve, E. Fiora, E. Mularoni, P. Massucco, P. Poy, A. Pomero, F. Cavalot, G. Anfossi, M. Trovati San Luigi Gonzaga Faculty of Medicine of the Turin University, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, Italy Diabetes Res Clin Pract 2010; 87: 246–51 Background: This study evaluated the effects of the frequency of SMBG policy on

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glycaemic control, taking into account compliance in type 2 diabetes patients not treated with insulin. Methods: A total of 273 patients with HbA1c > 7% already using SMBG were randomised as follows: group A, one BG profile per month with fasting and postprandial values; group B, one BG profile every 2 weeks with preprandial and postprandial values. Patients were followed by the same team with the same education and treatment policies every 3 months. At 3 and 6 months, SMBG profiles were evaluated and HbA1c measured. Results: Self-monitoring of blood glucose was performed as recommended by 73% of group A and 44% of group B patients. In compliant patients, HbA1c and BG were unchanged in group A, whereas in group B fasting, preprandial and two out of three postprandial BG values were reduced and HbA1c was significantly decreased (p < 0.001). Conclusions: The more intensive SMBG policy considered was associated with improved glycaemic control in compliant subjects. • Comment: This Italian study addresses the role of preprandial and postprandial BG monitoring in type 2 diabetes. This was a proper randomised control trial where half of the patients were randomised to one BG profile per month with fasting and postprandial glucose values and the second group was randomised to a frequency increase to every 2 weeks. The study concluded that frequent SMBG monitoring resulted in a better A1c drop. Unfortunately, this was only a 6-month clinical trial and no analysis was done for long-term health outcomes in these patients with type 2 diabetes not on insulin therapy; and thus the controversy continues.

Impact of self-measurement of blood glucose on complications of type 2 diabetes: economic analysis from a Czech perspective C. Weber,1 S. Kocher,1 K. Neeser,1 D. Bartaskova2 1 Institute for Medical Informatics and Biostatistics, Basel, Switzerland, and 2Motol University Hospital, Prague, Czech Republic Curr Med Res Opin 2010; 26: 289–96 Background: The objective of this analysis was to determine the economic impact of SMBG by comparing the cost share of selfmonitoring and the direct costs of diabetesrelated complications in SMBG users and non-users.

Methods: A matched-pair analysis based on the cohorts of patients with type 2 diabetes (ROSSO) was conducted. The average annual costs of diabetes monitoring, treatmentrelated services, complications and follow-up costs of the disease for SMBG users vs. nonusers were calculated. Analysis was performed to determine the main cost drivers. Results: Total annual costs were higher in non-users compared with users in patients treated with oral antidiabetic drugs (OADs) only, and in those treated with OADs + insulin. The main cost drivers were stroke and myocardial infarction in patients treated with OADs only, and stroke, dialysis and myocardial infarction in patients treated with OADs + insulin. Conclusions: Cost analysis indicated that SMBG provides a rapid return on initial investment. • Comment: A study from the Czech Republic addresses the impact of SMBG on longterm complications of type 2 diabetes. This was a large retrospective study and thus the conclusions deriving from it may need to be questioned. However, the main cost driver reported in the study was related to myocardial infarction, stroke and dialysis in patients on oral drugs and ⁄ or insulin therapy. The use of SMBG was reported to be beneficial as the major cost drivers were long-term complications of diabetes. Even though this study is retrospective in nature, we think it at least looks at a long-term health outcome in the Czech Republic.

Self-monitoring of blood glucose in patients with type 2 diabetes on oral anti-diabetes drugs: cost effectiveness in France, Germany, Italy and Spain

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training) were supplied by LifeScan and applied as appropriate for each country’s reimbursement policy. Cohort characteristics and assumed HbA1c effects came from a US longitudinal analysis of new SMBG users. Country-specific estimations for use of screening programmes, concomitant medications and mortality rates were used. Primary outcomes included total direct costs, gains in QALYs, and incremental cost effectiveness ratios (ICERs) over 40 years. Results: Incremental cost effectiveness ratios were largest in France and in Italy. Five-year ICERs for SMBG twice per day were below 40,000 euros ⁄ QALY for all four countries, and those for SMBG three times per day were below 45,000 euros ⁄ QALY. With the SMBG dis-utility, ICERs increased modestly in all scenarios except SMBG once per day in France and Italy. Conclusions: With cost assumptions reflecting current reimbursement levels in four European countries, SMBG was found to be cost effective across a 40-year time horizon, with all base case ICERs < 16,000 ⁄ QALY. This study documented the country-specific, long-term value of SMBG for type 2 diabetes patients treated with OADs. • Comment: The use of SMBG in type 2 diabetes and its controversies continues; this work done in France, Germany and Italy reported cost effectiveness across a 40-year time horizon in favour of SMBG. This study is important as it was looking at ICERs and QALYs in patients with type 2 diabetes on OADs alone.

Self-monitoring of blood glucose for type 2 diabetes patients treated with oral antidiabetes drugs and with a recent history of monitoring: cost effectiveness in the USA

S. L. Tunis,1 W. D. Willis,2 V. Foos3 1 IMS Health Inc., Falls Church, VA, USA, 2 LifeScan Inc., High Wycombe, Buckinghamshire, UK, and 3IMS Health Inc., Basel, Switzerland Curr Med Res Opin 2010; 26: 163–75

S. L. Tunis,1 M. E. Minshall2 1 IMS Health Inc., Falls Church, VA, USA, and 2Formerly with IMS Health Inc. Curr Med Res Opin 2010; 26: 151–62

Background: This study used the IMSCORE Diabetes Model to project the longterm (40-year) cost effectiveness of SMBG at once, twice or three times per day (vs. no SMBG) for patients with type 2 diabetes treated with OADs from national reimbursement system perspectives (in France, Germany, Italy and Spain). Methods: Self-monitoring of blood glucose input costs (strips, lancets, meters, nurse

Background: This study modelled the costeffectiveness of SMBG at frequencies of once, twice or three times per day for patients with type 2 diabetes mellitus on OADs and included those who had used SMBG in the previous year. Methods: A validated model was used to project 40-year clinical and economic outcomes for SMBG at once, twice or three times per day vs. no SMBG. Primary outcomes were

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differences in total costs, cumulative incidence of complications, QALYs and ICERs. Results: For patients using SMBG once, twice or three times per day, relative risks over 40 years were lower for 14 of 16 complications. Compared to no SMBG, QALYs increased with SMBG frequency. Some increased costs with SMBG were offset by reductions in costs for several diabetes-related complications. Results were most sensitive to time horizon, with SMBG not cost effective over a 5-year simulation period. Conclusions: Results showed that, compared with no SMBG, base case ICERs for each of the three SMBG frequencies examined were below $30,000, and that a portion of the increased costs associated with SMBG were offset by reductions in complication costs and by modest increases in QALYs. • Comment: The controversy on SMBG in type 2 diabetes continues; here is a study reported from the USA. This study also reports on subjects using SMBG once, twice or three times per day with type 2 diabetes not on insulin therapy. It concluded that the relative risks over 40 years were lower for 14 of the 16 complications in patients using SMBG, thus favouring the use of SMBG in non-insulin-requiring type 2 diabetes. This is an important study (not randomised) which addresses long-term health outcomes in type 2 diabetes not on insulin therapy and SMBG.

Self-monitoring of blood glucose in non-insulin-treated patients with type 2 diabetes: a systematic review and metaanalysis S. Allemann,1,2 C. Houriet,1 P. Diem,1 C. Stettler2,3 1 Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital, and University of Bern, Bern, Switzerland, 2Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland, and 3Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Bern, Bern, Switzerland Curr Med Res Opin 2009; 25: 2903–13 Background: To assess the effect of SMBG on glycaemic control in non-insulin-treated patients with type 2 diabetes. Methods: This is a systematic review and meta-analysis based on MEDLINE and the Cochrane Controlled Trials Register data of randomised controlled trials comparing SMBG with non-SMBG (primary analysis) or more frequent SMBG with less intensive SMBG (secondary analysis). The primary endpoint was HbA1c; secondary outcomes

included fasting glucose and the occurrence of hypoglycaemia. Results: Fifteen trials (3270 patients) were included in the analyses. SMBG was associated with a larger reduction in HbA1c compared with non-SMBG. The beneficial effect associated with SMBG was not attenuated over longer follow-up. SMBG significantly increased the probability of detecting hypoglycaemia. Frequency of SMBG did not result in significant changes of HbA1c. Conclusions: SMBG compared with nonSMBG is associated with a significantly improved glycaemic control in non-insulintreated patients with type 2 diabetes. The added value of more frequent SMBG compared with less intensive SMBG remains uncertain. • Comment: As in the other analyses above, SMBG in type 2 patients not receiving insulin resulted in a small and clinically debatable reduction in A1c. This study, however, adds another dimension to the question: the frequency of SMBG which at least for the metaanalysis has not been able to be well characterised. Assessing frequent, less frequent, ‘structured’ or no SMBG in one randomised trial under usual conditions for this population would be welcomed.

Interference studies with two hospital-grade and two homegrade glucose meters M. E. Lyon,1–4 L. B. Baskin,4 S. Braakman,5 S. Presti,6 J. Dubois,6 T. Shirey6 1 Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada, 2Department of Pediatrics, University of Calgary, Calgary, AB, Canada, 3Department of Pharmacology and Therapeutics, University of Calgary, Calgary, AB, Canada, 4Calgary Laboratory Services, Calgary, AB, Canada, 5 Calgary Health Region, Calgary, AB, Canada, and 6Nova Biomedical Corporation, Waltham, MA, USA Diabetes Technol Ther 2009; 11: 641–7 Background: Interference studies of four glucose meters (Nova Biomedical StatStrip – hospital grade; Roche Diagnostics Accu-Chek Aviva – home grade; Abbott Diabetes Care Precision FreeStyle Freedom – home grade; and LifeScan SureStep Flexx – hospital grade) were evaluated and compared with the clinical laboratory plasma hexokinase reference method. Methods: Within-run precision was determined using a freshly prepared whole blood sample spiked with concentrated glucose to give three glucose concentrations. Day-to-day precision was evaluated using aqueous control

materials supplied by each vendor. Common interferences, including haematocrit, maltose and ascorbate, were tested alone and in combination with one another on each of the four glucose testing devices at three BG concentrations. Results: Within-run precision for all glucose meters was < 5% except for the FreeStyle (up to 7.6%). Between-day precision was < 6% for all glucose meters. Ascorbate caused differences of > 5% with pyrroloquinolinequinone (PQQ)-glucose-dehydrogenase-based technologies (Aviva and Freestyle) and the glucose-oxidase-based Flexx meter. Maltose strongly affected the PQQ-glucose-dehydrogenase-based meter systems. When combinations of interferences were tested, the extent of the interference was up to 193% (Aviva), 179% (FreeStyle), 25.1% (Flexx) and 5.9% (StatStrip). The interference was most pronounced at low glucose (3.9–4.4 mmol ⁄ l). Conclusions: All evaluated glucose meter systems demonstrated varying degrees of interference by haematocrit, ascorbate and maltose mixtures. Aviva and Freestyle showed greater susceptibility than glucose Flexx meter. However, the modified glucose-oxidase-based amperometric method (Nova StatStrip) was less affected in comparison with the glucose-oxidase-based photometric method (LifeScan SureStep Flexx). • Comment: Imprecision due to the various known interfering substances is well known, but quantification of the inaccuracies is not as well appreciated. The good news is that the PQQ-glucose-dehydrogenase meters will probably be replaced by other chemistries in the near future. The ultimate goal needs to be a minimisation of all interfering substances with SMBG.

Performance of a new interference-resistant glucose meter S. Vanavanan,1 P. Santanirand,2 U. Chaichanajarernkul,1 A. Chittamma,1 J. A. Dubois,3 T. Shirey,3 M. Heinz3 1 Faculty of Medicine, Division of Clinical Chemistry, Department of Pathology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 2Faculty of Medicine, Microbiology Unit, Department of Pathology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, and 3Nova Biomedical Corporation, 200 Prospect Street, Waltham, MA, USA Clin Biochem 2010; 43: 186–92 Background: The study examined the analytical performance of the StatStrip glucose monitoring system.

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Methods: Linearity, percentage recovery and within-run imprecision were studied using glucose-spiked whole blood. A total of 120 samples were used in method comparison using plasma hexokinase as the comparison method. Common interferences were tested on the StatStrip, Accu-Chek Advantage and the MediSense Optium glucose meters at different glucose levels. Results: The StatStrip assay showed excellent linearity and recovery. The coefficients of variation for imprecision were < 5%. This meter correlated well with the comparison method. Of the three meters tested, only the StatStrip showed interference < 10% for all spiked levels of different interferences at different levels of glucose tested. Conclusions: The StatStrip meter showed good performance and is suitable for pointof-care hospital glucose testing. • Comment: The initial announcement in 2009 of 13 deaths from meters using PQQglucose-dehydrogenase chemistry has resulted in the entire diabetes community assessing the importance of accuracy in general but especially in the inpatient setting. The Nova StatStrip (Nova Biomedical Corporation, Waltham, MA, USA) appears to be an excellent example of a BG strip that could resolve many of the problems now noted with precision and interferences.

Frequency and motives of blood glucose self-monitoring in type 1 diabetes 1

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M. V. Hansen, U. Pedersen-Bjergaard, S. R. Heller,2 T. M. Wallace,3 A. K. Rasmussen,4,5 H. V. Jørgensen,4 S. Pramming,6 B. Thorsteinsson1 1 Department of Cardiology and Endocrinology, Hillerød Hospital, Hillerød, Denmark, 2 Clinical Sciences Centre, Northern General Hospital, Sheffield, UK, 3Endocrinology and Metabolism, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK, 4 Steno Diabetes Center, Gentofte, Denmark, 5Department of Endocrinology, Copenhagen University Hospital, Denmark, and 6Oxford Health Alliance, London, UK Diabetes Res Clin Pract 2009; 85: 183–8 Background: This study assessed the frequency of and motives for SMBG and compared SMBG behaviour with clinical, behavioural and demographic characteristics. Methods: A cross-sectional Danish–British multicentre survey of patients with type 1 diabetes (n = 1076) completed a detailed questionnaire on SMBG test frequency and motive as well as related issues. Results: SMBG was performed daily by 39% of the patients and less than weekly by

24%. Routine testing was reported by 67%, and the remaining patients only tested when hypoglycaemia or hyperglycaemia was suspected. Age, gender and level of diabetesrelated concern were associated with test pattern. Lower HbA1c was associated with more frequent testing. Reported frequencies of mild and severe hypoglycaemia and hypoglycaemia awareness were independently associated with testing behaviour, whereas the presence of late diabetic complications was not. Conclusions: Almost two-thirds of the patients do not perform daily SMBG and one-third does not perform routine tests. • Comment: This report underscores the challenges with diabetes therapy, particularly as it pertains to type 1 diabetes. Even though we have had the definitive proof for almost two decades that meticulous glycaemic control can improve long-term complications, the actual self-management of these patients is poor. For physicians who practise in specialised diabetes centres, the extent of the lack of self-management may be a surprise, but patients (at least in the USA) are clearly biased to where they obtain their care. Our speculation is that the general results from this report are likely to be applicable to most countries. The real issues are (i) what can be done to improve patient self-management practices; and (ii) would it be more efficient to instead use our resources to develop technologies that make successful control less dependent on patient actions? The latter point is obviously ideal but will probably be required to have more significant improvements in care.

The value of self-monitoring of blood glucose: a review of recent evidence A. St John A,1 W. A. Davis,2 C. P. Price,3 T. M. Davis2 1 ARC Consulting, Perth, W Australia, Australia, 2School of Medicine and Pharmacology, University of Western Australia, Fremantle, W Australia, Australia, and 3Department of Clinical Biochemistry, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK J Diabetes Complications 2010; 24: 129–41 Background: This study reviewed the recent literature relating to the role of SMBG and glycaemic control. Methods: A meta-analysis searching the MEDLINE and EMBASE databases was performed on randomised controlled trials in type 2 diabetes with HbA1c as an outcome measure. Results: There were 23 studies (13 nonexperimental and 10 experimental) including

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six randomised controlled trials of type 2 diabetes. The results of five of these randomised controlled trials in non-insulin-treated type 2 diabetic patients were combined in a metaanalysis with two earlier randomised controlled trials which yielded a significant pooled SMBG-related decrease in HbA1c of )0.22. Conclusions: The present meta-analysis showed an SMBG-related HbA1c reduction in non-insulin-treated type 2 diabetes patients. This finding is consistent with most observational studies of similarly treated patients. • Comment: This is another meta-analysis in non-insulin-requiring type 2 patients, and another finding of a small improvement of HbA1c of unclear significance. The consistency of these meta-analyses is noteworthy.

Predictors of glycaemic control in patients with type 1 diabetes commencing continuous subcutaneous insulin infusion therapy S. Shalitin, M. Gil, R. Nimri, L. de Vries, M. Y. Gavan, M. Phillip The Jesse Z and Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Diabet Med 2010; 27: 339–47 Background: This study aimed to identify variables that predict glycaemic control in type 1 diabetic patients switched to a continuous subcutaneous insulin infusion (CSII) regimen. Methods: Medical files of type 1 diabetic patients (n = 421) aged 2.6–39.8 years who initiated CSII treatment and used it for ‡ 1 year (mean time use 4.1 ± 2.1 years) were reviewed. Details about their background and disease-related and treatment-related variables were recorded. At pump initiation, the mean age was 15.9 ± 7.2 years, mean diabetes duration 6.4 ± 5.8 years. Good glycaemic control was defined by HbA1c stratified by age (American Diabetes Association target levels). Improvement in glycaemic control was defined as a reduction of ‡ 0.5% in HbA1c from baseline, and change in the rate of severe hypoglycaemia or diabetic ketoacidosis. Results: A significant sustained decrease in HbA1c with CSII for a long period without increased rates of hypoglycaemia was found. Achievement of target HbA1c was significantly associated with lower HbA1c (p < 0.001), younger age (< 12 years), shorter diabetes duration (p < 0.001) and more frequent daily SMBG (p < 0.01) at pump

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initiation. Improved glycaemic control was associated with longer CSII use (p = 0.032) and higher HbA1c at pump initiation (p < 0.001). Conclusions: Switching patients to CSII resulted in a sustained decrease in HbA1c. Young age, frequent SMBG and lower HbA1c at pump initiation were identified as predictors of achieving glycaemic targets with CSII. • Comment: This study conveys a fundamental point about CSII: without frequent SMBG full benefit and long-term improvement of glycaemic control will be lacking.

Associations between features of glucose exposure and A1c: the A1c-Derived Average Glucose (ADAG) study R. Borg,1 J. C. Kuenen,2 B. Carstensen,1 H. Zheng,3 D. M. Nathan,3 R. J. Heine,2 J. Nerup,1 K. Borch-Johnsen,1 D. R. Witte1 on behalf of the ADAG Study Group 1 Steno Diabetes Center, Copenhagen, Denmark, 2Vrije Universiteit Medical Center, Vrije Universiteit, Amsterdam, The Netherlands, and 3 Diabetes Center and Biostatistics Department, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Diabetes 2010; 59: 1585–90 Background: The objective of this study was to examine the relationship among common indexes of postprandial glycaemia, overall hyperglycaemia, glucose variability and HbA1c using detailed glucose measures, and to evaluate which BG values of the day provide the strongest prediction of HbA1c. Methods: In the HbA1c -Derived Average Glucose (ADAG) study, glucose levels were monitored with continuous glucose monitoring (CGM) and frequent SMBG during 16 weeks in participants with type 1 diabetes (n = 268) and type 2 diabetes (n = 159) and in non-diabetic subjects (n = 80). Several indexes of glycaemia were calculated. The association between glucose measurements at different times of the day and HbA1c was analysed. Results: Indexes derived with SMBG strongly correlated with those from CGM. The area under the glucose curve calculated from CGM 2 h after a meal correlated well with the 90-min SMBG postprandial measurements. Fasting BG levels were moderately correlated with indexes of hyperglycaemia and average or postprandial glucose levels. Preprandial glucose values had a stronger association with HbA1c than postprandial values for both diabetes types, but particularly for type 2 diabetes.

Conclusions: Indexes of glucose variability and average and postprandial glycaemia intercorrelate strongly within each category. Variability indexes are weakly correlated with the other categories, indicating that these measures convey different information. Preprandial glucose values have a larger impact on HbA1c levels than postprandial values. • Comment: Many of us recall how the only way diabetes was often assessed was with fasting plasma glucose measurements. It was certainly not appreciated how little this information provided. We also should not be surprised that preprandial glucose levels had better correlation with A1c than postprandial levels since, depending on the population (recall, this was in all patients studied), the postprandial glucose spikes will be short-lived. Much work is required to better understand all of the different measurements of glucose variability and it is not surprising that these metrics convey different information. The key for this in the future will be to best understand which of the measures are most dangerous as they pertain to hypoglycaemia and long-term complications.

Review of adverse events associated with false glucose readings measured by GDHPQQ-based glucose test strips in the presence of interfering sugars J. P. Frias, C. G. Lim, J. M. Ellison, C. M. Montandon Departments of Clinical, Medical, and Regulatory Affairs, LifeScan, Milpitas, CA, USA Diabetes Care 2010; 33: 728–9 Background: This study assessed the implications of falsely elevated glucose readings measured with glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ) test strips. Methods: A review of the FDA’s Manufacturer and User Facility Device Experience database and medical literature for adverse events associated with falsely elevated glucose readings with GDH-PQQ test strips in the presence of interfering sugars was conducted. Results: Eighty-two reports were identified: 20% were associated with death, 56% with severe hypoglycaemia and 15% with nonsevere hypoglycaemia. Although most events occurred in hospitalised patients, at least 17% occurred in outpatients. Agents most commonly associated with adverse events were icodextrin-containing peritoneal dialysate and maltose-containing intravenous immune globulin.

Conclusions: GDH-PQQ test strips pose a safety risk to patients treated with agents containing or metabolised to interfering sugars. • Comment: This report, coming after the FDA announcement, further emphasises the need to improve SMBG chemistries as they pertain to interferences, particularly in the hospital. It is not surprising that further review of database and literature resulted in the finding of more deaths and adverse events. Despite this report and the FDA announcement in August of 2009, there are still accidents ‘waiting to happen’ as not all providers are aware of the problem, particularly with the GDH-PQQ strips. Until new chemistry replaces this older technology, there will probably be more events.

Frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes R. Ziegler,1 B. Heidtmann,2 D. Hilgard,3 S. Hofer,4 J. Rosenbauer,5 R. Holl6 for the DPVWiss-Initiative 1 Clinic for Pediatric and Adolescent Diabetes, Muenster, Germany, 2Catholic Children’s Hospital, Wilhemstift, Hamburg, Germany, 3 Department of Paediatrics, Gemeinschaftskrankenhaus Herdecke, Herdecke, Germany, 4 Department of Pediatrics, Medical University of Innsbruck, Austria, 5Institute of Biometrics and Epidemiology, German Diabetes Centre, Leibnitz Centre for Diabetes Research at Heinrich Heine University, Du¨sseldorf, Germany, and 6University of Ulm, Department of Epidemiology, Ulm, Germany Pediatr Diabetes 2010 Mar 22 [Epub ahead of print] Background: The aim of this study was to correlate the frequency of SMBG to the quality of metabolic control as measured by HbA1c, frequency of hypoglycaemia and ketoacidosis events, and to see whether the associations between SMBG and these outcomes are influenced by the patient’s age or treatment regimen. Methods: Data from the DPV-Wiss database of 26,723 children and adolescents with type 1 diabetes were analysed. Background, disease-related and treatment-related variables were evaluated. Results: The frequency of SMBG was higher in the youngest age group of children (<6 years) than in children aged 6–12 years or in children aged >12 years (p < 0.001). Frequency of SMBG differed significantly also in the different groups of treatment

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(p < 0.001), but only for the CSII group was the frequency considerably higher than with multiple daily injections or conventional therapy. Adjusted for age, gender, diabetes duration, insulin regimen, body mass index standard deviation score, and centre difference, SMBG frequency was significantly associated with better metabolic control (p < 0.001). Increasing the SMBG frequency above five times per day did not result in further improvement of metabolic control. Conclusions: A higher frequency of SMBG measurements was related to better metabolic control. Among adolescents glycaemic control improved distinctly with two or more BG measurements. • Comment: This important report confirms what many have speculated for the paediatric population: the greatest SMBG frequency is in the younger groups (most probably due to greater parental involvement). In a nonrandomised population, those who opt for CSII will test more frequently; and greater SMBG frequency will result in lower A1c levels.

The business of self-monitoring of blood glucose: a market profile M. D. Hughes Enterprise Analysis Corporation, Stamford, CT, USA J Diabetes Sci Technol 2009; 3: 1219–23 SMBG meters and test strips are viewed by consumers and insurers as essentially generic products, with a dramatic growth in sales of SMBG products and declining glucose test strip prices. Thus, it will be challenging for new market entrants to displace wellentrenched existing competitors without a truly innovative technology. Market expansion can only occur through identification of more of the undiagnosed diabetes population and convincing existing diabetes patients to adopt glucose testing or to test more frequently. Ultimately, a combination of technology innovations, patient education and economic incentives may be needed to significantly expand the SMBG market. • Comment: Despite the growth of diabetes worldwide, given the lack of definitive data for SMBG in type 2 patients not receiving insulin it is probably unrealistic to think that glucose meter strips will continue to grow at the pace they have for the past 25 years. In many countries the marketing of test strips has changed since it is more difficult to differentiate meters and strips. More often the strips used for a given population are those

that go to the cheapest bidder. It is clear that newer forms of glucose monitoring, particularly CGM, are more likely to achieve the type of growth seen previously with SMBG.

Glucose meters: a review of technical challenges to obtaining accurate results K. Tonyushkina,1 J. H. Nichols2 1 Department of Pediatrics, Section of Endocrinology, Baystate Children’s Hospital, Tufts University School of Medicine, Springfield, MA, USA, and 2Department of Pathology, Baystate Medical Center, Tufts University School of Medicine, Springfield, MA, USA J Diabetes Sci Technol 2009; 3: 971–80 This paper reviews the challenges involved in obtaining accurate glucose meter results. Establishing the accuracy of glucose meters is challenging. Glucose meters can only analyse whole blood, in which glucose is unstable. Truth for whole blood has not been established, and cells must be separated from the whole blood before analysis by a method like isotope dilution mass spectrometry. Serum cannot be analysed by glucose meters, and isotope dilution mass spectrometry is not commonly available in most hospitals and diabetes clinics to evaluate glucose meter accuracy. Consensus standards recommend comparing whole blood analysis on a glucose meter against plasma ⁄ serum centrifuged from a capillary specimen and analysed by a clinical laboratory comparative method. Multiple complexities are involved in defining technical accuracy and there is no clear consensus among standards agencies and professional societies on accuracy criteria. Clinicians are more concerned with clinical agreement of the glucose meter with a serum ⁄ plasma laboratory result. Acceptance criteria for clinical agreement vary across the range of glucose concentrations and depend on how the result will be used in screening or management of the patient. A variety of factors can affect glucose meter results, including operator technique, environmental exposure and patient factors, such as medication, oxygen therapy, anaemia, hypotension and other disease states. • Comment: Issues pertaining to SMBG accuracy and precision are much more complex than most people appreciate. Many of the issues addressed in this paper do not include the problem of patient error, which further complicates the situation. The bottom line is

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that it may be more difficult than many expect to develop meters as accurate as desired.

Blood glucose test strips: options to reduce usage T. Gomes,6 D. N. Juurlink,1,3–6, B. R. Shah,1,3,5,6 J. M. Paterson,6–8 M. M. Mamdani 2,3,5,6 1 Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 2 St Michael’s Hospital, Toronto, ON, Canada, 3 Department of Medicine, University of Toronto, Toronto, ON, Canada, 4Department of Pediatrics, University of Toronto, Toronto, ON, Canada, 5Department of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada, 6Institute for Clinical Evaluative Sciences, Toronto, ON, Canada, 7Department of Family Medicine, McMaster University, Hamilton, ON, Canada, and 8Centre for Evaluation of Medicines, St Joseph’s Healthcare, Hamilton, ON, Canada CMAJ 2010; 182: 35–8

Background: The impact of more focused public-payor policies for the use of BG test strips was evaluated. Methods: A cross-sectional analysis of annual prescription claims for test strips was conducted for adult patients (‡ 65 years old) with diabetes. Patients were stratified into one of four hierarchical groups according to the most intensive glucose-lowering treatment received during each calendar year. Test strip use was calculated annually for each group over the study period and the effects of five hypothetical policy scenarios of more selective test strip use were assessed. Results: Test strip use increased by almost 250% during one decade; however, more focused policy scenarios could have reduced this number. Conclusions: Many people who self-monitor their BG are at relatively low risk for drug-induced hypoglycaemia. The economic benefits associated with more selective testing could be redirected to more effective interventions for patients with diabetes. • Comment: The economic implications of SMBG continue to achieve much attention. Furthermore, as clinicians use more incretins and less sulfonylureas, rationale let alone data to support SMBG may become even more limited. We should all expect more resistance from payors of SMBG strips for patients with type 2 diabetes given the data currently available.

Advanced Technologies and Treatments for Diabetes

Sensors Continuous glucose monitoring in 2010 T. Battelino,1 B. W. Bode2 1

UMC-University Children’s Hospital, Faculty of Medicine, University of Ljubljana, Slovenia Atlanta Diabetes Associates, Atlanta, GA, USA

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After the initial positive data several recent randomised controlled trials offer more firm evidence supporting the efficacy and safety of real-time continuous glucose monitoring (CGM) in type 1 diabetes (T1D). Integrating CGM with insulin pumps offers additional benefit. Improved metabolic control with significant lowering of glycated haemoglobin along with other parameters of glycaemia and without a concomitant increase in hypoglycaemia is demonstrated in all age groups, including children and adolescents. Reducing hypoglycaemia with CGM in well-controlled individuals with T1D remains to be demonstrated; however, evidence for reducing hypoglycaemia in critically ill patients seems convincing. Several important aspects of type 2 diabetes (T2D) were recently addressed by professional CGM. Adding predictive algorithms to CGM may considerably improve its efficacy and lead the way towards the closed loop.

Correspondence to: Tadej Battelino, UMC-University Children’s Hospital, Faculty of Medicine, University of Ljubljana, Slovenia Tel.: +386 1 522 9235 Fax: +386 1 232 0190 Email: tadej.battelino@mf.uni-lj.si Disclosures: BB is on the global medical board and speaker’s bureau of Medtronic and have received honorarium for speakers fee. BB has received consulting fees and grant support from DexCom and JNJ. TB’s institution received research grant support, with receipt of travel and accommodation expenses in some cases, from Abbott, Medtronic, Novo Nordisk and Diamyd. TB is on the speaker’s bureaux of Eli Lilly, Novo Nordisk, Bayer and Medtronic; and is a member of scientific advisory boards for Bayer, Life Scan and Medtronic. Endorsed by the International Conference on ATTD organized by Kenes International.

Effectiveness of sensoraugmented insulin pump therapy in type 1 diabetes

phia, PA, USA, and 11Helen DeVos Children’s Hospital, Grand Rapids, MI, USA N Engl J Med 2010; 363: 311–20

R. M. Bergenstal,1 W. V. Tamborlane,2 A. Ahmann,3 J. B. Buse,4 G. Dailey,5 S. N. Davis,6 C. Joyce,7 T. Peoples,8 B. A. Perkins,9 J. B. Welsh,8 S. M. Willi,10 M. A. Wood11 for the STAR 3 Study Group 1 International Diabetes Center at Park Nicollet, MI, USA, 2Yale University, New Haven, CT, USA, 3Oregon Health and Science University, Portland, OR, USA, 4University of North Carolina School of Medicine, Chapel Hill, NC, USA, 5 Scripps Institute, La Jolla, CA, USA, 6University of Maryland School of Medicine, Baltimore, MD, USA, 7Memorial University of Newfoundland, Health Science Center, St John’s, NL, Canada, 8Medtronic, Northridge, CA, USA, 9 Toronto General Hospital, Toronto, Canada, 10 Children’s Hospital of Philadelphia, Philadel-

Aims: Based on the data that continuous subcutaneous insulin infusion (CSII) therapy and also CGM reduce HbA1c without an increase in hypoglycaemia in adult populations with T1D this large randomised controlled trial aimed at comparing the use of a sensor-augmented insulin pump (SAP) with standard multiple daily injections (MDI) using insulin analogues. Methods: People with T1D aged 7–70 years using MDI with a long-acting insulin analogue and measuring blood glucose at least four times daily were randomly assigned to receive either therapy with SAP (Medtronic) or MDI with rapid- and long-acting insulin analogues. A detailed diabetes-treatmentrelated education was provided to all partici-

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pants. After age-stratified (paediatric 7–18, adult 19–70) randomisation, the SAP was introduced as CSII therapy followed by the sensor after 2 weeks. Visits were scheduled at 3, 6, 9 and 12 months, and patients had the possibility to contact healthcare professionals via the online diabetes management software CareLink. The primary outcome was change in HbA1c at 1 year and the secondary outcome events of severe hypoglycaemia, both calculated in the intention-to-treat population. Results: In total 244 participants (166 adults, mean age 41.9 ± 12.3; 78 children, mean age 11.7 ± 3.0) were randomised to the SAP, and 241 participants (163 adults, mean age 40.6 ± 12.0; 78 children, mean age 12.7 ± 3.1) to the MDI treatment. The baseline HbA1c (8.3% in both groups) decreased significantly at 3 months in the SAP group and remained significantly lower at 1 year:

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primary end-point 7.5% in the SAP group (absolute reduction 0.8% ± 0.8%) and 8.1% in the MDI group (absolute reduction 0.2% ± 0.9%), with a between-group difference of )0.6% (95% confidence interval (CI) )0.7 to )0.4; p < 0.001). The differences were also significant when calculated separately in the adult population (between-group difference of )0.6%; 95% CI )0.8 to )0.4; p < 0.001) and in children (between-group difference of )0.5%; 95% CI )0.8 to )0.2; p < 0.001), with adjustment for the statistical model. The rate of severe hypoglycaemia did not differ significantly between the groups, calculated in the total population (13.31 vs. 13.48 per 100 person-years, p = 0.58) or separately in adults (15.31 vs. 17.62 per 100 person-years, p = 0.66) and children (8.98 vs. 4.95 per 100 person-years, p = 0.35). The frequency of sensor use was positively associated with a greater reduction in HbA1c at 1 year (p = 0.003 with adjustment for the baseline HbA1c). Significantly more patients achieved the age-appropriate target HbA1c in the SAP group. The incidence of diabetic ketoacidosis was below 0.02 per 100 person-years in all groups and age-divided subgroups. Conclusions: The study demonstrated a statistically and clinically significant difference in HbA1c favouring SAP without an increase in the rate of severe hypoglycaemia or biochemical (sensor-observed) hypoglycaemia in adults and children with T1D. • Comment: The STAR 3 study was designed several years ago to generate evidence for the use of SAP in clinical practice (1), including a separate focus on the paediatric population. The Juvenile Diabetes Research Foundation (JDRF) trial, described in the ATTD Yearbook 2009, was designed and conducted in between and failed to demonstrate positive results for the entire paediatric and adolescent age groups regarding the overall use of CGM (2). The main strengths of the STAR 3 are its very robust design, duration of 1 year, considerable number of participants and clinically meaningful results. In addition to the fact that the use of SAP decreases the HbA1c on average by 0.6% compared with MDI (using insulin analogues) without an increase of severe or biochemical hypoglycaemia, the study shows that is feasible to successfully start a patient on SAP in two steps within 5 weeks. The SAP is as successful in the paediatric population (7–18 years) as in the adult. It is possible that in children and adolescents with T1D the use of CGM is more successful when combined with CSII, since the action required by the real-time glucose value on CGM is considerably easier to perform with a sophisticated insulin pump, where the integrated calculator will suggest

the required insulin dose and the insulin administration will only require pressing a button, than with MDI, where the person must decide on the dose (possibly also with a dose calculator) and administer it with an injection. The success of the CGM clearly depends on its use; however, lower percentage of use gave better results in the STAR 3 than in the JDRF study. The major problem with the STAR 3 study is that an arm with pump therapy only, allowing the effects of CSII and CGM to be separated, is missing. Trials that would demonstrate the effect of using CGM vs. not using CGM in patients using insulin pumps are warranted.

Factors predictive of use and of benefit from continuous glucose monitoring in type 1 diabetes Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group Diabetes Care 2009; 32: 1947–53 Aims: Several randomised controlled trials have demonstrated the effectiveness of CGM in people with T1D when used on a regular basis. This study focused on identifying factors observed during the JDRF trial to predict the outcome in the 6 months follow-up period after the trial. Methods: A 6-month follow-up of 232 patients that completed the CGM arm of the JDRF trial provided the data. Logistic regression analyses were used to evaluate the association between baseline demographic and clinical factors from the JDRF trial and successful CGM use during this follow-up. Results: Factors significantly associated with CGM use were adult age, frequency of pre-study self-monitoring of blood glucose, CGM use during the first month, a higher percentage of CGM values within 71– 180 mg ⁄ dl (3.9–10 mM) in the first month, and a lower percentage of CGM values > 180 mg ⁄ dl (10 mM) in the first month. Factors significantly associated with a reduction in HbA1c were higher initial HbA1c level and more CGM use over the 6 months. Importantly, differences in age were not significant after adjustment of sensor use. In all three age groups more CGM use was associated with a similar decrease in HbA1c. Children and adolescents who were using CGM on average at least 6 days per week had a significant mean absolute drop in HbA1c of at least 0.5%. Notably, none of the questionnaires for assessing baseline psychosocial variables such as fear of hypoglycaemia and perceived diabetes-associated burden were associated with CGM use.

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Conclusions: Long-term consistent use was more frequent in adults than in adolescents or children, but those who used CGM regularly had similar improvements in HbA1c regardless of age. The use of CGM in the first month may help in predicting the long-term benefit. Additional research is needed to identify psychosocial characteristics influencing CGM use. • Comment: This study is important in demonstrating that the apparent age difference in the effect of CGM on lowering HbA1c is entirely dependent on the amount of sensor use. A similar amount of sensor use brings comparable lowering of HbA1c regardless of age. Interestingly, existing surveys of fear of hypoglycaemia and perceived diabetes-associated burden failed to predict sensor use or benefit and new strategies in this field are warranted.

Sustained benefit of continuous glucose monitoring on A1c, glucose profiles, and hypoglycaemia in adults with type 1 diabetes Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group Diabetes Care 2009; 32: 2047–9 Aims: To investigate the benefit of CGM over an additional 6 months in adult participants from the JDRF trial. Methods: Of 86 individuals ‡ 25 years of age who were on CGM as part of the 6-month randomised clinical trial, 83 used the sensor for a median of 6.8 days (interquartile range 5.8–7.0) per week at 12 months. Results: An insulin pump was used by 90% of the participants. Mean change in HbA1c from baseline to 12 months was )0.4% ± 0.6% (p < 0.001) in subjects with baseline HbA1c > 7.0%, with most of the reduction visible within the first 8 weeks. HbA1c remained stable at 6.4% in those with baseline HbA1c < 7.0%. The incidence rate of severe hypoglycaemia decreased from 21.8 events in the first 6 months to 7.1 events per 100 personyears in the last 6 months (95% CI 0–16.7, p = 0.18). Time per day with glucose levels in the range of 71–180 mg ⁄ dl (3.9–10 mM) increased significantly (p = 0.02) from baseline to 12 months. Glucose value standard deviation (SD) (p = 0.02) and mean amplitude of glycaemic excursions (p = 0.03) decreased significantly from baseline to 12 months, indicating a reduction in glucose variability. Conclusions: The benefit of near-daily use of CGM in the adult population was sustained with less intensive follow-up similar to

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routine clinical care. Additionally, the absolute number of severe hypoglycaemia events decreased. • Comment: Clinically meaningful benefits with a further decrease in HbA1c and an increase in time spent in target glucose range clearly demonstrate the feasibility and efficacy of routine CGM use in motivated adults with T1D. An additional decrease in severe hypoglycaemia could be explained with more ‘realtime glucose’ experience over 12 months, but may also reflect lower glucose variability and possibly less hypoglycaemia unawareness. Interestingly, the group with initial HbA1c < 7% maintained an HbA1c value of 6.4% in the extension phase, yet not a single event of severe hypoglycaemia was reported.

Incremental value of continuous glucose monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes – the RealTrend Study D. Raccah,1 V. Sulmont,2 Y. Reznik,3 B. Guerci,4 E. Renard,5 H. Hanaire,6 N. Jeandidier,7 M. Nicolino8 1 University Hospital Sainte Marguerite, Marseille, France, 2American Memorial Hospital, Children’s Hospital, Reims, France, 3Coˆte de Nacre Hospital, Caen, France, 4Centre Hospitalier Universitaire de Nancy and University of Nancy, Nancy, France, 5Centre Hospitalier Universitaire de Montpellier and University of Montpellier, Montpellier, France, 6Centre Hospitalier Universitaire de Toulouse and University of Toulouse, Toulouse, France, 7University Louis Pasteur Hospital, Strasbourg, France, and 8 Hospital Femme-Me`re-Enfant, Lyon, France Diabetes Care 2009; 32: 2245–50 Aim: To evaluate the improvement in glycaemic control by starting insulin pump therapy with or without CGM. Methods: Subjects with T1D for at least 1 year and with an HbA1c > 8% on MDI were randomly assigned to either an SAP (Medtronic) or a regular pump. HbA1c levels were measured at screening, baseline (when the pump was started; CGM was started 12 days prior to baseline), 3 and 6 months. HbA1c and glucose variability from baseline to 6 months were the primary outcomes. Results: A total of 132 participants (51 children aged 2–18 years and 81 adults aged 19–65 years) were randomised but the analysed population consisted of 115 subjects, 55 in the SAP arm (22 children and 33 adults) and 60 in the CSII arm (24 children and 36

adults). For the per protocol population, an additional 24 patients were excluded due to sensor use < 70%. In the intention-to-treat analysis of the primary outcome HbA1c levels decreased significantly in both groups (p < 0.001) but the difference between groups failed to reach statistical significance. In the per protocol population HbA1c reduction was significantly greater in the SAP group (SAP –0.96% ± 0.93%, p < 0.001; control )0.55% ± 0.93%, p < 0.001; intergroup comparison, p = 0.004). In contrast, the reduction in mean blood glucose in the intention-totreat population was significantly greater in the SAP group than in the CSII group ()30.6 ± 54.0 vs. )10.8 ± 39.6 mg ⁄ dl; p = 0.005). Significant differences in favour of the SAP group were also observed in time spent in hyperglycaemia < 190 mg ⁄ dl (10.5 mM), in the hyperglycaemic area under the curve, in the mean amplitude of glycaemic excursions and in the SD of glucose values. Rates of severe hypoglycaemia (0.64 per 100 patient-years) and diabetic ketoacidosis (3.2 per 100 patient-years) were very low. Conclusions: The study confirms the superiority of CSII over MDI in subjects with poorly controlled T1D. Subjects using the SAP > 70% of the study period had an additional significant benefit in reducing HbA1c. • Comment: Although the study has some drawbacks related to relatively high attrition with the main outcome not significant, it clearly demonstrates the additional benefit of CGM in the per protocol population using the sensor for > 70% of time. The overall sensor use is age related in comparison to a similar study conducted in a routine clinical care environment (3). The need to identify patients who can benefit most or alternatively to diversify strategies of CGM use to attract more long-term commitment in adolescents and children is obvious.

Evaluation of an algorithm to guide patients with type 1 diabetes treated with continuous subcutaneous insulin infusion on how to respond to real-time continuous glucose levels – a randomised control trial A. J. Jenkins,1 B. Krishnamurthy,1 J. D. Best,1 F. J. Cameron,2 P. G. Colman,3 S. Farish,3 P. S. Hamblin,4 M. A. O’Connel,2 C. Rodda,6 K. Rowley,7 H. Teede,5 D. N. O’Neal1 1 Department of Medicine, University of Melbourne, St Vincent’s Hospital, Fitzroy, Victoria,

Australia, 2Department of Endocrinology and Diabetes, Royal Children’s Hospital, Melbourne, and Murdoch Children’s Research Institute, Parkville, Victoria, Australia, 3Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, Victoria, Australia, 4 Department of Endocrinology and Diabetes, Western Hospital, Footscray, Victoria, Australia, 5Department of Diabetes, Southern Health, Clayton, Victoria, Australia, 6Department of Pediatrics and School of Psychology, Psychiatry and Psychological Medicine, Monash University, and Monash Medical Centre, Clayton, Victoria, Australia, and 7Onemda VicHealth Koori Health Unit, Centre for Health and Society, School of Population Health, University of Melbourne, Parkville, Victoria, Australia Diabetes Care 2010; 33: 1242–8 Aim: To evaluate if using a decision algorithm together with CGM improves the time spent in normoglycaemia in patients using CSII as their treatment modality. Methods: Participants (age > 13 years, T1D > 1 year, > 3 months CSII with bolus calculator use, HbA1c £ 9.5%, self-monitoring of blood glucose ‡ 4 times daily, internet access) were recruited in pairs matched for age (within 5 years), gender and HbA1c (within 1%). At phase 1 all participants wore a prerandomisation 6-day masked CGM, followed by starting the SAP (Medtronic) at randomisation to either the algorithm (group A) or no additional CGM guidelines (group B) for 16 weeks. All were instructed to upload weekly to CareLink, review their CGM data, and act appropriately upon it. One week before the end of phase 1, the 6-day masked CGM was worn. A 16-week phase two followed where group A returned to standard CSII (without CGM and algorithm) and group B continued with SAP and started using the algorithm. One week before the end of phase 2 the 6-day masked CGM was worn again. The algorithm had a reactive proactive part, available both on paper and in an electronic version. Results: Mean sensor use was 4.5 + 1.3 days per week in phase 1 and did not differ between the groups, being higher in adults than adolescents (4.8 + 1.3 vs. 4.1 + 1.0 days; p = 0.02), and similar to group B in phase 2 (4.3 + 1.5 days). The primary end-point, time within glucose target, did not change within groups or between groups. More participants in group A than group B achieved HbA1c < 7.0%, p = 0.015. HbA1c was inversely related to sensor-use time (p = 0.028) and adulthood (p = 0.014). During phase 2 in group B the number of algorithm handset interactions correlated with percentage glucose target range time (p = 0.04), HbA1c at 32 weeks (p = 0.009)

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and change in HbA1c between 16 and 32 weeks (p = 0.04), with over 80% of handset use occurring during the first month. Conclusions: The use of a decision algorithm with SAP did not increase the time spent in normoglycaemia or significantly decrease HbA1c in between-group comparison; however, some aspects of metabolic control within user-group were significantly improved. • Comment: Usually various appliances from the vast spectrum of home technology compete for consumers – sophisticated paper and electronic user instructions were never popular. A medical device, intended to be used almost continuously by patients alone, should preferably not need separate paper and electronic instructions to be utilised successfully. This was confirmed by this study, where 80% of the handset use occurred in the first out of 4 months. While an obedient adult population did achieve some benefit with meticulous use of the algorithm handset, it had quite expectedly no influence on the adolescent population. Additionally, a more intuitive, patient-led use of similar devices demonstrated clinically and statistically significant benefit for metabolic control (3). An integrated automated algorithm, which would expand from current integrated dose calculators to data from the CGM part of the SAP, would probably fit ideally for all.

Prolonged nocturnal hypoglycaemia is common during 12 months of continuous glucose monitoring in children and adults with type 1 diabetes Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group Diabetes Care 2010; 33: 1004–8 Aim: To assess the amount of nocturnal hypoglycaemia from the 12 months of CGM data obtained during the JDRF trial and its extension. Methods: The data from 180 subjects assigned to the CGM group in the JDRF trial was analysed. The Hypoglycemia Fear Survey was completed at baseline, 6 months and 12 months. CGM data from 12 midnight to 6 am were evaluated. Four subjects had fewer than 42 nights with at least 4 h of glucose data and were not included in the analysis. The dataset included 36,467 nights from 176 subjects (median value of 217 nights per subject), with 86% of nights with the full 6 h of data. The occurrence of at least two CGM glucose values < 60 mg ⁄ dl within a 20 min period was required to define hypoglycaemia.

Results: Hypoglycaemic events occurred in 3083 (8.5%) of the 36,467 nights, with a median of 7.4% (interquartile range 3.7%–12.1%) of nights with hypoglycaemia per subject (approximately twice per month; maximum percentage of hypoglycaemic nights per subject was 27.8%; six subjects (3%) had no hypoglycaemic nights). Median duration of hypoglycaemia was 53 min (interquartile range 29–110 min) and the mean was 81 ± 75 min, with 47% of nights having at least 1 h, 23% at least 2 h and 11% at least 3 h of hypoglycaemia. Mean duration of hypoglycaemia was 73 min in subjects > 25 years and 88 min in subjects < 25 years (median 50 versus 58 min, p = 0.007). A higher incidence of nocturnal hypoglycaemia was associated with lower baseline HbA1c (p < 0.001) and the occurrence of hypoglycaemia on one or more nights during baseline blinded CGM use (p < 0.001). Scores on the Hypoglycemia Fear Survey were not predictive of the frequency of nocturnal hypoglycaemia. Conclusions: During treatment aimed at lowering HbA1c levels to £ 7.0% the occurrence of nocturnal hypoglycaemia was both frequent and prolonged despite CGM use. It seems that an automated closed-loop system is finally needed to optimally replace insulin during the night. • Comment: Hypoglycaemia persists in being a considerable problem in the management of T1D despite the substantial help of technology. Several reports demonstrate a high number of nocturnal hypoglycaemia events, especially those unrecognised or asymptomatic (4). Glucose concentration below 60 mg ⁄ dl (3.3 mM) seems to be rare in physiological conditions. In the JDRF study in 8–65-year-old, healthy, non-obese subjects with normal fasting glucose and normal glucose tolerance night-time sensor glucose values < 60 mg ⁄ dl were much less common than values between 61 and 70 mg ⁄ dl (median frequency 0.0 vs. 1.0%, respectively; p < 0.001) (5). It is therefore important to find novel solutions that will enable more efficient use of the existing technology, probably with an automated closed-loop algorithm that will command the overnight administration of insulin.

Relationships between daily acute glucose fluctuations and cognitive performance among aged type 2 diabetics M. R. Rizzo,1 R. Marfella,1 M. Barbieri,1 V. Boccardi,1 F. Vestini,1 B. Lettieri,2 S. Canonico,3 G. Paolisso1 1 Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples,

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Italy, 2Department of Anesthesiology and Emergency, Second University of Naples, Naples, Italy, and 3Department of Surgery, Second University of Naples, Naples, Italy Diabetes Care 2010; 33: 2169–74 Aim: To assess if mean amplitude of glycaemic excursions and postprandial glycaemia is associated with cognitive function independently of long-term metabolic control in elderly patients with T2D. Methods: All participants were screened for vascular disease by carotid ultrasound and for white ⁄ grey matter disease by nuclear magnetic resonance. CGM (Menarini) was applied to 121 elderly patients with T2D on oral antidiabetic medications after global cognitive function was assessed with the Mini-Mental State Examination (MMSE), corrected for educational levels of patients, and the Trail Making Test A and B, the Wechsler Adult, the Intelligence Scale – Revised Digit Span, the Backward Digit Span (DSP – Backward) and the Verbal Fluency Test. Z-scores from all tests but the MMSE were combined into a cognition composite score. Results: Mean age was 78 ± 6.7 years, 25% had hypertension, 11% hypercholesterolaemia, 11% smoked, and 24% had previous cardiovascular diseases. Fasting glycaemia was 153 ± 10.3 mg ⁄ dl, 2-h postprandial glycaemia 198 ± 27.4 mg ⁄ dl, fasting insulin 170 ± 55 pmol ⁄ l, post meal insulin 398 ± 109 pmol ⁄ l and HbA1c 7.9% ± 0.3%. Mean amplitude of glycaemic excursions was significantly correlated with MMSE (r = 0.83, p < 0.001) and with cognition composite score (r = 0.68, p < 0.001). Such relationship persisted after adjusting for the main anthropometric (body mass index and waist to hip ratio) or metabolic (fasting plasma glucose, postprandial glycaemia, HbA1c) and ⁄ or vascular (mean arterial blood pressure) covariables. Conclusions: The study demonstrates association between glucose variability and impaired cognitive performance in elderly patients with T2D. • Comment: This is a highly interesting study that adds to the scattered information on acute glucose changes and cognition. Its cross-sectional nature and a day or two differences between the cognitive tests and CGM recording limit its potential to demonstrate causal relationship between the observed variables; however, it opens possibilities for interventional studies addressing specifically postprandial glucose fluctuations in this patient cohort. An interesting study in the obese and new-onset T2D adult population (6) adds information on the importance of acute glucose variability markers of endothelial damage, occurring very early in the course

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of development of metabolic syndrome and diabetes. Glucose variability was associated with flow mediated dilatation and intima media thickness. Taken together, people with T2D and ⁄ or metabolic syndrome on oral medication only can benefit considerably from reducing glucose variability as assessed by CGM. CGM is becoming clinically relevant also in predicting cystic fibrosis related diabetes – glucose fluctuations recorded by CGM are the strongest predictor of progression to diabetes and detect considerably more patients than the standard oral glucose tolerance test (7).

Real-time continuous glucose monitoring in critically ill patients U. Holzinger,1 J. Warszawska,1 R. Kitzberger,1 M. Wewalka,1 W. Miehsler,1 H. Herkner,2 C. Madl1 1 Department of Medicine III, Intensive Care Unit, Medical University of Vienna, Vienna, Austria, and 2Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria Diabetes Care 2010; 33: 467–72 Aim: To assess the impact of CGM on glycaemic control in critically ill patients receiving intravenous insulin. Methods: Patients within 24 h after intensive care unit (ICU) admission, aged ‡ 18 years, intubated, receiving mechanical ventilation, and expected to stay > 48 h in the ICU after initiation of intensive insulin therapy, were randomised to either CGM (Medtronic) or a standard protocol with a blinded CGM, both for 72 h. The primary end-point was percentage of time at glucose < 110 mg ⁄ dl (6.1 mM). Secondary end-points were mean glucose levels and rate of severe hypoglycaemia (< 40 mg ⁄ dl, 2.2 mM). Results: Sixty-three patients were randomised to the CGM and 61 to standard protocol. The percentage of time spent < 110 mg ⁄ dl (or < 150 mg ⁄ dl) or the mean blood glucose did not differ significantly between the groups, but the rate of severe hypoglycaemia (< 40 mg ⁄ dl) was lower in the CGM group (1.6% vs. 11.5% in the control group, p = 0.031). Relative risk reduction for severe hypoglycaemia was 86% (95% CI 21%–98%) using real-time CGM, indicating an absolute risk difference of 9.9% (95% CI 1.2–18.6) and a number needed to treat of 10.1 (95% CI 5.4–83.3). Conclusions: Continuous glucose monitoring did not change time within target range,

but significantly decreased hypoglycaemia in critically ill patients. • Comment: Management of glucose concentration in critically ill patients remains controversial with increased morbidity and mortality being associated with both hyperglycaemia and hypoglycaemia. The present study demonstrated that using CGM the same glycaemic control can be achieved with significantly less hypoglycaemia. CGM is therefore a suitable system to improve patients’ safety while practising intensive insulin therapy. Conversely, a small randomised pilot trial in patients with ST elevated myocardial infarction compared SAP with a standard protocol (8) and demonstrated increased time spent < 140 mg ⁄ dl (7.8 mM) with concomitantly increased time spent < 70 mg ⁄ dl (3.8 mM). It seems that the experience of the local intensive care team with diabetes-related technology and the local ‘standard’ protocol play a major role in the interpretation of the obtained results. An automated algorithm for detection of hypoglycaemia or a closed-loop system would probably bring additional benefit.

Real-time hypoglycaemia prediction suite using continuous glucose monitoring: a safety net for the artificial pancreas E. Dassau,1,2 F. Cameron,3 H. Lee,4 B. W. Bequette,4 H. Zisser,1,2 L. Jovanovicˇ,2 H. P. Chase,5 D. M. Wilson,6 B. A. Buckingham,6 F. J. Doyle III1,2 1 Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA, USA, 2Sansum Diabetes Research Institute, Santa Barbara, CA, USA, 3Department of Aeronautics and Astronautics, Stanford University, Palo Alto, CA, USA, 4Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA, 5 Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, CO, USA, 6Department of Pediatrics, Division of Pediatric Endocrinology, Stanford Medical Center, Palo Alto, CA, USA Diabetes Care 2010; 33: 1249–54 Aim: To asses an automated algorithm that predicts developing hypoglycaemia, could stop insulin delivery and could prevent hypoglycaemia. Methods: The core of the hypoglycaemia prediction algorithm (HPA) is a set of five individual alarms (linear projection, Kalman filtering, hybrid infinite impulse–response filter, statistical prediction, numerical logical

algorithm) that are combined through a voting system into one combined alarm. If the number of algorithms that predict hypoglycaemia is above the voting threshold more than twice within 10 min or the sensor blood glucose is below the hypoglycaemic threshold, the alarm sounds. The HPA was tested on a dataset of 18 previously published CGM cases where hypoglycaemia was induced by 180% basal rate. Results: In a CGM case hypoglycaemia of 70 mg ⁄ dl (3.9 mM) was predicted by the different algorithms 55, 45, and 35 min ahead of the event. Depending on the quorum threshold an alarm could have been issued at 55 min if two different algorithms were to issue a positive vote twice in a 10 min window. If the number of positive alarms required was three or four, the warning time would have been 40 and 35 min, respectively. On a historical set of pump shutoff data the HPA predicted 91% of the events 35 min prior to the event using a voting threshold of three, where voting of four of five predicted 82% of the events 35–55 min ahead with a glucose threshold of 80 mg ⁄ dl. Conclusions: Hypoglycaemia prediction algorithm would predict most hypoglycaemic events within the time necessary for effective intervention. Its tuning allows flexibility and can be set to meet user needs. • Comment: Several prediction and alarm algorithms were recently developed to detect either hyperglycaemia (e.g. after a meal) or hypoglycaemia. As mentioned in several papers discussed above, prediction algorithms would supplement current CGM devices and probably considerably increase their efficacy. The HPA presented here by Dassau et al. seems effective, but lacks real clinical data that would allow approaching routine clinical use.

Conclusion CGM is becoming an indispensable tool in modern evaluation and treatment of various aspects of T1D and T2D, as well as cystic fibrosis related diabetes. Further technical development of sensors and CGM devices along with the introduction of diverse prediction algorithms will spread its use in everyday routine management, limited only by the current high price.

References 1 Davis SN, Horton ES, Battelino T, Rubin RR, Schulman KA, Tamborlane WV. STAR 3 randomized controlled trial to compare sensor-augmented insulin pump therapy with multiple daily injections in the treatment of type 1 diabetes: research design, methods, and baseline characteristics

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of enrolled subjects. Diabetes Technol Ther 2010; 12: 249– 55. 2 Bode BW, Battelino T. Continuous glucose monitoring. Int J Clin Pract Suppl 2010; 166: 11–15. 3 Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Effectiveness of continuous glucose monitoring in a clinical care environment. Diabetes Care 2010; 33: 17–22. 4 Meschi F, Bonfanti R, Rigamonti A et al. Patients’ evaluation of nocturnal hypoglycaemia with GlucoDay continu-

ous glucose monitoring in paediatric patients. Acta Diabetol 2010; 47: 295–300. 5 Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group, Fox LA, Beck RW, Xing D. Variation of interstitial glucose measurements assessed by continuous glucose monitors in healthy, nondiabetic individuals. Diabetes Care 2010; 33: 1297–9. 6 Buscemi S, Re A, Batsis JA et al. Glycaemic variability using continuous glucose monitoring and endothelial

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function in the metabolic syndrome and in type 2 diabetes. Diabet Med 2010; 27: 872–8. 7 Schiaffini R, Brufani C, Russo B et al. Abnormal glucose tolerance in children with cystic fibrosis: the predictive role of continuous glucose monitoring system. Eur J Endocrinol 2010; 162: 705–10. 8 Hermanides J, Engstro¨m AE, Wentholt IM et al. Sensoraugmented insulin pump therapy to treat hyperglycemia at the coronary care unit: a randomized clinical pilot trial. Diabetes Technol Ther 2010; 12: 537–42.

Advanced Technologies and Treatments for Diabetes

Pumps Insulin pumps J. Pickup King’s College London School of Medicine, Guy’s Hospital, London, UK

The last year has seen a continued uptake of insulin pump therapy in most countries. The USA is still a leader in pump use, with probably some 40% of type 1 diabetic patients on continuous subcutaneous insulin infusion (CSII), but the large variation in usage within Europe remains, with relatively high use (> 15%) in, for example, Norway, Austria, Germany and Sweden and low use (< 5%) in Spain, the UK, Finland and Portugal. There is much speculation on the factors responsible for this variation, and the possibilities include physician attitudes to CSII and knowledge about its benefits and indications for its use (and inappropriate beliefs about dangers), the availability of reimbursement from insurance companies or funding from national health services, the availability of sufficient diabetes nurse educators and dietitians trained in pump procedures, and clear referral pathways for the pump candidate from general practitioner or general hospital to specialist pump centre. There are now several comprehensive national guidelines on CSII use (see ATTD Yearbook 2009 ) but more work needs to be done in unifying uptake and ensuring all those who can benefit do so. Technology developments recently include increasing use of pumps with continuous glucose monitoring (CGM) connectivity (see elsewhere in this volume) and the emergence of numerous manufacturers developing so-called ‘patch pumps’, often for the type 2 diabetes market. Interestingly, the evidence base for CSII in this group is not well established, and for this reason the selected papers on CSII in this section include several in this area. The use of CSII in diabetic pregnancy is a long-established practice, in spite of the lack of evidence that it is superior to multiple daily injections (MDI), and few randomised controlled trials have been done in recent years. Several papers in this field this year continue the debate about the usefulness of CSII in diabetic pregnancy and are reviewed here. It is pleasing to see more research on the psychosocial aspects of CSII during the year, both from the point of view of how psychological beliefs influence outcomes on CSII (is there a type of patient who does particularly well or poorly on CSII?) and how CSII affects psychological factors like mood, behaviour and quality of life. Quality of life is a difficult topic with doubts that the instruments always capture the aspects of quality of life important to the patient, and there have been conflicting results over the years about whether CSII alters quality of life. Patients in the clinic usually say that it does, and more evidence for quality of life improvement in pump therapy is reviewed here.

CSII AND TYPE 2 DIABETES Insulin pump therapy in patients with type 2 diabetes. Safely improved glycaemic control using a simple insulin dosing regimen S. V. Edelman,1 B. W. Bode,2 T. S. Bailey,3 M. S. Kipnes,4 R. Brunelle,5 X. Chen,6 J. P. Frias6 1 University of California, San Diego, CA, USA, 2 Atlanta Diabetes Associates, Atlanta, GA, USA, 3North County Endocrine, Escondido, CA,

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USA, 4Cetero Research, San Antonio, TX, USA, 5 Bowsher Brunelle Smith LLC, Carmel, IN, USA, and 6Lifescan Inc., Milpitas, CA, USA Diabet Technol Ther 2010; 12: 627–33 Background: The purpose of this study was to investigate the insulin dosing patterns that are necessary to achieve good control in type 2 diabetic patients treated by both insulin injections and oral antidiabetic agents (OADs) who are switched to CSII. Methods: Type 2 diabetic subjects (n = 56) with suboptimal glycaemic control and treated by OADs, basal insulin ± OADs or MDI ± OADs were switched to CSII for

Correspondence to: John Pickup, King’s College London School of Medicine, Guy’s Hospital, London, UK Tel.: +44(20)78486024 Email: john.pickup@kcl.ac.uk Disclosures: JP has received consulting or speaker fees from Medtronic, Animas, CeQur and Nilimedix, manufacturers of insulin pumps. Endorsed by the International Conference on ATTD organized by Kenes International.

16 weeks and control was optimised to achieve the best glycaemic levels. Results: The insulin dose increased throughout the period of pump treatment in all three groups, with the mean basal:bolus ratio being 55:45 at completion. Most subjects (88%) were controlled on two or fewer basal rates. HbA1c declined in all three groups (mean )1.2%, p < 0.001), with those with an HbA1c > 8.5% having the greatest improvement (mean –2.1%, p < 0.001). There was no severe hypoglycaemia, and the mean weight increase at week 16 was 1.9 kg (p < 0.001). Treatment satisfaction improved on pump therapy.

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Conclusions: CSII using a simple one or two basal rate regimen significantly improves glycaemic control in poorly controlled type 2 diabetic patients whether treated by OADs, MDI or basal insulin only.

Using insulin pump therapy in poorly controlled type 2 diabetes P. Wolff-McDonagh, J. Kauffman, S. Foreman, S. Wisotsky, J. A. Wisotsky, C. Wexler C Graduate School of Nursing, Robert Morris University, Moon Township, PA, USA Diabetes Educator 2010; 36: 657–65 Background: Many type 2 diabetic patients remain poorly controlled on injection therapy but reimbursement for CSII usage is restricted in this group by many healthcare providers. This study was a retrospective analysis of the effect of CSII in poorly controlled type 2 diabetes in the setting of a suburban endocrine practice. Methods: Data were examined from 15 type 2 diabetic subjects with HbA1c >8% on MDI with or without OADs, who were switched to CSII and followed up over 1 year. Results: Although the HbA1c increased in one subject on pump therapy, for the remaining 14 people the HbA1c decreased significantly (from a mean of about 9.3% to 8.3%). The body mass index increased significantly on changing to CSII, reaching a plateau at 6 months. The basal insulin dose decreased over the course of pump treatment. Calculating cost of therapy based on pump or injection supplies and insulin use alone over 4 years (i.e. the lifetime of a pump, and not taking into account the effect of lowered HbA1c on outcomes), CSII was more expensive than MDI by about $5000 when daily insulin usage was < 100 units, but it was less expensive by about $600 when insulin usage was 100–150 units ⁄ day and less expensive by about $12,000 when usage was > 150 units ⁄ day. Conclusions: CSII achieves improved glycaemic control in most type 2 diabetic patients poorly controlled on MDI. It is likely to be cost effective in those with high insulin requirements (> 100 units ⁄ day).

Insulin pump use in type 2 diabetes B. W. Bode Atlanta Diabetes Associates, Atlanta, GA, USA Diab Technol Ther 2010; 12 (Suppl 1): S17– 21 This review discusses a number of topics relating to pump use in type 2 diabetes

including the limited number of randomised controlled trials comparing CSII and MDI in type 2 diabetes, the evidence that simpler insulin dosing regimens can be used with type 2 diabetes during CSII, such as a fixed basal rate, the use of U-500 insulin and the development of simpler patch pumps that might be more suitable in this group. The review concludes that the evidence base for the use of CSII in type 2 diabetes is not consistent, and suggests randomised controlled trials comparing CSII vs. MDI after the latter therapy has failed, and more studies on the cost effectiveness of CSII in type 2 diabetes. • Comment: The use of CSII in type 2 diabetes is likely to be of increasing interest in the coming years. Although the evidence for the superiority of pumps over MDI is inconsistent as judged by randomised controlled trials and therefore funding by healthcare providers is very limited, there are an accumulating number of uncontrolled studies that show that HbA1c is often reduced when poorly controlled, usually insulin-resistant, patients on MDI are switched to CSII (as shown by WolffMcDonagh et al.). As with type 1 diabetes, CSII seems to work best in those worst controlled on MDI, as indicated by Edelman et al. points out that pump manufacturers are developing smaller and potentially simpler patch pumps that may be more usable in type 2 diabetes. It seems that one fixed basal rate may be sufficient in many patients. As with type 1 diabetes, the issue of cost effectiveness will be important in ensuring the routine use of CSII in type 2 diabetes, and little work has been done in this area. WolffMcDonagh et al. show that, because the basal insulin dosage is less on pumps than MDI, the costs savings are high for those who are initially insulin resistant on injection therapy. Given the large number of very poorly controlled type 2 diabetic people, an improvement in control in only a small proportion would result in a huge increase in CSII uptake.

CSII IN PREGNANCY Continuous subcutaneous insulin infusion versus multiple daily injections in pregnant women with type 1 diabetes S. Gonza´lez-Romero,1,2 I. Gonza´lez-Molero,1 M. Ferna´ndez-Abella´n,3 M. E. Domı´nguezLo´pez,1 S. Ruis-de-Adana,1,2 G. Olveira,1,2 F. Soriguer1,2 1 Endocrinology and Nutrition Department, Hospital Regional Universitario Carlos Haya, Ma´laga, Spain, 2CIBER de Diabetes y Enfermed-

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ades Metabo´licas Asociadas, Barcelona, Spain, and 3Obstetrics and Gynecology Department, Universitario Carlos Haya, Ma´laga, Spain Diab Technol Ther 2010; 12: 263–9 Background: The aim of this study was to compare glycaemic control and obstetric and perinatal outcomes in pregnant women with type 1 diabetes who were treated by CSII compared to a control group managed by MDI. Methods: A case–control study of 35 pregnancies treated by CSII and 64 pregnancies treated by MDI was performed; women had similar age, diabetes duration and microvascular status. Results: Pregnancy planning was commoner in the CSII group who had a lower HbA1c at the start of pregnancy (6.6% vs. 7.6%, p < 0.05), but control during pregnancy was similar. The frequency of hypoglycaemia and ketoacidosis was not significantly different during MDI- and CSII-managed pregnancy. No differences in diabetes, obstetric or perinatal outcomes were seen, including retinopathy progression, pre-eclampsia, spontaneous miscarriage, congenital abnormalities, birth weight, neonatal hypoglycaemia and stillbirth. Although gross macrosomia was uncommon, many of the newborns were large for gestational age in both groups. Conclusions: The authors conclude that CSII is safe and effective during pregnancy in type 1 diabetes but there is no evidence for improved outcomes.

Glycaemic control and selected pregnancy outcomes in type 1 diabetes women on continuous subcutaneous insulin infusion and multiple daily injections: the significance of pregnancy planning K. Cyganek,1,2 A. Hebda-Szydlo,1,2 B. Katra,1,2 J. Skupien,3 T. Klupa,1,2 I. Janas,1 I. Kaim,2,4 J. Sieradzki,1,2 A. Reron,2,4 M. T. Malecki1,2 1 Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland, 2University Hospital, Krakow, Poland, 3 Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, MA, USA, and 4 Department of Obstetrics and Perinatology, Jagiellonian University Medical College, Krakow, Poland Diab Technol Ther 2010; 12: 41–7 Background: The aim of this study was to assess the safety and efficacy of CSII compared to MDI in an observational study of women with type 1 diabetes.

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Methods: Data were analysed from 116 planned and 153 unplanned pregnancies – 157 women were treated by MDI, 42 by CSII and 70 switched from MDI to CSII during the first trimester. Groups were of similar age, but CSII subjects had longer diabetes duration. Results: Those who planned pregnancy had a lower HbA1c in the first trimester, whether or not they were receiving CSII or MDI. Treatment by CSII or MDI resulted in similar HbA1c during pregnancy, but CSIItreated women gained more weight. There were no differences in birth weight, malformations, stillbirths or other outcomes. Conclusions: Both CSII and MDI can provide excellent control during pregnancy. Planning is beneficial independent of therapy.

Insulin pumps and their use in pregnancy A. D. Wollitzer, H. Zisser, L. Jovanovicˇ Sansum Diabetes Research Institute, Santa Barbara, CA, USA Diab Technol Ther 2010; 12 (Suppl 1): S33–6 This review again points out the lack of trial evidence for improved outcomes when CSII is used in diabetic pregnancy, but then moves to a useful discussion of the potential advantages and disadvantages of CSII during pregnancy in diabetic women. Much of this is extrapolated from non-pregnant people with type 1 diabetes and may or may not apply in pregnancy, but there is the possibility of less hypoglycaemia, less glycaemic variability, better adherence and treatment satisfaction. And on the downside, the learning curve required for the patient to become ‘pump-educated’ may be long compared to the short 20– 25 weeks of pump use in many pregnancies. Another potential disadvantage that is discussed is the risk of ketoacidosis if pump insulin delivery is interrupted – especially dangerous in pregnancy. • Comment: Insulin pump therapy in diabetic pregnancy continues to be a poorly investigated subject. There are still few randomised controlled trials of CSII vs. MDI during pregnancy. The above studies are useful in confirming what has been known for several decades, that average glycaemic control and pregnancy and fetal outcomes are similar during CSII and MDI, and CSII may be safely used in pregnancy. What we do not know (for formal trial evidence) is whether there are subsets of patients who would gain particularly by being switched to CSII during pregnancy. It would be useful, for example, to have a randomised controlled trial of those

who have failed to achieve satisfactory control on MDI during the first trimester because of elevated HbA1c or frequent hypoglycaemia on MDI who are then allocated to either CSII or continued MDI. Many healthcare professionals have anecdotal observations from their own clinic that there are women who have been very troubled by, for example, hypoglycaemia during pregnancy who have improved substantially by a switch to CSII. It is curious that the trial evidence to confirm or refute this indication for CSII continues to be weak.

PSYCHOLOGICAL ASPECTS OF CSII Psychological aspects in continuous subcutaneous insulin infusion: a retrospective study I. Aberle,1 U. Scholz,2 B. Back-Kliegel,3 C. Fischer,4 M. Gorny,5 K. Langer,5 M. Kliegel1 1 Department of Psychology, Technische Universita¨t, Dresden, Germany, 2Department of Psychology, University of Zurich, Switzerland, 3 Department of Metabolism Center, Hirslanden Clinic, Zurich, Switzerland, 4School Counseling Center, Schwa¨bisch Hall, Germany, and 5 Department of Internal Medicine, City Hospital Darmstadt, Germany J Psychol 2009; 143: 147–60 Background: The purpose of this study was to examine in type 1 diabetic subjects treated by CSII the influence of psychological factors such as coping strategy and locus of control on both metabolic control and psychological outcomes such as treatment satisfaction, depressive symptoms and quality of life. Methods: Psychological outcomes and HbA1c were examined in type 1 diabetic patients (n = 51) on CSII at a diabetes centre in Germany. Results: HbA1c was significantly lower on CSII than intensified conventional therapy (7.1% vs. 8.2%, p < 0.001). High HbA1c on CSII correlated with high external locus of control (i.e. the individuals had the general belief that they had little control over their lives and life events such as disease were dependent on external factors, luck and coincidence). High HbA1c was also correlated with more depressive symptoms. Treatment satisfaction and quality of life were associated with high self-efficacy (belief that one is competent to tackle difficult or novel tasks and cope with adversity in demanding situations). Conclusions: Psychological factors are important in the outcomes of CSII. Patients who feel more responsible for the process of

CSII have better control and those with more self-efficacy have a better quality of life and treatment satisfaction.

Investigation of quality of life and family burden issues during insulin pump therapy in children with type 1 diabetes mellitus – a large-scale multicentre pilot study E. Mu¨ller-Godeffroy, S. Treichel, V. M. Wagner on behalf of the German Working Group for Paediatric Pump Therapy Department of Paediatrics, Division of Paediatric Endocrinology and Diabetology, University of Luebeck, Luebeck, Germany Diab Med 2009; 26: 493–501 Background: Although it is assumed that CSII provides psychological and psychosocial as well as metabolic benefits, quality of life effects, for example, have given conflicting results to date. The aim of this study was to investigate changes in psychological factors and the family burden of diabetes in children switched from MDI to CSII. Methods: In a multicentre study, metabolic and psychosocial data were collected from 117 children before and after transfer from MDI to CSII. Results: Although general quality of life did not improve, parent-reported or self-reported diabetes-specific quality of life increased significantly, particularly in school-aged and younger children. Parents reported less frequent parenting stress, hypoglycaemia worry, and overall diabetes burden with regard to themselves and the child. Family conflict was not altered. Parents of younger children reported fewer problems with nutrition management. Conclusions: CSII has significant psychosocial benefits for both the child with diabetes and the family.

Improvements in cognition, mood and behaviour following commencement of continuous subcutaneous insulin infusion therapy in children with type 1 diabetes mellitus: a pilot survey S. Knight,1,2 E. Northam,1–3 S. Donath,1 A. Gardner,4 N. Harkin,4 C. Taplin,4 P. Joy,4 F. J. Cameron,1,3 G. R. Ambler4,5 1 Murdoch Children’s Research Institute, Melbourne, Vic, Australia, 2School of Behavioural Science, University of Melbourne, Vic,

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Australia, 3Royal Children’s Hospital, Melbourne, Vic, Australia, 4Institute of Endocrinology and Diabetes, Children’s Hospital at Westmead, Westmead, NSW, Australia, and 5 Discipline of Paediatrics and Child Health, University of Sydney, NSW, Australia Diabetologia 2009; 52: 193–9 Background: Children with type 1 diabetes are at risk of cognitive and behavioural difficulties that may be influenced by glycaemic fluctuations and long-term metabolic control. The aim of this study was to investigate whether improved glycaemic control with CSII was associated with improvements in cognition, mood and behaviour in children. Methods: Children (n = 32) with type 1 diabetes at two centres in Australia underwent behavioural and cognitive assessments before and 18 weeks after starting CSII. A 72-h period of CGM was used to assess glycaemic variability and hyperglycaemia and hypoglycaemia. Results: HbA1c improved from 8.2% to 7.5% after commencing CSII. Glycaemic

variability was also reduced. There were significant improvements in a number of measures of cognition such as perceptual reasoning, selective attention and working memory. From parents, teachers and selfreports, there were fewer mood-related symptoms and parents reported fewer behavioural problems. None of the changes in mood, behaviour or cognition correlated with improved HbA1c. Conclusions: The improvement in HbA1c afforded by CSII in children with diabetes is accompanied by improvements in mood, behaviour and cognition. • Comment: These interesting papers show that psychosocial factors determine (to some extent) the quality of control on CSII, and that the effects of CSII extend beyond reduced HbA1c, hypoglycaemia and microvascular risk to various interrelated psychological and social outcomes such as quality of life and mood. It is obvious that not all patients do well on CSII and there are several possible reasons why some have an unsatisfactorily high

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HbA1c. Aberle et al. show that such patients tend to have a high external locus of control, i.e. they usually feel less responsible for diabetes and CSII, that the diabetes is beyond their control and that they do not need to take action. Such studies emphasise that psychological care must be seen as an important part of diabetes education before and during CSII. We may well be able to improve metabolic outcome on CSII by attention to psychological health. It is striking how often patients in the clinic report improvements in thinking, mood and well-being after the start of CSII. This has been comparatively poorly studied to date, and the results from Knight et al. are important in confirming it. Particularly interesting is the apparent lack of correlation with HbA1c improvements or other glycaemic variables, suggesting that the effect might be either related to other CSII-related changes (insulin, other metabolites) or more probably the result of changes in hypoglycaemia exposure or blood glucose variability not assessed by the short period of CGM.

Advanced Technologies and Treatments for Diabetes

Closing the loop Closing the loop E. Dassau,1,2 E. Atlas,3 M. Phillip3 1

University of California at Santa Barbara, Santa Barbara, CA, USA Sansum Diabetes Research Institute, Santa Barbara, CA, USA 3 Schneider Children’s Medical Center of Israel, Petah Tikva, Israel 2

Closed-loop algorithms can be found in every aspect of everyday modern life. Automation and control are used constantly to provide safety and to improve quality of life. Closed-loop systems and algorithms can be found in home appliances, automobiles, aviation and more. Can one imagine nowadays driving a car without ABS, cruise control or even anti-sliding control? Similar principles of automation and control can be used in the management of diabetes mellitus (DM). The idea of an algorithmic ⁄ technological way to control glycaemia is not new and has been researched for more than four decades. However, recent improvements in both glucose-sensing technology and insulin delivery together with advanced control and systems engineering made this dream of an artificial pancreas possible. The artificial pancreas may be the next big step in the treatment of DM since the use of insulin analogues. An artificial pancreas can be described as internal or external devices that use continuous glucose measurements to automatically manage exogenous insulin delivery with or without other hormones in an attempt to restore glucose regulation in individuals with DM using a control algorithm. This device as described can be internal or external; can use different types of control algorithms with bi-hormonal or uni-hormonal design; and can utilise different ways to administer them. The different designs and implementations have transitioned recently from in silico simulations to clinical evaluation stage with practical applications in mind. This may mark the beginning of a new era in diabetes management with the introduction of semi-closed-loop systems that can prevent or minimise nocturnal hypoglycaemia, to hybrid systems that will manage blood glucose (BG) levels with minimal user intervention to finally fully automated systems that will take the user out of the loop. More and more clinical trials will be needed for the artificial pancreas to become a reality but initial encouraging results are proof that we are on the right track. We attempted to select recent publications that will present these current achievements in the quest for the artificial pancreas and that will inspire others to continue to progress this field of research.

CLINICAL EVALUATION OF A BI-HORMONAL CLOSED LOOP A bi-hormonal closed-loop artificial pancreas for type 1 diabetes F. H. El-Khatib,1 S. J. Russell,2 D. M. Nathan,2 R. G. Sutherlin,2 E. R. Damiano1 1 Department of Biomedical Engineering, Boston University, Boston, MA, USA, and 2 Diabetes Unit and Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA Sci Transl Med 2010; 2: 1–12

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Background: This paper is a report about the performance of a bi-hormonal artificial pancreas which aims to automatically control BG concentrations within the non-diabetic range in people with type 1 diabetes. This closed-loop control system, developed by the authors, delivers both insulin and glucagon to imitate the normal physiology of BG control in the human body. Methods: The closed-loop control system consists of three components: a venous BG monitor which measures BG concentration every 5 min, infusion pumps to deliver the fast-acting insulin analogue lispro and glucagon subcutaneously, and a computer-based control algorithm that automatically com-

Correspondence to: Eyal Dassau, University of California at Santa Barbara, Santa Barbara, CA, USA Tel.: +1 (805) 693-4727 Fax: +1 (805) 893-4731 Email: dassau@engineering.ucsb.edu Disclosures: EA and ED have no conflict of interest. MP’s institution received research grant support, with receipt of travel and accommodation expenses in some cases, from Medtronic and Dexcom. MP is a consultant for Animas, Medtronic and Bayer; and is a member of Scientific advisory boards for CGM3 Ltd., D-Medical and Physical Logic. Endorsed by the International Conference on ATTD organized by Kenes International.

putes insulin and glucagon doses to be delivered based on sampled BG concentrations. Eleven adults with type 1 diabetes and no endogenous insulin secretion were studied in 27-h experiments, which included three carbohydrate-rich meals. The study experiments were repeated with time-to-peak (tmax) plasma lispro concentration setting doubled, based on the results of the initial experiments. Results: Two patterns of BG control emerged in the first study (lispro tmax set to 33 min). In six subjects, the closed-loop system achieved a mean BG concentration of 140 mg ⁄ dl (lower than the target of £ 154 mg ⁄ dl recommended by the American

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Diabetes Association) with no instances of hypoglycaemia requiring treatment. The timeto-peak plasma lispro in the six subjects ranged from 56 to 72 min (mean, 64 ± 6 min). On the other hand, the other five subjects had a mean BG concentration of 144 mg ⁄ dl and experienced hypoglycaemia that required treatment; however, these subjects were later found to have slower lispro absorption kinetics than the six subjects who did not become hypoglycaemic. The time-to-peak plasma lispro in the five subjects ranged between 71 and 191 min (mean 117 ± 48 min). In the repeated study (lispro tmax set to 65 min), no hypoglycaemia occurred in either group and average aggregate mean BG concentration was controlled to 164 mg ⁄ dl. Conclusion: Automated closed-loop control of BG concentrations to the near-normal range without risk of hypoglycaemia will be feasible with a bi-hormonal artificial endocrine pancreas. • Comment: The authors demonstrated the feasibility of a bi-hormonal system that used both insulin and glucagon to regulate glycaemia. The overall results were extremely encouraging especially when one considers the big carbohydrate load during the study. However, details in the overall system design undermined these results as follows: (a) the logic behind using different control algorithms for insulin and glucagon was not clear; (b) insulin was delivered via a subcutaneous route using two pumps, one with U-100 insulin and a second one with U-10 insulin; (c) glucose measurements were collected via intravenous line which is infeasible in an outpatient system; (d) moreover, measurement delay and sensor errors were not considered in this design. As the authors stated, glucagon was used only to prevent or treat excursions of BG below 100 mg ⁄ dl. In terms of prevention, all subjects in both phases of the study reached BG levels below the desired 100 mg ⁄ dl level. In terms of glucose control, the results were quite similar to uni-hormonal systems. An important result that this study presented is the need to personalise controller tuning to subjects, as reflected by the change in the PK parameter in the second phase of the trials. The change of the PK parameter was the reason for the prevention of hypoglycaemia between the first and second phase of the experiments. Although glucagon was used during this study, the full benefit of the use of glucagon was not presented. The efficacy of glucagon should be tested compared to an insulin-only system. Glucagon should be integrated into a system that already has a mechanism to prevent overdose of insulin and considered to be activated as a rescue measure.

CLINICAL EVALUATION OF UNI-HORMONAL CLOSED LOOP Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial R. Hovorka,1,2 J. M. Allen,1,2 D. Elleri,1,2 L. J. Chassin,1,2 J. Harris,2 D. Xing,3 C. Kollman,3 T. Hovorka,1 A. M. F. Larsen,2 M. Nodale,1 A. De Palma,1 M. E. Wilinska,1,2 C. L. Acerini,1,2 D. B. Dunger1,2 1 Department of Paediatrics and 2Institute of Metabolic Science, University of Cambridge, Cambridge, UK, and 3Jaeb Center for Health Research, Tampa, FL, USA Lancet 2010; 375: 743–51 Background: Closed-loop systems that link subcutaneous continuous glucose measurements to subcutaneous insulin delivery are a promising way to better control BG levels in people with diabetes. This study attempts to establish whether closed-loop insulin delivery can control overnight BG in children and adolescents with type 1 diabetes. Methods: The study consisted of three randomised crossover sub-studies in 19 patients aged 5–18 years with type 1 diabetes of mean duration 6.4 years (SD 4.0). It compared standard continuous subcutaneous insulin infusion and closed-loop delivery (n = 13; APCam01); closed-loop delivery after rapidly and slowly absorbed meals (n = 7; APCam02); and closed-loop delivery and standard treatment after exercise (n = 10; APCam03). Allocation was by computer-generated random code. Participants were masked to plasma and sensor glucose. In APCam01, investigators were also masked to plasma glucose. During closed-loop nights, glucose measurements were fed every 15 min into a control algorithm calculating rate of insulin infusion, and a nurse then adjusted the insulin pump. During control nights, patients’ standard pump settings were used. Primary outcomes were time for which plasma glucose concentration was 3.91–8.00 mmol ⁄ l or 3.90 mmol ⁄ l or lower, and analysis was per protocol. Results: Seventeen patients were studied for 33 closed-loop and 21 continuous infusion nights. Primary outcomes did not differ significantly between treatment groups in APCam01 [12 analysed; target range, median

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52% (interquartile range 43–83) closed loop vs. 39% (15–51) standard treatment, p = 0.06; £ 3.90 mmol ⁄ l, 1% (0–7) vs. 2% (0–41), p = 0.13], APCam02 [six analysed; target range, rapidly absorbed meal 53% (48–57) vs. slowly absorbed meal 55% (37– 64), p = 0.97; £ 3.90 mmol ⁄ l, 0% (0–4) vs. 0% (0–0), p = 0.16] and APCam03 [nine analysed; target range 78% (60–92) closed loop vs. 43% (25–65) control, p = 0.0245, not significant at corrected level; £ 3.90 mmol ⁄ l, 10% (2–15) vs. 6% (0–44), p = 0.27]. A secondary analysis of data documented increased time in the target range [60% (51–88) vs. 40% (18–61); p = 0.0022] and reduced time for which glucose concentrations were 3.90 mmol ⁄ l or lower [2.1% (0.0–10.0) vs. 4.1% (0.0–42.0); p = 0.0304]. No events with plasma glucose concentration < 3.0 mmol ⁄ l were recorded during closedloop delivery, compared with nine events during standard treatment. Conclusions: Closed-loop systems could reduce the risk of nocturnal hypoglycaemia and allow for better BG control in children and adolescents with type 1 diabetes. • Comment: Dr. Hovorka and his collaborators have demonstrated the benefit of closing the loop to reduce the risk of nocturnal hypoglycaemia in children and adolescents. This study as indicated by the authors was designed to prove the concept but, technically, the loop was closed manually by a team member. The control algorithm was an adaptive model predictive control (MPC). Manual glucose measurements from continuous glucose monitoring (CGM) were entered to a user interface; the controller then suggested the new infusion rate and these values were manually entered to the insulin pump to close the loop. Three different randomised crossover studies were reported with the aim of demonstrating closed-loop control over several daily challenges such as slowly and rapidly absorbed meals and exercise. The study demonstrated that automatic glucose regulation is feasible and it can reduce the risk of hypoglycaemia; however, one of the exclusion criteria was recurrent severe hypoglycaemia which undermined the aim of the study. The closed-loop system should be investigated by the authors over an extended period of time with volunteers who experience recurrent severe hypoglycaemia to provide the necessary seal of approval. Closedloop or semi-closed-loop systems that can reduce the likelihood of nocturnal hypoglycaemia in young subjects with type 1 diabetes will most probably be the first to be commercialised.

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Closed-loop insulin delivery using a subcutaneous glucose sensor and intraperitoneal insulin delivery: feasibility study testing a new model for the artificial pancreas E. Renard,1 J. Place,1 M. Cantwell,2 H. Chevassus,3 C. C. Palerm2 1 Endocrinology Department, Le Centre Hospitalier Universitaire Montpellier and Unite´ Mixte de Recherche Centre National de la Recherche Scientifique 5232, University of Montpellier, Montpellier, France, 2Medtronic Diabetes, Northridge, CA, USA, and 3INSERM Clinical Investigation Centre 001, Le Centre Hospitalier Universitaire Montpellier, Montpellier, France Diabetes Care 2010; 33: 121–7 Background: Attempts to build an artificial pancreas by using subcutaneous insulin delivery from a portable pump guided by a subcutaneous glucose sensor have encountered delays in and variability of insulin absorption. In an effort to improve on the consistency and timeliness of such a closed-loop system, this paper tested closed-loop intraperitoneal (IP) insulin infusion from an implanted pump driven by a subcutaneous glucose sensor via a proportional–integral–derivative (PID) algorithm. Methods: Two-day closed-loop therapy (except for a 15-min pre-meal manual bolus) was compared with a 1-day control phase with IP open-loop insulin delivery, according to a randomised order, in a hospital setting with eight patients with type 1 diabetes treated with implanted pumps. The primary endpoint was the percentage of time spent with BG in the range 4.4–6.6 mmol ⁄ l. Results: During the closed-loop phases, the mean ± SEM percentage of time spent with BG in the 4.4–6.6 mmol ⁄ l range was significantly higher (39.1% ± 4.5% vs. 27.7% ± 6.2%, p = 0.05), and overall dispersion of BG values was reduced among patients. Better closed-loop glucose control came from the time periods excluding the two early postprandial hours with a higher percentage of time in the 4.4–6.6 mmol ⁄ l range (46.3% ± 5.3% vs. 28.6% ± 7.4%, p = 0.025) and lower mean BG levels (6.9 ± 0.3 vs. 7.9 ± 0.6 mmol ⁄ l, p = 0.036). Time spent with BG < 3.3 mmol ⁄ l was low and similar for both investigational phases. Conclusions: The results of this paper demonstrate the feasibility of IP insulin delivery for a closed-loop artificial pancreas and support the need for further study of this form of insulin delivery. The features of the

pre-meal bolus still need to be explored in terms of timing and amount. • Comment: Dr. Renard and collaborators have demonstrated the use of a hybrid closed-loop system that utilised prandial insulin delivery, subcutaneous glucose measurement and a PID algorithm. Subcutaneous insulin delivery is one of the limitations of a closed-loop system because of delays and modulation of insulin absorption. A closedloop insulin delivery system that will administer insulin via the IP route should achieve superior glucose control and minimal to no hypoglycaemic episodes due to the lake of subcutaneous depot and fast delivery method. The results presented in the study support the use of IP delivery for the artificial pancreas. Tighter glucose control was obtained in the non-postprandial periods compared to the control group. However, overnight control was as good as the control group and prandial control remained a challenge for the PID algorithm even with a 30% pre-meal bolus. IP insulin delivery may be one of the better methods to regulate glycaemia and to minimise hypoglycaemia using implantable or external pumps. The research of IP delivery as a way for faster insulin action is undergoing and should be considered as a substitute for subcutaneous delivery. The use of an external pump with IP delivery using U-100 insulin will be an improvement on the implantable system that uses U-400 and requires frequent maintenance. Future studies are needed; these studies should explore better and more sophisticated control strategies than the PID algorithm. Furthermore, reducing the occurrence of nocturnal hypoglycaemia and improving prandial glucose control without a pre-meal bolus given by the patient should also be investigated.

MD-Logic Artificial Pancreas system: a pilot study in adults with type 1 diabetes E. Atlas, R. Nimri, S. Miller, E. A. Grunberg, M. Phillip The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Diabetes Care 2010; 33: 1072–6 Background: The authors describe the principles and clinical performance of the MD-Logic Artificial Pancreas (MDLAP) system for controlling BG in adults with type 1 diabetes.

Methods: This system uses fuzzy logic theory to imitate the decision-making processes of experts in diabetes care. Seven adults with type 1 diabetes (aged 19–30 years, mean diabetes duration 10 ± 4 years, mean A1c 6.6% ± 0.7%) underwent 14 full closed-loop control sessions of 8 h (12 total) and 24 h (two total). During the 8-h sessions, subjects arrived at the clinic after an overnight fast, were connected to the MDLAP system and were monitored for 8 h in the fasted state or after a mixed meal consisting of 40–60 g carbohydrate. In the 24-h sessions, subjects consumed three mixed meals and slept approximately 8 h while connected to the MDLAP system. Results: Peak postprandial BG excursion was limited to 224 ± 22 mg ⁄ dl, returned to < 180 mg ⁄ dl within 2.6 ± 0.6 h and was kept stable in the normal range for at least 1 h in all cases. In the 24-h closed-loop control, BG levels were kept in the normal range (between 70 and 180 mg ⁄ dl) 73% of the time, were > 180 mg ⁄ dl 27% of the time and never fell below 70 mg ⁄ dl. Symptomatic hypoglycaemia was not noted during any of the trials. Conclusions: This pilot study shows the MDLAP system to be a promising tool for individualised glucose control in patients with type 1 diabetes. Postprandial glucose highs were minimised and hypoglycaemia was prevented. • Comment: This paper presents a fuzzy logic controller which is a different control strategy from the common modern control strategies such as MPC, PID with insulin feedback that make use of insulin–glucose dynamics. The method relies on a fuzzy model ⁄ set that is based on expert knowledge and relies on the subject’s clinical parameters. As reported by the authors, this is the first clinical evaluation of such a control strategy. Encouraging results were presented with good glucose control and no hypoglycaemia episodes. Prandial glucose peaks were reasonable, although glucose values at mealtime were missing. The time to maintain near normal glycaemia was good as well. However, these results are no different from other closed-loop systems. The advantage of fuzzy logic over other methods currently used was not proven and will require comparative studies in different daily life scenarios. As indicated by the authors the controller design is based on traditional treatment ⁄ individual subject treatment plan. This design may limit the system since there is a need to tune the patient’s basal rate and correction factor in order to reach good control. The system should therefore be further examined with moderately to poorly controlled patients. Closed-loop artificial pancreas systems will be based on different

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control strategies and it is unlikely that only one strategy will be used. Researchers should be encouraged to seek different good control methods such as fuzzy logic to overcome the glucose regulation problem of type 1 DM.

Closed-loop artificial pancreas using subcutaneous glucose sensing and insulin delivery and a model predictive control algorithm: preliminary studies in Padova and Montpellier D. Bruttomesso,1 A. Farret,2 S. Costa,1 M. C. Marescotti,1 M. Vettore,1 A. Avogaro,1 A. Tiengo,1 C. Dalla Man,3 J. Place,2 A. Facchinetti,3 S. Guerra,3 L. Magni,4 De Nicolao G4, C. Cobelli,3 E. Renard,2 A. Maran1 1 Department of Clinical and Experimental Medicine, Division of Metabolic Diseases, University of Padova, Padova, Italy, 2 Department of Endocrinology, University Hospital Centre, University of Montpellier, Montpellier, France, 3Department of Information Engineering, University of Padova, Padova, Italy, and 4Dipartimento di Informatica e Sistemistica, University of Pavia, Pavia, Italy J Diabetes Sci Technol 2009; 3: 1014–21 Background: MPC algorithms use data from an individual’s daily life events to build personalised, predictive models to optimise BG control. The authors describe the preliminary clinical experience using an MPC algorithm for closed-loop control of BG in patients with type 1 diabetes. Methods: A total of six patients with type 1 diabetes participated in two pilot studies (Montpellier and Padova, three in each study). Patients were aged 36 ± 8 and 48 ± 6 years, duration of diabetes 12 ± 8 and 29 ± 4 years, haemoglobin A1c 7.4% ± 0.1% and 7.3% ± 0.3%, body mass index 23.2 ± 0.3 and 28.4 ± 2.2 kg ⁄ m2, respectively, and were all currently using continuous subcutaneous insulin infusion. Each subject was studied during two separate 22-h overnight hospital admissions 2–4 weeks apart. In both trials, patients used a Freestyle Navigator continuous glucose monitor and an OmniPod (Insulet, Bedford, MA) insulin pump. During admission 1 patients followed their regular insulin dosing regimen (‘open loop’) while closed-loop control with the group’s MPC algorithm was used in admission 2. Results: In Montpellier, two out of three subjects had superior BG control in the closed-loop system compared to the open-

loop procedure. In Padova, mean overnight plasma glucose was 134 mg ⁄ dl in open-loop vs. 111 mg ⁄ dl in closed-loop. Percentage of time spent above 140 mg ⁄ dl was 45% vs. 12% and post-breakfast mean plasma glucose was 165 vs. 156 mg ⁄ dl during open-loop versus closed-loop trials. The closed-loop system provided a clear advantage in avoiding nocturnal hypoglycaemia in both studies. Conclusions: These studies demonstrate that closed-loop control using currently available continuous glucose monitors and insulin pumps along with an MPC algorithm is feasible and can be used to achieve improved BG control in patients with type 1 diabetes. However, the algorithm should be improved to offer better postprandial BG control.

Closed-loop artificial pancreas using subcutaneous glucose sensing and insulin delivery and a model predictive control algorithm: the Virginia experience W. L. Clarke,1 S. Anderson,2 M. Breton,3 S. Patek,4 L. Kashmer,1 B. Kovatchev3 1 Division of Pediatric Endocrinology, Department of Pediatrics, University of Virginia Health Sciences Center, Charlottesville, VA, USA, 2Department of Internal Medicine, University of Virginia, Charlottesville, VA, USA, 3Diabetes Technology Program, University of Virginia, Charlottesville, VA, USA, and 4 Department of Systems and Information Engineering, University of Virginia, Charlottesville, VA, USA J Diabetes Sci Technol 2009; 3: 1031–8 Background: The authors test the ability of a closed-loop system consisting of a personalised MPC algorithm in combination with a continuous glucose monitor and insulin pump to keep BG levels between 70 and 140 mg ⁄ dl overnight and to control postprandial BG levels. Methods: Eight adults with type 1 diabetes aged 27–51 years, average diabetes duration 3–26 years, all using continuous subcutaneous insulin infusion, participated in this pilot study. Each subject was studied overnight and for 4 h following a standardised meal, once using open-loop control and once using a closed-loop system controlled by the MPC algorithm. The authors compared the two trials for average BG levels, percentage of time with BG between 70 and 140 mg ⁄ dl, number of hypoglycaemic episodes and postprandial BG excursions.

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Results: The closed-loop system was effective in maintaining nocturnal BG levels between 70 and 140 mg ⁄ dl in seven out of eight subjects, with one subject’s BG falling to 65 mg ⁄ dl, which signalled the insulin pump to shut off. Closed-loop control resulted in significantly fewer nocturnal hypoglycaemic events compared with open-loop control (p = 0.001). Postprandial glucose levels were similar in the two groups. Conclusions: A closed-loop system using MPC is an effective means to control BG overnight and following a standard breakfast meal. This system clearly outperformed openloop control in preventing overnight hypoglycaemia, but did not offer a significant advantage following a morning meal. • Comment: The papers by Bruttomesso et al. and Clarke et al. present preliminary results from a pilot study conducted in three centres that compared an MPC-based artificial pancreas. The study protocol included overnight and breakfast control and lasted 4– 5 h post breakfast. The presented closed-loop system succeeded in preventing nocturnal hypoglycaemia in most cases and provided superior glucose control compared to openloop. However, in terms of other glucose control measures, glucose control during the night under closed-loop control was as good as under open-loop control. The authors used the open-loop session to personalise the MPC algorithm, i.e. the algorithm learned patient meal routine and had the ability to infuse insulin prior to the consumption of the meal, even though post breakfast glucose control under closed-loop was not better than the open-loop admission. These studies include two identical experimental sessions: in the first one the subjects followed their standard treatment (basal profile and bolus calculations) and the second one was a closed-loop study. It should be noted that on the one hand this protocol setting may help in reducing unknown factors such as meal size and mealtimes, but on the other hand the ‘white coat syndrome’ may affect the subject’s decision-making during the first admission and the study results from the first admission. It may be useful to compare the closed-loop performance with ambulatory data from the same individuals to demonstrate better the benefit of closed-loop control. The control algorithm was tailored to the subject via an aggressiveness parameter q that was designed using clinical parameters. Bruttomesso et al. reported in two cases that the value of the controller’s aggressiveness was insufficient and affected the system’s ability to improve glucose control. The overall results demonstrated the feasibility of closed-loop control and overnight

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Closing the loop

glycaemic control facing sensor dropouts and model mismatch. The authors reported results suggested that the controller managed to overcome a 50 g liquid breakfast meal; however, the trials ended, per protocol, prior to the demonstration of glucose stabilisation which undermined this conclusion. Further evaluation should consider sufficient time postprandial to ensure glucose stabilisation.

HYPOGLYCAEMIA PREVENTION AND CLOSED-LOOP CONTROL Real-time hypoglycaemia prediction suite using continuous glucose monitoring: a safety net for the artificial pancreas E. Dassau,1,2 F. Cameron,3 H. Lee,4 B. W. Bequette,4 H. Zisser,1,2 L. Jovanovicˇ,1,2 H. P. Chase,5 D. M. Wilson,6 B. A. Buckingham,6 F. J. Doyle III1,2 1 Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA, USA, 2Sansum Diabetes Research Institute, Santa Barbara, CA, USA, 3 Department of Aeronautics and Astronautics, Stanford University, Palo Alto, CA, USA, 4 Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA, 5Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, CO, USA, and 6 Department of Pediatrics, Division of Pediatric Endocrinology, Stanford Medical Center, Palo Alto, CA, USA Diabetes Care 2010; 33: 1249–54 Background: Although tight glycaemic control brings benefits to diabetic patients, it also increases the risk of hypoglycaemia, especially during sleep. The present study was targeted to develop an advanced algorithm that detects pending hypoglycaemia and then suspends basal insulin delivery. This approach can provide a solution to the problem of nocturnal hypoglycaemia. Methods: This real-time hypoglycaemic prediction algorithm (HPA) combines five individual algorithms: linear projection, Kalman filtering, hybrid infinite impulse– response filter, statistical prediction and numerical logical algorithm. All are based on CGM 1-min data. An alarm is issued if either a certain number (three, four or five) of the algorithms all predict hypoglycaemia, or the sensor interstitial glucose value is below the hypoglycaemic threshold (70, 80 or 90 mg ⁄ dl,

respectively). Each combination was assigned three different prediction horizons (V) of 35, 45 and 55. The HPA system was developed using data derived from 21 Navigator studies that assessed Navigator function over 24 h in children with type 1 diabetes. The function of HPA was confirmed using a separate dataset from 22 admissions of subjects with T1DM. During these admissions, hypoglycaemia was induced by gradually increasing the basal insulin infusion rate up to 1.8 times the subject’s own baseline infusion rate. Results: Using a prediction horizon of 35 min, a glucose threshold of 80 mg ⁄ dl, and a voting threshold of three out of five algorithms to predict hypoglycaemia (defined as FreeStyle plasma glucose readings < 60 mg ⁄ dl), the HPA predicted 91% of the hypoglycaemic events. When the voting threshold was changed to four of five algorithms, 82% of the events were predicted. Conclusions: The use of HPA will enable triggering of a warning alarm or automated insulin pump suspension in response to a pending hypoglycaemic event that has been detected prior to severe immediate complications.

Prevention of nocturnal hypoglycaemia using predictive alarm algorithms and insulin pump suspension B. Buckingham,1 H. P. Chase,2 E. Dassau,3 E. Cobry,2 P. Clinton,1 V. Gage,2 K. Caswell,1 J. Wilkinson,2 F. Cameron,4 H. Lee,5 B. W. Bequette,5 F. J. Doyle III3 1 Department of Pediatric Endocrinology, Stanford University, Stanford, CA, USA, 2 Department of Pediatrics, University of Colorado, Aurora, CO, USA, 3Department of Chemical Engineering, University of California, Santa Barbara, CA, USA, 4Department of Aeronautics and Astronautics, Stanford University, Stanford, CA, USA, and 5 Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA Diabetes Care 2010; 33: 1013–17 Background: Preventing nocturnal hypoglycaemia remains one of the most challenging goals in the treatment of diabetes. The aim of the present study was to develop a partial closed-loop system to safely prevent nocturnal hypoglycaemia in type 1 diabetes patients by suspending insulin delivery when hypoglycaemia was predicted. Methods: A total of 40 subjects with type 1 diabetes (age 12–39 years) were studied overnight in the hospital. The control group

(n = 14) and two experimental groups (n = 10 and n = 16) were all induced with hypoglycaemia by gradually increasing the basal insulin infusion rate. No pump-shutoff algorithms were used in the control group; in the experimental groups, pump shutoff occurred when either three of five (n = 10) or two of five (n = 16) algorithms predicted hypoglycaemia based on the glucose levels measured with the FreeStyle Navigator (Abbott Diabetes Care). The insulin pump was suspended manually for 90 min for each shutoff. The five algorithms are a modified linear prediction alarm, Kalman filtering, adaptive hybrid infinite impulse–response filter, statistical prediction and a numerical logical algorithm. Results: Hypoglycaemia occurred on 13 (93%) of the 14 nights in the control group. In the experimental group that required three algorithms to trigger insulin pump suspension, nocturnal hypoglycaemia was prevented for six (60%) out of 10 nights. In the experimental group that required only two algorithms to trigger insulin pump suspension, hypoglycaemia was prevented for 12 (75%) of 16 nights. There were 25 predictions of hypoglycaemia in this group because some subjects had multiple hypoglycaemia predictions during one night, and hypoglycaemia was prevented for 84% of these events. Conclusions: Using algorithms to suspend the insulin pump when hypoglycaemia is predicted, it is possible to prevent hypoglycaemia on 75% of nights (84% of events) when it would otherwise be predicted to occur. • Comment: One of the major obstacles in intensive insulin management is a higher tendency of hypoglycaemia. The striking fact is that most severe hypoglycaemic events occur overnight (1). Thus, an automatic system that will track BG concentrations and act accordingly may prevent the occurrence of nocturnal hypoglycaemia and improve night-time glucose control of people with type 1 DM. The HPA is an improved method for the prevention of nocturnal hypoglycaemia which is based on five different individual algorithms as presented by Dassau et al. and Buckingham et al. Each algorithm analyses the available glucose data, separately, and concludes whether a hypoglycaemic event is anticipated or not. The algorithms can be tuned using three parameters: threshold glucose concentration, prediction horizon (in min) and the required number of concurrent algorithms needed to issue an alarm. Using a voting algorithm the system decides whether to suspend insulin delivery for a predefined period of 90 min. This algorithm was initially designed and evaluated on historical clinical data and further evaluated on the University of

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Virginia ⁄ University of Padova metabolic simulator (2) (accepted by the US Food and Drug Administration) with promising results (3). Buckingham et al. reported a prospective clinical study aimed at evaluating the hypoglycaemia prevention system. A cohort of 26 patients was investigated during the clinical phase where with the first 10 patients a voting threshold of three methods out of five was used; with the last 16 patients this was modified to two out of five in order to improve the performance of the method. Hypoglycaemia was induced by increasing the basal rate of the patient 1.8-fold. In this study, the investigators used 80 mg ⁄ dl as a threshold level and a prediction horizon of 35 min. When a hypoglycaemic event was announced by the algorithm insulin was suspended for 90 min and was resumed to default basal rate. In the last 11 patients basal rate was resumed earlier if certain conditions were met. The ability of the algorithm to detect and prevent hypoglycaemic events was improved from the first part of the trial (71% of events were detected) to the second, in which 84% of events were prevented. Although this system presents good results it still cannot guarantee 100% prevention of an event. The use of an automated alert system (4) as well as automated glucagon administration should be investigated. One of the limits of the study is the clinical protocol to promote a high tendency for hypoglycaemia during the study nights, as discussed by the authors. In order to achieve a high rate of hypoglycaemia the investigators increased nocturnal basal rate until there was a > 80% risk of hypoglycaemia. This method may not be similar to the dynamics behind hypoglycaemia events in real life. In order to further examine the performance of this algorithm, a randomised control study evaluating the performance of the HPA vs. control in a group of patients with a tendency to hypoglycaemia should be performed.

UNDER THE HOOD – PROMISING DIRECTIONS FOR CLOSED-LOOP ALGORITHMS

University of California, Santa Barbara, CA, USA, and Sansum Diabetes Research Institute, Santa Barbara, CA, USA IEEE Trans Biomed Eng 2010; 57: 211–19 Background: This study proposes a combination of iterative learning control and MPC, called model predictive iterative learning control (MPILC), as a way of improving glycaemic control in patients with type 1 diabetes. Methods: MPILC combines frequent glucose readings via CGM with the repetitive nature of glucose–meal–insulin dynamics in a 24-h cycle. The proposed algorithm can learn from an individual’s lifestyle, allowing BG control to be improved from day to day. Results: After less than 10 days, BG concentrations can be kept within a range of 90– 170 mg ⁄ dl. In general, BG control under MPILC is better than that under MPC. The proposed methodology is also robust to random variations in meal timings within ± 60 min or meal amounts within ± 75% of the nominal value, which further validates MPILC’s superior robustness compared to run-to-run control. Conclusions: MPILC can improve BG control in people with type 1 diabetes. The algorithm can both improve control from day to day and take advantage of frequent glucose measurement to design the basal and bolus insulin simultaneously; it is also robust to meal variations and subject variability. Furthermore, the use of an adaptive set-point guarantees safe and stable convergence of the algorithm even when subjects are not well controlled and have high glucose levels. This algorithm may be especially useful in treatment of children and adolescents because it does not necessitate user intervention. • Comment: Inter- and intra-variability in insulin sensitivity is a well-known phenomenon among diabetes caregivers and patients. Insulin sensitivity tends to vary during the course of the day, from day to day and as a result of specific events such as physical activity, illness and stress. An artificial pancreas system, which relies on patient-specific

Closed-loop control of artificial pancreatic beta-cell in type 1 diabetes mellitus using model predictive iterative learning control Y. Wang, E. Dassau, F. J. Doyle III Department of Chemical Engineering and Biomolecular Science and Engineering Program,

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parameters, should incorporate algorithms that will allow it to learn and overcome the inherent variability in insulin sensitivity. The authors describe a novel methodology to implement a learning iterative control algorithm within a closed-loop system which is based on model predictive control (MPILC). This interesting combination does not rely on the subject’s input, and thus is very suitable for a closed-loop system. The MPILC is validated using in silico simulations for 50 days on a group of 10 adults. On the first day the in silico subjects were under open-loop control and on the other days they were under the control of the MPILC. Four different simulation settings were chosen in order to evaluate the robustness of the proposed system: (i) simulation day with a fixed amount of consumed carbohydrates at fixed times, (ii) variation of meal size, (iii) variation of mealtime and (iv) combination of the latter two. Although this method has great potential, performance results of the MPILC should be considered with caution, since diurnal as well as day to day insulin variability was not considered in this initial work. Extensive clinical trials are required to validate this method and its ability to regulate glucose control.

References 1 The Diabetes Control and Complications Trial Research Group. the effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86. 2 Kovatchev BP, Breton M, Dalla Man C, Cobelli C. In silico preclinical trials: a proof of concept in closed-loop control of type 1 diabetes. J Diabetes Sci Technol 2009; 3: 44–55. 3 Dassau E, Cameron F, Lee H, Bequette BW, Zisser H, Jovanovicˇ L, Chase HP, Wilson DM, Buckingham BA, Doye III FJ: Real-time hypoglycemia Prediction suite using continuous glucose monitoring: a safety net for the artificial pancreas. Diabetes Care 2010; 33: 1249–54. 4 Dassau E, Jovanovicˇ L, Doyle FJ III, Zisser H. Enhanced 911 ⁄ GPS Wizard: a telemedicine application for the prevention of severe hypoglycaemia – monitor, alert and locate. J Diabetes Sci Technol 2009; 3: 1501–6.

Advanced Technologies and Treatments for Diabetes

Insulin New insulins and insulin therapy T. Danne,1 J. Bolinder2 1

Diabetes-Zentrum fu¨r Kinder and Jugendliche, Kinderkrankenhaus auf der Bult, Hannover, Germany Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden

2

The introduction of the so-called ‘designer’ insulins, the insulin analogues, has offered new opportunities in the clinical management of diabetes. Two additional new entities are close to reaching clinical practice. LinjetaTM (formally called VIAject) is not an analogue but rather a different formulation of human insulin which may give it a more rapid onset of action, potentially even faster than the currently available rapid-acting insulin analogues. DegludecTM, on the other hand, is an insulin analogue molecule with an ultra-long clinical profile derived from the soluble multi-hexamer formation, resulting in a continuous slow and stable release of insulin degludec monomers which may last longer than currently available long-acting analogues. As with any new type of drug, the safety of the ‘designer’ insulins has to be closely scrutinised. Last year the increased cancer risk in diabetes entered the spotlight and the potential role of insulin analogues led to controversial discussions. In spite of recent new in vitro and observational data no new conclusive evidence became available. The need for multiple well-conducted and appropriately designed prospective observational studies to follow up the effectiveness and safety of the new insulins and the new insulin treatment regimens remains. In this chapter it was our mission to chose articles published about ‘‘new insulins’’ over the last year that have the most important contribution for the on-going development of ultra-fast- and ultra-long-acting insulin analogs and preparations and their potential side-effects, particularly cancer. This has been done by means of PubMed searches as well as a review of abstracts of the recent large international diabetes meetings such as ADA, EASD and ISPAD.

LINJETATM – A NEW RAPID ACTING INSULIN Postprandial vascular effects of VIAject compared with insulin lispro and regular human insulin in patients with type 2 diabetes T. Forst,1, A. Pfu¨tzner,1 F. Flacke,2 A. Krasner,2 C. Hohberg,1 E. Tarakci,1 P. Pichotta,2 S. Forst,1 S. Steiner2 1 Institute for Clinical Research and Development, Mainz, Germany, and 2Biodel, Danbury, CT, USA Diabetes Care 2010; 33: 116–20 Background: Prandial insulin delivery may influence the postprandial regulation of tissue

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blood flow. The effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function was compared in patients with type 2 diabetes. Methods: Fourteen patients (seven men) aged 61.5 ± 1.8 years, with mean diabetes duration of 6.6 ± 4.6 years and A1c 7.2% ± 0.5%, received a prandial injection of VIAject, human regular insulin and insulin lispro. The postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were checked at baseline and after a standardised liquid meal test (Ensure Plus), In addition, the postprandial effects on microvascular blood flow, skin oxygenation and vascular elasticity were measured. Results: A significant reduction in the peak postprandial generation of ADMA was found with VIAject treatment compared with

Correspondence to: Thomas Danne, Diabetes-Zentrum fu¨r Kinder and Jugendliche, Kinderkrankenhaus auf der Bult, Hannover, Germany Tel.: +49-511-8115-340 Fax: +49-511-8115-344 Email: danne@hka.de Disclosures: TD has received honoraria for speaking engagements or advisory board participation from several companies involved in the diabetes field. Furthermore he has received grant support from these companies (Abbott, Sanofi-Aventis, Bayer, Roche, Johnson&Johnson, Lilly, Medtronic, DexCom, NovoNordisk) for the conduct of studies or scientific meetings. JB is on the speaker’s bureaux of Abbott, Medtronic and Sanofi-Aventis; and is a member of scientific advisory boards for AstraZeneca, Medtronic and Merck, Sharp & Dohme. Endorsed by the International Conference on ATTD organized by Kenes International.

human insulin and insulin lispro (VIAject – 27.3 ± 22.6 nmol ⁄ l, human insulin 97.7 ± 24.4 nmol ⁄ l and insulin lispro 66.9 ± 33.9 nmol ⁄ l; p < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject – 0.22 ± 0.17 vs. human insulin 0.25 ± 0.15 lg ⁄ ml; p < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 lg ⁄ ml). After VIAject earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained compared with those after human insulin or insulin lispro (p < 0.05). All insulin formulations resulted in comparable improvements in central arterial elasticity. Conclusions: Treatment with VIAject had an advantage compared with human regular

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insulin or insulin lispro in reduction of postprandial oxidative stress and improved endothelial function. • Comment: LinjetaTM (formally called VIAject) is a more rapid-acting insulin formulation that is currently under review by the US Food and Drug Administration (1). Data presented so far only in abstract form at the American Diabetes Association and European Association for the Study of Diabetes 2010 congresses indicate that it has a more rapid onset of action than the insulin analogues (2,3). The paper by Forst et al. focuses on the potential benefits of such an insulin formulation on postprandial metabolism in patients with type 2 diabetes. LinjetaTM is not an insulin analogue but rather a different formulation of human insulin which may promote a more rapid absorption. Early studies were done with insulin at pH 4 and a concentration of 25 U ⁄ ml. The marketable formulation of pH 7 and 100 U ⁄ ml apparently retains these characteristics of a more rapid onset but this

has to be seen in larger trials (see figure). This insulin would be of particular benefit in type 1 diabetes, especially in insulin pump therapy. Early data suggest that it is biocompatible with insulin infusion sets (3). In current clinical practice, many patients claim that even when using rapid-acting insulin analogues the onset of action is still too slow to effectively provide postprandial glucose control. A large analysis of 1041 paediatric patients on continuous subcutaneous insulin infusion revealed the close correlation between the number of daily boluses and HbA1c. Only the subgroup of patients taking more than 12 boluses a day had an average HbA1c in the target range (n = 87, HbA1c 7.3 ± 0.9) (4). Such frequent bolussing is likely to predispose to insulin stacking. Thus, any insulin with a more rapid onset of action and a shorter duration theoretically would be beneficial. This need for a more rapid insulin is also echoed from researchers involved with the artificial pancreas.

LinjetaTM vs. Humalog PK and PD Data Linjeta (VIAject 7)

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DEGLUDECTM, A LONG-ACTING INSULIN ANALOGUE Insulin degludec, a new generation ultra-long-acting insulin, used once daily or three times weekly in people with type 2 diabetes: comparison to insulin glargine (Abstract) C. Mathieu,1 G. Fulcher,2 P. V. Rao,3 N. Thomas,4 L. Endahl,5 T. Johansen,5 A. J. Lewin,6 J. Rosenstock,7 M. Pinget,8 B. Zinmann9 1 UZ Gasthuisberg K.U. Leuven, Belgium,2Royal North Shore Hospital, University of Sydney, Australia, 3Nizam’s Institute of Medical Sciences University, Hyderabad, India, 4Christian Medical College, Vellore, India, 5Novo Nordisk A ⁄ S, Søborg,, Denmark, 6National Research Institute, Los Angeles, CA, USA, 7Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA, 8University Hospital Strasbourg, Strasbourg, France, and 9 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada Diabetologia 2010; 53 (Suppl 1): S8

Lispro

80

60 50 Plasma insulin (mU/ml)

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Figure 1 A novel pH-neutral formulation of the monomeric insulin VIAject has a faster onset of action

than lispro. Leszek Nosek, Tim Heise, Frank Flack2, Alan Krasner2, Philip Pichotta2, Lutz Heinemann, Solomon Steiner2, Profil Institute for Metabolic Research, Neuss, Germany, 2Biodel, Danbury, CT, USA. Adapted from the EASD 2010 oral presentation, with permission.

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 26–30

Background: Degludec (IDeg) is a neutral, soluble ultra-long-acting new generation insulin that forms multi-hexamer after subcutaneous injection. This randomised, four-arm, parallel group, treat-to-target trial examined the efficacy and safety of IDeg administered once daily vs. three times weekly in patients with type 2 diabetes who did not achieve good glycaemic control with oral antidiabetic medications. Methods: Patients with a mean HbA1c level of 8.7% were randomised to treatment with subcutaneous insulin injected in the evening as follows: once daily IDeg (n = 60), three times weekly IDeg (n = 62), once daily alternative IDeg formulation (n = 61) or insulin glargine once daily (n = 62), all in combination with metformin during a 16-week period. Results: At the end of the trial (16 weeks), the mean reduction from baseline in HbA1c and the final mean value of HbA1c were similar across the four treatment arms. Body weight remained stable and the rate of confirmed hypoglycaemia was low during the study in the four arms. No significant differences in adverse events (mainly mild or moderate in severity) were documented across the treatment arms. Conclusions: IDeg used once daily or three times weekly was safe and well tolerated with similar glycaemic control to glargine.

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Insulin degludec: less pharmacodynamic variability than insulin glargine under steady-state conditions (Abstract) T. Heise,1 L. Hermanski,1 L. Nosek,1 A. Feldmann,1 S. Rasmussen,2 T. K. Stryhn,2 H. Haahr2 1 Profil Institut fu¨r Stoffwechselforschung, Neuss, Germany, and 2Novo Nordisk A ⁄ S, Søborg, Denmark Diabetologia 2010; 53 (Suppl 1): S387 Background: Degludec (IDeg) is a new basal insulin analogue with action duration of more than 24 h. The aim of this randomised, double-blind, parallel group study was to compare the pharmacodynamic variability of IDeg with that of insulin glargine under steady-state conditions. Methods: Patients with type 1 diabetes (n = 54), aged 38 ± 10 years with a mean HbA1c of 7.7% ± 0.9%, were treated with 0.4 U ⁄ kg of IDeg or glargine once daily for 12 days. Pharmacodynamic profiles were investigated over 24 h with the euglycaemic glucose clamp technique. Within-subject variability was estimated on log-transformed pharmacodynamic end-points, which were derived from the glucose infusion rate profiles during the clamps. Results: IDeg produced significantly less pharmacodynamic variability than glargine on all protocol pharmacodynamic variability parameters, including total metabolic effect (p < 0.0001). The individual within-subject variability was consistently lower for IDeg compared with glargine. IDeg’s metabolic effect was exactly evenly distributed between the first and the second 12 h, and this distribution was less variable than with glargine (p < 0.001). Both insulin types were well tolerated, without serious adverse events and without severe hypoglycaemic episodes. The rate of hypoglycaemic episodes was 166 (20 nocturnal) in the IDeg group compared with 182 (37 nocturnal) in the glargine group. Conclusions: The results demonstrated that, under steady-state conditions, the IDeg administrated once daily is significantly less variable and more stable in glucose-lowering effect than glargine. • Comment: Degludec (NN1250) is a neutral, soluble ultra-long-acting new generation insulin with a duration of action of more than 24 h. So far no full publications are available, but these two abstracts were presented at this year’s diabetes meetings. Degludec has a very flat and smooth action profile. The product is

intended for basal insulin treatment of diabetes and has the potential to be used less than once daily. It will be marketed by Novo Nordisk as Degludec (insulin degludec) and Degludec Plus (70% Degludec, 30% insulin aspart) and shows the potential to control blood glucose levels in type 1 and type 2 diabetes when injected once daily or thrice a week. The ultra-long clinical profile is derived from a soluble multi-hexamer formation that is believed to lead to a continuous slow and stable release of insulin degludec monomers. Clinical studies published so far only in abstract form showed that, after 16 weeks of treatment with insulin degludec, mean HbA1c reductions were similar across the once-daily and three-times-weekly insulin degludec groups and comparable to insulin glargine. The potential advantage may be in a particularly low risk of hypoglycaemia. In the preliminary data presented, 77% of patients treated with insulin degludec three times weekly did not experience any confirmed hypoglycaemia (defined as low blood glucose levels or episodes that required assistance) and, of those patients using insulin degludec once daily, 92% did not experience any confirmed hypoglycaemia. However, these rates were not significantly different from insulin glargine.

NEW INSULINS AND THE RISK OF CANCER Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients E. Mannucci,1 M. Monami,2 D. Balzi,3 B. Cresci,4 L. Pala,4 C. Melani,3 C. Lamanna,1 I. Bracali,2 M. Bigiarini,4 A. Barchielli,3 N. Marchionni,2 C. M. Rotella4 1 Diabetes Agency, Careggi Teaching Hospital, Florence, Italy, 2Section of Geriatric Cardiology and Medicine, Department of Cardiovascular Medicine, University of Florence, and Careggi Teaching Hospital, Florence, Italy, 3 Epidemiology Unit, Local Health Unit 10, Florence, Italy, and 4Section of Endocrinology, Department of Clinical Pathophysiology, University of Florence, and Careggi Teaching Hospital, Florence, Italy Diabetes Care 2010; 33: 1997–2003 Background: Epidemiological studies published in the last few years suggested that some insulin analogues could be associated with increased risk of cancer. The aim of this study was to assess the long-term association of different insulin analogues with cancer incidence.

Methods: A nested case–control study dataset was generated from the cohort study dataset (n = 1340 insulin-treated diabetic outpatients) by sampling control subjects from the risk sets. For each case subject, the control subjects (up to five) were chosen randomly from those members of the cohort who were at risk for the same follow-up time as the case subject. Matching variables were based on 5-year age classes, sex and body mass index classes (< 18.5, 18.5–24.9, 25–29.9 and ‡ 30 kg ⁄ m2). Results: During a median follow-up of 75.9 months (interquartile range 27.4–133.7), case subjects of incident cancer (n = 112) were compared with matched control subjects (n = 370). In case subjects, the mean daily dose of glargine was significantly higher than in control subjects (0.24 vs.0.16 IU ⁄ kg ⁄ day, p = 0.036). Glargine treatment with a dose ‡ 0.3 IU ⁄ kg ⁄ day was associated with incident cancer even after adjusting for Charlson comorbidity score, other types of insulin administration, and metformin exposure [odds ratio 5.43, 95% confidence interval (CI) 2.18–13.53, p < 0.001]. No association between incident cancer and insulin doses was found for human insulin or other analogues. Conclusions: In light of the possible association between higher glargine doses and cancer, the dosage of glargine should always be considered in patients treated with this product.

Association of hyperglycaemia and insulin usage with the risk of cancer in type 2 diabetes: the Hong Kong diabetes registry X. Yang,1 G. T. Ko,2 W. Y. So,1 R. C. W. Ma,1 L. W. Yu,1 A. P. Kong,1 H. Zhao,1 C. C. Chow,1 P. C. Tong,1,2 J. C. Chan1–3 1 Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, People’s Republic of China, 2Hong Kong Institute of Diabetes and Obesity, Chinese University of Hong Kong, Hong Kong, People’s Republic of China, and 3Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, People’s Republic of China Diabetes 2010; 59: 1254–60 Background: Previous data have demonstrated that insulin has mitogenic effects and the presence of prolonged hyperglycaemia may be a risk factor for cancer in type 2 diabetes. However, it is unknown whether use of insulin with its effect on cell growth and proliferation increases cancer risk or its glucose-lowering effect decreases cancer risk.

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 26–30

Insulin

Methods: From a cohort of Chinese patients with type 2 diabetes (n = 4623), free of cancer and naı¨ve to insulin at enrolment, a 1:2-matched new insulin user cohort was selected based on age (± 3 years), smoking status, and likelihood of initiating insulin therapy (± 0.05). Stratified Cox regression analysis on the matched pairs was used to obtain hazard ratios (HRs) of insulin therapy and A1c for cancer risk. Results: Of 973 new insulin users, 971 had matched non-users (n = 1935). The cancer incidence was significantly higher in insulin non-users than in insulin users (49.2 vs. 10.2, per 1000 person-years, p < 0.0001). After further adjustment, A1c was associated with an increased cancer risk (HR per percentage 1.26, 95% CI 1.03–1.55), whereas use of insulin was associated with a decreased cancer risk (HR of insulin users vs. non-users 0.17, 95% CI 0.09–0.32). Similar results were found when including all 973 insulin users and 3650 non-users in the analyses. Conclusions: This study demonstrated that prolonged hyperglycaemia with elevated A1c levels was related to increased cancer risk, whereas insulin usage was associated with a reduced cancer risk among Chinese patients with type 2 diabetes. • Comment: We reviewed the issue of the risk of malignancy in patients treated with insulin analogues extensively in the 2009 Yearbook (5). Several additional position statements and commentaries and some new studies (6–11) have been published since then. Clearly, in vitro and pre-clinical studies themselves cannot be considered conclusive and should primarily inform design considerations for observational studies. The 2009 conclusion, that a relationship between insulin analogues, particularly glargin, and cancer cannot be confirmed or excluded on the basis of the currently available data, remains true also in 2010. In the paper by Mannucci et al. cited above, a monocentric case–control study from a small region in Florence with a total of 482 cases and a median follow-up of 75.9 months appears to support the 2009 paper of Hemkens et al. (12) as incident cancer was associated with a dose of glargin ‡ 0.3 IU ⁄ kg ⁄ day but no association was found for human insulin or other analogues. The primary objective of the Mannucci study was the question of an increased cancer rate in Lantus-treated patients. This was not found. As in the previous controversial studies, post hoc analyses have shown the association of Lantus dose and cancer. However, as in the previous studies several biases (no matching for body mass index etc.) have been introduced and the observations are based on 29 cases with Lantus, 13 above the arbitrary threshold of

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0.3 IU ⁄ kg and 16 below. Again significant differences in the overall type of insulin therapy were notable between Lantus and human insulin users, as approximately 85% of the Lantus users also had prandial insulin, compared with less than 60% of those on NPH. Also the cancer incidence in this region is about four times higher than usual with low rates of breast and colorectal cancer and a high rate of other gastrointestinal cancers. A recent Chinese study of 4623 patients with type 2 diabetes with a 5-year follow-up, of whom 973 were newly treated with insulin, found a higher incidence of cancer in non-insulin users (49.2 per 100 patient years) compared with insulin-treated patients (10.2 per 100 patient years) resulting in a decreased risk of cancer (hazard ratio 0.17) when using insulin. They found a relationship of HbA1c with cancer incidence, a factor that was not analysed in most of the previous studies, adding new complexity to the issue. A consensus report of US diabetologists and oncologists (13) concludes that there is an urgent need of multiple wellconducted and appropriately designed prospective observational studies.

and prandial insulin (0.45%; 95% CI 0.21– 1.65, p = 0.002), but with smaller decreases in fasting glucose of 0.93 mmol ⁄ l (95% CI 0.21– 1.65, p = 0.01) and 2.20 mmol ⁄ l (95% CI 1.70–2.70, p < 0.00001), respectively. Larger insulin doses at study end were observed with biphasic and prandial insulin regimens. There were no differences between the three insulin regimens with regard to major hypoglycaemic events, whereas minor hypoglycaemic episodes with biphasic or prandial insulin were variably observed as higher than or similar to basal insulin therapy. Compared with basal insulin, prandial insulin therapy resulted in a larger increase in body weight (1.86 kg; 95% CI 0.80–2.92, p = 0.0006). Conclusions: A more favourable effect on glycaemic control may be achieved by initiating insulin therapy in patients with type 2 diabetes with biphasic or prandial insulin rather than with basal insulin supplementation, but the risk of hypoglycaemia may be increased with the former regimens.

INSULIN THERAPY IN TYPE 2 DIABETES

R. R. Holman,1,2 A. J. Farmer,2,3 M. J. Davies,4 J. C. Levy,2 J. L. Darbyshire,1,2 J. F. Keenan,1,2 S. K. Paul,1,2 for the 4-T Study Group 1 Diabetes Trials Unit, 2Oxford Centre for Diabetes, Endocrinology and Metabolism, and 3 Department of Primary Health Care and National Institute for Health Research, School of Primary Care Research, University of Oxford, Oxford, UK, and 4Department of Cardiovascular Sciences, University of Leicester, Leicester, UK N Engl J Med 2009; 361: 1736–47

Optimal insulin regimens in type 2 diabetes mellitus: systematic review and meta-analyses D. S. Lasserson,1 P. Glasziou,1 R. Perera,1 R. R. Holman,2 A. J. Farmer1 1 Division of Public Health and Primary Health Care, University of Oxford, Oxford, UK, and 2Diabetes Trials Unit, Oxford Centre of Diabetes, Epidemiology and Metabolism, University of Oxford, Oxford, UK Diabetologia 2009; 52: 1990–2000 Background: To compare the effects of different insulin regimens (biphasic, basal or prandial insulin supplementation) on glucose control, clinical outcomes and adverse events in patients with type 2 diabetes. Methods: A systematic review and metaanalyses of randomised controlled trials reported up to October 2008 were carried out. Results: Twenty-two trials with altogether 4379 randomised patients were included. Pooled data from insulin-naı¨ve patients were used in the meta-analyses. Using basal insulin supplementation as reference, greater HbA1c reductions were registered with biphasic insulin (0.45%; 95% CI 0.19–0.70, p = 0.0006)

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 26–30

Three-year efficacy of complex insulin regimens in type 2 diabetes

Background: To investigate the optimal insulin regimen in patients with type 2 diabetes. Methods: The three-year, open-label, multicentre trial included patients with type 2 diabetes (n = 708) with suboptimal glycaemic control despite on-going combination therapy with metformin and sulphonylurea. The patients were randomised to insulin therapy based on biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal supplementation with insulin detemir once or twice daily. During the first year, sulphonylurea therapy was substituted by an additional type of insulin in the case of unacceptable hyperglycaemia (HbA1c > 10% or ‡ 8% on two consecutive occasions at or after 24 weeks of therapy), and thereafter if HbA1c was greater than 6.5%. Effects on HbA1c, proportion of patients with HbA1c

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Insulin

£ 6.5%, hypoglycaemia frequency and body weight were evaluated. Results: Median HbA1c was similar with the three insulin therapies: biphasic insulin 7.1%, prandial insulin 6.8%, and basal insulin supplementation 6.9%, respectively. Of the patients receiving biphasic insulin 31.9% attained HbA1c £ 6.5%, which was less than in the prandial group (44.7%, p = 0.006) and in the basal group (43.2%, p = 0.03). In total, 67.7% in the biphasic, 73.6% in the prandial and 81.6% in the basal insulin group, respectively, received an additional type of insulin (p = 0.002). Median rate of hypoglycaemia was highest in the prandial group (5.7 hypoglycaemic events per patient per year), intermediate in the biphasic group (3.0) and lowest in the basal group (1.7) (p < 0.001). The increase in body weight was higher in the prandial insulin group than in the biphasic and basal insulin groups. No differences in other adverse events were registered. Conclusions: In patients with type 2 diabetes with inadequate glycaemic control while on combined metformin and sulphonylurea therapy, addition of basal or prandial insulin resulted in better HbA1c control than in those who were given a biphasic insulin regimen. Basal insulin supplementation was associated with fewer hypoglycaemic events and lesser increase in body weight. • Comment: Owing to the progressive nature of the disease, many patients with type 2 diabetes will eventually require exogenous insulin supplementation to maintain adequate glucose control. While several types of insulin preparations (human, analogues, various forms of premixed) and a number of different insulin regimens are accessible, the optimal mode of insulin therapy in type 2 diabetes is a matter of uncertainty. Moreover, feasible combination therapies with other glucose-lowering agents as well as unwanted side-effects of the therapy regimens, such as risk of hypoglycaemia and weight gain, need to be considered. Seemingly, the two referenced studies arrived at contradictory conclusions: the meta-analyses by Lasserson et al. favoured biphasic (premixed) insulin supplementation when combined effects on glycaemic control, risk of hypoglycaemia and weight gain were considered, whereas the prospective trial by Holman and co-workers indicated superior outcomes when insulin therapy was initiated with basal insulin. These dissimilarities may be more apparent than real, however. The meta-analyses were based on a mixture of short-term studies (3–12 months) in insulin-naı¨ve type 2 diabetes patients who had ini-

tiated insulin therapy with conventional or analogue insulins alone or in various combinations with oral hypyglycaemic agents (metformin, sulphonylureas and ⁄ or thiazolidinediones). Complete information about titration algorithms, glycaemic targets and insulin doses at study end were not available. Although these variations were accounted for in the statistical evaluation of the data, some of the included trials may have been too short to allow sufficient up-titration of insulin. The referenced paper by Holman et al. is an extension of the 4-T study, in which patients with inadequate glycaemic control despite maximum tolerable doses of metformin and sulphonylurea were randomised to add-on therapy with biphasic (premixed insulin aspart), prandial insulin aspart or basal insulin supplementation with insulin detemir, using standardised insulin dosing algorithms. The 1-year results of the 4-T study published in 2007 (14) showed that prandial and biphasic insulin therapy resulted in greater reductions in HbA1c levels than basal insulin. The risk of hypoglycaemia and weight gain, on the other hand, were highest in the prandial group, intermediate in the biphasic group, and lowest in patients randomised to basal insulin therapy. Notably, these results were included in the meta-analyses by Lasserson et al., and most probably had a major influence on the outcome of these assessments. In contrast, in the 3-year evaluation of the 4T study – which was not included in the metaanalyses – the median HbA1c levels were comparable with the three insulin regimens, albeit with a greater proportion of patients attaining HbA1c £ 6.5% in the prandial and basal insulin groups than in the biphasic insulin arm. It should be emphasised that substitution of sulphonylurea therapy with the addition of a second type of insulin supplementation because of insufficient glycaemic control (defined as HbA1c £ 6.5%) was necessary in the majority of patients in all three groups; this was done by adding midday prandial aspart insulin in the biphasic group, bedtime basal insulin in the prandial group, and prandial aspart insulin three times daily in the basal insulin group, respectively. This occurred most frequently in the basal insulin group (82%), with intermediate frequency in the prandial group (74%) and least often in the biphasic insulin group (68%). In other words, approximately half the patients in each insulin arm who received additional insulin therapy attained the treatment goal of HbA1c £ 6.5%. Hence, within a relatively short period of time, more complex insulin regimens seem to be needed in most patients to maintain

the glycaemic target, irrespective of the initial mode of insulin therapy. Considering also the risk of hypoglycaemic events and weight gain, initiating add-on insulin therapy with basal insulin supplementation appears to be a feasible strategy in most patients who fail on oral therapy, with subsequent escalation to basal prandial insulin regimens when needed. Whether this should be carried out with human insulins or with the use of insulin analogues is another disputed issue. However, taking treatment convenience and quality of life aspects into account, less complex biphasicbased insulin regimens may still be appropriate in many cases.

References 1 Steiner S, Hompesch M, Pohl R et al. A novel insulin formulation with a more rapid onset of action. Diabetologia 2008; 51: 1602–6. 2 Nosek I, Heise T, Flacke F et al. A novel pH-insulin VIAject has a faster onset of action than lispro. Diabetologia 2010; 53(Suppl. 1): S9. (Abstract) 3 Flacke F, Musholt PB, Weise A et al. Biocompatability of the ultra-rapid insulin VIAject with continuous insulin infusion sets. Diabetologia 2010; 53(Suppl. 1): S386. (Abstract) 4 Danne T, Battelino T, Jarosz-Chobot P et al. Establishing glycaemic control with continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: experience of the PedPump study in 17 countries. Diabetologia 2008; 51: 1594–1601. 5 Danne T, Bolinder J. New insulins and the risk of cancer. Int J Clin Pract 2010; 166(Suppl.): 26–8. 6 Dejgaard A, Lynggaard H, Ra˚stam J, Krogsgaard Thomsen M. No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a metaanalysis. Diabetologia 2009; 52: 2507–12. 7 Home PD, Lagarenne P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia 2009; 52: 2499–506. 8 Mu¨ller K, Weidinger C, Fu¨hrer D. Insulin glargine and insulin have identical effects on proliferation and phosphatidylinositol 3-kinase ⁄ AKT signalling in rat thyrocytes and human follicular thyroid cancer cells. Diabetologia 2010; 53: 1001–3. 9 Rensing KL, Houttuijn Bloemendaal FM, Weijers EM et al. Could recombinant insulin compounds contribute to adenocarcinoma progression by stimulating local angiogenesis? Diabetologia 2010; 53: 966–70. 10 Mayer D, Chantelau E. Treatment with insulin glargine (Lantus) increases the proliferative potency of the serum of patients with type-1 diabetes: a pilot study on MCF-7 breast cancer cells. Arch Physiol Biochem 2010; 116: 73–8. 11 Yehezkel E, Weinstein D, Simon M, Sarfstein R, Laron Z, Werner H. Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulinlike growth factor-I receptor. Diabetologia 2010; 53: 2667–75. 12 Hemkens LG, Grouven U, Bender R et al. Risk of malignancies in patients with diabetes treated with insulin or insulin analogues: a cohort study. Diabetologia 2009; 52: 1732–44. 13 Giovannucci E, Harlan DM, Archer MC et al. Diabetes and cancer: a consensus report. Diabetes Care 2010; 33: 1674– 85. 14 Holman RR, Thorne KI, Farmer AJ et al. Addition of biphasic, prandial or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007; 357: 1716–30.

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Advanced Technologies and Treatments for Diabetes

Delivery New ways of insulin delivery L. Heinemann Du¨sseldorf, Germany

The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) – which is the only one still in clinical development – is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid-acting insulin analogues. The time–action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is even too short (see postprandial glycaemic excursions with test meals in the publication by Rosenstock et al. in The Lancet (1)). In the end a number of aspects are of relevance for the success of a given product; one key aspect is clearly the price. However, for patients also practical aspects (handling, need for regular pulmonary function test etc.) are of importance. We shall have to see how creatively MannKind will handle all such questions. Until now Al Mann and his colleagues were able to manage a number of challenges during the clinical development process successfully, so one can have hopes for the market success of TI. However, it is clear that at the same time, if TI fails like Exubera did before, this will be the end for pulmonary insulin in general. Not too many original publications presenting data from clinical trials were published in the last year when it comes to oral insulin (OI), nasal insulin or transdermal insulin developments; simply none with transdermal insulin. Also at the last international congresses not many studies about ARIA were presented. At least in part this might be still a reflection of the shockwaves that the failure of Exubera has sent out to pharmaceutical companies and venture capitalists; they are quite reluctant to invest in any of these developments. However, a considerable number of reviews (in some cases more than original papers!) were published about ARIA. These reviews are listed for completeness, but in most cases are not further commented. OI is still the area of research most companies are active in; however, in some cases it is not clear how active they really are (e.g. Diabetology). Nevertheless, at least some companies are quite active and progressed in their clinical development programme close to market approval, e.g. the large Indian company Biocon is in late phase 3 with IN105 and the small Israel-based company Oramed is in phase 2b. It appears that other interesting OI developments (e.g. Diasome) were not very active in the last year; at least they have not published new study results. It is clear that for companies that produce insulin themselves (e.g. Biocon) the costs of the good are not of such relevance as for companies that have to buy it commercially. For the latter ones a low bioavailability ⁄ biopotency compared with SC insulin administration can be a real hurdle when it comes to the price of their product. Despite some publications about nasal insulin, the overall activity with this route of insulin administration appears to be low; the same holds true for transdermal insulin.

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 31–46

Correspondence to: Lutz Heinemann, Kehler Str. 24, 40468 Du¨sseldorf, Germany Tel.: +492112926900 Email: lutz.heinemann@profil.com and lutz.heinemann@profilinstitut.com Disclosures: LH is a Partner of Profil Institut fu¨r Stoffwechselforschung GmbH, Neuss, Germany and Profil Institute for Clinical Research Inc., San Diego, US and an employee of the latter institute. These institutes perform clinical trials in cooperation with many pharmaceutical companies. LH is not stockholder in any of the companies with which the institutes performs clinical trials. LH is a member of numerous advisory boards and speakers bureaus and has received honoraria from such companies. Endorsed by the International Conference on ATTD organized by Kenes International.

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Insulin pens have gained more scientific interest in recent years, which is also reflected by an increase in publications, starting from practically nil 10 years ago to a solid number of five to 10 papers per year nowadays. Besides ARIA there are also attempts to increase the speed of insulin absorption after injection into the skin by applying it not into the SC tissue but intradermally or by heating up the skin above the SC insulin depot. Reading a number of papers that were not included in this chapter because they do not present any clinical data but are novel developments tested only in animal experiments so far, the clear message is that there is definitely not a lack of creativity ⁄ imagination amongst scientists; each year a plethora of new ideas for insulin application show up. Unfortunately not too many make it towards a full clinical development. As long as there is not a single successful product on the market that is based on a given ARIA approach, this area of research will not mature. For many patients, avoiding the need for SC injections is attractive; however, as long as no clear ‘advantage’ can be demonstrated, reimbursement will be difficult to achieve. Living in the time of evidence-based medicine it is clear that ‘relevant’ clinical advantages must be proven. The question is what is relevant. Is it just an improvement in metabolic control (= decrease in HbA1c)? Can this also mean that more patients are willing to start insulin therapy earlier than with conventional SC insulin therapy? With TI we have a product that has improved pharmacological properties (also in comparison to Exubera) for coverage of prandial insulin requirements. Subsequently, in the clinical trials performed, postprandial glycaemic excursions were lower than with SC injection of RHI or rapid-acting insulin analogues. This only in part (if at all) results in an improved metabolic control in general (= lower HbA1c) (see below). The outlook for 2011 is that there are chances that we shall have an inhaled insulin product on the market. Probably also the first OI will be submitted to the regulatory authorities for market approval or will even be available in less regulated markets. In order to select all relevant publications about new ways of insulin delivery I performed a PUBMED search and also checked the table of contents of a number of journals that publish heavily in this area of research as well references in the publications I found for additional references. Selection of the manuscripts from all publications was predominately based on the fact whether they presented data from clinical studies or not. The selected studies were critically reviewed for novelty and appropriate study design etc. In some cases also reviews about a given topic were selected if they provide relevant novel insights.

INHALED INSULIN

INHALED INSULIN – Exubera

When Pfizer stopped Exubera, a number of clinical trials were still ongoing, especially some long-term studies. It is not clear to me how many of the data that Pfizer had collected in such studies in total were published; however, at least some publications came out in the last year. Also a considerable number of papers about AIR insulin were published in a supplement issue of a journal that summarises the data obtained during the clinical development of this inhaled insulin before the development was stopped after the market withdrawal of Exubera. Unfortunately a number of these clinical studies were stopped before they reached the targeted study duration. This in turn limits the meaning of most of them. However, it should be highlighted very positively that Eli Lilly was willing to invest a certain amount of time and money into these publications despite the fact that AIR insulin will never become a product. From a scientific point of view this is highly appreciated; many companies fail to do this once a development is stopped and all the knowledge accumulated in the company in this respect gets lost.

Glycaemic exposure is affected favourably by inhaled human insulin (Exubera) as compared with subcutaneous insulin glargine (Lantus) in patients with type 2 diabetes M. Hompesch,1 A. Kollmeier,1 K. Rave,2 L. Heinemann,2 M. Mitnick,3 S. Davies,3 T. Strack3 1 Profil Institute for Clinical Research Inc., Chula Vista, CA, USA, 2Profil Institut fu¨r Stoffwechselforschung, Neuss, Germany, and 3 Pfizer Inc., New York, NY, USA Diabetes Technol Ther 2009; 11: 307–13 Background: The aim of this study was to evaluate the differences between two regimens on glycaemia: adding either inhaled insulin (Exubera, EXU) or SC insulin glargine (GLA) to the treatment regimens of patients with poorly controlled type 2 diabetes treated with oral antidiabetic drugs (OADs). Methods: In this crossover randomised study, 40 patients were treated with either EXU three times daily prior to meals or SC GLA once daily for a period of eight treatment days. Glucose concentrations were checked using a continuous glucose monitoring system for the final 72 h. Results: Total insulin dosage on the last treatment day was 40 ± 18 U ⁄ day EXU vs.

16 ± 5 U ⁄ day GLA. Over the 72-h continuous glucose monitoring period serum insulin levels were higher with EXU than with GLA (1091 ± 589 vs. 737 ± 386 pmol ⁄ ml ⁄ h). The glucose exposure over this period was lower with EXU than with GLA (380 ± 45 vs. 426 ± 89 mmol ⁄ l ⁄ h). The overall hypoglycaemic event rate was 8.7 events per subjectmonth in patients using EXU and 2.4 for those using GLA. Conclusions: Using a higher daily insulin dose in prandial insulin therapy with EXU reduces total daily glucose exposure more effectively, mainly postprandial glycaemia, than a long-acting insulin analogue. • Comment: The basic idea of this study was to investigate whether prandial insulin therapy with an inhaled insulin is accompanied by better metabolic control than treatment with a once daily SC injection of a long-acting insulin analogue in patients with type 2 diabetes who were poorly controlled with OADs alone. The improvement that could be observed with EXU depends, at least in part, on an insulin dose that was more than twice that with insulin glargine and an increase in hypoglycaemic events with inhaled insulin. Nevertheless, this study shows that combination of inhaled insulin with OADs is an attractive alternative to adding a long-acting insulin analogue to OADs in such patients. We shall have to see if an inhaled insulin with more favourable PK ⁄ PD properties (= TI; see below) is better than Exubera in such a headto-head comparison with respect to long-term outcome measures. This has to be studied in appropriately designed clinical studies.

Glycaemic control with preprandial versus basal insulin in patients with type 2 diabetes mellitus poorly controlled by oral antidiabetes agents T. Heise,1 C. Mathieu,2 J. Hey-Hadavi,3 T. Strack,3 D. Lawrence3 1 Profil Institut fu¨r Stoffwechselforschung, Neuss, Germany, 2University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium, and 3Global Medical Research and Development, Pfizer Inc., New York, NY, USA Diabetes Technol Ther 2010; 12: 135–41 Background: The aim of this study was to compare metabolic control with either once daily basal insulin (BI) (insulin glargine) or preprandial insulin EXU in patients with poorly controlled type 2 diabetes mellitus (T2DM) treated with at least two OADs.

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Methods: This was a 26-week, open-label, parallel group, randomised study where patients (n = 257) with mean HbA1c of 8.6% on OAD treatment for 3 months were also treated with either BI (n = 122) or EXU (n = 135). Based on self-monitored blood glucose levels, BI dose was titrated in the morning or before bedtime, whereas EXU dose was adjusted before each major meal. Results: After 26 weeks, more patients achieved HbA1c < 6.5% (28% vs. 19%) and < 7.0% (63% vs. 55%) with EXU than with BI. EXU had lower post-meal glucose increments, higher pre-breakfast glucose, more weight gain (1.1 kg), more frequent mild or moderate hypoglycaemic events, and less frequent nocturnal hypoglycaemic events compared with BI. Conclusions: EXU improved postprandial glucose and HbA1c levels significantly more than BI. More patients achieved metabolic control targets with EXU, at the expense of more hypoglycaemia and body weight gain. • Comment: This study evaluated the effect of prandial inhaled insulin therapy in the group of patients with type 2 diabetes not well controlled on OADs in whom insulin therapy is going to be started. The question addressed is which type of insulin therapy, is better under this condition: basal or prandial insulin. This relatively large and well-performed study shows with both types of insulin therapy an impressive improvement in metabolic control (decline in HbA1c by 1.2% from a baseline of 8.5%). A greater decline in fasting blood glucose was observed with the basal insulin in this study. In many other studies the inhaled insulin has induced also a larger decline in fasting blood glucose; however, the comparator in such cases was not basal insulin. It is a pity that enrolment in this study was terminated due to the market withdrawal of EXU.

Safety and efficacy of inhaled human insulin (Exubera) during discontinuation and re-administration of therapy in adults with type 2 diabetes: a 3-year randomised controlled trial J. Rosenstock,1 W. T. Cefalu,2 P. A. Hollander,3 S. S. Klioze,4 J. Reis,4 W. T. Duggan4 1 Dallas Diabetes and Endocrine Center, Dallas, TX, USA, 2Pennington Biomedical Research Center, Baton Rouge, LA, USA, 3Baylor University Medical Center, Dallas, TX, USA, and 4Pfizer Global Research and Development, New London, CT, USA

Diabetes Technol Ther 2009; 11: 697–705 Background: The aim of the study was to assess one of the key questions with inhaled insulin: what is the safety of this route of insulin administration over longer periods of time in adult T2DM patients? Methods: In all 316 patients were randomised to receive EXU and 311 to receive SC insulin for a 2-year ‘comparative phase’, followed by 6 months of SC insulin ‘washout phase’ and 6 months when the original therapy was given – ‘re-administration’. Lung function tests of a high standard were performed throughout all phases. Results: During the comparative phase, small non-progressive treatment group differences were observed early for parameters such as forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO). These differences resolved during washout and recurred to the same small size during re-administration. There were similar metabolic control and hypoglycaemic event rates in both groups. Insulin antibody (InsAb) levels reached a plateau at 9 months in the EXU group, declined to near baseline levels during washout, and increased during re-administration to levels of the comparative phase. Conclusions: Lung function changes observed during discontinuation and readministration of EXU therapy were consistent with a reversible, non-progressive and non-structural pathological effect on lung function in adults with T2DM. Re-administration of inhaled insulin was not associated with an augmented InsAb response. • Comment: Assuming that it is not of relevance which type of inhaled insulin is used for treatment of patients with diabetes, this is an important and large study investigating precisely measured changes in lung function over a relatively long period of time. Also the study design (investigating inhaled insulin discontinuation and re-administration) allows the effects of inhaled insulin ⁄ Exubera on InsAb formation etc. to be studied also. The observed changes in lung function were small with inhaled insulin; however, the differences between the treatment groups resolved within 4 weeks when EXU was stopped. With re-administration of EXU the changes in lung function showed up again. Of interest is the underlying physiological decline in lung function over time in patients of this age by 1– 2% per year. The changes in antibody titres observed over time do not hint towards any significant impact change on insulin therapy etc. However, this long-term study also shows that at least with EXU no difference in metabolic control could be achieved over time

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compared to SC insulin therapy. Also the differences in body weight were small. The previously observed phenomenon of lower fasting blood glucose levels with inhaled insulin, which is a prandial insulin, was observed again.

Titration of inhaled human insulin (Exubera) in a treatto-target regimen for patients with type 2 diabetes P. A. Hollander,1 W. T. Cefalu,2 M. Mitnick,3 D. Lawrence,3 J. Rosenstock4 1 Baylor University Medical Center, Dallas, TX, USA, 2Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA, 3Pfizer Inc., New York, NY, USA, and 4Dallas Diabetes and Endocrine Center, Dallas, TX, USA Diabetes Technol Ther 2010; 12: 185–91 Background: The aim of this study was to assess the feasibility of safely achieving target metabolic control (HbA1c £ 7%) by intensifying structured insulin titration regimens using EXU in patients with uncontrolled type 2 diabetes treated with OADs. Methods: In total 107 patients with type 2 diabetes with a mean baseline HbA1c of 8.6% taking two or more OADs participated in a randomised, open-label, parallel, 24-week multicentre trial. They were randomised to adjust EXU before meals following either weekly office visits or more intense twiceweekly telephone ⁄ office consultations, using a simple structured titration algorithm seeking to attain specific pre-meal glucose levels. Primary end-point was the percentage of patients reaching HbA1c £ 7%, and secondary endpoints were change in HbA1c, daily blood glucose profile and rate of hypoglycaemic events. Results: Metabolic control improved whether EXU was titrated once a week (6.8%) or twice weekly (6.8%), and two-thirds of patients in both groups attained HbA1c £ 7% (69% and 67%, respectively). Relative to baseline, blood glucose profiles were reduced at all time points, and postprandial excursion during meal tolerance improved to a similar extent in both groups. The rate of hypoglycaemic events was higher in the twice-weekly than in the once-weekly EXU titration. Conclusions: Inhaled insulin added to OADs safely allows good metabolic control to be achieved in many patients with type 2 diabetes inadequately controlled if a once- or twice-weekly structured titration regimen is used.

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• Comment: In this large US-based study the frequency of dose titration was studied. It is not surprising that no differences in the improvement of metabolic control etc. were observed. Clearly it would have been very interesting to add an SC prandial insulin control arm to this study (probably also a control arm in which no insulin was added) to see how much of the observed improvement was due to the study effect per se or would have also been achieved with another way of insulin administration. However, this can also be deut of an insufficient uptitration of the inhaled insulin dose.

INHALED INSULIN – air insulin AIR insulin capsules of different dose strengths may be combined to yield equivalent pharmacokinetics and glucodynamics A. de la Pen˜a1, M. Seger,1 K. Rave,2 L. Heinemann,2 B. Silverman,3 D. B. Muchmore4 1 Eli Lilly and Company, Indianapolis, IN, USA, 2Profil Institut fuer Stoffwechselforschung GmbH, Neuss, Germany, 3Alkermes Inc., Cambridge, MA, USA, and 4Halozyme Therapeutics Inc., San Diego, CA, USA Diabetes Technol Ther 2009; 11 (Suppl 2): S75–S80 Background: In this study the PK and PD properties of AIR insulin were assessed by combining capsules of different strengths in healthy subjects. Methods: Fifty-nine healthy, non-smoking, male or female subjects with normal pulmonary function participated in an open-label, randomised, crossover glucose clamp study. On the five study days one 6 unit-equivalent (U-eq) capsule containing 2.6 mg of insulin, three 2 U-eq (0.9 mg) capsules (2.7 mg total), one 10 U-eq (3.9 mg) capsule, one 6 U-eq capsule plus two 2 U-eq capsules (4.4 mg total), or two 10 U-eq capsules (7.8 mg total) were applied. Results: The PK and PD responses to administration of a 6 U-eq capsule were equivalent to three 2 U-eq capsules; 90% confidence interval (CI) was contained within the interval (0.8, 1.25). Similarly, PK ⁄ PD responses after administration of a 10 U-eq capsule were comparable to the 6 U-eq plus two 2 U-eq capsule combination. AIR insulin exhibited PK dose proportionality and dosedependent increases in PD responses over the 2.6–7.8 mg dose range.

Conclusions: After single-dose administration in healthy subjects, AIR insulin showed dose strength interchangeability and dose proportionality. • Comment: With Exubera there were interesting differences in the metabolic action induced by applying 3 mg vs. three times 1 mg inhaled insulin, which means that Exubera was not dose proportional and lacked dose strength equivalence. As this study nicely shows, AIR insulin showed a good dose–response relationship and capsules of different strength could be combined. However, the study also shows that the PD properties of AIR insulin were not optimal with respect to coverage of prandial insulin requirements. The onset of insulin action was relatively slow and the duration of action was long with this inhaled insulin. This is something to bear in mind when interpreting the results of the clinical trials presented next.

Efficacy and safety of AIR inhaled insulin compared to insulin lispro in patients with type 1 diabetes mellitus in a 6-month, randomised, non-inferiority trial A. L. Comulada,1 E. Renard,2 M. Nakano,3 N. Rais,4 X. Mao,5 D. M. Webb,5 Z. Milicevic6 1 Instituto de Endocrinologıa´, Diabetes and Metabolismo, Toa Baja, Puerto Rico, 2Endocrinology Department, Centre Hospitalier Universitaire and University of Montpellier, Montpellier, France, 3Eli Lilly Japan K.K., Kobe, Japan, 4Chowpatty Medical Center, Mumbai, India, 5Eli Lilly and Co., Indianapolis, IN, USA, and 6Eli Lilly Regional, Vienna, Austria Diabetes Technol Ther 2009; 11 (Suppl 2): S17–25 Background: The aim of this study was to compare AIR inhaled insulin vs. SC injection of a rapid-acting insulin analogue in patients with type 1 diabetes with respect to efficacy and safety. Methods: In all 500 patients with type 1 diabetes were included in this multicentre, 6-month, parallel group, non-inferiority trial. They were randomised to morning doses of basal insulin glargine plus either preprandial SC injections of insulin lispro or inhalation of AIR insulin. The hypothesis was that AIR insulin is non-inferior (upper bound of the 95% CI £ 0.4%) to insulin lispro for changefrom-baseline HbA1c. Results: Baseline HbA1c was 7.95% ± 0.08% for both groups. At end-

point, HbA1c was lower with SC insulin lispro than with inhaled AIR insulin by 0.3% (p < 0.001). Non-inferiority of inhaled insulin to SC prandial insulin was not demonstrated, but similar percentages of patients in each group achieved HbA1c < 7.0%. Overall daily blood glucose was similar between groups at baseline and end-point. Two-hour postprandial blood glucose change from baseline was higher (p < 0.001) with AIR insulin than with insulin lispro (20.8 ± 4.3 mg ⁄ dl vs. 3.3 ± 4.1 mg ⁄ dl at 3 months and 15.9 ± 3.1 mg ⁄ dl vs.1.7 ± 2.9 mg ⁄ dl at endpoint). Overall hypoglycaemia was comparable between treatment groups. Lung function of the patients in the AIR group showed a greater decrease in DCCO at end-point (p = 0.020) and greater incidence of cough (p = 0.024) and dyspnoea (p = 0.030). Body weight decreased with inhaled insulin and increased with SC prandial insulin. Conclusions: SC injection of a rapid-acting insulin analogue provided better metabolic control than inhaled insulin, but this may not be of clinical relevance. • Comment: This head-to-head comparison between the SC applied insulin lispro and AIR inhaled insulin confirm what was stated above – the PD properties of the inhaled insulin appear to be not as good as those of SC applied rapid-acting insulin analogues to cover prandial insulin requirements, i.e. the postprandial glycaemic excursions were higher with the inhaled insulin studied. Other inhaled insulins (i.e. TI) most probably have different PD properties from AIR insulin (no direct head-to-head comparison of different inhaled insulin has ever been performed!), which supports better postprandial glycaemic control being achieved with TI (see below).

Two-year efficacy and safety of AIR inhaled insulin in patients with type 1 diabetes: an openlabel randomised controlled trial S. K. Garg,1 C. Mathieu,2 N. Rais,3 H. Gao,4 J. A. Tobian,4 J. R. Gates,5 J. A. Ferguson,4 D. M. Webb,4 P. Y. Berclaz4 1 Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, School of Medicine, Aurora, CO, USA, 2University Hospital Gasthuisberg of the Catholic University of Leuven, Leuven, Belgium, 3Chowpatty Medical Centre, Mumbai, India, 4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA, and 5MedScriptus, Bioscience Research Section, Ooltewah, TN, USA Diabetes Technol Ther 2009; 11 (Suppl 2): S5–16

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Background: Intensive insulin therapy enables patients with type 1 diabetes to achieve optimal metabolic control. AIR inhaled insulin appears to be an efficacious and safe alternative to SC prandial insulin. Methods: In all 385 patients with type 1 diabetes were recruited for this phase 3, 2-year, randomised, open-label, active comparator, parallel group study. They were randomly assigned to receive preprandial AIR insulin or SC insulin (RHI or insulin lispro). Both groups of patients received SC insulin glargine once daily. Efficacy measures included change in HbA1c from baseline to end-point, eight-point self-monitored blood glucose profiles, and insulin dosage. Safety was also evaluated. Results: In both treatment groups, only 20% of subjects reached a good metabolic control indicated by an HbA1c < 7.0%. A significant difference of 0.44% in HbA1c was seen with SC insulin, but with no difference between the groups in insulin doses or hypoglycaemic events at end-point. Patients in both groups experienced progressive decreases in lung function, but larger (reversible) decrements in DLCO were associated with inhaled insulin. Greater weight gain was seen with SC insulin. Conclusions: Although the AIR inhaled insulin programme was terminated by the sponsor prior to availability of phase 3 data (for reasons unrelated to safety or efficacy), this trial provides evidence that AIR insulin was less efficacious in improving metabolic control. Inhaled insulin was also associated with a greater decrease in DLCO and increased incidence of cough. • Comment: This 24-month comparator trial was the longest controlled study in patients with type 1 diabetes performed with AIR insulin. The outcome was negative; the metabolic control achieved with SC RHI was better than with this inhaled insulin. The study confirms the statements made before that the postprandial metabolic control achieved with AIR insulin was not as good as with SC RHI or insulin lispro. The study provides a lot of interesting data in addition, about lung function using high-quality, centrally read Pulmonary Function Tests, insulin antibodies etc.

Initiation of prandial insulin therapy with AIR inhaled insulin or insulin lispro in patients with type 2 diabetes: a randomised non-inferiority trial J. L. Gross,1 M. Nakano,2 G. Colon-Vega,3 R. Ortiz-Carasquillo,4 J. A. Ferguson,5 S. Althouse,5 J. A. Tobian,5 P. Y. Berclaz,5 Z. Milicevic6 1 Centro de Pesquisas em Diabetes, Porto Alegre, Brazil, 2Eli Lilly and Company, Kobe, Japan, 3American Telemedicine Center, San Juan, Puerto Rico, 4Manati Medical Center, Manati, Puerto Rico, 5Eli Lilly and Company, Indianapolis, IN, USA, and 6Eli Lilly and Company, Vienna, Austria Diabetes Technol Ther 2009; 11 (Suppl 2): S27–34 Background: Many patients with type 2 diabetes delay the start of insulin therapy because of concerns about SC injections. The aim of this study was to compare the effects of AIR inhaled insulin with those of SC insulin on metabolic control and safety. Methods: This open-label, randomised study in patients with diabetes inadequately controlled by OADs was planned for 24 months. Following a 2-week baseline period, patients continued OADs and were randomised to AIR insulin (n = 208) or insulin lispro (n = 203) before meals. The primary end-point was change in HbA1c from baseline to 6 months. Non-inferiority was established if the upper limit of the 95% CI of the difference in HbA1c change was £ 0.4%. Results: The number of patients for the 12- and 24-month analyses got smaller by an early termination of the study, but not for the primary 6-month end-point analyses. AIR insulin and SC insulin groups had comparable baseline HbA1c values. Also changes in HbA1c from baseline to 6 months were similar and so were final HbA1c values for both AIR insulin and SC insulin. At 6 months, no differences were observed in eight-point blood glucose profiles, overall and nocturnal hypoglycaemia and weight gain. Greater decreases in pulmonary function were observed in the AIR insulin group at 12 months. Cough was the most frequently reported adverse event. Conclusions: Insulin treatment with AIR insulin resulted in similar improvement in metabolic control compared with insulin lispro. More frequent cough and greater decrease in lung function were observed with AIR insulin.

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• Comment: It is an interesting idea to start insulin therapy in patients with type 2 diabetes with inhaled insulin instead of SC insulin. One would assume that this is of help as many patients (and their treating physician) are reluctant to start insulin therapy because of the fear of injection pain (at least this is the reason stated). This study showed that AIR insulin was as effective as SC insulin for the initiation of insulin therapy without basal insulin coverage in this group of patients. Also in terms of safety no significant difference between inhaled and SC insulin in terms of adverse events was observed, although the effect on lung function after a longer term of treatment clearly would be of interest.

Comparison of prandial AIR inhaled insulin alone to intensified insulin glargine alone and to AIR insulin plus intensified insulin glargine in patients with type 2 diabetes previously treated with once daily insulin glargine J. Rosenstock,1 F. G. Eliaschewitz,2 C. R. Heilmann,3 D. B. Muchmore,4 R. P. Hayes,3 R. M. Belin3 1 Dallas Diabetes and Endocrine Center, Dallas, TX, USA, 2Hospital Albert Einstein, Sa˜o Paulo, Brazil, 3Eli Lilly and Company, Indianapolis, IN, USA, and 4Halozyme, San Diego, CA, USA Diabetes Technol Ther 2009; 11 (Suppl 2): S63–73 Background: Many patients with type 2 diabetes start their insulin therapy with SC injection of a long-acting insulin analogue once per day. With progression of the disease many of them intensify their insulin therapy to improve metabolic control. The aim of this study was to compare three different intensification approaches: switching from insulin glargine to preprandial AIR inhaled insulin (IN), intensifying glargine (IG), or adding AIR insulin plus intensifying glargine (AIR+IG). Methods: Patients (n = 560) with HbA1c of 7.5%–10.5%, on one or more oral hypoglycaemia drugs (OADs) and on once daily IG for ‡ 4 months were randomly distributed to one of the three treatments lasting 52 weeks. Primary end-point was the between-group differences in metabolic control as changes from baseline to 24 weeks using last-observation-carried-forward (LOCF) in the intent-to-treat population.

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Results: After 24 weeks the HbA1c was reduced from a mean baseline of 8.5% to 7.7%, 7.9% and 7.5% for the AIR, IG and AIR+IG groups, respectively. AIR produced a 0.2% greater decrease in HbA1c than IG. AIR+IG had a 0.35% greater HbA1c decrease vs. IG ()0.57, )0.13). The )0.15% difference between AIR+IG and AIR was not significant. More hypoglycaemia categorised as severe occurred with AIR alone vs. IG alone at LOCF end-points. More nocturnal hypoglycaemia occurred with IG alone vs. AIR alone and AIR+IG. Conclusions: To apply inhaled insulin preprandially is an option for patients with type 2 diabetes not having optimal metabolic control with a long-acting insulin analogue. A number of aspects, like quality of metabolic control, hypoglycaemic risk, delivery preference and regimen complexity, must be considered when selecting the best insulin therapy to start with and optimisation regimens. • Comment: This interesting and large study was designed to compare three approaches for intensifying insulin therapy in patients with type 2 diabetes who did not achieve optimal control on once daily insulin glargine and OADs. After 24 weeks patients on inhaled insulin only had a larger change in metabolic control compared with patients on a long-acting insulin analogue alone. Combining prandial with basal insulin supply clearly further improved metabolic control, but without reaching significance vs. prandial insulin alone. However, one has to acknowledge that the quality of metabolic control achieved by many patients was not good; intensification of insulin therapy in this study was inadequate. Also study quality suffered from early termination due to the stopping of this inhaled insulin development.

Does availability of AIR insulin increase insulin use and improve glycaemic control in patients with type 2 diabetes? R. M. Bergenstal,1 N. Freemantle,2 M. Leyk,3 G. B. Cutler,3 R. P. Hayes,3 D. B. Muchmore3,4 1 International Diabetes Center, Minneapolis, MN, USA, 2University of Birmingham, Birmingham, UK, 3Eli Lilly and Company, Indianapolis, IN, USA, and 4Halozyme Therapeutics Inc., San Diego, CA, USA (present address) Diabetes Technol Ther 2009; 11 (Suppl 2): S45–52 Background: The question studied was whether the availability of AIR inhaled insulin

leads to greater initiation and maintenance of insulin therapy in patients with type 2 diabetes compared with existing treatment options alone. The idea is that when insulin therapy is going to be started the physician and the given patient discuss treatment options, explore the impact of treatment decisions from the patient’s perspective, and make treatment choices together. This might be different depending on the availability of inhaled insulin as a treatment option. Methods: In a 9-month, multicentre, parallel, open-label study, adult non-smoking patients with diabetes not optimally controlled by two or more OADs were randomised to the standard options group (n = 516) or the standard options plus AIR insulin group (n = 505), in which patients had the same choices plus AIR insulin. The primary end-points were the proportion of patients in each group using insulin at endpoint and change in HbA1c from baseline to end-point. Results: At end-point, 53% of patients in the standard options group and 59% in the standard options plus AIR insulin group were using insulin (p = 0.07). Both groups improved metabolic control by about 1.2% and reported increased well-being and treatment satisfaction. The most common adverse event with AIR insulin was transient cough. Conclusions: The increase in therapeutic options for insulin therapy by inhaled insulin did not affect overall use of insulin at endpoint or metabolic control. Regardless of group assignment, the shared decision-making approach studied resulted in improved treatment satisfaction and metabolic control at end-point. Therefore, increasing patient involvement in treatment decisions may improve outcomes. • Comment: This ‘real world’ study in which patients had different options showed the interesting result that patients are not ‘jumping’ on a needle-free option as one would expect in view of the fact that many patients are reluctant to start insulin therapy. This indicates that it is not the ‘needle’ per se – which is regarded more as the sign – but the insulin therapy in general that is the obstacle. The outcome of this study is different from that of a similar study performed before with EXU; however, there were a number of differences in details of the study design that might explain this. It is in line with the outcome of the previously discussed studies that also in this study AIR insulin was not associated with an improved metabolic control compared with SC insulin.

Safety and efficacy of AIR inhaled insulin compared with subcutaneous insulin in patients having diabetes and asthma: a 12-month, randomised, noninferiority trial E. Ang,1 M. K. Lawrence,2 C. R. Heilmann,3 J. A. Ferguson,4 J. A. Tobian,4 D. M. Webb,4 P. Y. Berclaz4 1 Cardinal Santos Medical Center, San Juan, Philippines, 2Down East Medical Associates, Morehead City, NC, USA, 3US Medical Division, Lilly USA, LLC, and 4Lilly Research Laboratories, Eli Lilly and Company, IN, USA Diabetes Technol Ther 2009; 11 (Suppl 2): S35–44 Background: The aim of this study was to establish the long-term safety and efficacy of AIR insulin in patients with diabetes and asthma. Methods: This was a 1-year, randomised, open-label, active comparator, two-arm, parallel study. In this the safety and efficacy of AIR insulin was compared with that of SC insulin in patients having type 1 or type 2 diabetes and asthma. Patients with type 2 diabetes continued to take their pre-study OADs. Results: Change in HbA1c from baseline to end-point was similar for the AIR insulin and SC insulin groups, but non-inferiority failed to be achieved (upper limit of the 95% CI )0.053 to 0.555 was > 0.4%). Total daily prandial insulin dose increased more in the AIR insulin group than in the SC group (0.15 U ⁄ kg and 0.04 U ⁄ kg, respectively, p = 0.002). Safety profiles were generally comparable between treatments. At end-point, the ratio of Forced Expiratory Volume in 1 s to Forces Vital Capacity (FVC) post bronchodilator ()0.016 ± 0.005 vs. 0.002 ± 0.005, p = 0.006) and DCCO ()1.21 ± 0.33 vs. )0.38 ± 0.31 l ⁄ min ⁄ torr, p = 0.028) both decreased more in the AIR insulin group than in the SC group, but the differences were not present at follow-up. FEV1 and FVC were similar between treatment groups at endpoint. Incidences of hypoglycaemia were comparable between groups. InsAb binding increased more in the AIR insulin group. The most common adverse event was cough; however, there was no difference in incidence between the AIR group and SC group. Conclusions: AIR insulin demonstrated glycaemic efficacy similar to SC insulin in patients who have diabetes and asthma. Also the safety profile of AIR insulin in patients with and without asthma is consistent.

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• Comment: It is not easy to recruit a considerable number of patients with diabetes who also have asthma for a clinical study; however, the relatively large number of patients that discontinued (42 SC insulin, 39 AIR insulin) is a limitation of this study. The main reason for this was the sponsor decision to terminate the development of the AIR insulin system. In that sense this is an important study with inhaled insulin that adds to the limited data available on this subgroup of patients.

INHALED INSULIN – technosphere Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial J. Rosenstock,1 D. L. Lorber,2 L. Gnudi,3 C. P. Howard,4 D. W. Bilheimer,4 P. C. Chang,4 R. E. Petrucci,4 A. H. Boss,4 P. C. Richardson4 1 Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA, 2Diabetes Control Foundation Center, Flushing, NY, USA, 3 Unit of Metabolic Medicine, Cardiovascular Division, King’s College London, UK, and 4 MannKind Corporation, Valencia, CA, USA Lancet 2010; 375: 2244–53 Background: Many patients with T2DM delay the start of their insulin therapy. In this study the efficacy and safety of prandial TI was compared with twice daily SC biaspart insulin injections. Methods: In this randomised, open-label, parallel group study, 677 adult patients with type 2 diabetes and poor glycaemic control despite insulin therapy, with or without OADs, were enrolled from 10 countries. Patients were randomly allocated in a 1:1 ratio to receive 52 weeks’ treatment with prandial TI plus bedtime insulin glargine or twice daily pre-mixed biaspart insulin. The primary end-point was a comparison of change in HbA1c from baseline to week 52 between treatment groups; the non-inferiority margin was 0.4%. Results: In all, 334 patients were allocated to TI plus insulin glargine, and 343 to biaspart insulin; after drop-out, 211 patients on TI and 237 on biaspart insulin were included in per-protocol analyses. Improvement in metabolic control with TI was similar and non-inferior to that with biaspart insulin. The between-group difference was 0.07% (SE

0.102, 95% CI )0.13 to 0.27). Patients had lower weight gain and fewer mild-to-moderate and severe hypoglycaemic events on TI than on biaspart insulin. The safety and tolerability profile was similar for both treatments, apart from increased occurrence of cough and change in pulmonary function in the group receiving TI. Conclusions: This study addresses the efficacy and tolerability of use of TI in a wide variety of patients. • Comment: It is good to see that the improvement in metabolic control was comparable between the two groups; however, one wonders if it would not have been a better study design if patients in the control arm had used a rapid-acting insulin analogue and a long-acting insulin analogue instead of an insulin mixture (with 30% prandial insulin only). That more insulin was prevailing in the bloodstream early with the meals with TI in comparison to the SC insulin mixtures can be clearly seen in differences of the postprandial glycaemic excursions with the meal challenge tests. From a lower preprandial value the increase in glycaemia was smaller in the first 60–120 min with TI; interestingly enough the maximal blood glucose values reached after 120 min were comparable. Glycaemia declined more slowly thereafter with TI than with SC insulin. This observation can be interpreted as a too rapid decline in metabolic effect of TI after a meal. The insulin doses applied with the two different insulin administration routes are not easy to calculate and compare from the numbers given in the publication. However, with both insulin regimens a rapid initial improvement in metabolic control was observed, by 0.8% in 14 weeks. It is of interest to note that also with TI fasting blood glucose was lower than with SC insulin, acknowledging the impact that the SC applied insulin glargine could also have had on this parameter in this patient group. A relatively high number of patients dropped out with both types of insulin therapy in this study; there were also a high number of screening failures. Adverse events such as cough and changes in lung function with TI have also to be acknowledged. Despite some limitations, this 1-year study showed that use of TI as prandial insulin allows good to acceptable metabolic control to be achieved in many patients with type 2 diabetes with a reduced risk of hypoglycaemic events.

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A review of inhaled Technosphere insulin J. J. Neumiller,1 R. K. Campbell,2 L. D. Wood1 1 Department of Pharmacotherapy, College of Pharmacy, Washington State University ⁄ Elder Services, Spokane, WA, USA, and 2Department of Pharmacotherapy, Washington State University College of Pharmacy, Pullman, WA, USA Ann Pharmacother 2010; 44: 1231–9 (See also Neumiller and Campbell (2) Background: To review the pharmacology, pharmacokinetics, efficacy, safety and clinical use of TI. Methods: A MEDLINE search (1966– March 2010) was conducted for English language papers using the terms AFREZZA, AFRESA, TI, pulmonary insulin and inhaled insulin. Abstracts from the American Diabetes Association and European Association for the Study of Diabetes annual meetings, presented in 2004–2009, were also searched for relevant data. English language papers pertinent to the pharmacology, pharmacokinetics, efficacy and safety of TI were reviewed. Results: TI is an inhaled insulin product with a PK profile suitable to meet prandial insulin needs in patients with diabetes. TI has demonstrated efficacy in terms of postprandial and overall glycaemic control, with efficacy and safety outcomes maintained for up to 4 years in one study. The overall tolerability profile for TI in clinical trials published to date has demonstrated a relatively low risk of hypoglycaemia and weight gain compared with SC prandial insulins. Clinical trials to date have demonstrated safety in terms of pulmonary function, and the absorption of TI is not significantly altered in patients with chronic obstructive pulmonary disease or in those who smoke. Conclusions: The Technosphere delivery system allows for the rapid absorption of TI via the lung, making this product a potential option for prandial insulin coverage in both type 1 and type 2 diabetes. The device to administer the insulin is well designed, small and easy to use. TI may provide a useful treatment option for patients resistant to or fearful of initiating prandial insulin injections. • Comment: This is a good review of the literature published about TI and worthwhile reading.

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Effect of Technosphere inhaled insulin on quality of life and treatment satisfaction M. Peyrot,1,2 R. R. Rubin2,3 1 Department of Sociology, Loyola University Maryland, Baltimore, MD, USA, 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, and 3 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA Diabetes Technol Ther 2010; 12: 49–55 Background: This randomised controlled trial assessed the impact of TI delivered via the MedTone inhaler on quality of life and treatment satisfaction in adults with type 2 diabetes. Methods: Patients (n = 119) were insulinnaı¨ve with starting HbA1c > 6.5%: 58 in the active inhaled insulin arm and 61 in the inhaled placebo arm. Subjects completed a measure of health-related quality of life (the SF-36) and a measure of treatment satisfaction [the Insulin Treatment Questionnaire (ITQ), which assesses diabetes worries, perceptions of insulin therapy, and inhaler performance] before starting insulin treatment and approximately 12 weeks later. Results: No significant change was observed in any SF-36 factor or the ITQ during the trial in either arm. There were no between-arm differences in change of any of these measures. Perceptions of insulin therapy improved during the trial in the active medication arm (effect size for composite measure 0.56, p = 0.002) but not in the placebo arm; there were no significant betweenarm differences in change. The majority of subjects gave positive ratings of inhaler performance on all items (median: 93% positive ratings). Conclusions: Treatment with TI was well tolerated, clinically efficacious and associated with positive patient-reported outcomes, including improved attitudes toward insulin therapy and high treatment satisfaction. No negative impact on health-related quality of life or worries about diabetes was reported with this treatment. • Comment: Patient acceptance of a given new diagnostic or therapeutic option is of great relevance for its market success. In the abstract it is not stated that this was a double-blind study: active inhaled TI vs. placebo inhaled TI. Patients in the active TI group applied approximately 30 U TI (= 10 U SC insulin) per meal and had an improved metabolic control. One wonders if the patients in this group did not know that they were in the

active group, simply by measuring blood glucose. This is of interest to keep in mind when interpreting the data reported, i.e. that there were no differences in SF-36 and the ITQ, but that perception of insulin therapy differs. Believing that the patients in the active group were happy with using TI and the inhaler, it would have been of interest to know what patients in an additional study arm would have stated if these had used a modern insulin pen for SC insulin therapy. In the Discussion section it is stated that such studies are on their way now. It appears that at least some patients were not too happy with the inhaler performance (see Table 5 of the publication) (3).

INHALED INSULIN – others The effect of terbutaline on the absorption of pulmonary administered insulin in subjects with asthma A. H. Petersen,1,2 S. Korsatko,1 G. Ko¨hler1, A. Wutte,1 H. Olschewski,1 T. Sparre,3 J. Ra˚stam,3 P. Wollmer,4 T. R. Pieber1 1 Medical University of Graz, Graz, Austria, 2 University of Aarhus, Aarhus, The Netherlands, 3Novo Nordisk A ⁄ S, Bagsvaerd, Denmark, and 4Lund University, Malmo¨, Sweden Br J Clin Pharmacol 2010; 69: 271–8

chodilator administration for the Rev) group (p = 0.044) and the whole group (p = 0.032). Conclusions: Administration of a bronchodilator in people with asthma and reversible bronchoconstriction prior to administration of inhaled insulin led to increased absorption of insulin. In contrast, no effect on insulin absorption could be observed in subjects without significant reversibility. • Comment: As with each route of insulin administration, there are a number of aspects that are of clinical relevance when treating real patients. In the case of pulmonary insulin it is important to know what impact different types of lung diseases per se have on insulin absorption in the lung and also what impact the treatment of a given lung disease has on insulin absorption. The authors of the paper have performed a number of systematic investigations about practically relevant questions, e.g. about the impact of exercise on insulin absorption in the context of pulmonary insulin application. This study shows that not only does the bronchodilatation induced by a specific co-medication have an impact on insulin absorption, but also that the status of the disease (in this case asthma) is of relevance. This is important information for the diabetologist who is interested in treating his ⁄ her patients, who also have asthma, with inhaled insulin.

ORAL INSULIN Background: The aim of this study was to investigate the effect of prior administration of the bronchodilator terbutaline on the absorption of inhaled insulin in people with asthma treated with inhaled corticosteroids. Methods: This randomised, open-label, two-period crossover trial was carried out in non-diabetic subjects (n = 41) with asthma treated with inhaled steroids: 25 with reversible bronchoconstriction (Rev+) and 16 without reversible bronchoconstriction (Rev)). An insulin dose of 0.10 U ⁄ kg inhaled insulin was administered on each dosing day with or without prior administration of terbutaline. Results: Administration of terbutaline led to a 44% increase in insulin absorption over 6 h for the subjects in the Rev+ group compared with no prior administration of bronchodilator (p = 0.004), whereas no effect was seen for the Rev) or the whole group. Maximal insulin levels (Cmax) increased by 34% for the Rev+ group (p = 0.018) and 17% for the whole group (p = 0.046), whereas no effect was seen for Rev). Time to Cmax was not different for the Rev+ group, whereas it was approximately 30% longer after bron-

Each year a number of new approaches for OI are published in pharmaceutical journals. Usually in these studies the metabolic effects of a given OI are studied in a more or less large number of rats. In practically all of these publications, the same statement is used in the last sentence of the paper and this is that this OI is a ‘promising development’. However, only a very small number (if any at all!) of these approaches are transferred into clinical development. In view of this fact it is of no surprise that only three original papers were published in the last year in which data from clinical– experimental studies in humans are presented. In contrast, the number of reviews published about this topic (four) is higher (two reviews focus more on clinical studies while the other two focus on important techniques for OI formulations). However, two of the original papers are from companies (Emisphere and Diabetology with their Capsulin development) which appear to have ‘limited activity’ in oral insulin development nowadays (see the respective homepages). In contrast, Biocon is in phase 3 studies with IN-105. It will be of interest to see

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whether Biocon will focus on the large Indian market in the first step with their OI or whether they will also try to get market approval in the USA and EU, and whether the regulatory authorities will regard their OI as safe and effective. Also the small Israelbased company Oramed is quite active and in the late phase of clinical development. In contrast, Novo Nordisk is in an early development phase with their OI (NN-1952), which is a co-development with the Irish company Merrion Pharmaceuticals. There is a recent review about the pharmacological approach used with this OI; however, no human ⁄ clinical data are presented (4). The Chinese company Biolaxy has also announced that they are developing an OI and have performed pilot clinical studies with patients with type 2 diabetes, but no data have been presented so far. Other companies like Access Pharmaceuticals – which has an OI in which the insulin is bound to cobalamin (vitamin B12) – announced plans to initiate clinical trials; however, again no data have been presented so far.

Open-label study to assess the safety and pharmacodynamics of five oral insulin formulations in healthy subjects R. Eldor,1 M. Kidron,1,2 E. Arbit2 1 Diabetes Unit, Hadassah University Hospital, Jerusalem, Israel, and 2Oramed Pharmaceuticals, Hi-Tech 2 ⁄ 5, Givat Ram, Jerusalem, Israel Diabetes Obes Metab 2010; 12: 219–23 Background: The ability of OI to mimic the natural route of endogenous insulin secreted by the pancreas into the portal vein and directly to the liver is assumed to have therapeutic advantages in diabetes therapy compared to SC injected prandial insulin. Oramed Pharmaceuticals is developing an OI product which consists of unmodified recombinant human insulin combined with adjuvants that protect it from enzymatic degradation in the gastrointestinal tract and promote its absorption from the gut. The aim of this study was to determine the optimal ratio between adjuvants and insulin with respect to the best pharmacodynamic properties, while maintaining the safety of the product. Methods: Eight healthy, male volunteers participated in this open-label study which included five study days. During each study day, the subjects swallowed one of the five encapsulated OI formulations which contained equal amounts of insulin but varying

proportions of adjuvants. Parameters assessed included safety, Cmax and Tmax for insulin and Cmin, Tmin and area under the curve (AUC) for glucose and serum C-peptide. Comparisons were made between formulations and between post-treatment time periods within each visit. Results: All five OI insulin formulations were well tolerated and no serious adverse events were reported. Also all formulations resulted in a significant response in the response period (60–300 min) in comparison to baseline (0–60 min); this was captured in both the serum C-peptide response and the blood glucose response (all formulations p < 0.05). None of the formulations turned out significantly different in response from the others. However, formulation five showed the highest reduction in C-peptide when AUC0–60 (baseline) was compared to AUC60– 300 (p < 0.007). Conclusions: All five OI formulations resulted in blood glucose and serum C-peptide reductions. Formulation five was deemed the lead formulation to be advanced to future clinical studies. This study demonstrated that OI maintains its biological activity after delivery, suggesting a potential role for insulin therapy. • Comment: In this small study eight healthy subjects swallowed capsules with different amounts of carrier and adjuvants (it is not stated which substances these are) and the decline in blood glucose ⁄ C-peptide levels was monitored. Unfortunately no individual profiles are provided, but a difficult to interpret table only. That all OI formulations showed a metabolic effect is positive; however, the question is how strong this will be in connection with a meal. One also wonders why c-peptide is not written as C-peptide as is done usually.

Glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes S. D. Luzio,1 G. Dunseath,1 A. Lockett,2 T. P. Broke-Smith,2 R. R. New,2 D. R. Owens1 1 Diabetes Research Unit, University Hospital Llandough, Penarth, South Glamorgan, UK, and 2Diabetology Ltd, London Bioscience Innovation Centre, London, UK Diabetes Obes Metab 2010; 12: 82–7 Background: In this study the PK and PD properties of SC RHI and oral insulin in a capsule form (Capsulin) were compared. Methods: This was a randomised, open, single-centre, two-way crossover study in

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adult patients (n = 16, 12 males) with type 2 diabetes on OADs [age 60.2 ± 5.5 years, body mass index (BMI) 28.3 ± 3.4 kg ⁄ m2, HbA1c 7.4% ± 1.1%]. Two 6-h isoglycaemic glucose clamps were conducted 11 days apart. All patients received in random order 12 U RHI SC on one study day and either 150 U or 300 U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and serum C-peptide levels were determined throughout each clamp. Between the clamp study days, all patients received 150 U Capsulin twice daily, dropping all their standard OADs apart from metformin. Self-monitored blood glucose levels were taken four times a day between the clamp study days. Results: Administration of either RHI or Cap (150 and 300 U) slowly increased GIRs, reaching maximum values at approximately 280–330 min. Overall values for maximum GIR values were higher for RHI than either dose of Cap (p < 0.05). The greater systemic insulin concentrations following RHI were reflected in the AUC0–6 h (910 ± 270 vs. 472 ± 245 pmol h ⁄ l; 950 ± 446 vs. 433 ± 218 pmol h ⁄ l; both p < 0.05 for RHI vs. 150 U Cap and 300 U Cap, respectively). No difference was observed between 150 U and 300 U Cap. During the repeat-dosing period, good safety and tolerability were observed with Cap, and self-monitoring of blood glucose levels remained stable. At the post-study visit, significant falls in HbA1c, weight and triglycerides were observed. Conclusions: Administration of the OI Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h, while circulating plasma insulin concentrations increased minimally. • Comment: After a number of inconclusive studies with this OI presented in previous years, this is the first full clinical–experimental study investigating the PK and PD properties of Capsulin. In contrast to other OIs, Capsulin shows a slow onset of the metabolic effect induced. The missing dose–response relationship (identical metabolic effect with 150 and 300 U) is puzzling. Also the findings that in the 10 days in which this OI was used for prandial insulin therapy blood glucose remained high (and that no hypoglycaemic events were observed) can be regarded as an indication of a low bioavailability ⁄ biopotency. Because of the degrading of insulin in the liver directly after absorption (and the control on hepatic glucose production this might induce), the correlation between PK and PD data with OI is not as close as with SC insulin administration.

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Oral insulin: a comparison with subcutaneous regular human insulin in patients with type 2 diabetes C. Kapitza,1 E. Zijlstra,1 L. Heinemann,1 M. C. Castelli,2 G. Riley,2 T. Heise1 1 Profil Institut fu¨r Stoffwechselforschung, Neuss, Germany, and 2Emisphere Technologies, Cedar Knolls, NJ, USA Diabetes Care 2010; 33: 1288–90 Background: The aim of this study was to determine the PK and PD properties of an OI compared with SC injected RHI. Methods: Patients with type 2 diabetes (n = 10) with mean HbA1c 7.0 ± 1.1% received either 300 U of insulin combined with 400 mg of delivery agent orally or 15 IU RHI SC under isoglycaemic clamp conditions. Results: Maximum serum insulin concentrations were higher and onset of action was faster with OI (Cmax 93 ± 71 vs. 33 ± 11 lU ⁄ ml; AUCGIR 0–1h 173 ± 86 vs. 27 ± 32 mg ⁄ kg; p < 0.05). Mean serum insulin levels and glucose infusion rate returned to baseline within 3 h after OI administration. Relative bioavailability of OI was 7% ± 4% (first 2 h). Conclusions: OI has a rapid absorption (under fasting conditions), and it also led to a clinically relevant increase in glucose consumption. However, the inter-individual variability in insulin absorption ⁄ insulin action was considerable. • Comment: This study shows that under fasting conditions a significant amount of insulin was absorbed rapidly into the bloodstream after application of this OI. Subsequently also a rapid increase in glucose infusion rates was observed to keep blood glucose constant in this glucose clamp study. When the study was performed, this was the first PD proof that with OI a sufficient amount of insulin could be transferred into the bloodstream to cover prandial insulin requirements. In view of the fact that the euglycaemic glucose clamp technique provides the clearest (and unbiased) understanding of the PD properties of a given insulin formulation, this methodological approach should be used more systematically to study the PD properties of other OIs (and also other ARIAs). However, this study was performed some years ago and Emisphere is not developing this OI any further. The main reason for this is that in clinical trials performed under non-fasting conditions, the degree of insulin absorption with this OI was low in many subjects and quite variable. The intra- and interindividual variability of insulin absorption is

a key issue with any OI. It appears that this variability was not formally studied in any clinical study to date. It is of great practical relevance to understand which factors influence this variability with OIs.

Oral insulin – a review of current status H. Iyer, A. Khedkar, M. Verma R&D, Biocon Ltd, Bangalore, Karnataka, India Diabetes Obes Metab 2010; 12: 179–85 If an OI formulation becomes available that works in daily practice, this would offer considerable advantages: it should improve patient convenience, provide rapid insulinisation of liver and adequate insulin delivery avoiding peripheral hyperinsulinaemia while potentially avoiding adverse effects of weight gain and hypoglycaemia. It is also evident that an earlier start of intensive insulin therapy accompanied by improved metabolic control results in substantial delay of the development of diabetes-related complications. All this makes an effective OI product very attractive for the management of patients with diabetes. However, despite decades of intensive work using a wide variety of technologies, until now no development of an OI formulation has been successful because of several barriers. This review summarises the development status of OI which is publicly reported to be undergoing clinical studies. Two OI products are currently in an advanced stage of clinical development. Data from the first study reporting long-term therapy with an OI are expected to be available in the second half of 2010. • Comment: This is an interesting review by the scientists that are the driving force behind the OI development at Biocon. After a short introduction to diabetes and diabetes treatment, the potential role of OI and ways to develop OIs are presented. As well as covering the different OI technologies they also provide an overview about the different companies that are working in this area of research. Unfortunately they do not review their own development in great detail.

Efficacy of oral/buccal insulin in the treatment of diabetes mellitus [Article in Spanish] Z. Herrador Ortiz, A. Llanos Me´ndez Agencia de Evaluacio´n de Tecnologı´as Sanitarias de Andalucı´a, Sevilla, Espan˜a Aten Primaria 2010; 42: 316–21

Background: The aim of this review was to evaluate the efficacy and safety of administering oral ⁄ buccal insulin by an analysis of published studies. Methods: Databases like MEDLINE, EMBASE, Scopus, Current Contents, Web of Science and Cochrane Library, and the European Drugs Agency, Food and Drug Administration, International Network of Technological Evaluation Agencies, European Network for New and Emerging Technologies (EuroScan) and gravel research registers were searched for this systematic review. Unfortunately only two clinical trials were found and in none of these studies is a head-to-head comparison between a given oral ⁄ buccal insulin and the standard treatment with SC injected insulin made. Results: Buccal insulin produced a greater and earlier reduction in postprandial blood glucose excursion 30 min after insulin application in the intervention group compared with the control group (decrease of 55 mg ⁄ dl). Also the increase in serum insulin was different, i.e. higher maximal levels (98 vs. 65 lU ⁄ ml) were observed with buccal insulin. Postprandial blood glucose levels with OI were comparable with those obtained with SC injected insulin, despite the fact that higher maximum serum insulin levels were observed (110 ± 130 vs. 96.3 ± 69.7 lU ⁄ ml). Conclusions: Oral ⁄ buccal insulin provides, at least, metabolic control that is similar to that obtained with standard treatment. However, the studies have serious methodological problems of internal and external validity. • Comment: Employing a rigorous selection procedure resulted in a very small number of studies that the authors of this review were able to identify. They analysed these two papers in detail. It appears that they were not at all happy with the quality of the studies, a perception that is definitely true.

Design of oral insulin delivery systems T. W. Wong Particle Design Research Group, Faculty of Pharmacy, and Non-Destructive Biomedical and Pharmaceutical Research Centre, Universiti Teknologi MARA Malaysia, Puncak Alam, Selangor, Malaysia J Drug Target 2010; 18: 79–92 Despite many years of research to replace the painful SC route of insulin administration, no OI is commercially available. Many different attempts, involving nanoparticles, microparticles, hydrogel, capsule, tablet and film patches were tested for OI delivery. These are usually formulated with polymeric

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adhesive, protease inhibitor, insulin aggregation inhibitor and functional excipients to improve transcellular, paracellular, Peyer’s patches, or receptor-mediated transport of insulin in gastrointestinal tract into the bloodstream. Superporous matrix, intestinal patches and charged-coupled micromagnet microparticles are other recent attempts to improve OI absorption. It is hoped that increasing the bioavailability of insulin can be achieved by having a formulation that emphasises an assembly of insulin and excipients in a physical structure which provides an element of drug targeting that maintains stability. In order to overcome the intestinal transport capacity limit muco-adhesiveness appears to be of importance to achieve a prolonged retention of dosage form in the intestinal tract. This translates into cumulative insulin release and absorption. Therefore, synthesis and use of muco-adhesive excipients, chemical modification of insulin to promote its physicochemical and biological stability for encapsulation in dosage form with prolonged retention characteristics and identification of potential insulin adjuncts are necessary efforts needed to accelerate the speed of obtaining a functional OI delivery system. • Comment: Ignoring the lengthy introduction about diabetes, diabetes therapy etc., this is a good, systematic and easy to read introduction into the different pharmacological options ⁄ techniques for OI formulation.

Challenges and advances in nanoparticle-based oral insulin delivery R. M. Ramesan, C. P. Sharma Biosurface Technology Division, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India Expert Rev Med Devices 2009; 6: 665–76 The development of an OI formulation that works in daily practice has not been successful so far, despite rigorous efforts for many decades. However, our understanding of the development of biocompatible and biodegradable polymers, synthesis of nanopeptide delivery systems, biocompatibility and its cellular uptake mechanisms has evolved tremendously over the past few years. Therefore the development of nanoparticle-based oral peptide delivery systems seems to be feasible. Nanoparticles enhance bioavailability by facilitating insulin uptake into the bloodstream via a transcellular or paracellular pathway. Clearly, biocompatibility and the half-life of the particles in the bloodstream are of para-

mount relevance. In this review, the various approaches adopted for nanoparticle-based OI delivery, uptake mechanisms, biocompatibility and bioavailability of the nanoparticle are discussed. • Comment: This is another interesting review, focused more on the methodological aspects of OI development.

NASAL INSULIN Only one paper was published in the last year reporting about a clinical study in humans when insulin was applied to the nose. This publication is by the company CPEX (http:// www.cpexpharma.com), which is a spinoff from Bentley. The company has also published in previous years about their ‘Nasulin’ development (which was in phase 2a), but according to a statement on their homepage the company is currently seeking to sell or out-licence their Nasulin programme. It appears that the number of companies that are active in this area of research has decreased in the last few years. However, as with OI, a number of papers (also reviews) were published in pharmaceutical journals about novel approaches for nasal insulin in the last year, but only reporting data obtained in rats.

Comparison pharmacokinetics of two concentrations (0.7% and 1.0%) of Nasulin, an ultrarapid-acting intranasal insulin formulation R. Stote,1 T. Marbury,2 L. Shi,3 M. Miller,3 P. Strange3 1 CPEX Pharmaceuticals Inc., Exeter, NH, USA, 2Orlanso Clinical Research Center, Orlando, FL, USA, and 3Integrated Medical Development, West Windsor, NJ, USA J Diabetes Sci Technol 2010; 4: 603–9 Background: The aim of this PK study was to characterise the dose response of two concentrations (0.7% and 1%) of a nasal insulin spray in healthy subjects. Additional dosing options of Nasulin would allow greater titration flexibility. Method: A five-period crossover study was carried out with 24 healthy, non-smoking subjects. Subjects were in a fasted state for 5 h before and 45 min after administration for PK assessment and were then given a meal. Each spray contained 100 ll. Doses tested were 25, 35, 50, 70 and 100 U. Maximum concentration (Cmax) and AUC was estimated for each dose group.

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Results: A dose response was demonstrated by baseline-adjusted Cmax of 22, 27, 56, 62 and 84 lU ⁄ ml for the 25, 35, 50, 70 and 100 U doses (p < 0.0001), respectively, and by baseline-adjusted AUC0–45 min values of 491, 592, 1231, 1310 and 1894 lU ⁄ ml ⁄ min (p < 0.0001). Glucose AUC0–45 min determinations also demonstrated a PD dose response. Conclusions: PK and PD parameters showed proportional and linear dose responses with the two concentrations of Nasulin applied, making multiple doses available for clinical development. • Comment: A considerable number of subjects were studied for this pure PK study, which unfortunately was not a glucose clamp study to evaluate the PD properties at the same time. Only data from five of the eight study days are presented. It would have been of interest to learn how much time the application of the different insulin doses requires in practice. It appears that the different doses provide a linear relationship with the maximal plasma insulin levels, but with large inter-individual differences in the increase in insulinaemia observed. Nasal insulin application induces ‘adverse events (that) were probable administration site reactions and, in order of decreasing frequency, included application site irritation, sneezing, increased lacrimation, throat irritation, dysgeusia, headache, cough, nasal congestion, ocular hyperemia, nasal discharge, and mucosal paresthesia’.

BUCCAL INSULIN In contrast to the considerable number of press releases that Generex, the only company which is developing a buccal insulin formulation (Oral-lyn), has released in the last year and which have resulted in a lot of reports in the lay press and TV (http://www.generex. com), the number of scientific publications is limited (one review). This might be due to the fact that Oral-lyn has for some time now been in a large phase 3 trial and that all phase 1 and 2 studies have been completed (and published?). Most probably the company is currently preparing all documents that are necessary for submission to the regulatory authorities for market approval. The limited number of publications in this phase of clinical development of Oral-lyn is in contrast to, for example, the considerable number of papers published by MannKind about TI and cannot be attributed to a shortage of good scientists and people with excellent background in the pharmaceutical industry (e.g. Joseph Rubinfeld is their Chief Scientific Advisor). Generex was also able to secure a good source for the insulin needed – sanofi-aventis has signed a supply contract with them.

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Review of clinical trials: update on oral insulin spray formulation P. Pozzilli,1 P. Raskin,2 C. G. Parkin3 1 Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy, 2 Department of Internal Medicine, Southwestern Medical Center at Dallas, Dallas, TX, USA, and 3CGParkin Communications Inc., Carmel, IN, USA Diabetes Obes Metab 2010; 12: 91–6 That an improvement in metabolic control has beneficial effects by reducing the risk of developing long-term microvascular complications was shown in patients with type 1 and type 2 diabetes. Improving metabolic control often requires use of multiple daily insulin injections (intensified insulin therapy). Unfortunately current methods of insulin administration are not optimal; many patients view insulin therapy as inconvenient and uncomfortable. Patients with type 2 diabetes in particular delay the start of insulin therapy because of this. OI administration (spraying insulin into the mouth to be absorbed via the buccal mucosa) provides an alternative to injectable and inhaled insulin. The system allows a liquid oral spray insulin formulation to be delivered into the mouth via an aerosol spray. The active pharmaceutical ingredient is recombinant human insulin. However, the time–action profile shows that this insulin formulation behaves more similarly to the rapid-acting insulin analogues. In clinical studies with healthy subjects and patients with type 1 and type 2 diabetes, the OI spray was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action compared with regular insulin injected SC. In all studies OI spray was generally well tolerated. Some healthy subjects and patients with type 1 diabetes experienced transient (1–2 min) mild dizziness during dosing; these symptoms were mild and self-limited. No other side effects were noted. The ease of use of the insulin spray formulation may increase patient acceptance and thereby enhance treatment compliance. Subsequently this potentially reduces complications and provides improved quality of life for patients with diabetes. This review provides an overview of the safety profile and proposed mechanism of action of this insulin formulation and presents findings from trials which studied its effects in patients with type 1 and type 2 diabetes. • Comment: When two well-known diabetologists write a review about a development that they are familiar with, the assumption is that they will provide a critical and detailed

discussion of the data available about the mechanism of insulin absorption via the buccal mucosa and the clinical studies performed. In the short Discussion section of this review some critical remarks are made; however, in general this is more an overview of all published studies without an in-depth analysis.

INSULIN PENS That insulin pens have gained more scientific interest in recent years also reflects the important market share these devices have nowadays for SC insulin administration in many countries; the percentage of users also continues to grow in the USA. The first ‘reviews’ about this topic are published now (5) and supplement issues of journals focused on diabetes technology are filled by papers about insulin pens. As discussed before, practically all of these studies were sponsored by one of the manufacturers and in nearly all cases the product of the sponsor turned out to be ‘better’ than the other products studied.

Dosing accuracy of insulin pens versus conventional syringes and vials Y. M. Luijf, J. H. DeVries Department of Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands Diabetes Technol Ther 2010; 12 (Suppl 1): S73–77 Background: In many countries insulin pens have acquired a pivotal role in insulin delivery, surpassing the use of syringes. The aim of this review was to determine differences in dosing accuracy between insulin pens and conventional syringes and vials. Methods: A literature search in PubMed for relevant literature identified seven papers. Results: The consensus was that pens are more accurate, especially at doses <5 IU. Pens tend to under-dose compared to syringes, but they do this with a high degree of consistency. No significant difference was found with respect to metabolic control in one study; however, fasting blood glucose levels decreased more in pen users compared to syringe users (p = 0.003). This study also showed that insulin pens improved healthrelated quality of life compared to syringes. Conclusions: There is sufficient evidence to recommend the use of insulin pens when delivering doses <5 IU with respect to accuracy. For insulin doses >5 IU there is no clear benefit for the pen in terms of accuracy. • Comment: It is of note to see how low the number of publications is (n = 5) that deal with the accuracy of insulin pens (and there

are many different pens on the market) compared with that of syringes. Also the methods used in the different studies differed considerably. The critical approach used in this review is something to keep in mind when reading other publications about this topic (see below).

Comparison of usability and patient preference for insulin pen needles produced with different production techniques: ‘thin-wall’ needles compared to ‘regular-wall’ needles: an openlabel study T. Siegmund, H. Blankenfeld, P. M. SchummDraeger Clinic of Endocrinology, Diabetes and Vascular Medicine, Teaching Hospital Munich-Bogenhausen of the Technical University, Munich, Germany Diabetes Technol Ther 2009; 11: 523–8 Background: The aim of this study was to evaluate if insulin pen needles that have ‘thin walls’, i.e. have the same outer diameter but a relatively larger inner diameter compared to needles produced with a ‘regular wall’, are different with respect to pen user habits as well as patient’s appraisals and ratings. Methods: In this multicentre open-label, single-arm study with patients with diabetes mellitus (n = 97) two different types of 31gauge pen needles were studied: ‘thin-wall’ needles vs. ‘regular-wall’. Patients use one type of needles for 2 weeks each, starting with a regular-wall period followed by a thin-wall period. After each period patients filled in questionnaires. Results: Patients reported reduced pain, bleeding, skin irritation, injection strain, needle occlusion and insulin leakage from the needle tip after injection when using thin-wall needles (p < 0.001). Also a higher proportion of patients expressed an overall preference for the thin-wall needles compared with the regular-wall needles ((78% vs. 8%, p < 0.001). Conclusions: It appears that thin-wall 31gauge needles for insulin pens are more userfriendly and consequently preferred by the patients. Additional larger-scale trials using blinded and randomised study designs are needed to validate these findings. • Comment: The last sentence of the abstract of this paper is probably the key point. It might very well be that the larger inner diameter of the thin-wall needles has relevance for patients; however, one wonders if the outcome of this study would have been that

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positive if the study were performed in a blinded manner. It should be mandatory that all such studies (if this is possible) are performed with such a study design. This statement might sound trivial; however, in many (if not in most) an unblinded study design was employed.

Skin and subcutaneous adipose layer thickness in adults with diabetes at sites used for insulin injections: implications for needle length recommendations M. A. Gibney, C. H. Arce, K. J. Byron, L. J. Hirsch BD (Beckton, Dickinson and Company), Franklin Lakes, NJ, USA Curr Med Res Opin 2010; 26: 1519–30 Background: Inadvertent intramuscular injections of insulin may increase pain and ⁄ or adversely affect glucose control. In this study the most appropriate needle length was measured in adults with diabetes (28% with type 1 diabetes), in relation to skin thickness (ST) and the distance to muscle fascia. Methods: Adult patients aged 18–85 years of different ethnicity in the USA were divided into three BMI subgroups: < 25, 25–29.9 and > 30 kg ⁄ m2. Each subject had ultrasound measurements of ST and subcutaneous adipose layer thickness (SCT) at four injection sites. Results: Patients had a BMI of 19.4– 64.5 kg ⁄ m2. Multivariate analyses showed that body site, gender, BMI and race are statistically significant factors for ST, but effects were small. Thigh ST was <0.6 mm thinner than the buttocks. Differences of 10 kg ⁄ m2 account for 0.2 mm ST variation. Mean SCT were arm 10.8 mm, thigh 10.4 mm, abdomen 13.9 mm and buttocks 15.4 mm. Females had 5.1 mm greater SCT. Differences of 10 kg ⁄ m2 account for 4 mm SCT variation. Conclusions: SCT has a wider range. Needles > 8 mm, inserted perpendicularly, may frequently apply insulin intramuscularly in limbs of males and those with BMI < 25 kg ⁄ m2. With 90  insertion, needles of 4–5 mm enter the SC tissue with minimal risk of intramuscular injection in virtually all adults. • Comment: Interestingly, this is one of the first studies in which the ST was systematically evaluated by means of modern ultrasound methods and well-trained operators in a considerable number of patients with diabetes. The study provides relevant data for the selection of needle length depending on the

preferred injection site in patients, and also in lean and obese subjects (range of BMI 19.6– 64.5 kg ⁄ m2). The ST is just above 2 mm at most common injection sites, varying significantly with factors like BMI, gender, diabetes type, race etc. The SC thickness ranged from 10 mm in the thigh to 15 mm in the buttocks, clearly with a much higher inter-individual variability than the ST depending on BMI, gender and body site. Combining ST and SC thickness allows the ‘ideal’ needle length to be estimated without raising a skin fold and inserting at 90  or 45 . With a 90  insertion and a needle length of 5 mm > 98% of all insertions will be in the SC tissue. With 12.7 mm the insulin would be delivered intramuscularly 45% of the time; even with a 45  insertion this would happen in 21% of insertions. Acknowledging that old studies using outdated methods to study insulin PK showed no impact if insulin was applied in deep or superficial SC levels, one would like to see such studies repeated with more appropriate PK and PD measurements.

Comparative glycaemic control, safety and patient ratings for a new 4 mm 3 32 gauge insulin pen needle in adults with diabetes L. J. Hirsch,1 M. A. Gibney,1 J. Albanese,1 S. Qu,1 K. Kassler-Taub1, L. J. Klaff,2 T. S. Beiley3 1 BD (Beckton Dickinson and Company), Franklin Lakes, NJ, USA, 2Rainer Clinical Research Center, Renton, WA, USA, and 3 AMCR Institute, San Diego, CA, USA Curr Med Res Opin 2010; 26: 1531–41 Background: In this study the safety, efficacy and patient ratings of a new 4 mm · 32 gauge pen needle for SC insulin therapy were evaluated. Methods: In total 173 patients with type 1 and type 2 diabetes and HbA1c 5.5%–9.5% participated in this randomised non-inferiority crossover trial. Patients used 4 mm · 32 gauge pen needles and either 5 mm · 31 gauge pen needles or 8 mm · 31 gauge pen needles in two 3-week treatment periods; order of needle use was controlled. Patients were either ‘low dose’ or ‘regular dose’ users (highest single insulin dose <20 U and 21– 40 U, respectively). Percentage absolute change in serum fructosamine was the primary end-point. Results: Of the 168 patients who completed the study, 163 were included in the fructosamine analyses)83 and 80 in the

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4 ⁄ 5 mm and 4 ⁄ 8 mm groups, respectively. Subjects were 56% male, mean 52.6 years, 63% type 2, HbA1c 7.5% ± 1.0% and fructosamine 301 ± 55 mmol ⁄ l. Change in percentage fructosamine was 4.9% and 5.5%, respectively, for the 4 ⁄ 5 mm and 4 ⁄ 8 mm groups, meeting glycaemic equivalence criteria; results were similar in both dose groups. Unexplained severe hypoglycaemic and hyperglycaemic episodes were infrequent and not different between pen needles. The 4 mm pen needle was rated significantly less painful and preferred by approximately two-thirds of subjects (p < 0.01). All three pen needles had similar reported injection site leakage. Conclusions: The 4 mm · 32 gauge pen needle provided equivalent metabolic control to the 31 gauge 5 mm and 8 mm pen needles with reduced pain and was preferred by patients. • Comment: Not too many studies have been published so far that compare the impact of needle length on metabolic control and on patient preference; most of these are ‘old’ (published > 10 years ago) and focused on PK and not on PD parameters. It is impressive to see that the 4-mm needle length has such an impact on a number of parameters, especially on pain, not so much on metabolic control. The difference in pain might be explained not only by the different length, but also by the difference in diameter. Knowing that the majority of patients today use an 8 mm needle, one wonders if patients will switch to one that has just half the length. Clearly one would like to see this study repeated with a longer study duration (focusing on HbA1c) and in different patient groups, and also in different countries.

The best insulin injection pen device for caregivers: results of injection trials using five insulin injection devices F. Yakushiji,1 H. Fujita,2 Y. Terayama,3 M. Yasuda,1 K. Nagasawa,4 M. Shimojo,5 K. Taniguchi,1 K. Fujiki,1 J. Tomiyama,1 H. Kinoshita1 1 Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan, 2 Department of Transfusion Medicine, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan, 3 Department of Pharmacy, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan, 4Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan, and 5Department of Internal Medicine, Kanagawa Prefectural Shiomidai Hospital, Kanagawa, Japan Diabetes Technol Ther 2010; 12: 143–8

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Background: Insulin pens are primarily used by patients with diabetes. However, because of demographic changes there are an increased number of patients who cannot self-inject insulin. In such cases the insulin is applied by caregivers (‘other-injection’). The aim of this study was to evaluate insulin pens for ‘other-injection’ use. Methods: Five devices – OptiClik (sanofiaventis, Paris, France), SoloSTAR (sanofiaventis), MirioPen without an antiskid tool (Eli Lilly, Indianapolis, IN), MirioPen with an antiskid tool (Eli Lilly, Hyogo, Japan) and FlexPen (Novo Nordisk, Bagsværd, Denmark) – were evaluated. Twenty-two respondents (age 43 ± 9 years) injected themselves (self-injection) and others (otherinjection). They evaluated the ease of use and feel of the pen devices via questionnaires. Results: For self-injection FlexPen was selected as the best device but as the worst for other-injection. OptiClik was selected as the second worst device for self-injection but as the best device for other-injection. Moreover, for other-injection, FlexPen was too long and less stable, had poor dial visibility, was difficult to recap, and was comprehensively inferior. Conclusions: Caregivers identified problems that were not apparent during studies with patients with diabetes. Devices meant for other-injection should have different features from those designed for self-injection. • Comment: In a world with a rapidly aging population (focusing on industrialised countries), the number of patients that live at home but require daily medical support is also increasing rapidly. Not only does this induce a massive increase in costs, but it is an aspect that diagnostics and pharmaceutical companies do not have in their focus when developing new options for diabetes therapy. However, as this study shows, interesting differences in the preference of caregivers exist with respect to different insulin pens. It is of note which aspects are of relevance for them: ‘FlexPen was too long, less stable, had poor dial visibility, was difficult to recap, and was comprehensively inferior’. Interestingly, the FlexPen has a length of 140 mm, whereas that of OptiClik is 167 mm.

Lessons learned during the development of HumaPen Memoir, an insulin pen with a memory feature S. D. Breslin,1 D. A. Ignaut,2 D. E. Boyd3 1 Delivery Device Research and Development, Eli Lilly and Company, Indianapolis, IN, USA, 2 Diabetes ⁄ Endocrine Medical, Eli Lilly and

Company, Indianapolis, IN, USA, and 3Medical Device Solutions, Battelle Memorial Institute, Columbus, OH, USA J Diabetes Sci Technol 2010; 4: 540–6 The major advantages of insulin pens are their ease of use, portability and discreetness. The development of new insulin pens can pose significant challenges to the development team in that they must balance substantial accuracy requirements with aesthetic desires. The lessons learned by a team that developed the HumaPen Memoir throughout the development process are described. The team must decide whether to use a quality functional deployment or a system-engineering-based development plan. Additionally, they have to recognise where proof of concept ends and product development begins to maintain a strict timeline for the project. In order to ensure a timely and high-quality product launch to the marketplace, a proficiency in understanding and managing technical risk is critical. • Comment: Many people believe that the development of a new medical device (an insulin pen in this case) is something a group of good engineers can easily handle in 3 months. In other words, construction of some simple plastic pieces appears to be a relatively simple and straightforward task. Reading this paper might be an eye-opener to many people. It is intriguing to read how complex and time demanding such a development is in reality. Unfortunately, these are aspects companies normally do not report. It is worth noting that the team which developed this new insulin pen with an electronic memory was often near the bleeding edge with certain aspects of the design.

Dose accuracy of SoloSTAR and FlexPen as assessed in a clinical setting A. Friedrichs LWS Risk Management Consult GmbH, Brannenburg, Germany Diabetes Technol Ther 2009; 11: 609–13 Background: The aim of this study was to compare the accuracy of SoloSTAR (sanofiaventis) and FlexPen (Novo Nordisk) to deliver doses of insulin when used by insulin ⁄ device-naı¨ve people. Methods: For determination of dose accuracy, SoloSTAR containing insulin glargine and FlexPen containing insulin aspart were used for all tests. The participants received instructions by an independent monitor on how to use the pens and were trained to hold

the pens in situ for 10 s at the end of injection to ensure that the full dose was injected. With each pen type the 48 subjects performed three dose deliveries of 20 U into a sponge. Results: The delivery of 144 individual doses of 20 U was no different (p = 0.187) between SoloSTAR (19.8 ± 0.3 U) and FlexPen (19.8 ± 0.3 U). However, 2% of doses from both devices were < 19 U; 98% were within 19–21 units. Conclusions: Both insulin pens were similarly accurate when used by device-naı¨ve subjects to deliver insulin. • Comment: The interesting aspect of this evaluation is that it was not performed in a hospital ⁄ academic setting but in a local healthcare practice in Germany. The criticism of many practitioners is that such studies are usually performed in specialised centres and not under the conditions of daily care in a busy practice. Clearly one can challenge a number of aspects of study performance in this study; however, it would be worth performing such evaluations in practices treating patients every day as well. Reading the Author Disclosure Statement and who has supported the study makes clear why, despite the fact that no significant differences were observed, some positive sentences for one of the two pens show up in the Conclusion section; one can clearly foresee that these will show up in the marketing activities for this pen.

MISCELLANEOUS The following three papers do not refer to new ways to deliver insulin in the strict sense. However, two present interesting new approaches to improve insulin absorption from the SC tissue by either increasing local blood flow as a reaction induced by heat applied to the skin for some minutes after insulin administration or by injecting the insulin not into the SC compartment but in the skin. With both approaches a significantly more rapid increase in insulinaemia and onset of metabolic effect could be observed compared to the control situation. Such improved PD properties should enable a better postprandial glycaemic control. In the end, it is the willingness of the patients (and ⁄ or of the healthcare funds) to pay for new ways of insulin delivery that counts, i.e. without a commercial success none of the novel developments will survive once they are able to make it to the market. However, such aspects have gained not too much attention in the past (at least not much was published about such studies).

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Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles J. Gupta,1,2 E. I. Felner,1,2 M. R. Prausnitz1,3 1 School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA, 2Department of Pediatrics, Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA, and 3 Wallach J Coulter Department of Biomedical Engineering, Emory University School of Medicine, Atlanta, GA, USA Diabetes Technol Ther 2009; 11: 329–37 Background: The aim of this study was to investigate if insulin delivery into human skin is possible by microneedles. Previously they have only been studied in animal models. The study hypothesis was that hollow microneedles allow a sufficient amount of insulin to be delivered to patients with type 1 diabetes. Methods: In two adult patients with type 1 diabetes insulin lispro was applied as a bolus using a hollow microneedle compared to a catheter infusion set (9 mm needle length). In order to determine the minimum depth of microneedle insertion, these were inserted 1, 3.5 and 5 mm into the skin of the fasting patients. It was also studied if, with an insertion depth of 1 mm of the microneedles, a reduction in postprandial glycaemic excursions could be induced. Results: Microneedles inserted at the shallowest depth of 1 mm within the skin already led to rapid insulin absorption and reduction in blood glucose levels. Bolus insulin delivery via the microneedles prior to consumption of a standardised meal showed that this route of insulin administration is effective in reducing postprandial blood glucose levels. Patients reported no pain from microneedle insertion, and there were no adverse events. Conclusions: Intradermal insulin delivery by means of hollow microneedles allowed bolus insulin to be effectively delivered to patients with type 1 diabetes. • Comment: It is impressive to see that even with a sample size of n = 2 it is possible to get a paper accepted in a peer-reviewed journal. Intradermal application of insulin has been tested before; already these previous PK and PD studies have shown that with application in this compartment a more rapid absorption ⁄ action than with SC application is possible. However, the needles used in the studies were very short conventional needles, i.e. with a length of 1.5 mm. The needles used in this (micro-) study were glass pipettes. The insulin was applied by means of a syringe

pump, i.e. the insulin was infused and not injected. The interesting data presented in this preliminary study should be reproduced in a formal clinical study.

Effect of a local heating device on insulin and glucose pharmacokinetic profiles in an open-label, randomised, twoperiod, one-way crossover study in patients with type 1 diabetes using continuous subcutaneous insulin infusion I. Raz,1 R. Weiss,1 Y. Yegorchikov,2 G. Bitton,2 R. Nagar,2 B. Pesach2 1 The Diabetes Center, Hadassah Hebrew University School of Medicine, Jerusalem, Israel, and 2Insuline Medical Ltd, Petah Tikva, Israel Clin Ther 2009; 31: 980–7 Background: Improvement of postprandial glycaemic control is of great interest for patients with diabetes. Previous studies have shown that local heating of the insulin injection site accelerates insulin absorption by increasing local blood flow. The aim of this study was to assess the effect of local heating by means of the InsuPatch (InsuLine Medical Ltd, Petach-Tikva, Israel) on PK properties of a rapid-acting insulin analogue and on postprandial glycaemia. Methods: This was an open-label, randomised, one-way crossover study using a meal tolerance test (MTT) protocol in patients with type 1 diabetes mellitus (n = 17) treated with continuous subcutaneous insulin infusion. An insulin bolus of 0.15 U ⁄ kg was applied prior to a standardised liquid meal. Results: The postprandial glucose excursions (AUC0–120 min) were reduced in the group of patients that used the device compared with those that did not (104 ± 65 vs. 155 ± 56 mg ⁄ dl ⁄ h; p < 0.005). The PK data were assessed in nine subjects. With local heating, time to maximal insulin levels was reduced (tmax 45 ± 28 vs. 78 ± 35 min) and time to half-maximum levels as well (t50%max 20 ± 11 vs. 28 ± 10 min; both p < 0.05). Cmax also increased (118 ± 35 vs. 86 ± 16 mU ⁄ l; p < 0.05). Conclusion: Local heating was associated with improved PK properties of an SC infused rapid-acting insulin analogue, resulting in a lower postprandial glucose excursion. • Comment: That local warming of the skin above the injection site improves insulin absorption has been known for decades. However, this is the first time that an attempt has been made to develop a system ⁄ device

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that can be used routinely in daily life by patients with diabetes. One interesting question, how much it is the blood flow in the dermis that is altered and not the flow in the SC compartment, remains to be studied. The effect of heating of the skin might have a different influence on the blood flow in these two compartments. An additional question is, if the nerve control of both compartments is known to be different, how much do environmental effects impact the effect of local heating on insulin absorption? In other words, what is the intra- and inter-individual variability of the induced increase in blood flow? The study presented in this publication has some shortcomings, e.g. PK data were not obtained for all subjects (also not completely for those in whom blood samples for PK measurements were collected), but the message is clear.

Socioeconomic differences in preferences and willingness-topay for insulin delivery systems in type 1 and type 2 diabetes C. Guimara˜es,1,2 C. A. Marra,2 L. Colley,2 S. Gill,2 S. Simpson,3 G. Meneilly,2 R. H. Queiroz,1 L. D. Lynd2 1 University of Sa˜o Paulo, Sa˜o Paulo, Brazil, 2 University of British Columbia, Vancouver, BC, Canada, and 3University of Alberta, Edmonton, AB, Canada Diabetes Technol Ther 2009; 11: 567–73 Background: Unfortunately most often patients’ preferences are not taken into account when different insulin delivery systems are discussed. This study was performed to investigate the association between socioeconomic status (SES) and patients’ preferences and willingness to pay (WTP) for various attributes of insulin administration for diabetes management. Methods: By means of a discrete choice experiment patients’ preferences and their WTP for hypothetical insulin treatments were determined. Differences in treatment preferences and WTP for different attributes of treatment across different levels of SES were explored by means of self-reported annual household income and education completed. Results: In total 274 patients successfully completed the discrete choice experiment questionnaire. Overall, metabolic control was the most valued attribute by all socioeconomic groups. In contrast, the route of insulin delivery was not as important. Not surprisingly patients with higher incomes were willing to pay significantly more for better metabolic control and to avoid adverse

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events compared with lower income groups. They were also willing to pay more for an oral rapid-acting insulin compared with the low income group (p < 0.01). However, there were no differences in preferences when the sample was stratified by level of education. Conclusions: This study showed that preferences and WTP for insulin therapy are influenced by income but not by level of education. Interestingly, the higher the income, the greater desire for an oral insulin delivery system, whereas an inhaled route becomes less important for patients. • Comment: One has the impression that many devices for diagnostic and therapeutic purposes are developed by excellent engineers and scientists, but not in close communication with patients with diabetes. However, in

the end the patients have to use these devices 24 ⁄ 7. Ideally such devices would be designed in a manner such that the patients do not regard them as medical devices anymore but as lifestyle devices like modern cell phones. Also, with ARIAs the key question is, are the (potential) advantages of these approaches so profound that patients will be willing to pay some extra for them? To evaluate such aspects is not a trivial undertaking; however, in this study the authors present quite interesting data in this respect. In the end such evaluations should be an integrated part of each new development. Let us wait and see if patients are willing to pay extra – as an example for a novel inhaled insulin with improved PK ⁄ PD properties (= Technosphere insulin) – or not.

References 1 Rosenstock J, Lorber DL, Gnudi L, Howard CP, Bilheimer DW, Chang PC, Petrucci RE, Boss AH, Richardson PC. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial. Lancet 2010; 375: 2244–53. 2 Neumiller JJ, Campbell RK. Technosphere insulin: an inhaled prandial insulin product. BioDrugs 2010; 24: 165–72. 3 Rubin RR, Peyrot M. Psychometric properties of an instrument for assessing the experience of patients treated with inhaled insulin: the Inhaled Insulin Treatment Questionnaire (IITQ). Health and Quality of Life Outcomes 2010; 8: 32. 4 Maher S, Leonard TW, Jacobsen J, Brayden DJ. Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic. Adv Drug Deliv Rev 2009; 61: 1427–49. 5 Pearson T. Practical aspects of insulin pen devices. J Diabetes Sci Technol 2010; 4: 522–31.

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Advanced Technologies and Treatments for Diabetes

Information Technology Information Technology in the Service of Diabetes Prevention and Treatment N. Kaufman UCLA School of Medicine and Public Health, Los Angeles, CA, USA

In the year since the first ATTD yearbook was published the field of internet and cell phone interventions has made major advances. This chapter contains clinical studies and reviews of the state-of-the-art regarding the ability of technologyenabled self-management education and support to improve outcomes for patients with, or at risk for, diabetes. The reviews and papers in this chapter demonstrate increased understanding of the underlying basis for effective interventions – a prerequisite for improving the effectiveness and efficiency of these approaches. The research studies described demonstrate that internet interventions are effective for a variety of patients and for specific outcomes (e.g. diabetes selfmanagement for teens as well as older patients, medication adherence, empowerment, psychosocial well-being, helping patients become more active, and helping patients lose weight and keep it off). As additional and more sophisticated studies are completed and the evidence base is expanded one can hope that payors will recognise their value and begin to pay for these treatments. That is what ultimately will bring effective treatments to those who need them. The associate editors’ mission was to choose articles that would give the non-technology skilled reader a general overview of the field of information technology and the prevention and treatment of obesity and diabetes. Articles were selected because they either provided a significant review of the state-of the art of the field or were the results from studies that could give the reader a better understand of the benefits and challenges associated with information technology use in clinical settings.

The role of technology and the chronic care model L. M. Siminerio University of Pittsburgh Diabetes Institute, Pittsburgh, PA, USA J Diabetes Sci Technol 2010; 4: 470–5 Background: To provide an overview of the role of information technology in improving outcomes for patients with chronic illness. Methods: The author summarises the ways information technology can support the chronic care model and lead to improved outcomes for patients with diabetes. Results: Information technology has the potential to improve outcomes for patients in partnership with their healthcare providers and within the context of their families and

communities. Some of the ways technology can support the components of the chronic care model include the following: at the health system level technology can facilitate patient tracking and longitudinal care and can link quality with financial incentives; communities can use technology to outreach to individuals in under-served populations, provide information to large numbers of people and monitor individuals in their homes; technology is improving self-management by empowering patients to learn new practices and routines related to their illness, by supporting patients, both educationally and motivationally, in their day-to-day decisions, and by allowing small, portable and inexpensive sensors to measure a wide range of clinical indicators and provide instantaneous feedback; decision support and clinical information systems have ensured that providers

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Correspondence to: Neal Kaufman, UCLA Schools of Medicine and Public Health, Los Angeles, CA Tel.: 310-444-0636 Email: kaufman@DPSHealth.com Disclosures: NK is the founder and CEO of DPS Health, a software development company that creates and implements researchproven, online self-management support interventions and therefore have a general interest in online and cell phone interventions. NK has a specific conflict of interest with the article by McTigue, et al. DPS Health provided the technology platform and team that helped the authors build this intervention and has licensed the programme for delivery by healthcare providers. Endorsed by the International Conference on ATTD organized by Kenes International.

have access to current and relevant information and support to make appropriate diagnoses and treatment decisions; delivery system redesign is facilitated by technology-enabled integration of services, improved communications between providers and the availability of real-time access to up-to-date medical record systems. Conclusions: The increasing prevalence of diabetes and the complex nature of care requirements make the broad use of information technology key to improving outcomes for patients with diabetes. Today’s technological environment can help overcome barriers that make the provision of diabetes care less than ideal. • Comment: This review paper provides an overview of potential ways information technology can be used to transform healthcare delivery and patient education and support.

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In many ways what present day healthcare needs is a disruptive technology that will shake up the delivery system and the providers within it, so that new approaches to care will emerge. Healthcare is decades behind other industries in the modern use of technology – a situation we can no longer afford.

Using the internet to promote health behaviour change: a systematic review and meta-analysis of the impact of theoretical basis, use of behaviour change techniques, and mode of delivery on efficacy T. L. Webb,1 J. Joseph,2 L. Yardley,2 S. Michie3 1 Department of Psychology, University of Sheffield, Sheffield, UK, 2School of Psychology, University of Southampton, Southampton, UK, and 3Research Department of Clinical, Educational and Health Psychology, University College London, London, UK J Med Internet Res 2010; 12 (1): e4 Background: To investigate which characteristics of internet-based interventions best promote behaviour change. Methods: The authors conducted a literature search (2000–2008) to identify studies in which the primary components of the intervention were delivered via the internet (not including CD-ROMs, SMS text messaging or other computer applications), participants were randomly assigned to conditions, and a measure of behaviour related to health was taken after the intervention (not just symptoms, cognitions, outcomes secondary to behaviour changes or behaviours unrelated to health). Results were subjected to meta-analysis. Results: Eighty-five studies were found providing a sample size of 43,236 participants. On average, interventions had a small but significant positive effect on related behaviour(s). More extensive use of behaviour change theory and behaviour change techniques in the construction and delivery of the intervention was associated with increased effect size. The effectiveness of internet-based interventions was enhanced by the use of additional methods of communicating with participants, especially the use of SMS (text) messaging. Small but significant effects were observed for interventions that targeted physical activity, alcohol consumption and smoking cessation. When more than one behaviour was addressed effects were still positive but smaller than when a single behaviour was addressed. The most commonly used behav-

iour change techniques included providing information on the consequences of behaviour in general, prompting self-monitoring of behaviour, identifying barriers and ⁄ or problem solving, The largest effects were seen with providing stress management and general communication skills training. Other effective techniques included modelling, relapse prevention ⁄ coping planning, facilitating social comparison, goal setting, action planning and provision of feedback on performance. The common modes of delivery were automated functions (tailored more effective than nontailored; enriched information environment effective), communicative functions (access to advisor to request advice was more effective than providing schedule contact with the advisor), and use of supplementary modes (most effective was the use of text messaging, effective was telephone-based support and to a lesser degree email). Conclusions: The review provides evidence supporting the use of behaviour change theory and specific behaviour change techniques in the development and implementation of internet-based behaviour change interventions. It also provides a potential framework for researchers that can help to clarify the effectiveness of various approaches toward and components used by internet-based interventions. • Comment: This academic analysis of the emerging field of technology-enabled behaviour change interventions adds its voice to the attempt to have science guide the field – a very noble and worthwhile goal. It is a very difficult task to try not only to build the emerging behaviour change road while travelling on it, but to add thoughtful analysis and theorybased development into the process. This is made all the more challenging by the rapid pace of technological changes, the diverse nature of the behaviours being addressed and the incredible diversity of the individuals who are the subject of these interventions. The best one can hope for are guiding principles based on what science and experience have to offer, coupled with dynamic and frequent evaluation and refinement of the interventions based on advances in technology and new wisdom. Adding to the complexity is the requirement that for many important interventions (think medication adherence, use of glucose sensors and ⁄ or pumps) regulatory requirements make it nearly impossible to implement and enhance interventions in a timely manner. Compare that to programmes that are direct to the consumer (think iPhone apps), that require nearly no evidence or regulatory scrutiny and are judged not by the outcomes they get but by the number of individuals who access them. And to make matters more complicated, clinically linked interventions are not reimbursed or in-

centivised by most healthcare systems at present, and consumers are unwilling to pay for them, although they are willing to pay large amounts for unproven interventions. We are in for a very wild and crazy next several years.

Health technologies for monitoring and managing diabetes: a systematic review E. Russell-Minda,1 J. Jutai,2 M. Speechley,3 K. Bradley,3 A. Chudyk,1 R. Petrella1 1 Aging, Rehabilitation, and Geriatric Care Research Centre, Lawson Health Research Institute, London, ON, Canada, 2Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada, and 3Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada J Diabetes Sci Technol 2009; 3: 1460–71 Background: To determine the effectiveness of self-monitoring devices and technologies for individuals with diabetes. Methods: A systematic review of the literature between 1985 and 2008 revealed 18 trials in which the device components of interventions included self-monitoring of blood glucose, pedometers, and cell phones or wireless technologies. Results: There is moderately strong evidence that self-monitoring of blood glucose is an effective way to improve glycaemic control in patients with non-insulin-treated type 2 diabetes. There was limited evidence supporting the effectiveness of pedometer-based interventions to improve overall fitness and metabolic control; however, pedometers can still help motivate patients to become more active and track their personal performance. Wireless technologies can improve diabetes self-care. There were no studies that integrated diabetes self-management devices with blood pressure devices, heart rate monitors and other technologies. Conclusions: Although self-monitoring of glucose continues to be an effective tool and wireless technologies can also improve outcomes additional studies are needed that address the interactions of the various technologies. • Comment: There is great promise that technology will improve outcomes for patients with diabetes. However, the impact of technology will only be as good as the clinicians and patients who use it. Until there is an artificial pancreas that does not need to be managed by people it is unrealistic to think that one single technology will be powerful enough to modify outcomes that are based on a balance between insulin, diet, physical activity and stress.

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Effectiveness of web-based interventions on patient empowerment: a systematic review and meta-analysis D. Samoocha,1–3 D. J. Bruinvels,1–3 N. A. Elbers,1,3 J. R. Anema,1,2 A. J. Van der Beek1,2 1 Department of Public and Occupational Health, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands, 2Research Centre for Insurance Medicine AMC-UWV-VUmc, Amsterdam, The Netherlands, and 3IGER, Amsterdam Interdisciplinary Centre of Law and Health, Amsterdam, The Netherlands J Med Internet Res 2010; 12 (2): e23 Background: To determine if there is evidence that web-based intervention can increase patient empowerment compared to usual care or face-to-face interventions. Methods: The authors performed a literature review (January 1985–January 2009) to find relevant randomised controlled trials (medical conditions varied; some with diabetes) and used meta-analysis to determine the impact of these interventions on patient empowerment – ‘the ability of patients to actively understand and influence their own health’. The authors state that ‘Patient empowerment focuses on control in individuals’ experience of health, disease, and illness, as well as the roles of health care organisations, communities and the broader health care system’. Components of empowerment looked for in the literature review included self-efficacy, mastery, self-control, self-esteem, perceived control, perceived competence, or involvement in the decision-making process. Results: The web-based interventions studied were found to improve empowerment, including self-efficacy (in general and in disease-specific studies such as diabetes) and mastery compared to usual care or face-to-face. The confidence in this conclusion was somewhat limited by the relatively small number of studies and methodologically weaknesses of many of the studies. Conclusions: Because of the low quality of the published literature and the small but positive treatment effects found, it is hard to definitely state the effect of web-based empowerment interventions. More research is needed. • Comment: These findings, some improved empowerment with web-based interventions, are compatible with the growing evidence on the effectiveness of eHealth interventions. Clinicians should consider referring their patients to empowerment websites if they are

available and appealing to the patient. Researchers need to more precisely define and conceptualise empowerment so that more accurate reviews and studies can be performed to determine which individuals and under what circumstances particular individuals could benefit from empowerment interventions. I expect that the more tailored the intervention to the specific circumstance of the individual the more powerful the results.

Patient and parent views on a Web 2.0 diabetes portal – the management tool, the generator, and the gatekeeper: qualitative study S. Nordfeldt,1–3 L. Hanberger,2 C. Bertero¨4 1 Centre for Medical Technology Assessment, Department of Medicine and Health Sciences, Linko¨ping University, Linko¨ping, Sweden, 2 Division of Pediatrics, Department of Clinical and Experimental Medicine, Linko¨ping University, Linko¨ping, Sweden, 3Division of Child and Adolescent Psychiatry, Department of Clinical and Experimental Medicine, Linko¨ping University, Linko¨ping, Sweden, and 4Division of Nursing Sciences, Department of Medical and Health Sciences, Linko¨ping University, Linko¨ping, Sweden J Med Internet Res 2010; 12 (2): e17 Background: To gain understanding from patients with type 1 diabetes and their parents about a web portal tailored to the needs of youth with diabetes. Methods: Five patients (aged 11–18 years old) and 19 parents were given access to a portal with social networking tools such as message boards and blogs, locally produced self-care and treatment information and interactive educational materials. Participants each wrote an essay about their experience with the portal and the comments were analysed. Results: Three main categories of portal users’ attitudes were found: management tool – the ability to find reliable information easily on a range of topics, having the feeling of security and being in control on the site; the generator – finding answers to questions the user did not know he or she needed, and message boards and chats increased the use; the gatekeeper – the requirement to have a password, while increasing security, led to logistical challenges and decreased use. Conclusions: A well-designed portal for a specific target population can be a useful adjunct to medical care. It needs to be carefully maintained and updated by healthcare

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providers who are alert and active on the site with new information and updates. Login procedures should be simple and minimised as much as possible. Practitioners should be educated on the use of portals. • Comment: This paper provides insight into what patients and parents might want from a portal. It is important to get information from users of websites to make them more relevant and useful. Details of actual use of the various components of the portal would have made the information contained in this paper more useful. Since this website was mostly public information the need for a password seemed to unnecessarily inhibit use. Security could have been used prior to entry into the message boards or chat rooms.

Preventing the obesity epidemic by second generation tailored health communication: an interdisciplinary review H. P. K. Enwald, M. L. A. Huotari Finnish, Information Studies and Logopedics, Centre of Excellence in Research, Faculty of Humanities, University of Oulu, Oulu, Finland J Med Internet Res 2010; 12 (2): e24 Background: To review the literature on the impact of second generation tailored health communications on the ability of an intervention (addressing nutrition, physical activity or weight management) to prevent obesity and related health problems at the individual level. Methods: A literature search was performed on papers published prior to August 2009 and 23 relevant papers were analysed (21 of which were randomised controlled trials all focusing on behaviour change). Ten studies focused on nutrition, seven on physical activity, two on nutrition and physical activity, and four on weight management. The review was not a structured meta-analysis. First generation tailoring is considered computer-tailored using print delivered materials (e.g. pamphlets); second generation tailoring is the use of interactive media; and third generation tailoring is communication delivered via mobile and remote devices such as mobile phones and handheld computers. Results: Tailoring was found to be more effective in nutrition interventions than in physical activity or weight management interventions. The researchers believed that this might have been due to specific biases in the intervention designs of physical activity and weight interventions. Several modes of delivery were used (e.g. email, internet site and ⁄ or

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programme, computer delivered feedback letters, newsletters and CD-ROM). The study was unable to determine the effect of the delivery mechanism on outcomes. Conclusions: There is insufficient information to determine the true impact of tailoring on second generation health communication. Flaws in research design need to be overcome to make interpretation more robust. • Comment: Tailoring of messages to the unique characteristics and performance of the individual is the hallmark of the master clinician. A reasonable person would assume that tailoring health communications would have a large effect. But just as some clinicians are better communicators than others, some tailoring approaches are certainly better than others. The requirement that the tailoring be personalised on a variety of characteristics simultaneously adds to the technical challenge. The delivery approach is also key and needs to be matched to the particular preferences of the individual. All this while assuring that the content is accurate and timely make implementing these approaches quite challenging. Evaluating their effectiveness is even harder given the range of experiences any particular patient might have. It is, however, the future – just think about the revolution in online marketing that customises the advertisements you see while surfing the net based on your characteristics, prior viewing and purchasing history. Healthcare, although far behind, might someday catch up, especially if payors realise that money can be saved when patients adopt and sustain healthpromoting behaviours.

Online diabetes selfmanagement programme: a randomised study K. Lorig,1 P. L. Ritter,1 D. D. Laurent,1 K. Plant,1 M. Green,1 V. B. B. Jernigan,2 S. Case3 1 Stanford University School of Medicine, Palo Alto, CA, USA, 2Stanford University – Stanford Prevention Research Center, Palo Alto, CA, USA, and 3Yale School of Medicine, New Haven, CT, USA Diabetes Care 2010; 33: 1275–81 Background: To determine in adults with type 2 diabetes the impact of a 6-week-long internet-based intervention on their self-management behaviours and diabetes-related outcomes. Methods: A total of 761 patients, recruited primarily through the internet, were randomised to either usual care, or the internet programme, or the internet programme with email reinforcement. The sample included

110 American Indians ⁄ Alaska Natives (AI ⁄ AN) who were also analysed separately. The internet intervention provided 6 weekly sessions in which specific topics were addressed and a discussion centre with interactive threaded bulletin boards addressing action planning, problem solving, difficult emotions and celebrations. Tools were provided for meal and physical activity planning and tracking, and glucose monitoring, and links to other diabetes websites were offered. Participants could also email or call a moderator for assistance and support. Reinforcement consisted of access to a listserv discussion group of fellow participants. Results: At 6 months individuals who received the internet intervention compared to usual care had improved A1c, patient activation and self-efficacy. The AI ⁄ AN participants had improvements in health distress and activity limitations compared to usual care participants. There was no added benefit from reinforcement. At 18 months, self-efficacy and patient activation were improved in those who received the internet programme. A1c was not measured. Conclusions: An online diabetes selfmanagement programme was acceptable to patients with type 2 diabetes and may have had a beneficial effect on A1c at 6 months. • Comment: This study, done by one of the gurus in behaviour change, Kate Lorig, and her colleagues, is very important not only for what it demonstrated – that a relatively short (6 weeks) intervention can have some effects – but also for what it says about the state-ofthe-art of technology-enabled behaviour change interventions. The time is near when these approaches will be mainstream and part of a range of approaches clinicians and patients can and will use. In this case the intervention was not delivered in the context of a trusted therapeutic relationship. I can only wonder if that would have made it all the more effective.

Web-based comprehensive information system for selfmanagement of diabetes mellitus J. H. Noh,1 Y. J. Cho,2 H. W. Nam,2 J. H. Kim,3 D. J. Kim,1 H. S. Yoo,4 Y. W. Kwon,5 M. H. Woo,6 J. W. Cho,7 M. H. Hong,8 J. H. Yo,9 M. J. Gu,9 S. A. Kim,10 K. E. An,11 S. M. Jang,12 E. K. Kim,13 H. J. Yoo14 1 Department of Internal Medicine, Inje University, Ilsan Paik Hospital, Goyang, Republic of Korea, 2Department of Internal Medicine, Hallym University College of

Medicine, Seoul, Republic of Korea, 3 Department of Internal Medicine, Sung Ae Hospital, Seoul, Republic of Korea, 4 Department of Nutrition, Chung-Ang University Hospital, Seoul, Republic of Korea, 5 Department of Nutrition, National Medical Center, Seoul, Republic of Korea, 6Department of Nutrition, Kyunghee University Medical Center, Seoul, Republic of Korea, 7Department of Nutrition, Samsung Medical Center, Seoul, Republic of Korea, 8Nursing Department, Inje University, Seoul Paik Hospital, Hallym University College of Medicine, Seoul, Republic of Korea, 9Nursing Department, Seoul National University Hospital, Hallym University College of Medicine, Seoul, Republic of Korea, 10 Nursing Department, Asan Medical Center, Seoul, Republic of Korea, 11School of Nursing, University of Texas Medical Branch, Galveston, TX, USA, 12Department of Social Welfare, Cheongju University, Cheongju, Republic of Korea, 13Department of Social Work, Hallym University Sacred Heart Hospital, Seoul, Republic of Korea, and 14Department of Internal Medicine, Hallym University Sacred Heart Hospital, Seoul, Republic of Korea Diabetes Technol Ther 2010; 12: 333–7 Background: To determine if a web-based information system for self-management improves outcomes for patients with type 2 diabetes. Methods: Forty patients with type 2 diabetes were randomised to receive access to internet and cell phone based diabetes selfmanagement information or usual diabetes care. The system provided real-time access to information about diet, dining out, hypoglycaemia, sick-day management, stress management and diabetes management. Results: A1c and postprandial glucose were significantly decreased over the 6 months of the intervention in the experimental group but not the control group. Those subjects who used more cell phone components of the intervention had better outcomes than those who did not. Conclusions: A convenient web-based informational system was effective in improving diabetes outcomes. • Comment: This study from Korea demonstrated that an intervention primarily based on the convenient provision of relevant information was able to improve outcomes at 6 months. One can only wonder how much more successful the programme could have been if it had included more active goal setting, monitoring and tracking, not to mention ways to increase social support.

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An internet-based programme to improve self-management in adolescents with type 1 diabetes S. A. Mulvaney,1,2 R. L. Rothman,3 K. A. Wallston,1 C. Lybarger,1,2 M. S. Dietrich1,4 1 School of Nursing, Vanderbilt University Medical Center, Nashville, TN, USA, 2 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA, 3 Center for Health Services Research, Vanderbilt University Medical Center, Nashville, TN, USA, and 4Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA Diabetes Care 2010; 33: 602–4 Background: To determine the effectiveness of a specific internet-based self-management support intervention for adolescents with type 1 diabetes. Methods: In all, 72 adolescents (aged 13– 17) were randomised to usual care or usual care plus internet intervention that addressed problem solving barriers to successful selfmanagement. Results: There were no differences between the two groups when using intent-to-treat analyses; as-treated analysis showed a positive effect of the internet support on problem solving and self-management. A1c increased slightly at follow-up (12 weeks) in the usual treatment group and stayed the same in the internet group but did not reach statistical significance. The intervention was highly rated by participants and they used many of the features. Conclusions: The authors conclude that given the limitations of the study (small size, short duration etc.) few generalisable conclusions can be drawn. The intervention did improve problem solving and self-management and appeared to offset the typical increase in A1c seen during adolescence. • Comment: This small study adds to a growing body of literature that indicates properly designed internet (and cell phone) interventions have the potential to help patients manage their chronic illnesses. The proof will be in the pudding – sugar free no doubt – as the field collectively learns what makes a good intervention for each unique individual and then delivers it to him ⁄ her just in time, with what he ⁄ she needs, and in the manner in which he ⁄ she wants to receive it, all linked to a trusted clinician who can put the recommendations into context and offer a higher level of service when needed.

Effects of a web-based intervention on psychosocial well-being among adults aged 60 and older with diabetes: a randomised trial G. E. Bond,1 R. L. Burr,2 F. M. Wolf,3 K. Feldt1 1 College of Nursing, Seattle University, Seattle, WA, USA, 2Department of Biobehavioral Nursing and Health Systems, University of Washington, Seattle, WA, USA, and 3Department of Biomedical and Health Informatics, University of Washington, Seattle, WA, USA The Diabetes Educator 2010; 36: 446–56 Background: To determine the impact of a 6-month web-based intervention on the wellbeing of individuals older than 60 years with diabetes. Methods: In all, 62 individuals with diabetes who were older than 60 years were randomised to receive usual care or usual care plus a 6-month web-based intervention. The webbased intervention emphasised the patient’s role in maintaining health and the importance of setting goals and ways to overcome barriers. Intervention strategies included using behavioural and motivational strategies, using cues to modify perceptions of self-efficacy, and using cues to modify personal beliefs regarding the subject’s ability to affect the progress of the disease by changing behaviours. Participants had access to synchronous and asynchronous communication via email with the study nurse. There was access to the study website that allowed participants to access materials about diabetes; receive online advice and counselling; submit personal diary information; receive tailored self-management instructions; participate in biweekly chat sessions; access a bulletin board; and submit a daily log of self-management activities and results. Results: The intervention group showed significant improvement compared with controls on measures of depression, quality of life, social support and self-efficacy. Measures of diabetes control were not given. Conclusions: The authors state that this study supports the conclusion that web-based interventions can be effective in improving older individuals’ psychological well-being. The long-term effect and the effect on diabetes metabolic control need to be studied. • Comment: This study is important for a few reasons. It helps to dispel the notion that individuals of a certain age (i.e. > 60 years old) will not and cannot use the internet. That is just hogwash, and the elderly are the

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fastest growing users of the internet. For an intervention to be effective with people in that age group (or any age group for that matter) it needs to be designed to fit the learning style and technical skills of the user. I doubt you can get the over 60 crowd to play a multi-player, violence-oriented, fantasy game – don’t even try. Instead, use something that is appropriate for the target population. Another reason this study is important is that it demonstrates that web-based interventions can impact psychosocial challenges that patients with chronic disease often face. These challenges are often a real barrier to improving outcomes and clinicians need all the help they can get since most of us are not particularly good at helping patients with depression, anxiety etc.

Diabetes Interactive Diary: a new telemedicine system enabling flexible diet and insulin therapy while improving quality of life – an open-label, international, multicentre, randomised study M. C. E. Rossi,1 A. Nicolucci,1 P. Di Bartolo,2 D. Bruttomesso,3 A. Girelli,4 F. J. Ampudia,5 D. Kerr,6 A. Ceriello,7 C. De La Questa Mayor,8 F. Pellegrini,1 D. Horwitz,9 G. Vespasiani10 1 Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, Santa Maria Imbaro (CH), Italy, 2Diabetes Unit, Presidio Ospedaliero, Ravenna, Italy, 3 Clinical and Experimental Medicine, Policlinico Universitario, Padua, Italy, 4Diabetes Unit, Spedali Civili, Brescia, Italy, 5Unit of Endocrinology, Hospital Clı´nico Universitario, Valencia, Spain, 6Centre of Postgraduate Medical Research and Education, Bournemouth University, Bournemouth, UK, 7Warwick Medical School, University of Warwick, Coventry, UK, 8Unit of Endocrinology, Hospital Universitario Virgen Macarena, Sevilla, Spain, 9Medical and Clinical Affairs, LifeScan, Milpitas, CA, USA, and 10Diabetes Unit, Madonna del Soccorso Hospital, San Benedetto del Tronto (AP), Italy Diabetes Care 2010; 33: 109–15 Background: To determine the effectiveness and efficiency of Diabetes Interactive Diary (DID) – a telemedicine (via texting) carbohydrate-counting support programme – on metabolic and weight control, time required for education, quality of life and treatment satisfaction in adult patients with type 1 diabetes.

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Methods: A total of 130 adults were randomly assigned to DID or standard education and followed for 6 months. Results: Time for education was 6 h for the DID group and 12 h for the control. A1c reduction, fasting blood sugar and body weight change were similar in both groups. Well-being, physical health perceptions and satisfaction were slightly better for the DID group. Conclusions: DID is at least as effective and safe to use in adults with type 1 diabetes. It requires less education time and improved measures of well-being and satisfaction. • Comment: Automating components of patient education and care might be a good way to incrementally get to a more efficient and effective approach to patient self-management education and support. It is not trivial to be able to get similar results with less education time. This will only be worthwhile from a system’s perspective when the cost (time, money, opportunity) is less significant than the cost to educate the large numbers of patients needing support. We are already at that point but the funding mechanisms to pay the up-front development costs are very difficult to find. If we had a real free market in which products were developed and commercialised based on demand this would be easy, but since that is not the case, time will tell if we are able to benefit from all of the technological potential. I sure hope so.

Incorporating tailored interactive patient solutions using interactive voice response technology to improve statin adherence: results of a randomised clinical trial in a managed care setting J. N. Stacy,1 S. M. Schwartz,2 D. Ershoff,3 M. S. Shreve4 1 Humana Inc., Louisville, KY, USA, 2 HealthMedia Inc., Ann Arbor, MI, USA, 3 AstraZeneca, Tarzana, CA, USA, and 4 Kentfield, CA, USA Population Health Management 2009; 12: 241–54 Background: To determine if an intervention using tailored interactive voice response (IVR) technology can improve statin adherence. Methods: Potential subjects (1219) were contacted by IVR technology; 497 gave informed consent and were randomised to receive standard support or tailored IVR to increase medication adherence. Control sub-

jects received printed materials; the study subjects received tailored IVR information re motivation, overcoming barriers, developing a habit, commitment enhancement, verbal reinforcement ⁄ praise, cost–benefit analysis, a tailored letter with verbal reinforcement ⁄ praise, self-efficacy enhancement, education (cholesterol, adherence, diet, exercise), a follow-up IVR call with current adherence assessment, barriers, verbal reinforcement ⁄ praise, commitment enhancement; and a follow-up IVR call with motives, barriers, setting priorities, self-efficacy, commitment to refill medicines. Statin adherence was measured at 6 months via pharmacy claims data. Results: Subjects in the experimental group had a significantly higher use of statins than controls. Conclusions: Results suggest that a behavioural support programme using IVR technology can be a cost effective modality to address patient non-adherence. • Comment: This study, looking at a single modality, IVR technology, on a single behaviour, adherence to prescribed medication, is somewhat exciting but until and unless we are able to couple these types of approaches into comprehensive interventions we will continue to make only modest gains on outcomes. In this case, medication adherence without lifestyle change would not be expected to have a major impact on the real hoped for outcome, decreased cardiovascular mortality associated with elevated lipids (and obesity and poor fitness). So, while identifying what works as a single approach might be helpful in developing comprehensive interventions, we must find the political will to make coverage for comprehensive interventions available so there will be real incentives to spend the resources needed to build and deploy them.

Using the internet to translate an evidence-based lifestyle intervention into practice K. M. McTigue1,2, M. B. Conroy1-3, R. Hess,1,3 C. L. Bryce,1,2 A. B. Fiorillo,3 G. S. Fischer,1,3 N. C. Milas,2 L. R. Simkin-Silverman2 1 Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA, 2Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA, and 3University of Pittsburgh Medical Center, Pittsburgh, PA, USA Telemedicine and e-Health 2009; 15: 851–8 Background: To determine the effectiveness of the translation to the internet of an evidence-based lifestyle programme (the National Institutes of Health’s Diabetes Pre-

vention Program, DPP) for deployment from a primary care setting. Methods: The authors conducted a before and after pilot study of an internet-based programme that adapted the DPP’s intensive lifestyle curriculum. It contains 16 weekly and 8 monthly 30–45 min audio-narrated lessons addressing the DPP lifestyle intervention. The programme incorporates behavioural tools such as email prompts for online self-monitoring of diet, physical activity and weight, and automated weekly progress reports. Electronic counselling provides further support. Physician referral, automated progress reports and as-needed communication with lifestyle coaches integrate with clinical care. Results: In total, 50 overweight and sedentary patients were enrolled in the intervention from a large academic general internal medicine practice with at least one weight-related cardiovascular risk factor and internet access. Patients were 76% female, with a body mass index of 36.43 kg ⁄ m2. At 12 months of enrolment, 50% of participants had logged on within 30 days. Completers (45 ⁄ 50) lost 4.79 kg by 3 months of enrolment with minimal regained weight, systolic blood pressure dropped 7.33 mmHg, and diastolic pressure changed minimally. Conclusions: The results showed promise for providing intensive lifestyle counselling (diet and physical activity) at a lower allocation of coaching time than the intensive support from the original DPP. Automating the educational content of the intervention allowed the coaches to focus their time on supporting behaviour change and tailoring dietary and physical activity advice specific to the participant needs. An internet-based lifestyle intervention may be able to overcome significant barriers to preventive counselling and facilitate the incorporation of evidencebased lifestyle interventions into primary care. • Comment: I want to acknowledge my conflict of interest regarding this study. My company (DPS Health) provided the technology platform and team that helped the authors build this intervention and has licensed the programme for delivery by healthcare providers. The programme, the online version of the NIH’s Diabetes Prevention Program, is an example of researchers transforming a proven face-to-face intervention to an internet environment in an attempt to expand the reach and decrease the cost of the original intervention. Although this study demonstrated effectiveness, it points out the challenge with providing sufficient evidence to document effectiveness of behaviour change interventions. If we require large randomised controlled trials before interven-

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tions can be implemented and before clinicians can be reimbursed, it will be very difficult for interventions to be widely deployed. This will probably drive patients to programmes created and marketed direct to consumers with minimal evidence and not linked to therapeutic relationships or clinical settings. I expect that these approaches will be less effective in the long-term since they won’t be in the context of clinical care.

Development of an internetbased obesity prevention programme for children J. M. Gabriele,1 T. M. Stewart,2 A. Sample,3 A. B. Davis,2 R. Allen,2 C. K. Martin,2 R. L. Newton Jr,2 D. A. Williamson2 1 G.V. (Sonny) Montgomery VA Medical Center, Mental Health, Jackson, MS, USA, 2 Pennington Biomedical Research Center, Baton Rouge, LA, USA, and 3Department of Nutrition and Food Systems, University of Southern Mississippi, Hattiesburg, MS, USA J Diabetes Sci Technol 2010; 4: 723–32 Background: To determine the impact of a targeted internet-based secondary obesity prevention programme in a rural childhood population. Methods: Thirty-three schools were randomised to receive either primary prevention, primary and secondary prevention or no intervention control. Participants included volunteering school children in 4th to 6th grade. Only those schools which were in the primary and secondary prevention group received the internet intervention. The student’s website had four components: lesson of the week; fun games and activities; email your internet counsellor; chat with your internet counsellor. The counsellor’s website had six components: email your students; chat with your students; directory; lessons; quiz check; counselling availability. The intervention was delivered by a combination of in-class experiences ⁄ lessons and online (a total of 37 lesson topics), targeted to the student’s original weight status (overweight or not overweight). Results: Between 26% and 52% of eligible students agreed to participate in the overall study. Between 33 and 103 students at the study sites agreed to participate in the internet component of the study (percentage not available). No outcomes data were reported for the intervention. Conclusions: The authors conclude that the study provides an important contribution to research in the field of school-based obesity

prevention programmes and internet approaches to weight management. • Comment: I put this study in the yearbook – if one can call a description of an intervention without data a study – because of the importance of early primary and secondary prevention of obesity in childhood and the lack of good data-rich studies that provide wisdom regarding what is most likely to work with a particular patient population. I hope the results of this and other studies get to the literature very soon – our kids really need it.

Effectiveness of active-online, an individually tailored physical activity intervention, in a real-life setting: randomised controlled trial M. Wanner,1,2 E. Martin-Diener,1 C. Braun-Fahrla¨nder,2 G. Bauer,3,4 B. W. Martin1,3 1 Swiss Federal Institute of Sport Magglingen, Magglingen, Switzerland, 2Institute of Social and Preventive Medicine, University of Basel, Basel, Switzerland, 3Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland, and 4Center for Occupational and Organizational Sciences ETH Zurich, Zurich, Switzerland J Med Internet Res 2009; 11 (3): e23

Comparison of trial participants and open access users of a web-based physical activity intervention regarding adherence, attrition, and repeated participation M. Wanner,1,2 E. Martin-Diener,1 G. Bauer,3,4 C. Braun-Fahrla¨nder,2 Martin BW 3 1 Swiss Federal Institute of Sport Magglingen, Magglingen, Switzerland, 2Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland, 3Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland, and 4Division of Public and Organizational Health, University and ETH Zurich, Zurich, Switzerland J Med Internet Res 2010; 12 (1): e3 Background: The aim of this study (written in two reports) was to determine if a web-based, individually tailored physical activity intervention was able to increase physical activity in a general adult population and what characteristics of the participants

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(such as frequency of use) impact on the patients’ success. Methods: Participants were recruited via a variety of methods and randomised to the study website or a control website without tailored information. Individuals who accessed the tailored site spontaneously were also compared to study subjects. The experimental website provided tailored counselling and motivational feedback. The subject could choose between two separate modules – one targeting everyday activities, the other endurance training. The feedback was tailored based on the participant’s readiness to change, decisional balance, processes of change, and selfefficacy. Methods to track and learn more about physical activity were also available. Participants assigned to the non-tailored website received general information on physical activity and health with no reminder emails. A subgroup of patients had objective measurement of physical activity (accelerometry). Follow-up occurred 6 weeks, 6 months and 13 months after baseline. Adherence to the web intervention was defined as the number of pages viewed, the proportion of visits during which a tailored module was begun, and the time spent in the tailored modules, and was analysed according to the period and context (trial or open access) based on first visit and longest visit. Results: A total of 681 experimental and 688 control subjects were entered into the study. In addition, 162 users accessed the site spontaneously. Average age was 43.7 years and 74.9% were women. There was a significant increase in self-reported mean minutes reported in moderate and vigorous intensity physical activity among the experimental group although there was no increase in physical activity in those measured objectively (133 ⁄ 1531). Individuals who used the application more had increased self-reported physical activity. Adherence was highest for open access participants; trial participants visited fewer pages, and the proportion that started a tailored module, spent at least 3 min in the module and received a least one tailored feedback was smaller. Trial participants who started a module tended to stay in the intervention longer. Differences in adherence, attrition and repeated participation between trial participants and open access users favoured open access users. Reminder emails had a greater positive effect on study participants. Conclusions: The tailored website was found to increase physical activity especially among those who spent more time on the site. Since there were differences in attrition and adherence between open access and trial participants it is important to monitor for these differences.

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Information technology

• Comment: This very complicated programme and study – the website was first designed in Germany and then culturally and linguistically modified for deployment in Italy and France – demonstrates many of the exciting and challenging aspects of this field. The complexity of the study design and analysis make it hard for most mere mortals to understand, myself included, but this level of sophistication is what is necessary to truly advance the field. The changing technology over the 8 years of the website’s existence just adds to the challenge. Bottom line – well thought out websites with specific theories behind them can offer effective interventions. It is nonetheless important to constantly evaluate them and have the means to modify them relatively frequently as outcomes become available and as technology evolves.

Feasibility and effectiveness of online physical activity advice based on a personal activity monitor: randomised controlled trial S. M. Slootmaker,1 M. J. M. Chinapaw,1 A. J. Schuit,2,3 J. C. Seidell,3 W. Van Mechelen1 1 EMGO Institute, Department of Public and Occupational Health, Body@Work Research Center, Physical Activity, Work and Health, TNO-VU University Medical Center, Amsterdam, The Netherlands, 2National Institute for Public Health and the Environment, Bilthoven, The Netherlands, and 3 Institute of Health Science, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands J Med Internet Res 2009; 11 (3): e27 Background: To determine the impact of a 3-month intervention in which healthy and active adults (ages 20–40) were provided with a personal activity monitor (accelerometer)

coupled with simple and concise web-based tailored advice. Methods: In all, 102 participants were randomly assigned equally to either the study intervention or written brochures with brief general physical activity information. The website provided tailored physical activity goals, ways to track performance, advice on how to meet the goal, the user’s preferred physical activity, and potential barriers. Outcomes were measured at 3 months and 8 months after enrolment. Results: Of the intervention group 48 ⁄ 51 completed the 3-month follow-up and 38 the 8-month follow-up; of the control group 50 ⁄ 51 completed the 3-month follow-up and 42 completed the 8-month follow-up. In total 67% of the population was active enough to meet recommended guidelines at baseline. Of the intervention group 73% reported wearing the accelerometer regularly and the website was accessed almost once per week. There were no significant improvements in any level of physical activity, aerobic fitness and body composition at 3 months or 8 months. Conclusions: The intervention was easy to use but not helpful in increasing physical activity. More attention should have been given to the quality and appropriateness of the tailored advice. • Comment: Negative studies are important – though hard for researchers to write and to get accepted. This study teaches us that just because something sounds good does not mean it will work. The approach to behaviour change in this programme was relatively limited: give the person information (accelerometer data) and advice and try to see if they will adopt and sustain a new pattern of behaviour. That generally does not work except for those who probably do not need the advice, and in this case 67% of the subjects were already active. Perhaps this approach might have been more effective in a sedentary population but I doubt it. Helping

people adopt new health-promoting behaviours is hard work and often needs a lot of different elements to have a real impact.

SUMMARY Clinicians need enhanced ways to provide increasing numbers of patients with the knowledge, attitudes, skills and behaviours to allow them to successfully manage the often complex and difficult-to-implement diabetes treatments and health-promoting behaviours. Information technology – internet and cell phones – have the potential to transform the way clinicians and patients interact. No longer will the dominant approach be restricted to the four walls of the clinical setting. No longer will patients get the majority of their health-related information and support directly from their healthcare provider. No longer will patients be passive in their pursuit of the skills to successfully manage their own conditions. The new era of rapidly changing, technology-enabled education and interventions provide an amazing array of possible approaches. One of the clinician’s roles will be to help guide patients through the variety of options. Direct to consumer approaches, often untested and not necessarily based on evidence, are nonetheless proliferating and providing patients with much needed access to useful knowledge and support. The challenge to clinicians will be to offer effective programmes that are research proven and linked to a trusted clinician for added benefit. Clinicians need to actively seek out and evaluate technology-based approaches that improve patient outcomes and advocate for enhanced funding for those that are effective. The papers in this chapter demonstrate the improving evidence for the effectiveness of these approaches and provide promise for the future of the field.

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Advanced Technologies and Treatments for Diabetes

Pregnancy Technology and pregnancy J. Nudell,*1 A. Slade,*1 L. Jovanovicˇ,1 M. Hod2 1

Sansum Diabetes Research Institute, Santa Barbara, California, USA Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel

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The World Health Organisation projects that the number of diabetes-related deaths will double between the years 2005 and 2030. An important method for reducing the number of new cases of diabetes is by screening for and controlling glucose in women with gestational diabetes, the form of diabetes that afflicts up to 10% of the pregnant population. Uncontrolled gestational diabetes mellitus results in an increased risk of complications due to maternal hyperglycaemia and the resultant fetal hyperinsulinaemia. These complications include macrosomia and an increased risk of metabolic disorders including diabetes later in the child’s life. Advances in the treatment of gestational diabetes have shown promising results in minimising fetal complications; they have also helped to slow the vicious cycle of women who contract gestational diabetes mellitus producing children with a high risk of developing diabetes later in life. A comprehensive literature review with an emphasis on technology has resulted in the following collection of papers relating to pregnancy and diabetes. Last year there were several technological advances in glucose monitoring. This year the applications of telemedicine in the treatment of gestational diabetes and the use of ultrasound for early detection of the disease have been at the forefront. The authors aimed to include articles that were not only relevant to the field of diabetes technology in pregnancy, but that also improved treatment and advanced understanding. The study design and results were also carefully examined in considering the articles. The selected articles contain findings that provide new techniques for diagnosing gestational diabetes mellitus as well as provide additional treatment methods for those affected by the disease.

Reduced incidence of gestational diabetes with bariatric surgery A. E. Burke,1 W. L. Bennett,2 R. M. Jamshidi,1 M. M. Gilson,3 J. M. Clark2,5, J. B. Segal,2 A. D. Shore,4 T. H. Magnuson,3 F. Dominici,6 A. W. Wu,2,3,5 M. A. Makary3 1 Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA, 5Department of Epidemiology, Johns Hopkins Bloomberg School of Public

Health, Baltimore, MD, USA, and 6Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA J Am Coll Surg 2010; 3: 1–7 Background: Bariatric surgery used today for overweight patients allows for significant weight loss. Obesity during pregnancy is known to increase the risk of many complications, including diabetes. This study is designed to show any association between bariatric surgery and the incidence of gestational diabetes mellitus (GDM), including its related complications. Methods: A retrospective study was performed comparing rates of GDM and related outcomes (caesarean section, large-for-gestational-age infant, shoulder dystocia, and infection) between a group of women who delivered before having bariatric surgery and

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Correspondence to: Lois Jovanovicˇ, Sansum Diabetes Research Institute, Santa Barbara, California, USA Tel.: 805-682-7638 Fax: 805-682-3332 Email: ljovanovic@sansum.org *These two authors are both considered first authors and are listed alphabetically. Disclosures: The authors declare no conflict of interest. Endorsed by the International Conference on ATTD organized by Kenes International.

a group who delivered after. Data were collected from a private insurance claims database on 23,594 women who had bariatric surgery between 2002 and 2006. Results: There were 354 women who had bariatric surgery before pregnancy, and 346 women who had bariatric surgery after giving birth. Women who had bariatric surgery before giving birth had lower incidences of GDM [8% vs. 27%, odds ratio (OR) 0.23, 95% confidence interval (CI) 0.15–0.36] and caesarean section (28% vs. 43%, OR 0.53, 95% CI 0.39–0.72) than women who had the surgery after giving birth. Conclusions: Bariatric surgery before pregnancy is associated with a decreased incidence of GDM and caesarean section in following pregnancies. Bariatric surgery should be considered for obese women of childbearing age.

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• Comment: Bariatric surgery is known to cause significant weight loss and reduce symptoms of obesity, including incidences of diabetes. This study extends the knowledge of the benefits of bariatric surgery to include a reduction of the risk of developing gestational diabetes. The large sample size (700 women) helps to validate this paper’s claims. It appears evident that obese women should consider bariatric surgery before pregnancy.

CONTINUOUS SUBCUTANEOUS INSULIN INFUSION VERSUS MULTIPLE DAILY INJECTIONS Continuous subcutaneous insulin infusion versus multiple daily injections in pregnant women with type 1 diabetes S. Gonzalez-Romero,1,2 I. Gonzalez-Molero,1 M. Fernandez-Abellan,3 M. E. DominguezLopez,1 S. Ruiz-de-Adana,1,2 G. Olveira,1,2 F. Soriguer1,2 1 Endocrinology and Nutrition Department, Hospital Regional Universitario Carlos Haya, Malaga, Spain, 2CIBER de Diabetes y Enfermedades Metabolicas Asociadas, Barcelona, Spain, and 3Obstetrics and Gynecology Department, Hospital Regional Universitario Carlos Haya, Malaga, Spain Diabetes Technol Ther 2010; 12: 263–9 Background: Continuous subcutaneous insulin infusion (CSII) is an alternative treatment to multiple daily injections (MDI) for people with type 1 diabetes mellitus. However, no clear difference has been established for treatment in pregnant women with type 1 diabetes. This study aims to compare the effects of CSII vs. MDI on metabolic control and obstetric and perinatal outcome of pregnancies in women with type 1 diabetes. Methods: Thirty-five pregnant women were treated with CSII and 64 pregnant women were treated with MDI. Metabolic control and obstetric and perinatal outcome of the pregnancies were analysed. Results: Women in both groups lowered their glycosylated haemoglobin (A1c) during pregnancy and there was no significant difference in metabolic control or obstetric and perinatal outcome. Conclusions: CSII is a safe and valid treatment for women with type 1 diabetes during pregnancy. Thus far CSII has not been associated with any improved pregnancy outcome.

Continuous subcutaneous insulin infusion and multiple dose insulin injections in type 1 diabetic pregnant women: a case–control study L. Volpe,1 F. Pancani,1 M. Aragona,1 C. Lencioni,1 L. Battini,2 A. Ghio,1 V. Resi,1 A. Bertolotto,1 S. del Prato,1 G. Di Cianni1 1 Department of Endocrinology and Metabolism, Section of Diabetes, University Hospital of Pisa, Pisa, Italy, and 2Division of Gynaecology and Obstetrics, University Hospital of Pisa, Pisa, Italy Gynecol Endocrinol 2010; 26: 193–6 Background: CSII is an alternative treatment to MDI for people with type 1 diabetes mellitus. No clear difference has been established for treatment in pregnant women with type 1 diabetes mellitus. This study aims to compare the effects of CSII vs. MDI on metabolic control and obstetric and perinatal outcome of pregnancies in women with type 1 diabetes. Methods: This study uses retrospective analysis of 42 women with type 1 diabetes mellitus; 20 were treated with CSII and 22 with MDI. The outcomes considered include the mother’s weight gain, change in A1c, total daily insulin dose, episodes of severe hypoglycaemia, macrosomia, frequency of caesarean sections, pre-term deliveries, birth weight, retinopathy and nephropathy. Results: In almost all of the considered outcomes there were no significant differences between patients receiving CSII or MDI. Insulin requirement was significantly lower (p = 0.009) in CSII than in MDI. In all, 45% vs. 22.7% had large-for-gestational-age infants with CSII vs. MDI. Conclusions: CSII and MDI are both safe and valid treatments for women with type 1 diabetes mellitus during pregnancy.

Glycaemic control and selected pregnancy outcomes in type 1 diabetes women on continuous subcutaneous insulin infusion and multiple daily injections: the significance of pregnancy planning

Poland, 2University Hospital, Krakow, Poland, 3 Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, MA, USA, and 4 Department of Obstetrics and Perinatology, Jagiellonian University Medical College, Krakow, Poland Diabetes Technol Ther 2010; 12: 41–7 Background: CSII and MDI are common methods to maintain glycaemic control in pregnant women with type 1 diabetes mellitus. The effect of pregnancy planning (treatment started before conception) on pregnancy outcome in women with type 1 diabetes was assessed, as well as the efficacy and safety of CSII and MDI during pregnancy. Methods: A total of 269 pregnant women with type 1 diabetes mellitus were followed; 157 were treated with MDI, 42 with CSII, and 70 switched from MDI to CSII in the first trimester. Of the 269, 116 woman planned pregnancy: 58 in the MDI group, 38 in the CSII group, and 20 in the MDI ⁄ CSII group. Results: The A1c in the first trimester differed significantly in women who had planned pregnancy and those who had not. In the second trimester A1c improved by 1.5% in the not-planning women and 0.9% in the planning women, although still lower overall in the planning group. In the third trimester women in the planned pregnancy group still had a lower overall A1c than the non-planned group. Women treated with CSII had a weight gain greater by 2 kg than those in the MDI group. Conclusions: For women with type 1 diabetes mellitus, both CSII and MDI provide excellent glycaemic control although CSII seems to result in greater maternal weight gain. Additionally, planning the pregnancy improved glycaemic control. • Comments: Each of these papers makes the point that CSII for the treatment of diabetes during pregnancy is not inferior to MDI. While this is good news for those able to afford the convenience CSII has to offer, it also means that women with low incomes will not receive inferior treatment using MDI. In today’s economy MDI provides a lower cost alternative to CSII for the treatment of diabetes during pregnancy while maintaining similar glycaemic control. Planning pregnancies seems to provide further benefits and improved glycaemic control.

K. Cyganek,1,2 A. Hebda-Szydlo,1,2 B. Katra,1,2 J. Skupien,3 T. Klupa,1,2 I. Janas,1 I. Kaim,2,4 J. Sieradzki,1,2 A. Reron,2,4 M. I. Malecki1,2 1 Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow,

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Pregnancy

TELEMEDICINE The outcomes of gestational diabetes mellitus after a telecare approach are not inferior to traditional outpatient clinic visits N. Perez-Ferre, M. Galindo, M. D. Fernandez, V. Velasco, I. Runkle, M. J. de la Cruz, P. M. Rojas-Marcos, L. del Valle, A. L. Calle-Pascual Endocrinology and Nutrition Department, Hospital Clinico Universitario San Carlos, Madrid, Spain Int J Endocrinol 2010; 2010: 1–6 Background: Over the past decade there have been many advances in the field of telemedicine, which allow for more frequent and convenient interactions with healthcare providers. GDM is a condition best cared for through tight metabolic control and accurate patient monitoring. This study aims to evaluate the use of a telemedicine-based system using the internet and short message services to monitor women with GDM. Methods: Ninety-seven women with GDM were studied; 48 women received traditional face-to-face visits and 49 women were placed in an intervention group with a telemedicine system for transmission of capillary glucose data and short text messages with weekly professional feedback. Results: There was no significant difference between the two groups, despite a significant reduction in clinic visits in the experimental group, particularly in insulin-treated women. No significant differences were seen in A1c levels, normal vaginal deliveries and largefor-gestational-age newborns. Conclusions: The telemedicine-based system achieved similar pregnancy, delivery and newborn outcomes compared with traditional treatment, significantly reducing the need for outpatient clinic visits.

The effect of telemedicine on outcome and quality of life in pregnant women with diabetes M. G. Dalfra,1 A. Nicolucci,2 A. Lapolla1 1 Dipartimento di Scienze Mediche e Chirurgiche, Universita di Padova, Italy, and 2 Farmacologia Epidemiologia, Consorzio Mario Negri Sud, S Maria Imbaro, Italy J Telemed Telecare 2009; 15: 238–42 Background: Over the past decade there have been many advances in the field of tele-

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medicine, which allow for more frequent and convenient interactions with healthcare providers. GDM is a condition best cared for through tight metabolic control and accurate patient monitoring. This study evaluates the effects of telemedicine on maternal and fetal outcome in women with diabetes. Methods: A total of 276 pregnant women with diabetes were enrolled in the study and sequentially assigned to a telemedicine or a control group. The women in the telemedicine group submitted their glucose data every week by phone and had a medical examination at a diabetes clinic once a month. The women in the control group received a medical examination every two weeks. Questionnaires measuring depression, health-related quality of life, stress and distress for the impact of diabetes were used to assess the non-clinical variables of the treatment. Results: Telemedicine provided better metabolic control in the third trimester in women with GDM and a lower rate of caesarean sections and macrosomia. Women in the telemedicine group also showed lower levels of frustration and concerns about their diabetes, and better acceptance of their diabetic condition. Conclusions: Telemedicine provides a convenient method for monitoring women with diabetes during pregnancy. The outcomes of telemedicine are just as good and in many cases better than traditional methods.

face-to-face visits and 49 women were placed in an intervention group with a telemedicine system for transmission of capillary glucose data and short text messages with weekly professional feedback. Results: Compared to the control group, the telemedicine group reduced the number of unscheduled face-to-face visits by 62%, and by 82.7% in the subgroup of insulintreated patients. Conclusions: Telemedicine is a valid means of monitoring women with GDM; it decreases the number of visits to a physician while achieving similar pregnancy and perinatal outcomes as traditional treatment. • Comments: These three papers effectively address several aspects of implementing telemedicine for the treatment of diabetes during pregnancy. It appears that telemedicine’s use is not only feasible, but also capable of providing the same glycaemic control and perinatal outcome with fewer visits to a physician. While this appears beneficial from a patient standpoint, one must also consider the economic impact at the physician’s side. With fewer visits doctors would be making less money to provide the same care, not to mention the costs of creating a telemedicine system. If telemedicine in the treatment of diabetes during pregnancy proves to be mutually beneficial, it could drastically change current treatment methods.

A telemedicine system based on internet and short message service as a new approach in the follow-up of patients with gestational diabetes

Gestational diabetes mellitus screening based on the gene chip technique

N. Perez-Ferre, M. Galindo, M. D. Fernandez, V. Velasco, M. J. de la Cruz, P. Martin, L. del Valle, A. L. Calle-Pascual Endocrinology and Nutrition Department, San Carlos University Hospital, Madrid, Spain Diabetes Res Clin Pr 2010; 87: 15–17 Background: Over the past decade there have been many advances in the field of telemedicine, which allow for more frequent and convenient interactions with healthcare providers. GDM is a condition best cared for through tight metabolic control and accurate patient monitoring. This study aims to evaluate the feasibility of a telemedicinebased system using the internet and short message services to monitor women with GDM. Methods: Ninety-seven women with GDM were studied; 48 women received traditional

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DIABETES SCREENING

Z. Liang,1 M. Dong,2 Q. Cheng,2 D. Chen1 1 Obstetric Department, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China, and 2Central Laboratory, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China Diabetes Res Clin Pr 2010; 89: 167–73 Background: GDM is currently defined as diabetes first diagnosed during pregnancy, which often includes women with diabetes before pregnancy yet undiagnosed until pregnant. The standard method of diagnosing the disease is with an oral glucose tolerance test (GTT). This study looks at genetics using gene chip technology as the basis for diagnosing the risk of developing GDM. Methods: Blood samples were collected from 50 women with GDM and 80 healthy pregnant women. DNA samples were sequenced and probed for single nucleotide

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polymorphisms (SNPs) known to be associated with diabetes. Results: Four SNPs were identified to be significantly different between GDM and control patients. When the gene chip technique was used on a random cohort of pregnant women with and without GDM, the gene chip results were precisely matched by DNA sequencing. Conclusions: The gene chip technique provides a viable option for diagnosing an increased risk of developing GDM. • Comment: Early detection and treatment for GDM have been shown to result in better glycaemic control during pregnancy, thereby improving perinatal outcome. Although expensive and difficult to perform at this point, the gene chip technique could significantly improve metabolic control in women with GDM given its capability of diagnosing GDM early in pregnancy. Standard glucose challenge tests are time consuming and may cause vomiting among other problems in some pregnant women, which would not be an issue using the gene chip technique.

Computerised analysis of fetal heart rate in pregnancies complicated by gestational diabetes mellitus, gestational hypertension, intrauterine growth restriction and premature rupture of membranes G. Buscicchio, L. Gentilucci, A. L. Tranquilli Institute for Maternal and Child Sciences, Marche Polytechnic University, Ancona, Italy J Matern Fetal Neonatal Med 2010; 23: 335–7 Background: GDM complicates approximately 2%–5% of all pregnancies. The offspring of women with GDM are prone to adverse effects such as macrosomia and various types of birth trauma. This study sought to compare the fetal heart rate, as determined by computer analysis, in pregnancies complicated by GDM with the fetal heart rate in normal non-diabetic pregnancies. Methods: The study consisted of large populations for comparison: 100 pregnant woman affected by GDM were treated with diet therapy, 100 pregnant woman affected by GDM were put on insulin therapy, 100 pregnant woman affected by pregnancy-induced hypertension, 100 pregnant women affected by intrauterine growth restriction, 100 with

premature rupture of membranes far from term and 100 normal pregnancies. Computerised fetal heart rate monitoring was performed by computerised cardiotocography on all women for at least 30 min and the results were assessed using Dawes and Redman parameters. Results: The duration of episodes of low fetal heart rate variation and short-term variation were significantly higher in pregnancies complicated by GDM. Conclusions: Although these changes in fetal heart rate were only slight, they reflect fetal well-being. Computerised cardiotocography may be the only device capable of detecting these slight alterations. • Comment: This study shows further evidence for the rationale to treat GDM. It is an important finding because it shows that there are already complications in utero before the difficult delivery takes place. The episodes of low fetal heart rate variation and short-term variation represent a sign of fetal distress.

Conclusions: Mass spectrometry of amniotic HSA is a viable method for identifying women at risk for GDM. This study also implies that the progression towards GDM may be set prior to 15 weeks’ gestation. • Comment: Women not characterised as being at high risk for developing GDM usually do not have a diagnostic glucose challenge test until 24 weeks of gestation. While amniocentesis is a risky procedure, if a woman is having one performed for another purpose unrelated to diabetes screening, it would be worthwhile to have the HSA analysed, especially since the estimated cost is $8.00.

Increased oxidative modifications of amniotic fluid albumin in pregnancies associated with gestational diabetes mellitus

T. Tantanasis, A. Daniilidis, C. Giannoulis, M. Tzafettas, K. Dinas, A. Loufopoulos, K. Papathanasiou Second University Department of Obstetrics and Gynecology, Hippokratio General Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece Eur J Obstet Gynecol Reprod Biol 2010; 152: 157–62

M. R. Boisvert,1 K. G. Koski,2 C. D. Skinner1 1 Department of Chemistry and Biochemistry, Concordia University, Montreal, Quebec, Canada, and 2School of Dietetics and Human Nutrition, McGill University (Macdonald Campus), Montreal, Canada Anal Chem 2010; 82: 1133–7 Background: It is known that abnormal distributions of protein isoforms can be related to a variety of pathological states and have been used for the diagnosis or prognosis of several diseases. Human serum albumin (HSA) is the must abundant protein in amniotic fluid and can undergo several modifications in response to oxidative stress. This study seeks to explain how differences in oxidative modifications of HSA can be measured using mass spectrometry and used as a diagnostic tool for GDM. Methods: Amniotic fluid samples were extracted from 26 GDM and 26 non-GDM women at 15 weeks’ gestation. HSA was extracted from the samples and oxidative modifications were analysed by mass spectrometry. Results: The relative contribution of permanently oxidised HSA in women with GDM was greater (p = 0.002) than for non-GDM women, and reversibly oxidised HSA was lower (p = 0.006).

ULTRASOUND Sonographic assessment of fetal subcutaneous fat tissue thickness as an indicator of gestational diabetes

Background: Currently a GTT is the most frequently used diagnostic test for GDM. The GTT is a very time consuming process and is poorly tolerated among patients. This study aimed to use ultrasound to measure fetal subcutaneous fat in pregnancies with abnormal and normal GTTs as a means to diagnose gestational diabetes. Methods: Thirty-five women with singleton pregnancies between 24 and 26 weeks’ gestation participated in the study. Using ultrasound, fetal subcutaneous fat thickness was measured in 20 women with abnormal GTTs and 15 women with normal GTTs. Fat thickness was measured at three different points on the fetal body: the biparietal diameter, the abdominal circumference and the thoracic spine. At least two measurements were taken for each parameter and the mean value was recorded. Results: The values of the three variables in the abnormal group were higher at statistically significant values than the normal group. Conclusions: This study suggests the possibility of using ultrasound to measure fetal subcutaneous fat measurements as an additional criterion to distinguish women at high

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risk for gestational diabetes. The screening method is non-invasive and cost effective. • Comment: This study confirms that ultrasound measurements of fetal body mass are a good indicator of gestational diabetes. Oral GTTs can be time consuming and uncomfortable for patients. Ultrasound represents a non-invasive and cost effective solution to this problem. Further studies need to be done with larger numbers of patients but this presents a nice basis for further research.

Sonographic prediction of fetal macrosomia: the consequences of false diagnosis N. Melamed, Y. Yogev, I. Meizner, R. Mashiach, A. Ben-Haroush Helen Schneider Hospital for Women, Rabin Medical Center, Petach Tikva, Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel J Ultrasound Med 2010; 29: 225–30 Background: The prenatal sonographic diagnosis of macrosomia can often be imprecise and, unfortunately, false diagnosis is common. The prediction of macrosomia, whether it is accurate or inaccurate, has considerable effects on obstetrical management. The aim of this study was to assess the consequences of a false diagnosis on maternal and neonatal outcomes when the estimated fetal weight was below the threshold that mandated caesarean delivery in the Helen Schneider Hospital for Women. Methods: This was a case–control study that assessed women (n = 1938) who underwent fetal weight estimation up to 3 days before delivery and delivered a neonate weighing between 3500 and 4499 g. The falsepositive and false-negative groups were compared with the true-negative and true-positive groups, respectively and the results were analysed. Results: The caesarean delivery rate was 2 to 2.5 times higher when estimated fetal weight was 4000–4499 g regardless of actual birth weight. Failure to detect macrosomia resulted in a higher rate of major perineal trauma, 5-min Apgar scores of less than 7, and neonatal trauma, mostly related to the higher rate of instrumental deliveries. The use of another sonographic model with a lower false-positive rate could lower the caesarean delivery rate by 5%. Conclusions: False diagnosis of macrosomia leads to higher caesarean delivery rates and neonatal ⁄ maternal complications.

• Comment: This study is a good reference for the consequences of a false diagnosis of macrosomia. Macrosomia is a harmful condition that can lead to neonatal and maternal complications. The diagnosis alone of macrosomia has been shown to increase the rate of caesarean delivery regardless of birth weight. This study shows the need for further studies to determine the optimal regression formula for predicting fetal macrosomia.

Improved ultrasonographic estimation of birth weight in macrosomic fetuses by application of a correction factor to the gestation-adjusted projection method C. M. Zelig, S. H. Deering, P. G. Napolitano Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Madigan Army Medical Center, Tocoma, WA, USA J Ultrasound Med 2009; 28: 1357–64 Background: In 1996, Mongelli and Gardosi (1) introduced the gestation-adjusted projection (GAP) method, which uses a single third-trimester ultrasonographic examination to predict birth weight. In two subsequent studies, the GAP method was shown to be a more accurate predictor of fetal weight than an ultrasonographic examination close to delivery. The positive predictive value for predicting macrosomia in these studies was slightly lower at 44% and 52%. The purpose of this study was to develop a mathematical model to improve the GAP method in predicting macrosomia. Methods: A total of 411 singleton pregnancies delivered after 37 weeks’ gestation that had undergone an ultrasonographic examination between 34 and 36.9 weeks’ gestation were reviewed. For each woman, the GAP method was used to estimate birth weight. Error in the GAP method was calculated by comparing the estimated fetal weight to the actual birth weight. A correction factor was derived for the GAP method and then applied to a new population of 317 patients. Results: The study’s model improved specificity for macrosomia in both the derivation and verification groups but the change in sensitivity for macrosomia was not significant. Conclusions: The false-positive rates of macrosomia were significantly reduced using the study’s corrected GAP method.

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Performance of 36 different weight estimation formulae for fetuses with macrosomia M. Hoopmann, H. Abele, N. Wagner, D. Wallwiener, K. O. Kagan Department of Obstetrics and Gynecology, University of Tu¨bingen, Tu¨bingen, Germany Fetal Diagn Ther 2010; 27: 204���13 Background: Several studies have shown continuously high errors in predicting birth weight in macrosomic fetuses. This study aimed to compare 36 commonly used weightestimating formulae in predicting the weight of fetuses of 4000 g or more. Methods: This was a retrospective study of women with singleton pregnancies that resulted in a fetus weighing 4000 g or more. All pregnant women were given an ultrasound examination shortly before delivery and these data were plugged into the different formulae. The accuracy of the formulae was compared by mean percentage error and mean absolute percentage error, by the frequency distribution of differences between estimated fetal weight and fetal birth weight, and by comparing detection and false-positive rates in screening for fetuses at various weights. Results: Mean percentage error ranged from )62.2% to 9.6% and was closest to zero with the Hart formula. Mean absolute percentage error was 10% or less with 12 of the 36 formulae and smallest with the Hart formula at 3.9%. The mean detection rate among all formulae for fetuses with a birth weight greater than or equal to 4000, 4300 and 4500 g was 29%, 24% and 22% respectively. Conclusions: Some formulae showed advantages over others but none reached a detection rate and false-positive rate good enough for clinical recommendation. • Comment: The derivation of an accurate weight estimation formula is crucial in predicting and controlling fetal macrosomia. Among the 36 different weight estimation formulae, none displayed results that stood out. The corrected GAP method from the first study, however, did show decreased false-positive rates and increased positive predicting values for predicting macrosomia. This corrected GAP method needs to be studied further in different patient populations.

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GLUCOSE MONITORING Weekly compared with daily blood glucose monitoring in women with diet-treated gestational diabetes J. S. Hawkins, B. M. Casey, J. Y. Lo, K. Moss, D. D. McIntire, K. J. Leveno Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA Obstet Gynecol 2009; 113: 1302–12 Background: Self-monitoring of blood glucose in pregnant woman with overt diabetes has been associated with improved glycaemic control and improved neonatal outcomes. This study aimed to determine whether daily blood glucose self-monitoring compared to weekly office testing in women with diet-treated gestational diabetes reduces cases of macrosomia. Methods: The design was a retrospective cohort study of women with diet-treated GDM between January 1991 and March 2001. Initially, the standard treatment for women with diet-treated GDM at the Parkland Memorial Hospital included routine office monitoring of fasting blood glucose levels. Beginning in 1998, four times daily blood glucose self-monitoring became the standard treatment. Women in these groups were compared in two outcomes of interest including frequency of macrosomia and large-forgestational-age infants. Results: A total of 315 women who used daily blood glucose self-monitoring were compared to 675 women who underwent weekly office-based glucose testing. The

self-monitoring groups had fewer macrosomia and large-for-gestational-age neonates and gained significantly less weight. Conclusions: Daily blood glucose selfmonitoring, compared to weekly office-based testing, is associated with a reduction in the incidence of macrosomia. • Comments: This study shows further evidence that self-monitoring of blood glucose in pregnancy improves neonatal outcomes, such as macrosomia and large-for-gestational-age infants. This can be a costly treatment method but, as shown by this and numerous other studies, glucose meters are an essential device in the treatment of gestational diabetes.

Comparison in the performance of glucose meters in blood glucose during pregnancy G. W. S. Kong,1 W. H. Tam,1 M. H. M. Chan,2 W. Y. So,3 C. W. K. Lam,2 I. P. I. C. Yiu,1 K. M. Loo,3 C. Y. Li1 1 Departments of Obstetrics and Gynaecology, Prince of Wales Hospital, Hong Kong, SAR, China, 2Chemical Pathology, Prince of Wales Hospital, Hong Kong, SAR, China, and 3 Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, SAR, China Gynecol Obstet Invest 2010; 69: 264–9 Background: As home blood glucose monitoring forms an essential part in achieving glycaemic control in pregnancies, the accuracy of these meters becomes an important part of this assessment. The glycaemic range for pregnancies demands a lower range than that for a typical diabetic patient. Further-

more, there is limited data describing how accurately these meters perform during pregnancy. This study aimed to compare the performance of four of the latest glucose meters during pregnancy. Methods: Four glucose meters were tested on 208 women with GDM. The four meters were Ascensia EliteF, Accu-Chek Advantage II, CareSens 505B and Optium. Each subject underwent simultaneous finger prick capillary blood glucose testing with venipunctures. The performance of the four different meters was compared using error grid analysis. A Bland– Altman plot was also used to assess the agreement between the glucose meter readings and the plasma glucose values. Results: Elite, Advantage II and CareSens had more than 90% of readings in the acceptable target range for error grid analysis. CareSens had the lowest mean bias by Bland– Altman analysis while Advantage II had the highest proportion of readings within 5% difference from plasma glucose. Conclusions: The performance of the four meters appeared very similar. • Comment: Patients today want the best care possible, and as a result they are often concerned to get the best possible glucose meters. This study shows that the differences between these meters during pregnancies are very minor and that there is no need for the patient to worry. The most important thing for doctors to do is inform their patients of the need for self-monitoring of blood glucose.

Reference 1 Mongelli M, Gardosi J. Gestation-adjusted projection of estimated fetal weight. Acta Obstet Gynecol Scand 1996; 75: 28–31.

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Advanced Technologies and Treatments for Diabetes

Immunomodulation Immune intervention for type 1 diabetes mellitus J. S. Skyler Division of Endocrinology, Diabetes and Metabolism; and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA

The major form of type 1 diabetes (T1D) is characterised by immune-mediated pancreatic islet b-cell destruction, and has also been called type 1A diabetes to distinguish it from idiopathic forms of islet b-cell loss. Since the first demonstration of islet cell antibodies in 1974, the concept has been that this form of diabetes is autoimmune in nature. The commonly accepted concept is that antibodies (representing the humoral arm of the immune system) do not mediate the b-cell destruction but rather serve as markers of that destruction, while the cellular arm of the immune system, specifically T-lymphocytes, mediate the b-cell destruction. Yet, the T-lymphocytes do not act alone. They receive help in initiating the response from antigen-presenting cells such as dendritic cells and macrophages, and appear to receive help also from B-lymphocytes. In addition, the initial immune response engenders secondary and tertiary responses – involving the whole immunological army – which collectively result in impairment of b-cell function, progressive destruction of b-cells, and consequent development of type 1A diabetes. The process is insidious and may evolve over many years, with the overt expression of clinical symptoms becoming apparent only when most b-cells have been destroyed. Yet, the process clearly evolves at different speeds – much more rapidly in young children, much more slowly in older individuals. And, although it has been thought that ultimately there is complete b-cell destruction, several studies have now demonstrated some degree of persistent b-cell function or existence (at autopsy) in long-standing T1D. A major focus of investigation in T1D is the preservation of b-cell function (and, it is hoped, of b-cells themselves), in the expectation that continuing endogenous insulin secretion will contribute towards better glycaemic control, reduce episodes of severe hypoglycaemia, and slow the development of complications such as retinopathy and nephropathy. Thus, there have been many studies designed to interdict the T1D disease process, mostly by altering the immune system, both during the stage of evolution of the disease and at the time of disease onset. This chapter of the Yearbook of Advanced Technology and Treatments in Diabetes reviews the key papers that have appeared in this field between July 2009 and June 2010. Articles selected were confined to studies in human beings. All immune intervention studies reported in this time frame were included. In addition, the author selected other relevant articles dealing with mechanisms, markers, triggers, and pathology of human type 1 diabetes.

IMMUNE INTERVENTIONS STUDIES IN HUMAN TYPE 1 DIABETES The first group of papers involves reports of immune intervention studies in human type 1 diabetes, mostly in recent-onset T1D.

Four-year metabolic outcome of a randomised controlled CD3antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual b-cell mass B. Keymeulen,1 M. Walter,2 C. Mathieu,3 L. Kaufman,4 F. Gorus,1 R. Hilbrands,1 E. Vandemeulebroucke,1 U. Van de Velde,1 L. Crenier,5 C. De Block,6 S. Candon,7 H. Waldmann,8 A. G. Ziegler,2 L. Chatenoud,7 D. Pipeleers1

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Correspomdence to: Jay S. Skyler, Division of Endocrinology, Diabetes, and Metabolism; and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA Tel.: 305-243-6146 Fax: 305-243-4484 Email: jskyler@miami.edu Disclosures: JSS is Chairman of Type 1 Diabetes TrialNet, a clinical trials network conducting multiple studies designed to interrupt the type 1 diabetes disease process. Also, recipient of grant support from Bayhill Therapeutics and Osiris Therapeutics. The author serves on the Board of Directors of Amylin Pharmaceuticals, and chairs the Type 1 Diabetes Advisory Board for sanofi-aventis. Endorsed by the International Conference on ATTD organized by Kenes International.

1 Diabetes Research Center and University Hospital, Brussels Free University-VUB, Brussels, Belgium, 2Hospital Mu¨nchenSchwabing, Munich, Germany, 3Department of Endocrinology, Katolieke Universiteit LeuvenKUL, Leuven, Belgium, 4Department of Biostatistics and Medical Informatics, Brussels Free University-VUB, Brussels, Belgium, 5 Hoˆpital Erasme, Universite´ Libre de BruxellesULB, Brussels, Belgium, 6Department of Diabetology, University Hospital Antwerp, Edegem, Belgium, 7INSERM U580-IRNEM, Hoˆpital Necker, Paris, France, and 8Sir William Dunn School of Pathology, Oxford, UK Diabetologia 2010; 53: 614–23

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Background: The authors previously reported the results of their initial randomised, controlled 18-month trial in which a short course of the humanised Fc-mutated recombinant aglycosylated anti-human CD3 antibody, ChAglyCD3 (now called otelixizumab), was given for six consecutive days shortly after diagnosis of T1D. In their earlier report, they demonstrated preservation of bcell function – as measured by C-peptide – and equivalent glycaemic control with lower insulin doses. The current paper extends follow-up to 4 years. Methods: The original study included 80 subjects (40 treated with anti-CD3, 40 treated with placebo), ages 12–39. Four-year followup data are reported on 64 subjects (33 of the anti-CD3 subjects, 31 of the placebo subjects). Change in insulin dose over 48 months was the primary end-point. Results: Treatment with anti-CD3 delayed the rise in insulin requirements of subjects with recent-onset T1D and reduced the magnitude of that rise over 48 months of followup. Using multivariate analysis, this effect was correlated with higher baseline b-cell function and younger age. Conclusions: Anti-CD3 therapy shortly after onset of T1D has sustained effects for 48 months.

Treatment of patients with new-onset type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years K. C. Herold,1,2 S. Gitelman,3 C. Greenbaum,6 J. Puck,3 W. Hagopian,7 P. Gottlieb,8 P. Sayre,10 P. Bianchine,9 E. Wong,4 V. Seyfert-Margolis,10 K. Bourcier,10 J. A. Bluestone,5,10 Group Immune Tolerance Network ITN007AI Study 1 Department of Immunobiology, Yale University, New Haven, CT, USA, 2Department of Medicine, Yale University, New Haven, CT, USA, 3Department of Pediatrics, University of California at San Francisco, CA, USA, 4 Department of Statistics, University of California at San Francisco, CA; PPD Inc., Wilmington, NC, USA, 5Department of Medicine, University of California at San Francisco, CA, USA, 6Benaroya Research Institute, Seattle, WA, USA, 7Department of Medicine, Pacific Northwest Research Institute and University of Washington, USA, 8Department of Medicine, University of Colorado, Denver, CO, USA,

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National Institute for Allergy Immunology and Infectious Diseases, Bethesda, MD, USA, and 10 Immune Tolerance Network, Bethesda, MD, USA Clin Immunol 2009; 132: 166–73 Background: The authors previously reported the 1- and 2-year results of an openlabel trial in which a short course of the humanised Fc-mutated CD3-specific monoclonal antibody, hOKT3c1 (Ala-Ala) (now called teplizumab), was given for 14 consecutive days shortly after diagnosis of T1D. In the reports of that study, they demonstrated preservation of b-cell function – as measured by C-peptide – and both better glycaemic control and lower insulin doses. The current paper reports on a smaller second trial that had enrolment interrupted due to adverse events. Methods: The study enrolled 10 subjects before being halted for adverse events that seemed to be a consequence of higher doses of the drug used in this trial. The subjects were followed, nonetheless. Results: At 2 years, the treated subjects (n = 6) had lower insulin doses than the comparison subjects (n = 4), and a trend towards better maintained C-peptide. The Cpeptide levels in the treated subjects remained fairly constant between 2 and 5 years of follow-up. The authors concluded that the higher doses resulted in more adverse events without increased efficacy. Conclusion: This small study suggests that anti-CD3 therapy shortly after onset of T1D may have prolonged effects with fairly constant C-peptide levels between 2 and 5 years. • Comment: These two studies demonstrate that relatively short courses of treatment (6 or 14 days) with an anti-CD3 monoclonal antibody can have sustained effects on b-cell function – as measured by C-peptide – for as long as 4 to 5 years. Both of the anti-CD3 antibodies used – otelixizumab and teplizumab – are now being studied in full-scale phase 3 trials for potential commercialisation for use in recent-onset T1D. Thus, the fact that there are long-term beneficial effects is important. Nonetheless, in the original trials with both of these antibodies, there was progressive decline in b-cell function, suggesting that there may be a need for repeated courses of administration. Alternatively, the efficacy of these antibodies might be improved if used in combination therapy with another agent (or agents) acting synergistically to improve b-cell function.

Cyclosporin and methotrexate therapy induces remission in type 1 diabetes mellitus D. O. Sobel, A. Henzke, V. Abbassi Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA Acta Diabetol 2010; 47: 243–50 Background: Studies reported in the late 1980s and early 1990s had shown that cyclosporine appears to have beneficial effects in recent-onset T1D, as long as treatment is maintained, but at the price of significant adverse effects, particularly induction of renal damage. The current study was designed as a pilot study to determine whether lower doses of cyclosporine could avert the adverse effects, and if combined with methotrexate might still demonstrate the beneficial effects. Methods: The study was an open nonrandomised pilot study, in which seven subjects with recent-onset T1D were treated with cyclosporine plus methotrexate, and compared to 10 subjects not so treated. Only the clinical course was evaluated, and b-cell function was not reported. Results: During the 1 year of follow-up, during which treatment was maintained in the intervention group, that group had lower insulin doses, greater likelihood of discontinuing insulin, and at the 12-month time point lower A1c. Adverse effects were said to be less than in earlier cyclosporine studies. Conclusion: The combination of low-dose cyclosporine plus methotrexate may improve the course of T1D over 1 year. • Comment: This study attempts to take advantage of an oft utilised medical principle that using lower doses of two drugs may obviate the adverse effects of higher doses, whilst still achieving efficacy. The study was a very small pilot study in which only seven subjects were treated. That small number makes it impossible to assess the risk of adverse effects. Also, the absence of measurement of b-cell function makes it impossible to compare the outcome with that in other contemporary studies. Finally, most current studies in recent-onset T1D do not intentionally attempt to reduce insulin doses to achieve ‘remission’, but rather do so only to avert hypoglycaemia, maintaining the highest insulin dose that does not result in significant hypoglycaemia. This makes the claim of achieving ‘remission’ because insulin was able to be discontinued difficult to interpret.

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Failure to preserve b-cell function with mycophenolate mofetil and daclizumab combined therapy in patients with new-onset type 1 diabetes P. A. Gottlieb,1 S. Quinlan,2 H. Krause-Steinrauf,2 C. J. Greenbaum,3 D. M. Wilson,4 H. Rodriguez,5 D. A. Schatz,6 A. M. Moran,7 J. M. Lachin,2 J. S. Skyler,8 Type 1 Diabetes TrialNet MMF ⁄ DZB Study Group 1 Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver, Aurora, CO, USA, 2Biostatistics Center, George Washington University, Rockville, MD, USA, 3Benaroya Research Institute, Diabetes Clinical Research, Seattle, WA, USA, 4Pediatric Endocrinology Department, Stanford University, Stanford, CA, USA, 5Department of Pediatrics, Indiana University, Indianapolis, IN, USA, 6 Department of Pediatrics, University of Florida, Gainesville, FL, USA, 7Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA, and 8Diabetes Research Institute, University of Miami, Miami, FL, USA Diabetes Care 2010; 33: 826–32 Background: The authors evaluated the use of mycophenolate mofetil (MMF), either alone or in combination with daclizumab (DZB), in recent-onset T1D. MMF has potent cytostatic effects on lymphocytes, and has been effective in other autoimmune diseases and in diabetic animal models. DZB is a humanised monoclonal antibody that binds to CD25, the a-subunit of the interleukin-2 (IL-2) receptor expressed on the surface of activated lymphocytes, and has been effective in other autoimmune diseases as well as in islet transplant protocols. The combination of MMF and DZB had a beneficial synergistic effect in diabetic animal models. Methods: The study included 126 subjects, ages 8–45, randomised to MMF alone, MMF plus DZB, or placebo. Two DZB (or placebo) infusions were administered – one initially and one 2 weeks later. MMF (or placebo) was given continuously, with a planned study end-point at 2 years. Results: The Data Safety and Monitoring Board halted the study early due to the projected futility of achieving a beneficial result. There was a similar decline in b-cell function in all three groups – MMF alone, MMF plus DZB, and placebo. In addition, A1c and insulin dosage were similar in all three groups. Conclusions: MMF, either alone or in combination with DZB, failed to prevent

decline in b-cell function in recent-onset T1D. • Comment: This large, well-powered study failed to demonstrate preservation of b-cell function in recent-onset T1D. Although many interventions have shown benefit in recent-onset T1D, this study reminds us that not all interventions which show promise in animal models will work in human beings. The study does represent one of the first, if not the first, fully powered study using combination therapy in recent-onset T1D. There will no doubt be other combination therapy trials. In designing them, one might note one feature of this study – half of the treated subjects received an infusion of DZB, and half of the placebo subjects received an infusion of DZB. This maintained masking, while not requiring all subjects to receive infusions. This is a design that can be used if a single agent is being compared to its use in combination. Another approach would be a factorial design. Attention to design of combination studies will be an important consideration in future T1D trials.

Rituximab, B-lymphocyte depletion, and preservation of b-cell function M. D. Pescovitz,1 C. J. Greenbaum,2 H. Krause-Steinrauf,3 D. J. Becker,4 S. E. Gitelman,5 R. Goland,6 P. A. Gottlieb,7 J. B. Marks,8 P. F. McGee,3 A. M. Moran,9 P. Raskin,10 H. Rodriguez,1 D. A. Schatz,11 D. Wherrett,12 D. M. Wilson,13 J. M. Lachin,3 J. S. Skyler,8 Type 1 Diabetes TrialNet Anti-CD20 Study Group 1 Indiana University School of Medicine, Indianapolis, IN, USA, 2Benaroya Research Institute, Seattle, WA, USA, 3George Washington University Biostatistics Center, Rockville, MD, USA, 4University of Pittsburgh, Pittsburgh, PA, USA, 5University of California, San Francisco, CA, USA, 6Columbia University, New York, NY, USA, 7University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA, 8University of Miami Diabetes Institute, Miami, FL, USA, 9University of Minnesota, Minneapolis, MN, USA, 10University of Texas Southwestern Medical School, Dallas, TX, USA, 11University of Florida, Gainesville, FL, USA, 12Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, and 13Stanford University, Stanford, CA, USA N Engl J Med 2009; 361: 2143–52 Background: There is growing evidence that B-lymphocytes play a role in many

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T-lymphocyte mediated diseases, by serving as antigen-presenting cells or generating cryptic peptides to which T-lymphocytes are not tolerant. This study used the anti-CD20 antibody, rituximab, to selectively deplete B-lymphocytes in recent-onset T1D. Methods: The study randomised 87 subjects (57 assigned to anti-CD20, 30 assigned to placebo), ages 8–45. Intervention consisted of four weekly infusions. The primary endpoint was b-cell function – as measured by C-peptide – at 1 year, with 78 subjects included in the analysis. Results: At 1 year, the mean level of Cpeptide was significantly higher in the rituximab group than in the placebo group, and declined at a slower rate. The rituximab group also had significantly lower A1c levels and required less insulin. Adverse effects were minimal and mostly occurred during the first rituximab infusion. Conclusions: The anti-CD20 antibody rituximab showed beneficial effects on b-cell function in recent-onset T1D, suggesting a potential role for B-lymphocytes in T1D pathogenesis. • Comment: This study demonstrates that a relatively short course of treatment (weekly infusions over 4 weeks) with an anti-CD20 monoclonal antibody can have beneficial effects on b-cell function – as measured by C-peptide – at 1 year. Nonetheless, there is progressive decline in b-cell function, as in virtually all intervention trials in recent-onset T1D, again suggesting that there may be a need for repeated courses of administration, or, alternatively, for combination therapy with another agent. An important feature of this study is the demonstration that B-lymphocytes contribute to the pathogenesis of T1D. This may have important implications for the design of combination therapy regimens for evaluation in T1D.

Six months of diazoxide treatment at bedtime in newly diagnosed subjects with type 1 diabetes does not influence parameters of b-cell function and autoimmunity but improves glycaemic control M. A. Radtke,1,2 I. Nermoen,3 M. Kollind,4 S. Skeie,5 J. I. Sørheim,6 J. Svartberg,7,8 I. Hals,1 T. Moen,9 G. H. Dørflinger,1 V. Grill1,2 1 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway, 2Department of Endocrinology, St Olavs Hospital ⁄

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University Hospital of Trondheim, Trondheim, Norway, 3Department of Endocrinology, Akershus University Hospital, Lørenskog, Norway, 4 Endocrinology Unit, Department of Internal Medicine, Levanger Hospital, Levanger, Norway, 5Section of Endocrinology, Division of Medicine, Stavanger University Hospital, Stavanger, Norway, 6Section of Endocrinology, Department of Medicine, Haukeland University Hospital, Bergen, Norway, 7Section of Endocrinology, Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway, 8Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway, and 9 Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway Diabetes Care 2010; 33: 589–94 Background: Diazoxide provides b-cell rest by reversibly suppressing glucose-induced insulin secretion. Previous studies have shown that diazoxide may preserve b-cell function in recent-onset T1D, but with frequent adverse effects consisting of lanugo hair growth, oedema and hypotension. The current study was designed to test whether a lower dosage of diazoxide would eliminate side effects and still exert beneficial effects. Methods: The study randomised 41 subjects (22 to diazoxide, 19 to placebo), ages 18–40, with recent-onset T1D. Subjects received 6 months of treatment with placebo or 100 mg diazoxide at bedtime, and were followed for a subsequent 6 months. Outcome measures were C-peptide (fasting and glucagon stimulated), A1c and insulin dose. Results: A1c levels at both 6 months and 1 year were lower in the diazoxide group, but there was no difference in insulin dose, C-peptide levels (either actual levels or C-peptide ⁄ glucose ratios), or in proportion of Tregs (regulatory T-lymphocytes). There was more weight gain in the placebo group. Insulin sensitivity, as assessed by HOMA-S% (homeostatic model assessment for insulin sensitivity), increased in the diazoxide group but remained stable in the placebo group. Conclusions: Low dose diazoxide averted adverse effects but failed to improve outcome in recent-onset T1D. • Comment: Diazoxide, at higher doses, has previously been shown to have beneficial effects in preserving b-cell function in recentonset T1D. However, its use has been limited due to intolerability from side effects. In the current randomised controlled trial, a lower dose was better tolerated but failed to demonstrate preservation of b-cell function. Interestingly, there were differences in A1c, which was lower in the diazoxide group. This may

have been a consequence of greater insulin sensitivity and less weight gain in the diazoxide group. The authors propose that low-dose diazoxide could serve as a component in a combination therapy regimen. Indeed, that may be worth exploring.

No effect of the altered peptide ligand NBI-6024 on b-cell residual function and insulin needs in new-onset type 1 diabetes M. Walter,1 A. Philotheou,2 F. Bonnici,2 A. G. Ziegler,1 R. Jimenez,3 NBI-6024 Study Group 1 Diabetes Research Institute, Forschergruppe Diabetes e.V., Munich, Germany, 2Diabetes Clinical Trials Unit, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa, and 3Clinical Development, Neurocrine Biosciences, San Diego, CA, USA Diabetes Care 2009; 32: 2036–40 Background: Insulin B (9–23) peptide is thought to be an important antigen of T-lymphocytes in autoimmune diabetes in animals and in human beings. It is possible to target specific autoreactive T-lymphocyte activation using a soluble altered peptide ligand (APL) to block or change that activation. NBI-6024 is an APL that contains two amino acid substitutions in the (9–23) sequence of the B-chain of insulin: alanine is substituted for tyrosine at position 16, which is a key contact site at the T-lymphocyte receptor; and alanine also is substituted for cysteine at position 19. The resulting APL (Ala16,19) (also known as NBI-6024) does not activate insulin B (9–23) reactive murine or human T-lymphocytes. Methods: The study randomised 188 subjects, ages 10–35, to three different doses of the APL (50 subjects to 0.1 mg, 48 subjects to 0.5 mg, 43 subjects to 1.0 mg) or to placebo (47 subjects). Intervention consisted of subcutaneous injections at randomisation, 2 weeks, 4 weeks and monthly until 24 months. The primary end-point was b-cell function – as measured by C-peptide – at 2 years. Results: At 2 years, the mean peak C-peptide concentration showed no significant difference between any of the treated groups and the placebo group. C-peptide declined linearly in all groups. Conclusions: The insulin B (9–23) APL (Ala16,19) (NBI-6024) failed to show benefit in any of three doses tested in a large doseranging study. • Comment: Antigen-specific therapy is thought to be a highly desirable strategy to

interrupt the immune processes that result in T1D. Such therapies are generally quite safe, are specific for T1D, and are not expected to alter generalised immune responses. The insulin B (9-23) APL (Ala16,19) (NBI-6024) was shown to alter the course of diabetes in the NOD mouse and prevented activation of both murine and human T-lymphocytes in the laboratory. Preliminary studies demonstrated that there were no safety issues. Thus, the current dose-ranging study was awaited with considerable enthusiasm. The study was well designed and carefully conducted. Unfortunately, the APL had no impact on b-cell function. A critical question is whether an adequate dose was given. It is impossible to measure blood levels of the APL or a marker that would indicate that a given dose was altering some biological response. This is a vexing question that has hampered other studies with antigen-specific interventions. Extrapolation of effective doses from mice to human beings is always a game of roulette. It is unlikely that this particular APL will be further pursued. That is unfortunate.

Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy T. Orban,1 K. Farkas,1 H. Jalahej,1 J. Kis,1,2 A. Treszl,1,3 B. Falk,4 H. Reijonen,4 J. Wolfsdorf,5 A. Ricker,1 J. B. Matthews,6 N. Tchao,6 P. Sayre,6 P. Bianchine7 1 Joslin Diabetes Center, Boston, MA, USA, 2 Polyclinic of the Hospitaller Brothers, Budapest, Hungary, 3Zentrum fu¨r Experimentelle Medizin Institut fu¨r Medizinische Biometrie und Epidemiologie, Hamburg, Germany, 4 Benaroya Research Institute at Virginia Mason, Seattle, WA, USA, 5Children’s Hospital Boston, MA, USA, 6Immune Tolerance Network, University of California, San Francisco, CA, USA, and 7National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA J Autoimmun 2010; 34: 408–15 Background: Insulin B-chain contains the insulin B (9–23) peptide, which is a major epitope recognised by the immune system and thought to be a diabetes-specific antigen. The insulin B-chain fragment is metabolically inactive. Incomplete Freund’s adjuvant (IFA) has been used in a number of vaccines as a delivery system that promotes regulatory immune responses. The current report describes a pilot study testing insulin B-chain administered with IFA in T1D. Methods: The study randomised 12 subjects (six to 2 mg insulin B-chain in IFA, six

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to placebo, IFA alone), ages 18–35, with recent-onset T1D. Subjects received a single intramuscular injection of test substance, and were followed for 2 years. Outcome measures were b-cell function – as measured by C-peptide – and insulin-specific humoral and T-lymphocyte responses. Results: There was no statistical difference in b-cell function, measured every 6 months, between arms. All patients in the experimental group who received insulin B-chain, but none who received placebo, developed robust insulin-specific humoral and T-lymphocyte responses, including insulin B-chain-specific CD4+ T-lymphocytes that were cloned and showed characteristics of regulatory T-lymphocytes. Conclusions: Insulin B-chain, given together with IFA, may beneficially impact immune response in T1D. • Comment: This is another test of an antigen-specific therapy in T1D. It was only a very small pilot study involving 12 subjects, six who received a single injection of insulin B-chain in IFA, and six who received IFA alone. Although claimed to be safe, it is impossible to assess safety in such a small study. Also impossible to assess in a small study is b-cell function, which here was carefully measured with meal tolerance tests. Although there was no statistical difference between groups, the C-peptide levels were persistently higher in the placebo group. Had the results been reversed, it would not be surprising for the authors to claim a beneficial ‘trend’. This illustrates the difficulty in interpretation of small pilot studies. Intriguingly, the cloned T-lymphocytes from the experimental group had characteristics of regulatory T-lymphocytes. But, what if there was also activation of effector T-lymphocytes that was not demonstrated. Could that have resulted in a subtle greater loss of b-cell function? Despite these questions, the results are sufficiently provocative to support further studies with insulin B-chain. Questions that can be raised, however, are whether 2 mg is the right dose and whether a single intramuscular vaccination is the right number of vaccinations. Only full-scale dose-ranging studies can answer these questions. These preliminary data suggest that such studies are warranted.

No effect of the 1a,25dihydroxyvitamin D3 on b-cell residual function and insulin requirement in adults with new-onset type 1 diabetes M. Walter,1 T. Kaupper,1 K. Adler,1 J. Foersch,1 E. Bonifacio,2 A. G. Ziegler1 1 Diabetes Research Institute, Forschergruppe Diabetes e.V., Munich, Germany, and 2 Deutsche Forschungsgemeinschaft Center for Regenerative Therapies, Dresden, Germany Diabetes Care 2010; 33: 1443–8 Background: Mechanistic studies show that 1a,25-dihydroxyvitamin D3 [1,25(OH)2D3] modulates dendritic cell maturation in vitro and in vivo and facilitates a shift from a Th1 to a Th2 immune response. Studies in the NOD mouse show that 1,25(OH)2D3 reduces the incidence of insulitis and diabetes. Thus, the current study was conducted to determine whether 1,25(OH)2D3 is safe and improves bcell function in patients with recent-onset T1D. Methods: Two studies were conducted – a safety study in 25 subjects, all treated with 1,25(OH)2D3 and followed for 18 months, and an efficacy study in which 40 subjects, ages 18–39, with recent-onset T1D, were randomised either to 1,25(OH)2D3 (n = 22) or to placebo (n = 18). The primary endpoint was b-cell function – as measured by C-peptide – at 18 months. Careful safety assessments were performed. Results: There was a similar decline in bcell function in both groups – 1,25(OH)2D3 and placebo. In addition, A1c and insulin dosage were similar in both groups. The treatment was safe. Conclusion: 1,25(OH)2D3 was shown to be safe, but did not have a beneficial effect in adults with recent-onset T1D.

Maternal intake of vitamin D during pregnancy and risk of advanced b-cell autoimmunity and type 1 diabetes in offspring L. Marjama¨ki,1 S. Niinisto¨,2,3 M. G. Kenward,4 L. Uusitalo,1,2 U. Uusitalo,2 M. L. Ovaskainen,2 C. Kronberg-Kippila¨,2 O. Simell,5 R. Veijola,6 J. Ilonen,7,8 M. Knip,9,10 S. M. Virtanen1,2,9,11 1 Tampere School of Public Health, University of Tampere, Tampere, Finland, 2Department of Lifestyle and Inclusion, National Institute for Health and Welfare, Helsinki, Finland, 3Department of Public Health, University of Helsinki, Helsinki, Finland, 4Department of Epidemiology and Population Health,

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Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, UK, 5 Department of Pediatrics, University of Turku, Turku, Finland, 6Department of Pediatrics, University of Oulu, Oulu, Finland, 7 Immunogenetics Laboratory, University of Turku, Turku, Finland, 8Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland, 9Department of Pediatrics, Tampere University Hospital, Tampere, Finland, 10Hospital for Children and Adolescents and Folkha¨lsan Research Center, University of Helsinki, Helsinki, Finland, and 11 Research Unit, Tampere University Hospital, Tampere, Finland Diabetologia 2010; 53: 1599–607 Background: Maternal intake of vitamin D from food or use of vitamin-D-containing supplements during pregnancy was weakly associated with decreased risk of early b-cell autoimmunity in two cohort studies and with clinical T1D in one case–control study. Methods: Mothers of 3723 infants born between 1997 and 2002 completed a 181-item food frequency questionnaire, including questions on dietary supplements. Offspring were observed at 3–12 month intervals for appearance of T1D-associated autoantibodies and for the development of T1D. Results: Maternal mean daily intake of vitamin D was 5.1 lg from food and 1.3 lg from supplements. Maternal intake of vitamin D, either from food or from supplements, was not associated with the risk of b-cell autoimmunity or with the risk of T1D in offspring. Conclusions: Maternal intake of vitamin D did not appear to influence the T1D process in offspring. • Comment: For some time, the potential role of vitamin D as a preventative intervention for T1D has been raised. There are clearly effects of vitamin D in vitro and some beneficial effects in animal models, particularly in vitamin-D-deficient animals. In human beings, cohort studies and meta-analyses of studies done in infants have suggested potential benefit. Thus, the use of vitamin D remains an attractive hypothesis for prevention of T1D, the best case being for its use in infants. In the two studies described above, there was no support for this hypothesis. The intervention study with 1,25(OH)2D3 was conducted in adults after the development of T1D. Although a small study, it failed to show a beneficial effect. Intervention with vitamin D at that stage might not be expected to have beneficial effects. The Finnish study evaluated maternal intake of vitamin D and whether it correlated with b-cell autoimmunity or with the risk of T1D in offspring. There

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are two important points to note, however. First, this was not an intervention study, which might better have permitted assessment of the impact of vitamin D. Second, although the food questionnaire has been validated, it is difficult to assess how well it reflected vitamin D intake, and whether the range of vitamin D intake was sufficient to allow assessment of its impact.

Regeneration of insulin production by autologous bone marrow blood autotransplantation in patients with type 1 diabetes E. Esmatjes,1,6,7 X. Montan˜a,2 M. I. Real,2 J. Blanco,1 I. Conget,1,6,7 R. Casamitjana,3,6,7 M. Rovira,4,6 R. Gomis,1,6,7 P. Marin5,6 1 Diabetes Unit, Hospital Clinic Universitari, Barcelona, Spain, 2Interventional Angioradiology Unit, Hospital Clinic Universitari, Barcelona, Spain, 3Biochemistry and Molecular Genetics Department, Hospital Clinic Universitari, Barcelona, Spain, 4Bone Marrow Transplant Unit, Hospital Clinic Universitari, Barcelona, Spain, 5Hemotherapy Unit, Hospital Clinic Universitari, Barcelona, Spain, 6Institut d’Investigacions Biome`diques August Pii Sunyer (IDIBAPS), Barcelona, Spain, and 7CIBER de Diabetes y Enfermedades Metabo´licas Asociadas (CIBERdem), Barcelona, Spain Diabetologia 2010; 53: 786–9 Background: Some experimental reports suggest that the bone marrow harbours cells capable of differentiation into b-cells, or as a facilitator of b-cell regeneration, or as an immune modulator, and thus use of bone marrow cells has been proposed as treatment for T1D. Methods: A pilot study was conducted in three subjects with established T1D and absent b-cell function. Autologous bone marrow was harvested and subsequently injected via selective arteriography as an intrapancreatic infusion. Results: Data were available for two of the three subjects. There was no evidence of b-cell function during 6 months of follow-up. Conclusions: Intrapancreatic autologous bone marrow infusion had no impact in two subjects with long-standing T1D.

Autologous umbilical cord blood transfusion in very young children with type 1 diabetes M. J. Haller,1 C. H. Wasserfall,2 K. M. McGrail,2 M. Cintron,1 T. M. Brusko,3 J. R. Wingard,4 S. S. Kelly,5 J. J. Shuster,6 M. A. Atkinson,2 D. A. Schatz1 1 Department of Pediatrics, University of Florida, Gainesville, FL, USA, 2Department of Pathology, University of Florida, Gainesville, FL, USA, 3Diabetes Center, University of California at San Francisco, San Francisco, CA, USA, 4Department of Medicine, University of Florida, Gainesville, FL, USA, 5Department of Pediatrics, University of Texas, Houston, TX, USA, and 6Department of Epidemiology and Health Policy Research and the General Clinical Research Center, University of Florida, Gainesville, FL, USA Diabetes Care 2009; 32: 2041–6 Background: Umbilical cord blood contains a population of immature unprimed functional regulatory T-lymphocytes. These cells could, in theory, limit inflammatory cytokine responses and anergize effector T-lymphocytes, which are thought to mediate cellular autoimmune processes. Methods: Children aged > 1 year who developed T1D and had banked umbilical cord blood at an approved centre were recruited into this study. Fifteen subjects enrolled in an open-label phase 1 study using autologous umbilical cord blood infusion. They were followed for 1 year. Results: There was no evidence at 1 year of maintenance of preservation of b-cell function – as measured by C-peptide – while insulin doses increased over time. No changes were observed in autoantibody titres, regulatory Tlymphocyte numbers, or other immune parameters. There were no significant adverse events. Conclusions: Autologous umbilical cord blood infusion was safe, but had no beneficial effect in children with T1D. • Comment: Many investigators believe that cellular therapies for T1D hold substantial promise. A study from Brazil (1) discussed in last year’s Yearbook evaluated the effects of non-myeloablative autologous haematopoietic stem cell transplantation (AHSCT) in recentonset T1D. In that study, 20 of 23 subjects became insulin free, some for protracted periods of time. Although many have attributed the results to the infused cells, it is not possible to distinguish whether the putative effects of AHSCT were due to immune reconstitution or otherwise altering the immune-mediated b-cell destruction that eventuates in T1D, to regeneration of b-cells,

or more probably to the effects of the profound immunosuppression given at the outset with AHSCT serving to rescue the patient from death from destruction of their immune system. Thus, in human beings there is no clear evidence yet of beneficial effects of any cellular treatment per se in T1D (other than pancreatic or islet transplantation). The two studies described above also failed to show beneficial effects. These negative outcomes, however, should not be cited as a reason to halt research of cellular therapies. In animal models and laboratory experiments, there is clearly much promise for cellular based therapies. Eventually, success will be achieved.

Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group J. B. Matthews,1 T. P. Staeva,2 P. L. Bernstein,1 M. Peakman,4,5 M. von Herrath,3 and ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group 1 Immune Tolerance Network, San Francisco, CA, USA, 2Juvenile Diabetes Research Foundation International, New York, NY, USA, 3La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA, 4Department of Immunology, King’s College London, UK, and 5NIHR Biomedical Research Center at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK Clin Exp Immunol 2010; 160: 176–84 • Comment: This paper describes the results of a workshop conducted by the Immune Tolerance Network (ITN) and the Juvenile Diabetes Research Foundation (JDRF) to review strategies for developing combination therapies for T1D. The advantages of a combination strategy include the ability to minimise toxicities and realise synergies to enhance and prolong efficacy. The paper notes that a clear framework must be developed that specifies the type and quality of preclinical data, including which animal models are acceptable, as well as toxicology and pharmacodynamic data expectations that will be required for a combination to meet acceptable safety standards to justify human trials. It points out that there is a major need for surrogate end-points based upon beneficial immunological responses that manifest soon after treatment, which would facilitate rapid assessment and prioritisation of any

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individual T1D therapeutic and would be particularly important for selection of potential combinations. The paper notes that biomarkers could speed clinical assessments by providing surrogate end-points, permit stratification of analysis of trial data, and facilitate personalised medicine by informing treatment decisions. The authors gave priority rankings of combination immune-based therapies for T1D, favouring approved agents, favouring combination of immune modulators with antigen-specific therapies, and limiting initial proposals to two agents in combination. The paper is cognizant of regulatory hurdles and the need for negotiations with commercial sponsors. It is a solid paper worth reading by anyone conducting investigations in the field.

MECHANISMS, MARKERS, TRIGGERS, PATHOLOGY The second group of papers includes reports of studies in human T1D that focus on mechanisms, markers, triggers and pathology.

Progression to diabetes in relatives of type 1 diabetic patients: mechanisms and mode of onset E. Ferrannini,1 A. Mari,2 V. Nofrate,2 J. M. Sosenko,3 J. S. Skyler,3 DPT-1 Study Group 1 Department of Medicine, University of Pisa School of Medicine, Pisa, Italy, 2C.N.R. Institute of Biomedical Engineering, Padua, Italy, and 3Division of Endocrinology, University of Miami, Miami, FL, USA Diabetes 2010; 59: 679–85 Background: The Diabetes Prevention Trial – Type 1 (DPT-1) studied relatives of T1D patients at enhanced risk of developing T1D. This study explored the mode of onset of hyperglycaemia and how insulin sensitivity and b-cell function contribute to the progression of the disease. Methods: The study analysed results from 328 non-diabetic relatives from the control arms of the DPT-1 studies. Subjects had sequential oral glucose tolerance tests performed at baseline, every 6 months, and an average of 2.7 years later, when 115 subjects became diabetic. b-cell glucose sensitivity (slope of the insulin secretion ⁄ plasma glucose dose–response function) and insulin sensitivity were obtained by mathematical modelling of the oral glucose tolerance test glucose ⁄ Cpeptide responses.

Results: Progressors to T1D and non-progressors had similar baseline insulin sensitivity, fasting insulin secretion and total postglucose insulin output. In contrast, b-cell glucose sensitivity was impaired at baseline and predicted development of diabetes. Moreover, glucose sensitivity began to decline significantly before any changes in plasma glucose, while insulin secretion and insulin sensitivity remained stable. Conclusions: A defect in b-cell glucose sensitivity is detectable in at-risk subjects years before diagnosis, and anticipates plasma glucose increments. ��� Comment: The failure of the b-cell to adequately respond to glucose – b-cell ‘blindness’ to glucose – is a characteristic pathophysiological abnormality in both T1D and type 2 diabetes. It results in a lack of adequate early insulin secretory response that eventuates in significant postprandial hyperglycaemia. Here it is demonstrated that this defect is present very early in the disease process, before other metabolic abnormalities. Teleologically, it may be a way the injured b-cell manifests itself. Presumably, in T1D, the b-cell has been injured via immunological attack. Indeed, if humoral anti-islet antibodies are a marker of the immune attack, all of the subjects included in DPT-1 already had that under way, as an entry criterion was presence of antibodies. It would be interesting to do similar modelling in studies involving genetically high risk individuals who do not yet have anti-islet antibodies, as it is possible that a defect in b-cell glucose sensitivity is genetically determined and may indicate that a particular subject is more vulnerable to immune-mediated damage.

Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial – Type 1 T. Orban,1 J. M. Sosenko,2 D. Cuthbertson,3 J. P. Krischer,4 J. S. Skyler,2 R. Jackson,1 L. Yu,5 J. P. Palmer,6 D. Schatz,7 G. Eisenbarth,5 Diabetes Prevention Trial – Type 1 Study Group 1 Joslin Diabetes Center, Boston, MA, USA, 2 Division of Endocrinology, University of Miami, Miami, FL, USA, 3Pediatrics Epidemiology Center, University of South Florida, Tampa, FL, USA, 4Division of Informatics and Biostatistics, University of South Florida, Tampa, FL, USA, 5Barbara Davis Center for Childhood Diabetes, Denver, CO, USA,

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Division of Endocrinology ⁄ Metabolism, University of Washington, Seattle, WA, USA, and 7Division of Endocrinology, University of Florida, Gainesville, FL, USA Diabetes Care 2009; 32: 2269–74 Background: In another report from the DPT-1 studies, the prediction of T1D by specific types of pancreatic islet autoantibodies, either alone or in combination, was explored. Methods: The study included two cohorts from DPT-1, both derived from initial screening for islet cell autoantibodies (ICAs). Also measured were antibodies to GAD65, ICA512 and insulin. Participants were followed for the occurrence of T1D. One cohort, called ‘Trials’, included 528 DPT-1 participants (83.3% ICA+) who were randomised in the DPT-1 studies. The other cohort, called ‘Questionnaire’, included 28,507 individuals (2.4% ICA+) who did not enter the DPT-1 trials but responded to questionnaires as to T1D status. Results: In both cohorts autoantibody number was highly predictive of T1D. In the Questionnaire cohort, as single autoantibodies, ICA (3.9%), GAD65 (4.4%) and ICA512 (4.6%) were similarly predictive of T1D, whereas no subjects with only insulin autoantibodies developed T1D. Conclusions: The number of autoantibodies is predictive of T1D. However, there are differences in prediction based on antibody type and titre. • Comment: The finding that autoantibody number predicts T1D is consistent with other studies. However, this represents the largest prospective study of relatives yet to be reported. It confirms that an individual with only a single antibody being positive is far less likely to develop T1D than those with two or more antibodies. It also finds that the particular type and titre of an autoantibody can influence prediction. Over the years, our tools for prediction of T1D have continued to improve. This has been demonstrated in the DPT-1 studies, in the ENDIT (European Nicotinamide Diabetes Intervention Trial) study and many others. Yet, the focus of many studies has been on relatives of individuals with T1D. It is probably time to advance screening and prediction efforts more widely into the general population. This might best be accomplished with screening at birth for high risk HLA genotypes, as has been done in studies such as DIPP (Diabetes Prediction and Prevention), DAISY (Diabetes Autoimmunity Study in the Young) and TEDDY (The Environmental Determinants of Diabetes in the Young).

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Preservation of b-cell function in autoantibody-positive youth with diabetes C. J. Greenbaum,1 A. M. Anderson,2 L. M. Dolan,3 E. J. Mayer-Davis,4 D. Dabelea,5 G. Imperatore,6 S. Marcovina,7 C. Pihoker,8 SEARCH Study Group 1 Diabetes Research Program, Benaroya Research Institute, Seattle, WA, USA, 2Wake Forest University School of Medicine, WinstonSalem, NC, USA, 3Cincinnati Children’s Hospital and Medical Center, Cincinnati, OH, USA, 4 Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, and the Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC, USA, 5Department of Epidemiology, Colorado School of Public Health, University of Colorado, Denver, CO, USA, 6Division of Diabetes Translation, National Center for Chronic Disease Prevention and the Health Promotion Centers for Disease Control and Prevention, Atlanta, GA, USA, 7Department of Medicine, University of Washington, Seattle, WA, USA, and 8Department of Pediatrics, University of Washington, Seattle, WA, USA Diabetes Care 2009; 32: 1839–44 Background: SEARCH is a populationbased study conducted at six centres in the USA, including existing (prevalent) and newly diagnosed (incident) cases of diabetes in youth. This report describes the extent of bcell function in youth with diabetes who have GAD65 and ⁄ or IA2 autoantibodies. Methods: Fasting C-peptide levels were obtained from 2789 GAD65 and ⁄ or IA2 autoantibody-positive youth aged 1–23 years. Preserved b-cell function was defined on the basis of cut points derived from the Diabetes Control and Complications Trial (DCCT) (fasting C-peptide ‡ 0.23 ng ⁄ ml) and from the adolescent population of the National Health and Nutrition Examination Survey (NHANES) 5th percentile for fasting C-peptide (‡ 1.0 ng ⁄ ml). The clinical characteristics between those with and without preserved bcell function were compared. Results: Within the first year of diagnosis, 82.9% of youth had a fasting C-peptide ‡ 0.23 ng ⁄ ml and 31.2% had values ‡ 1.0 ng ⁄ ml. Among those with 5 or more years of diabetes, 10.7% had preserved b-cell function based on the DCCT cutoff and 1.0% were above the NHANES 5th percentile. Conclusions: Early on, the vast majority of antibody-positive youth with diabetes have significant residual b-cell function, but by 5 years of diabetes, only 10% do.

• Comment: The SEARCH study data, as well as the control groups in the intervention studies discussed earlier, clearly demonstrate that b-cell function is not rapidly lost after diagnosis of diabetes, but rather that over 80% of youth have significant residual b-cell function within the first year of diagnosis, and 10% continue to have significant residual b-cell function after 5 years. This may have important implications as successful intervention strategies evolve, as those with significant residual b-cell function may potentially benefit from intervention, which in most trials is currently being studied only in recent-onset T1D.

Breastfeeding patterns of mothers with type 1 diabetes: results from an infant feeding trial S. Sorkio,1 D. Cuthbertson,2 S. Ba¨rlund,1 A. Reunanen,3 A. M. Nucci,4 C. L. Berseth,5 K. Koski,6 A. Ormisson,7 E. Savilahti,8 U. Uusitalo,2 J. Ludvigsson,9 D. J. Becker,10 J Dupre´,11 J. P. Krischer,2 M. Knip,8,12,13 H. K. Akerblom,6 S. M. Virtanen,1,14,15 TRIGR Study Group 1 Nutrition Unit, National Institute for Health and Welfare, Helsinki, Finland, 2 Pediatrics Epidemiology Center, University of South Florida, Tampa, FL, USA, 3National Institute for Health and Welfare, Helsinki, Finland, 4Division of Nutrition, School of Health Professions, College of Health and Human Sciences, Georgia State University, Atlanta, GA, USA, 5Bristol-Myers Squibb, Evansville, IN, USA, 6Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland, 7Department of Paediatrics, University of Tartu, Tartu, Estonia, 8Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland, 9 Division of Pediatrics, Department of Health and Environment, Faculty of Health Sciences, University of Linko¨ping, Linko¨ping, Sweden, 10Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA, 11 Robarts Research Institute, London, ON, Canada, 12Folkhlsan Research Center, University of Helsinki, Helsinki, Finland, 13 Department of Pediatrics, Tampere University Hospital, Tampere, Finland, 14Tampere School of Public Health, University of Tampere, Tampere, Finland, and 15Research Unit, Tampere University Hospital, Tampere, Finland Diabetes Metab Res Rev 2010; 26: 206–11 Background: It had previously been reported that mothers with T1D are less

likely to breastfeed their children or breastfeed for a shorter period of time than nondiabetic mothers. The aim of this study was to prospectively examine the breastfeeding patterns among mothers with and without T1D. Methods: Families from an infant feeding study (TRIGR) included 2160 babies; 1096 were born to women with T1D and 1064 to unaffected women. Information on infant feeding was acquired by frequent prospective dietary interviews. Results: Most (> 90%) of the infants were initially breastfed, regardless of the mother’s T1D status. However, breastfeeding rates declined more steeply among mothers with T1D than without T1D, being 50% and 72% at 6 months, respectively. After adjusting for age, educational status, timing of delivery and caesarean section rate, all factors associated with the termination of breastfeeding, there was no difference in the duration of breastfeeding among mothers with and without T1D. Conclusions: Maternal diabetes status was not itself associated with shorter breastfeeding. Shorter duration of breastfeeding in mothers with T1D could be explained by their more frequent caesarean sections, earlier delivery and lower age and education. • Comment: Although mothers with T1D breastfed for a shorter duration, this did not seem to be related to T1D itself, but rather to other confounding factors, i.e. differences in the mode of delivery, length of gestation, parental age and education. Breastfeeding has substantial health advantages and thus is desirable for all infants, and should be encouraged. It also may impact the frequency of development of T1D. Yet, the TRIGR study (2), from which this study is derived, is evaluating the content of infant formula – cow’s milk based versus casein hydrolysate – in order to ascertain whether early introduction of cow’s milk may serve as an environmental trigger for T1D. It will be several years before the results of this important study become available. In the meantime, breastfeeding defers the introduction of any formula, and prolonged breastfeeding may be beneficial in terms of forestalling T1D. It would be unfortunate if the presence of maternal T1D directly led to shorter duration of breastfeeding. This study also highlights a separate issue. Namely, one has to wonder whether greater efforts should be made to have women with T1D progress to spontaneous labour and vaginal delivery in contrast to the not uncommon practice of early delivery by caesarean section.

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Prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes S. J. Richardson,1 A. Willcox,1 A. J. Bone,2 A. K. Foulis,3 N. G. Morgan1 1 Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Plymouth, UK, 2School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK, and 3Department of Pathology, Royal Infirmary, Glasgow, UK Diabetologia 2009; 52: 1143–51 Background: Much evidence suggests that enterovirus infection may be an important environmental trigger of T1D. This study examined pancreatic islets in autopsy specimens for evidence of enteroviral infection. Methods: Pancreatic autopsy specimens were examined, including 72 from recentonset T1D (mean age 12.65 ± 1.1 years, range 1–42 years, and a mean time since diagnosis of 8.2 ± 4.1 months, range 0–6 years). A large number of control specimens were examined, including 25 pancreases from adult patients with type 2 diabetes. Serial sections were stained for insulin, glucagon, enteroviral capsid protein vp1, protein kinase R (PKR) (which is unregulated in islets with enterovirus infection), MHC class 1 and CD45. Double immunofluorescence staining was performed. Islets were classified as insulincontaining islets (ICIs), presumably residual b-cells, or insulin-deficient islets (IDIs). (In the T1D pancreases, 60% of islets are IDIs.) Results: The majority (44 of 72, 61%) of recent-onset T1D cases were positive for enteroviral vp1 antigen. Enteroviral capsid protein vp1 immunostaining was restricted to ICIs, and double immunofluorescence demonstrated that this is restricted to b-cells. Other markers of infection (PKR, MHC-1) were also present. Enteroviral capsid protein vp1 was detected in a few cells in the pancreases of three of 39 (7.7%) non-diabetic paediatric cases. A total of 40% of type 2 diabetic pancreases also stained for enteroviral capsid protein vp1. Conclusions: Enterovirus staining is common in pancreases from recent-onset T1D. Interestingly, it is also seen in some pancreases from individuals with type 2 diabetes. • Comment: These findings provide further support for a potential role of enterovirus infection as an environmental factor leading to T1D. There is a growing body of evidence supporting this concept, which is being studied in detail by the TEDDY Study Group (3). Identification of environmental factors that

are important in the aetiology or pathogenesis of T1D may facilitate the development of intervention strategies to reduce or eliminate the impact of such factors, and thus may be important in the eventual prevention of T1D.

Recurrence of type 1 diabetes after simultaneous pancreas– kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells F. Vendrame,1 A. Pileggi,1,2 E. Laughlin,3 G. Allende,1 A. Martin-Pagola,1 R. D. Molano,1 S. Diamantopoulos,1 N. Standifer,3,4 K. Geubtner,3 B. A. Falk,3 H. Ichii,1,2 H. Takahashi,2 I. Snowhite,1 Z. Chen,5 A. Mendez,1,6 L. Chen,2 J. Sageshima,2 P. Ruiz,2 G. Ciancio,2 C. Ricordi,1,2,5,6 H. Reijonen,3 G. T. Nepom,3 G. W. Burke,1,2 A. Pugliese1,5,6 1 Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA, 2Department of Surgery, Division of Transplantation, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA, 3Benaroya Research Institute, Seattle, WA, USA, 4Clinical Immunology, Amgen Inc., Seattle, WA, USA, 5Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA, 6Department of Medicine, Division of Endocrinology and Metabolism, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA Diabetes 2010; 59: 947–57 Background: Recurrent autoimmunity was first described in pancreas transplants from identical twin donors, who did not need immunosuppression to prevent graft rejection. The current study explores the nature of recurrent diabetes in pancreas–kidney transplant recipients who were receiving immunosuppression therapy. Methods: In three patients with recurrent diabetes after pancreas–kidney transplantation, there was serial monitoring of antibodies and autoreactive T-lymphocytes, as well as pancreas biopsy. Results: Pancreas transplant biopsies were taken after hyperglycaemia recurrence and revealed b-cell loss and insulitis, and no evidence of graft rejection. From the time of biopsy and on further follow-up, both antibodies and autoreactive T-cells were repeatedly demonstrated. Immune monitoring

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during immunosuppressive therapy showed that autoimmunity was not resolved by the agents used. Conclusions: Recurrent autoimmunity may be responsible for hyperglycaemia recurrence in pancreatic transplant recipients, despite immunosuppressive therapy. • Comment: Loss of function after time is a common feature in recipients of pancreas or islet transplants. There are many possible reasons for this, one of which is the recurrence of autoimmunity. Yet, it might be expected that the immunosuppressive agents used to prevent allograft rejection would also prevent recurrent autoimmunity. In the patients described here, that is clearly not the case, as there was no evidence of rejection either in the pancreas biopsy or in the function of the transplanted kidney. Yet, biopsies revealed bcell loss and insulitis, and both autoantibodies and autoreactive T-lymphocytes were demonstrable. This causes one to conclude that the mechanisms responsible for allograft rejection and for autoimmunity are different, and may require different forms of immune intervention to control each. This has profound importance in transplantation of these organs, particularly because simultaneous pancreas and kidney transplantation is the procedure of choice for treatment of end stage renal disease in individuals with T1D. It also offers important insights into evolving appropriate immune modulation strategies to interrupt the T1D disease process, either for prevention or to sustain b-cell function in recent-onset T1D.

Dimorphic histopathology of long-standing childhood-onset diabetes R. Gianani,1 M. Campbell-Thompson,2 S. A. Sarkar,1 C. Wasserfall,2 A. Pugliese,3 J. M. Solis,1 S. C. Kent,4 B. J. Hering,5 E. West,1 A. Steck,1 S. Bonner-Weir,6 M. A. Atkinson,2 K. Coppieters,7 M. von Herrath,7 G. S. Eisenbarth1 1 Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA, 2Department of Pathology, University of Florida at Gainesville, Gainesville, FL, USA, 3Diabetes Research Institute, Miami, FL, USA, 4Center for Neurologic Diseases, Brigham, and Women’s Hospital Harvard Medical School, Boston, MA, USA, 5Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, USA, 6Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA, and 7 La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA Diabetologia 2010; 53: 690–8

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Background: Analysis of C-peptide in children characterised at diabetes onset for autoantibodies shows heterogeneous preservation of insulin secretion in longstanding diabetes. This study sought to characterise pancreases of childhood-onset diabetes in order to define the pathological basis of that heterogeneity. Methods: Pancreases were evaluated from 20 cadaveric organ pancreases from individuals with childhood-onset (mean age of onset 11.2 years, range 3–18 years) long-term (mean duration 14 years, range 1–35 years) T1D. Pancreatic histology, islet autoantibodies and C-peptide of patients were analysed. Results: Most (70%) of the pancreases had only IDIs. C-peptide was not present in patients lacking histological evidence of b-cells. Of six patients with extant b-cells, these could be divided into two patterns. In pattern A, there were mostly insulin-deficient islets (IDIs) and lobular retention of areas with ‘abnormal’ b-cells; islets retaining b-cells contained survivin and enhanced HLA class 1, had low or no C-peptide, and were positive for anti-islet autoantibody at time of death. In pattern B, none had IDIs, with all islets containing normal-appearing but quantitatively reduced b-cells, without survivin or HLA class 1; they were antibody-negative with relatively high C-peptide, and lacked high risk HLA alleles. Conclusions: The data suggest that C-peptide secretion in long-standing diabetic patients can be explained by two different patterns of b-cell survival, one (pattern A) that probably reflects autoimmune type 1A diabetes, and the other possibly reflecting a different subset of T1D. • Comment: The investigators used pancreases collected by the JDRF nPOD (Network for Pancreatic Organ Donors with Diabetes) consortium to evaluate the histology of patients with long-standing childhood diabe-

tes. Although most patients had the expected lack of b-cells and lack of C-peptide, 30% showed persistent C-peptide, and these could be divided into two patterns. One pattern was consistent with classical type 1A diabetes presumably on an immune basis. The other pattern appeared to be totally different, with normal-appearing islets, relatively high C-peptide, absence of high risk HLA, and lack of antibodies at the time of death. All were said to have had the typical clinical appearance of T1D at the time of diagnosis. This suggests that we still have a lot to learn about the evolution of T1D, and that we need better tools at diagnosis to better characterise individuals. This may prove to be particularly important if we are to appropriately select patients with recent-onset T1D for newer immunological interventions, either in the context of clinical trials or for treatment when such agents are approved by regulatory agencies.

OVERALL COMMENTARY This year has been marked by a stunning number of papers relating to immune intervention of T1D. Longer term observations suggest that there may be sustained effects of a short course of anti-CD3 monoclonal antibody, which depletes T-lymphocytes and on recovery seems to favour regulatory T-lymphocytes over effector T-lymphocytes. That B-lymphocytes might be involved in T1D pathogenesis was suggested by positive results from a trial with an anti-CD20 monoclonal antibody, rituximab. There were also provocative observations from an extraordinarily tiny study with insulin B-chain given with IFA. Yet, most intervention studies were negative – mycophenolate mofetil given alone or in combination with daclizumab, low-dose diazoxide, vitamin D, an altered peptide ligand of insulin B (9–23), autologous bone marrow

blood injected into the pancreatic arterial system, and umbilical cord blood transfusion. The combination of low-dose cyclosporine and methotrexate in a very small pilot study was impossible to interpret, and is unlikely to be pursued further anyway. That negative studies continue to dominate the field, and that the positive ones still show decline in bcell function over time, has led to more calls for combination approaches. When I have advanced such prospects at meetings of paediatric diabetologists, I hear groans. Yet when I have advanced these prospects at meetings of immunologists and transplant surgeons, I hear cheers. Hopefully, preclinical studies will provide further guidance to support combination therapies, and hopefully regulatory agencies will offer a path for evaluation of these in human beings. Meanwhile, a number of interesting studies have offered further insights into the pathology and pathogenesis of T1D, the pathways by which it may unfold, and how better to quantify who is at risk of developing T1D. These studies have also suggested that T1D is not the same in everybody who appears to develop it. And, perhaps most importantly, that autoimmunity may not be able to be addressed with the same therapeutic agents that are used to prevent transplant rejection. It has been a very exciting year, indeed.

References 1 Couri CE, Oliveira MC, Stracieri AB et al. C-peptide levels and insulin independence following autologous nonmyeloablative haematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2009; 301: 1573–9. 2 TRIGR Study Group. Study design of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR). Pediatr Diabetes 2007; 8: 117–37. 3 The TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design. Pediatr Diabetes 2007; 8: 286–98.

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Advanced Technologies and Treatments for Diabetes

Exercise Exercise and diabetes H. Zisser,1,3 P. Gong,1 C. M. Kelley,1 J. S. Seidman,1 M. C. Riddell2 1

Sansum Diabetes Research Institute, Santa Barbara, CA, USA School of Kinesiology and Health Science, York University, Toronto, ON, Canada 3 University of California at Santa Barbara, Santa Barbara, CA, USA 2

Diet and exercise form the foundation of a healthy lifestyle. These are especially important for people living with diabetes mellitus, as they are the most practical non-pharmacological means by which patients may significantly improve their blood glucose levels. Exercise increases insulin sensitivity (both short and long term), lowers blood sugar levels, reduces body fat and improves cardiovascular (CV) function. Because of this, exercise offers enormous benefit to patients with diabetes. Blood glucose levels can significantly drop during and after physical activities, due to the increased utilisation of glucose as a fuel during exercise and the up-regulation of glucose transport into working muscles. Therefore, patients (especially those with type 1 diabetes) must account for the effects of exercise and adjust their medications and nutrition accordingly. Improvements in real-time continuous glucose monitoring and optimisation of basal insulin dosing may offer significant benefit to preventing hypoglycaemia in patients with type 1 diabetes who regularly exercise. Diverse exercise programmes and devices can also assist patients in monitoring their activities as well as motivating them to achieve their exercise goals. For patients with type 1 diabetes, questions such as how much, how long, how strenuous and what kind of exercise must be addressed in order for healthcare professionals to offer maximum benefit to their patients. Additionally, since patients with type 2 diabetes often have other significant co-morbidities such as obesity and CV disease, care providers must evaluate each patient’s risk factors before designing an exercise programme. Several publications in the last year have addressed these issues and may serve as a valuable resource to provide safe and effective recommendations to patients and their healthcare providers. To be included in the Exercise and Diabetes chapter for the 2010 YEARBOOK, we reviewed leading peer-reviewed manuscripts that were published in the period July 2009 to June 2010. PubMed was used in the initial screening of articles.

Plasma glucose and hypoglycaemia following exercise in people with type 1 diabetes: a comparison of three basal insulins V. Arutchelvam,1 T. Heise,2 S. Dellweg,2 B. Elbroend,3 I. Minns,3 P. D. Home1 1 School of Clinical Medical Sciences – Diabetes, Newcastle University, Newcastle upon Tyne, UK, 2Profil Institut fu¨r Stoffwechselforschung, Neuss, Germany, and 3Novo Nordisk, Crawley, UK Diabet Med 2009; 26: 1027–32

Background: Exercise changes the absorption and blood-glucose-lowering effectiveness of different types of insulin. This study aims to compare the effects of exercise on plasma glucose (PG) excursions in people with type 1 diabetes when using each of three basal insulins: insulin detemir, neutral protamine Hagedorn (NPH) insulin or insulin glargine. Methods: Fifty-one people with type 1 diabetes (age ± SD, 39 ± 10 years; 67% men) were enrolled in a multinational, open-label, randomised, three-period, crossover clinical trial sponsored by Novo Nordisk. Subjects were managed with insulin regimens during three periods: one period with mealtime insulin (aspart) plus basal insulin detemir (twice

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Correspondence to: Howard Zisser, Sansum Diabetes Research Institute, Santa Barbara, CA, USA Tel.: +1-805-682-7638 Fax: +1-805-682-3332 Email: hzisser@sansum.org Disclosures: No conflicts of interest. Endorsed by the International Conference on ATTD organized by Kenes International.

daily), one period with aspart and NPH (twice daily), and the other period with glargine (once daily). Before the start of exercise programmes, insulin doses were optimised over 4 weeks. In each treatment arm, subjects were exercised for 30 min, 5 hours after the last mealtime and basal insulin injection. Results: At initiation of exercise, PG was numerically but not statistically different for each insulin, with a modestly lower level for glargine by a mean of 0.7 mmol ⁄ l. During exercise or 150 min after exercise, subjects did not show significant differences in PG excursions. During the 30 min of exercise, five subjects (11%) on detemir, six (12%) on NPH and 18 (38%) on glargine developed

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minor hypoglycaemia. From the end of exercise to 150 min, five subjects (11%) on detemir, seven (14%) on NPH and nine (19%) on glargine developed minor hypoglycaemia. In total, from start of exercise to 150 min after exercise, 10 subjects (12%) on detemir developed minor hypoglycaemia compared with 13 (27%) on NPH and 27 (57%) on glargine (p < 0.001 glargine vs. detemir and NPH). Subjects on detemir and NPH had lower maximum plasma cortisol levels than glargine. Conclusions: Insulin detemir was associated with less hypoglycaemia than insulin glargine but not NPH insulin during and after exercise in relatively well-controlled people with type 1 diabetes. • Comment: One drawback associated with taking a basal insulin is the fact that once it is delivered there is no turning it off. It will continue to deliver active insulin until it is fully metabolised. This presents a problem if one wishes to interrupt basal insulin delivery in the event of planned or unplanned exercise or in the event of hypoglycaemia. If one were using a pump to deliver the insulin, one would be able to reduce or suspend insulin delivery as needed. Under the conditions of this study (i.e. exercising 5 h post insulin injection for 30 min), it would appear that detemir offers more protection against hypoglycaemia than NPH or glargine insulin in multiple daily injection patients and this may be an important distinction for those considering the choice of basal insulin for active individuals. Variability of insulin absorption and timing of insulin injection relative to when the exercise occurred probably had significant effects on PG concentrations following exercise in these subjects, however. In addition, the manufacturer of insulin detemir, Novo Nordisk, supported this study; two of the authors are also employees of Novo Nordisk. This may be a source of potential bias in generating the conclusion that detemir is associated with less hypoglycaemia provoked by exercise in people with type 1 diabetes.

The ageing athlete: screening prior to vigorous exertion in asymptomatic adults without known cardiovascular disease J. Freeman, V. Froelicher, E. Ashley Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA Br J Sports Med 2009; 43: 696–701 Background: This paper reviews the current literature on screening for CV conditions

in order to determine the best form of screening for asymptomatic adults without known CV disease prior to the initiation of a vigorous exercise programme. Methods: The study offers a review of various screening studies, including ECG sensitivity testing, ECG screenings in subpopulations (men over 45, women over 55, asymptomatic adults with CV risk factors, asymptomatic adults with diabetes) and the cost effectiveness of various forms of pre-exercise screening tests. Results: Studies have shown that there are benefits of ECG as a screening method in various subpopulations. Exercise ECG testing is currently considered the best available method for screening asymptomatic adults, despite the fact that there have been no studies that demonstrate a significant impact of exercise ECG on morbidity and mortality of completely asymptomatic patients. Conclusions: Given its test characteristics, widespread availability and cost, and due to an otherwise lack of conclusive evidence on the subject, the authors recommend exercise ECG screening before beginning a vigorous exercise programme for asymptomatic men with diabetes and asymptomatic men over age 45 with two or more CV risk factors. Consideration should also be given to screening asymptomatic middle aged and elderly patients with fewer than two risk factors and asymptomatic patients younger than 45 with strong risk factor exposure. • Comments: Although diabetes is not the focus of this study, it is nevertheless a relevant paper given the higher risk of CV complications in people with diabetes relative to the general population. Understanding which form of CV screening is most effective and most cost effective will have an important effect on people with diabetes and could help them to avoid and prevent the serious CV complications that can often arise. Although a number of professional organisations including the American College of Sports Medicine and the American Diabetes Association recommend exercise stress tests with ECG prior to the onset of any new exercise regimen in older individuals with diabetes, clear evidence for these recommendations is rather scarce. This paper helps make the case that these recommendations are indeed reasonable, although one would hope that delays in screening would not be a major barrier to getting patients with diabetes more physically active.

Continuous, non-invasive measurement of the haemodynamic response to submaximal exercise in patients with diabetes mellitus: evidence of impaired cardiac reserve and peripheral vascular response D. Joshi,1 A. Shiwalkar,1 M. R. Cross,2 S. K. Sharma,3 A. Vachhani,1 C. Dutt1 1 Torrent Research Centre, Village Bhat, Gandhinagar, Gujarat, India, 2Veeda Clinical Research, Old Convent of Notre Dame, Derriford, Plymouth, UK, and 3Veeda Clinical Research, Ambawadi Ahmedabad, Gujarat, India Heart 2010; 96: 36–41 Background: Impaired supply of oxygen and nutrients, resulting from limitations in cardiac function and microvascular dysfunction, to exercising muscles is thought to account for reduced exercise capacity in patients with diabetes. The authors studied the changes in cardiac function and microvascular utilisation during exercise in individuals with type 2 diabetes compared with age-matched controls during exercise and recovery. Methods: This study consisted of 101 subjects divided into three age-matched groups: HbA1c < 8 (n = 31), HbA1c ‡ 8 (n = 38) and control subjects without type 2 diabetes (n = 32). Subjects were continuously monitored while they exercised on a bicycle ergometer at a constant output of 50 W for 10 min, followed by recovery. Cardiac function was measured by impedance cardiography, microvascular flow by laser Doppler shift and haemoglobin oxygen saturation by white light spectroscopy. Results: Cardiac reserve, as measured by capacity to maximally increase cardiac output during exercise, was significantly less in diabetic patients than the control group (p < 0.001). Maximal rise in stroke volume, the key parameter limiting elevation of cardiac output, was significantly reduced in patients with diabetes, more so in the group with HbA1c ‡ 8 (p > 0.002). Cardiac output during recovery, while greater than resting baseline in all groups, was also lower in the patients with diabetes and significantly lower when comparing the higher A1c group with normal subjects (p < 0.05). Regional blood flow to exercising muscles was significantly reduced in the group with HbA1c ‡ 8 (p < 0.05). Oxygen desaturation during exercise was greater in the patients with diabetes, and was more pronounced in the group with HbA1c ‡ 8 (p < 0.05). Oxygen debt during

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recovery was also significantly greater in both groups of patients with diabetes (p < 0.05) and regional flow during recovery was greater compared with the control group. Conclusions: Cardiac response and skeletal muscle profusion during and after submaximal exercise are reduced in patients with diabetes. Thus, patients with diabetes experience greater oxygen desaturation and oxygen debt. These changes may be responsible for reduced exercise capacity observed in patients with diabetes. • Comments: Previous studies have reported reduced exercise capacity in patients with type 2 diabetes without coronary heart disease (1) and several studies have demonstrated a correlation between left ventricular dysfunction and impaired exercise capacity in patients with type 2 diabetes (2). In this study, patients with poorer glycaemic control had more severe cardiac and peripheral dysfunction. This is consistent with previous investigations done by others in which A1c was shown to have an inverse correlation with maximum oxygen uptake (3), work capacity (4) and exercise duration (5). Patients with type 2 diabetes also had an impaired response during the recovery period, which appears to have caused accumulation of a large oxygen debt after exercise. There are numerous proposed mechanisms underlying impaired exercise response in patients with type 2 diabetes. These include both systolic and diastolic abnormalities, endothelial dysfunction, altered sympathetic activity stemming from abnormal insulin signalling and widespread CV dysfunction due to the proinflammatory and procoagulant effects of advanced glycation end-products. This confirms the fact that exercise is a very useful tool to quantify the CV limitations of patients with diabetes.

Exercise training ameliorates the effects of rosiglitazone on traditional and novel cardiovascular risk factors in patients with type 2 diabetes mellitus N. P. E. Kadoglou,1,2 F. Iliadis,3 N. Sailer,1 Z. Athanasiadou,1 I. Vitta,1 A. Kapelouzou,4 P. E. Karayannacos,4 C. D. Liapis,5 M. Alevizos,3 N. Angelopoulou,6 I. S. Vrabas2 1 First Department of Internal Medicine, ‘Hippokratio’ General Hospital of Thessaloniki, Greece, 2Department of Physical Education and Sports Science (Serres), Aristotle University of Thessaloniki, Greece, 3First Propedeutic Department of Internal Medicine, AHEPA

University Hospital of Thessaloniki, Greece, 4 Center of Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Greece, 5Department of Vascular Surgery, Medical School, University of Athens, Greece, and 6Department of Physical Education and Sports Science, Aristotle University of Thessaloniki, Greece Metabolism 2010; 59: 599–607 Background: Type 2 diabetes mellitus predisposes one to CV diseases. Recently, rosiglitazone (RSG), a member of a class of insulin-sensitizing drugs, thiazolidinediones, has been suggested to increase the risk of ischaemic heart events and CV mortality (6). The present study investigated the effects of RSG and ⁄ or exercise training on novel CV risk factors in patients with type 2 diabetes. Methods: One hundred overweight ⁄ obese individuals with type 2 diabetes, with HbA1c > 7% despite combined treatment with gliclazide and metformin, were randomised into four groups (each n = 25): (1) control group: maintenance of habitual activities; (2) RSG group: add-on RSG therapy (8 mg ⁄ day); (3) exercise group: adjunctive exercise training; and (4) RSG + exercise group: RSG therapy (8 mg ⁄ day) plus exercise training. No participant had diabetic vascular complications or was receiving lipid-lowering therapy. Anthropometric parameters, cardiorespiratory capacity, glycaemic and lipid profile, apolipoprotein (apo) A-I, apo B, interleukin (IL) 10, IL-18, insulin resistance and blood pressure were measured before and after 12 months of intervention. Results: Compared with the control group, both the RSG and exercise groups experienced significantly (p < 0.05) reduced glycaemic indexes, insulin resistance, blood pressure and IL-18. RSG and exercise groups showed significantly (p < 0.05) increased high-density lipoprotein, cardiorespiratory capacity and IL-10. Exercise-treated participants presented a notable down-regulation in the rest of the lipid parameters (total cholesterol, low-density lipoprotein, cholesterol, triglycerides, apo B) and body fat content (p < 0.05) compared with the control group. In contrast, the RSG group in comparison with the control group showed remarkably increased apo A-I levels and body mass index (p < 0.05). Furthermore, the RSG + exercise group (vs. control group) yielded prominent beneficial changes in glycaemic indexes, lipid profile, insulin resistance, blood pressure, IL-10, IL-18, apo A-I and apo B (p < 0.05). Last, but not least, exercise in the RSG + exercise group counteracted the negative effects of RSG on body weight, low-density lipoprotein and total cholesterol.

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Conclusions: RSG was best taken in combination with exercise, as they both elicited complementary benefits on body composition, glycaemic control and novel CV risk factors in type 2 diabetes mellitus patients. • Comments: RSG is reported in a recent study on elderly diabetic patients to be associated with an increased risk of such serious CV events as stroke and heart failure compared to pioglitazone, the other thiazolidinedione marketed in the USA (7). On the other hand, regular aerobic exercise is known to enhance insulin sensitivity, promote cardiorespiratory functions and reduce CV risks in patients with pre-diabetes and diabetes (8–10). The study of exercise combined with RSG in the treatment for type 2 diabetes provides a new prospective in evaluating the advantages and disadvantages of current RSG therapies. Unfortunately, probably because of the short nature of the study and the small sample size, cardiac events during the study were not reported. Importantly, however, using RSG alone was shown to increase weight gain, which could have a detrimental effect on an individual’s health and self-esteem, but exercise countered this effect in addition to raising markers associated with high-density lipoprotein (apo A-I) and decreasing those associated with low-density lipoprotein (apo B). It is interesting to note that exercise alone induced a greater decrease in total cholesterol and low-density lipoprotein than did the combined therapy of RSG and exercise.

Pedometer use among adults at high risk of type 2 diabetes, Finland, 2007–2008 E. E. Korkiakangas, M. A. Alahuhta, P. M. Husman, S. Keina¨nen-Kiukaanniemi, A. M. Taanila, J. H. Laitinen Finnish Institute of Occupational Health, Oulu, Finland Prev Chronic Dis 2010; 7: A37 Background: This study was conducted in order to qualitatively describe the experiences of persons at high risk of type 2 diabetes using pedometers to promote exercise. Methods: Seventy-four people at high risk of type 2 diabetes were selected to participate in 6 months of group counselling and pedometer use. The group sessions were used to collect data through questionnaires, theme interviews and video recordings. Data collection took place from April 2007 to April 2008. Results: Most participants agreed that pedometers were useful for observing levels of physical activity, setting personal goals and

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evaluating whether or not those goals were met. Problems associated with pedometers included equipment failure, unsuitability for exercise other than walking, and the standard goal of 10,000 steps per day, which many found to be too high. Conclusion: The pedometer can be used as a motivational tool to increase the exercise level of sedentary adults, provided that they are informed of the experiences of other regular users and that they set realistic goals for walking. • Comments: In last year’s yearbook, we highlighted a study illustrating that pedometers do not necessarily increase walking behaviour or metabolic outcomes in people with type 2 diabetes (11). In contrast, this study effectively shows the positive motivational effects that these inexpensive simple devices may have in persons at high risk for the disease. Again, pedometers are limited to just walking exercise, however, which might not be motivating enough for some people and regular counselling and goal setting are critical for effective behaviour change (see paper by Shenoy et al., below).

Effectiveness of an aerobic walking programme using heart rate monitor and pedometer on the parameters of diabetes control in Asian Indians with type 2 diabetes S. Shenoy, R. Guglani, J. S. Sandhu Department of Sports Medicine and Physiotherapy, Guru Nanak Dev University, Amritsar, India Prim Care Diabetes 2010; 4: 41–5 Background: India is often termed the ‘diabetes capital of the world’ because of the overwhelming number of people with diabetes on the subcontinent. Prevention and management of diabetes is now a high priority in this geographic region. Walking is a low impact, easy to perform, and therefore acceptable physical activity for people with type 2 diabetes. This study analyses the effects of 8 weeks of aerobic walking, using a heart rate monitor (HRM) and pedometer for monitoring exercise intensity, on glycaemic outcomes, fasting blood glucose, CV fitness and well-being in patients with type 2 diabetes. Methods: Forty adults with type 2 diabetes, not treated with insulin, were randomly divided into either an 8-week supervised walking programme using an HRM and pedometer (group A, n = 20) or the control

group (group B, n = 20). All outcomes (glycaemic and metabolic outcomes, anthropometric and body composition, CV indices and general well-being) were determined at baseline and after the 8-week training period. Results: Overall, the exercise training programme generated an improvement in group A with a significant decrease in fasting blood glucose level by 37% (p < 0.05). Body mass index decreased by 3.9% in the exercising group (A) whereas it increased by 2.2% in the control group (B). General well-being of group A improved by 28.8% (p < 0.05). All parameters associated with CV health of the exercising group (A) were also improved. Conclusions: Monitoring an exercise programme in patients with type 2 diabetes using an HRM and pedometer was effective, and decreased the HbA1c level, fasting blood glucose level and body mass index and improved general well-being. Additionally, using an HRM helped investigators to attribute all improvements to the exercise intensity used in the study. • Comment: This relatively small-scale trial shows nicely the motivational effects of tracking the intensity of physical activity in people with type 2 diabetes. The study also shows that exercise improves quality of life, since the intervention group scored far higher on their test of general well-being. However, in order to truly measure the effectiveness of using a pedometer and HRM on monitoring physical activity, a second study should be done using a control group that still exercises, but without anything to keep track of their intensity. As it is, the study shows that exercising with a pedometer and HRM is better for treating hyperglycaemia than remaining sedentary – which is a good thing.

Exercise and glucose metabolism in persons with diabetes mellitus: perspectives on the role for continuous glucose monitoring – a review article M. Riddell,1 B. A. Perkins2 1 School of Kinesiology and Health Science, Muscle Research Centre, Faculty of Health, York University, Toronto, ON, Canada, and 2 Division of Endocrinology and Metabolism, University of Toronto and University Health Network, Toronto, ON, Canada J Diabetes Sci Technol 2009; 3: 914–23

fullest potential for active patients with type 1 or type 2 diabetes mellitus. The paper explains the technical features, performance characteristics and clinical utility of current CGMs whilst also warning against limitations that may be exacerbated during physical activity. Methods: The paper is a teaching manual for CGM use as it relates to exercise. It explains the challenges involved with monitoring blood glucose during aerobic and anaerobic activity, how CGMs work, how they can help improve glucose control during and after exercise, and the technological strengths and limitations of the devices. Results: Advancements include up to the minute glycaemic information when sedentary and during moderately intense exercise, helping reduce the risk of late-onset post exercise hypoglycaemia. ‘Alerts’ can warn patients not just when they are already hypoglycaemic but when their glucose level is dropping quickly and hypoglycaemia may be imminent. The CGM reduces the need to constantly record self-monitored blood glucose levels, an advance that is much more convenient during exercise and for some forms of activity may be the only practical way of monitoring glucose levels. Conclusions: CGMs are a great way for physically active individuals with diabetes to maintain their active lifestyles with greater security and reassurance due to real-time information regarding their trends towards hyperglycaemia or hypoglycaemia. They allow people with type 1 diabetes to be more in control of their blood glucose levels and along with lifestyle interventions they can motivate people with type 2 diabetes to exercise and improve their glycaemic control. These devices allow a greater degree of freedom and ease of use during exercise and in general, but they are still not accurate enough to replace capillary blood glucose testing. • Comment: CGM technology may be considered one of the best recent inventions for people with type 1 diabetes who struggle to maintain good glycaemic control. Exercise itself is just one more variable that can make good control challenging as it can be associated with more glycaemic variation. This paper attempts to provide some of the useful CGM tools available that allow the user to be much more proactive in maintaining good glycaemic levels before, during and after exercise. Future study on the usefulness of these devices to improve overall glycaemic management in active patients is urgently needed, however.

Background: To help the reader use a continuous glucose monitor (CGM) to its

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Resistance exercise training lowers HbA1c more than aerobic training in adults with type 2 diabetes S. Bweir,1 M. Al-Jarrah,2 A. M. Almalty,1 M. Maayah,2 I. V. Smirnova,3 L. Novikova,3 L. Stehno-Bittel3 1 Department of Physiotherapy, Allied Medical Sciences, Hashemite University, Zarqa, Jordan, 2Department of Physiotherapy, Applied Medical Sciences, Jordan University of Science and Technology, Irbid, Jordan, and 3Department of Physical Therapy and Rehabilitation Science, University of Kansas Medical Center, Kansas City, KS, USA Diabetol Metab Syndr 2009; 10: 27 Background: Both aerobic and resistance training are recommended to control blood glucose in people with diabetes. However, only a few studies have attempted to compare the benefits from the two forms of exercise. This study directly compared the effects of 10 weeks of resistance or treadmill exercises on blood sugar levels before and after exercise and also HbA1c. Methods: The study included 20 inactive subjects (mean age 53.5 years) with type 2 diabetes. After obtaining baseline measurements of each subject’s HbA1c, blood glucose levels, heart rate and blood pressure, subjects were matched to age, waist circumference and sex and assigned to either resistance or treadmill exercise groups. Both intervention groups met three times per week for 10 weeks under supervision of an exercise therapist. In both groups, exercise intensity progressively increased over the course of the study. Special care was taken to ensure that total energy expenditure, perceived exertion and heart rate were equivalent between treatments. Blood glucose was measured immediately prior to and immediately after each exercise session. HbA1c was measured at the beginning and end of the trial. Results: Pre- and post-exercise blood glucose levels as well as HbA1c values were improved in both groups. However, the resistance training group clearly had greater bene-

fit in achieving glycaemic control. After the 10-week resistance programme, 80% of the subjects had post-exercise blood glucose levels within the normal range, while only 20% of the aerobic group reached this goal. Additionally the resistance training group had significantly greater reductions in HbA1c compared with the aerobic group (p < 0.006). Although aerobic training did result in statistically significant reduction in HbA1c (p < 0.05), none of the subjects in the aerobic group reached the target HbA1c < 7.0% while 40% of the resistance exercise group achieved this goal. Indeed, resistance training reduced the value of HbA1c by an average of 18% compared with an 8% reduction in the aerobic group. Blood pressure and resting heart rate did not change over the 10-week course in either group. Conclusion: Ten weeks of resistance training resulted in significantly better improvements in glycaemic control compared to isocaloric and equally difficult aerobic exercise. • Comments: Few studies have examined the potential benefits of resistance training in patients with type 2 diabetes and even fewer have directly compared it with aerobic exercise. Evidence is mounting, however, that resistance exercise may be as good as or even superior to endurance exercise for people with type 2 diabetes for a number of reasons (12,13). In line with this, the authors in this study point out that the HbA1c value was reduced by 18% in the resistance training vs. 8% in the aerobic exercise group. Major strengths of this study in establishing clinical importance are that the two groups were equal in not only calorie expenditure but also perceived exertion and were very similar in total workout time. Thus, from a patient’s point of view, the results of this study indicate that greater results may be obtained through resistance training with equal effort compared to aerobic training. This study was performed on inactive patients and therefore does not address the potential benefits to adding an exercise programme to more active individuals with diabetes (e.g. who perhaps have more physically demanding jobs). As

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devotion to an exercise plan should be a long-term commitment to aid in glycaemic control, larger and longer studies should be performed comparing the benefits after many months or years of aerobic and resistance exercise.

References 1 Estacio RO, Regensteiner JG, Wolfel EE, Jeffers B, Dickenson M, Schrier RW. The association between diabetic complications and exercise capacity in NIDDM patients. Diabetes Care 1998; 21: 291–5. 2 Fang ZY, Sharman J, Prins JB, Marwick TH. Determinants of exercise capacity in patients with type 2 diabetes. Diabetes Care 2005; 28: 1643–8. 3 Vanninen E, Uusitupa M, Siitonen O, Laitinen J, La¨nsimies E. Habitual physical activity, aerobic capacity and metabolic control in patients with newly-diagnosed type 2 (non-insulin-dependent) diabetes mellitus: effect of 1-year diet and exercise intervention. Diabetologia 1992; 35: 340– 6. 4 Barkai L, Peja M, Va´mosi I. Physical work capacity in diabetic children and adolescents with and without cardiovascular autonomic dysfunction. Diabet Med 1996; 13: 254–8. 5 Baum VC, Levitsky LL, Englander RM. Abnormal cardiac function after exercise in insulin-dependent diabetic children and adolescents. Diabetes Care 1987; 10: 319–23. 6 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 1–15. 7 Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, Kelman JA. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010; 304: 411–18. 8 Boule NG, Kenny GP, Haddad E et al. Meta-analysis of the effect of structured exercise training on cardiorespiratory fitness in type 2 diabetes mellitus. Diabetologia 2003; 46: 1071–81. 9 Tanasescu M, Leitzmann MF, Rimm EB, Hu FB. Physical activity in relation to cardiovascular disease and total mortality among men with type 2 diabetes. Circulation 2003; 107: 2435–9. 10 Burr JF, Rowan CP, Jamnik VK, Riddell MC. The role of physical activity in type 2 diabetes prevention: physiological and practical perspectives. Phys Sportsmed 2010; 38: 72–82. 11 Bjørgaas MR, Vik JT, Stølen T, Lydersen S, Grill V. Regular use of pedometer does not enhance beneficial outcomes in a physical activity intervention study in type 2 diabetes mellitus. Metabolism 2008; 57: 605–11. 12 Sigal RJ, Kenny GP, Boule´ NG, Wells GA, Prud’homme D, Fortier M, Reid RD, Tulloch H, Coyle D, Phillips P, Jennings A, Jaffey J. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med 2007; 147: 357–69. 13 Reid RD, Tulloch HE, Sigal RJ, Kenny GP, Fortier M, McDonnell L, Wells GA, Boule´ NG, Phillips P, Coyle D. Effects of aerobic exercise, resistance exercise or both, on patient-reported health status and well-being in type 2 diabetes mellitus: a randomised trial. Diabetologia 2010; 53: 632–40.

Advanced Technologies and Treatments for Diabetes

Paediatrics Diabetes technology and treatments in the paediatric age group S. Shalitin,1 H. Peter Chase2 1

Institute of Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO, USA

2

Type 1 diabetes (T1D) is one of the most common chronic childhood diseases and its incidence has doubled during the last decade. The goals of intensive management of diabetes were established in 1993 by the Diabetes Control and Complications Trial (DCCT) (1). Children with T1D and their caregivers continue to face the challenge to maintain blood glucose levels in the near-normal range. It is important to prevent sustained hyperglycaemia which is associated with long-term microvascular and macrovascular complications and to avoid recurrent episodes of hypoglycaemia or hyperglycaemia, especially in young children, which may have adverse effects on cognitive function and impede efforts to achieve the recommended glycaemic targets. Advances in the use of technology that may help maintain the metabolic control goals for young people with T1D were centred on continuous subcutaneous insulin infusion (CSII) (2–4), continuous glucose monitoring (CGM) (5–7), and combining both technologies into a closed-loop system (8–10). The dilemma in paediatrics of patient selection for insulin pump therapy was found to be most successful in those with more frequent self-monitoring of blood glucose (SMBG) and younger age prior to pump initiation (2). Similarly, those who used a dual-wave bolus probably paid closer attention to their management and had lower HbA1c levels (3). The advantage of using a pre-meal bolus to improve postprandial glucose levels was shown to offer another potential method to improve glycaemic control (4). SMBG is an important component of therapy in patients with diabetes, especially in the paediatric age group. Standard use of glucose meters for SMBG provides only intermittent single blood glucose levels, without giving the ‘whole picture’ of glucose variability during the 24 h, and especially during the night, when blood glucose levels are seldom measured. Therefore, the use of a device such as real-time continuous glucose monitoring (RT-CGM) that provides continuous glucose measurements can help patients optimise glycaemic control. These devices may have the potential to increase the proportion of patients who are able to maintain target HbA1c values, to decrease glucose excursions and to decrease the risk of severe hypoglycaemia. Previous studies in paediatric T1D patients (11,12) have demonstrated that the frequency of CGM use was significantly associated with the effect of lowering HbA1c levels. The important STAR 3 study of 485 patients (156 children) with T1D showed the benefit of sensor-augmented pump therapy over remaining on multiple daily injections (MDI) (10). The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF-CGM) studies were initially described in the 2009 Yearbook (13). Further reports of youths and adults in this study found that those with initial low HbA1c levels (< 7%) show a significant benefit from the use of CGM (5). Prolonged nocturnal hypoglycaemia was shown to continue to be a common occurrence in the entire cohort using CGM (7). Thus, there is an obvious need for closing the loop. Many patients with diabetes and especially parents of diabetic children dream about the invention of an ‘artificial pancreas’. CSII and RT-CGM can be combined to form closed-loop systems. Insulin is then delivered according to RT-CGM data, as directed by a control algorithm, rather than at pre-programmed rates. Few closed-loop prototypes have been developed with advanced control algorithms, such as those that are based on model predictive control (14). The group at Cambridge studied 19 young people in closed-loop systems and was able to demonstrate that exercise and diet variations could be aptly managed (9). It is expected that closed-loop studies in young people will continue to multiply in future years. T1D is characterised by immune-mediated pancreatic b-cell destruction. Thus, a major goal in the treatment of T1D in youth will be in the area of prevention. The identification of increased levels of inflammatory markers in the SEARCH study of young people with T1D may provide an important clue (15). Most of the studies countered the diabetes process by immunomodulation and ⁄ or enhancement of b-cell proliferation and regeneration (16). An initial pilot trial of a tumour necrosis factor a (TNF-a) binding agent, Entanercept, showed benefit in preserving C-peptide production in 18 young people with newly diagnosed T1D.

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Correspomdence to: Shlomit Shalitin, The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National center for childhood Diabetes. Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Tel.: +972-3-9253282 Fax: +972-3-9253836 Email: shalitin@netvision.net.il Disclosures: No conflicts of interest. Endorsed by the International Conference on ATTD organized by Kenes International.

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HbA1c levels were also lower in the treatment group (5.9% ± 0.5% vs. 6.98% ± 1.2%; p < 0.05) (17). Similarly, b-cell function was shown to be preserved in children receiving the lower of two doses of ingested human recombinant interferon-a (hrINF-a) in comparison with subjects who received placebo (18). A future larger trial of both of these agents will be of interest. In this review of the literature we have tried to select recent publications that offer some insight into these issues in paediatric patients with T1D.

CONTINUOUS SUBCUTANEOUS INSULIN INFUSION THERAPY – INSULIN PUMPS Predictors of glycaemic control in patients with type 1 diabetes commencing continuous subcutaneous insulin infusion therapy S. Shalitin, M. Gil, R. Nimri, L. de Vries, M. Y. Gavan, M. Phillip Institute of Endocrinology and Diabetes, Schneider Children’s Medical Center, Petah Tikva, Israel Diabet Med 2010; 27: 339–47 Background: Technological improvements of CSII have led to its increased use. However, selecting the best candidates for CSII poses a major clinical challenge. This retrospective study sought to identify variables that predict glycaemic control in patients with T1D switched to a CSII regimen, with the aim of improving prospective patient selection for this treatment. Methods: The medical files of 421 patients with T1D aged 2.6–39.8 years (43.9% younger than 18 years) who initiated CSII treatment and used it for at least 1 year (mean time of CSII use 4.1 ± 2.1 years) were reviewed. Details about their background, diseaserelated and treatment-related variables were recorded. At pump initiation, the mean age was 15.9 ± 7.2 years, mean diabetes duration 6.4 ± 5.8 years. The end-points were (1) achievement of good glycaemic control, defined by HbA1c stratified by age (American Diabetes Association recommendations), (2) improvement in glycaemic control, defined as a reduction of at least 0.5% in HbA1c from baseline, and (3) change in the rate of severe hypoglycaemic or diabetic ketoacidosis events. Results: A significant sustained decrease in HbA1c was observed with CSII for an average of 6 years, without increased rates of hypoglycaemia. The rate of severe hypoglycaemic episodes decreased during pump treatment (p = 0.023), whereas the rate of diabetic ketoacidosis increased with CSII (p = 0.004). Achievement of target HbA1c was significantly

associated with the following parameters at pump initiation: lower HbA1c, younger age (< 12 years), shorter diabetes duration, and more frequent daily SMBG. Improved glycaemic control was associated with longer CSII use and higher HbA1c at CSII initiation. Conclusions: Switching patients to CSII resulted in sustained decrease in HbA1c and improved glycaemic control in patients with high HbA1c. Young age, frequent SMBG and lower HbA1c at pump initiation were identified as predictors of achieving glycaemic targets with CSII. • Comment: CSII is the most physiological therapy of insulin replacement regimens, and therefore it is expected that pump therapy may be associated with long-term improvement in HbA1c. However, meta-analyses of randomised controlled studies of paediatric cohorts using insulin pumps have shown either no benefit in HbA1c or only modest benefits in the range of 0–0.9% (19). The identification of factors that predict or affect glycaemic control during pump therapy is important for proper patient selection. This large observational cohort study found that switching to CSII was followed by a sustained decrease in HbA1c, with significant reduction in the rate of severe hypoglycaemic episodes. The predictors that were identified as related to achieving the HbA1c target during CSII treatment may indicate that the best profiting patients from pump therapy were young paediatric patients, those with an already better glycaemic control, and patients who adhere to intensive diabetes management with frequent blood glucose monitoring. In this study, indications for CSII that were significantly associated with achieving HbA1c targets were recurrent hypoglycaemic episodes, needle fear, use for toddlers and aboveHbA1c target. These data suggest that the switch to CSII, particularly at younger ages, may reduce the anxiety associated with frequent injections and reduce the frequency of recurrent hypoglycaemic episodes, thus improving treatment compliance and allowing achievement of metabolic control targets. A higher HbA1c at initiation of CSII was significantly associated with a greater reduction in HbA1c during CSII use, which may indicate that a switch to CSII can greatly improve outcome in patients with HbA1c > 9.0%.

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Timing of meal insulin boluses to achieve optimal postprandial glycaemic control in patients with type 1 diabetes E. Cobry, K. McFann, L. Messer, V. Gage, B. VanderWel, L. Horton, H. P. Chase Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA Diabetes Tech Ther 2010; 12: 173–7 Background: Families and care providers have assumed that, with the availability of rapid-acting insulins, boluses ⁄ injections of insulin prior to food intake are not necessary. Methods: A prospective study involved 23 subjects with T1D, ages 12–30 years, involving three outpatient clinic visits. The three randomised treatment arms involved bolus insulin administration 20 min prior to a meal (Pre), at the start of the meal (Start) or just after the meal (Post). Results: Blood glucose levels 60 and 120 min after meal initiation and area under the curve (AUC) were all significantly lower in the Pre arm compared to the Start and Post arms as indicated in the paper. Conclusions: A bolus of rapid-acting insulin 20 min prior to a meal results in significantly better postprandial glucose control than when the meal insulin bolus is given just prior to the meal or 20 min after meal initiation. • Comment: This study shows the need for retraining families and care providers regarding optimal timing of insulin injections to food intake. As blood glucose levels are often the highest of the day in the postprandial periods, this area of care needs attention. The development of new, more rapid-acting insulins may eventually be possible. This will be essential in the development of the closedloop pancreas, as has already been noted (20).

Application of novel dual-wave meal bolus and its impact on glycated haemoglobin A1c level in children with type 1 diabetes E. Pankowska, A. Szypowska, M. Lipka, M. Szpotanska, M. Blazik, L. Groele

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Second Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland Pediatric Diabetes 2009; 10: 298–303 Background: One of the most important factors, which impacts on a better HbA1c level, is an increased number of boluses applied by the patient per day. Boluses are programmed individually by patients to cover food intake or to correct hyperglycaemia. In the insulin pump the bolus can be delivered in several modes: standard (normal, N), in which insulin is delivered rapidly on demand to match food intake and to correct hyperglycaemia, square wave (S-W), in which insulin is delivered during an extended period of time, and dual wave (D-W), which combines a normal bolus with a square wave bolus, which allows a certain percentage of insulin to be programmed for immediate delivery and the remainder over an extended time period. The aims of the current study were to assess in the paediatric age group the implementation of treatment with different boluses, and to evaluate whether the use of D-W ⁄ S-W boluses has an impact on HbA1c. Methods: The study included 499 records of patients aged 0–18 years. Data from the insulin pump memory provided information on the number of D-W ⁄ S-W boluses during a 2-week period, insulin dosage, and the percentage of basal insulin. Mealtime insulin dose in D-W ⁄ S-W bolus was calculated based on the amount of carbohydrate, fat and protein in the food. Results: The number of applied D-W ⁄ S-W boluses was 16.6 ± 0.77 per 14 days. In all 18.8% of patients did not use D-W ⁄ S-W boluses. A better glycaemic control was found in patients using ‡ 2 D-W ⁄ S-W boluses ⁄ day compared to those who programmed boluses occasionally, especially in patients who were not in remission. Patients with at least 1–3 D-W ⁄ S-W boluses ⁄ day had a significantly lower requirement for basal insulin than patients using only N boluses. Conclusions: Paediatric patients using at least one D-W ⁄ S-W bolus ⁄ day achieved better glycaemic control. • Comment: The option of delivering insulin in different bolus modes for different contents of the meals offered by modern insulin pumps can improve the HbA1c. It has to be considered that the meal fat and protein content should be covered by an extended insulin infusion, probably due to its slower absorption compared with the carbohydrate content.

CONTINUOUS GLUCOSE MONITORING Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group The introduction of new real-time CGM systems has raised great interest because these devices may have the potential to increase the proportions of patients who are able to maintain target HbA1c values, to decrease glucose excursions, and to decrease the risk of severe hypoglycaemia. In order to try and address these issues, the JDRF-CGM Study Group initiated some trials during the last few years. The Study Group included 10 participating centres. Major eligibility criteria included age ‡ 8 years, T1D for at least 1 year, and use of either an insulin pump or MDI. In a multicentre randomised controlled trial, the JDRF-CGM Study Group evaluated the effectiveness of CGM compared with standard blood glucose monitoring in 451 adults and children ‡ 8 years old with T1D, 322 of whom had baseline HbA1c levels ‡ 7% (21). The patients in the CGM group were asked to use the CGM on a daily basis for 6 months. Patients were provided with instructions on how to make real-time insulin dose adjustments. They found that in patients with baseline HbA1c levels ‡ 7%, CGM improved the glycaemic control during 6 months of follow-up without increasing the risk of hypoglycaemia in adults ‡ 25 years of age, whereas in younger patients the improvement was more limited. CGM use was substantially higher in adults than in children, and as a presumed consequence the benefit of the device in lowering the HbA1c was greater in adults than in children (13). Results of other studies of this group are presented in the next three abstracts.

Effect of continuous glucose monitoring in well-controlled type 1 diabetes Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group Diabetes Care 2009; 32: 1378–83 Background: Hypoglycaemia remains the major limiting factor for achieving euglycaemia in T1D. The introduction of real-time glucose monitoring (CGM) may have the potential to increase the proportion of patients who are able to maintain target

HbA1c values and limit the risk of severe hypoglycaemia. The aim of this randomised trial was to evaluate the efficacy and safety of CGM in well-controlled children and adults with T1D. Methods: The study included 129 adults and children (29 subjects aged 8–14 years, 33 subjects aged 15–24 years and 67 adults ‡ 25 years old) with intensively treated T1D (HbA1c < 7%) who were randomly assigned to continuous or standard glucose monitoring for 26 weeks. Patients in both groups were provided with instructions on how to use the devices, and to make real-time insulin dose adjustments. The main outcomes were HbA1c level, time with glucose level £ 70 mg ⁄ dl, and severe hypoglycaemic events. Results: At the end of the study, hypoglycaemia with blood glucose levels £ 70 mg ⁄ dl was less frequent in the CGM group than in the control group, but without a statistically significant difference. Time with glucose levels £ 70 or >180 mg ⁄ dl was significantly lower in the CGM group than in the control group. Mean HbA1c at the end of the study (adjusted for baseline) was significantly better in the CGM group. In the three age groups results of treatment group comparisons were similar to those of the overall analysis. No significant difference was found in the rate of severe hypoglycaemic episodes between the CGM and the control groups. Conclusions: Better HbA1c level and less time with hypoglycaemia or hyperglycaemia (> 180 mg ⁄ dl) suggest that CGM is beneficial for individuals with T1D who have already achieved the metabolic control target. • Comment: Hypoglycaemia remains a major limiting factor in achieving glycaemic control targets (22). In a previous reported randomised trial of 322 adults and children (29 children aged 8–14 years were included in the study) with T1D and baseline HbA1c level ‡ 7%, the JDRF-CGM Study Group demonstrated that CGM improved HbA1c levels without increasing the frequency of hypoglycaemia in adults > 25 years of age, whereas the decrease in HbA1c levels in the paediatric population was more limited (13). The same group in the present study tried to look whether there are any benefits in the use of CGM in a population with T1D with excellent metabolic control. We have to realise that these patients already at baseline adhere to intensive diabetes management with frequent blood glucose monitoring, averaging 6–7 times ⁄ day. As expected, consistent with pre-study management behaviours, adherence to GCM use was high during this study in all age groups.

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The study demonstrated that even wellcontrolled patients can benefit from the use of CGM. The use of CGM in these patients helped them to keep the good HbA1c level or even improve it, with increased time within target glucose levels (70–180 mg ⁄ dl) and decreased time with hypoglycaemic levels (< 70 mg ⁄ dl) also in the paediatric age group. However, the use of CGM did not resolve the problem of severe hypoglycaemic episodes, which still remains a cardinal problem especially among paediatric patients with T1D.

Effectiveness of continuous glucose monitoring in a clinical care environment. Evidence from the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Trial Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group Diabetes Care 2010; 33: 17–22 Background: Achieving and maintaining HbA1c targets with minimal glucose excursions is the aim of diabetes patients and their caregivers. Previous JDRF-CGM studies demonstrated the efficacy of CGM in a controlled environment of a randomised trial with intensive subject monitoring and supervision. The aim of this study was to examine if CGM is effective in the management of T1D in the standard clinical practice. Methods: After the end of a 6-month randomised controlled trial evaluating the use of CGM in T1D patients (8,9), the device was initiated in the control group of the study (n = 214, 73 subjects were 15–24 years old, 61 subjects were 8–14 years old) with less intensive training and follow-up compared with those of the trial itself. Patients had an outpatient training session, four visits in the clinic and two follow-up phone calls during a 6-month period. The primary outcome was a change in HbA1c after 6 months in subjects with baseline HbA1c ‡ 7%. Results: There was a significant decrease (p < 0.001) in the use of CGM after 6 months in all age groups, although less in the adult group. In subjects with a baseline HbA1c‡ 7%, the frequency of CGM use was associated with a significant HbA1c reduction after 6 months. Subjects who used the device consistently saw a significant increase in the amount of time spent in the target glucose range and decreased exposure to hyperglycaemia. A trend was observed in the decrease of

severe hypoglycaemic episodes after 6 months (p = 0.08). Conclusions: This extension arm of the study also demonstrated that sustained frequent use of CGM is less likely in children and adolescents. However, frequent use of the device in a clinical care setting may improve metabolic control.

Prolonged nocturnal hypoglycaemia is common during 12 months of continuous glucose monitoring in children and adults with type 1 diabetes Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group Diabetes Care 2010; 33: 1004–8 Background: Even with the use of advanced technology of insulin analogues and insulin pumps, severe hypoglycaemia, especially nocturnal, is common in T1D patients. The aim of the present study was to evaluate the amount of nocturnal hypoglycaemia during 12 months of CGM use, and factors associated with it among patients who participated in the JDRF-CGM randomised trial. Methods: The CGM data were evaluated from midnight to 6.00 am. Only patients with readings from at least 42 nights during 12 months (n = 176, 64 patients 8–14 years old and 42 patients 15–24 years old) and only nights having at least 4 h of glucose readings were included in the analysis. A hypoglycaemic event was defined as the occurrence of at least two CGM glucose values £ 60 mg ⁄ dl within a 20-min period. The percentage of nights with at least one hypoglycaemic event was computed for each patient. Results: Median percentage of nights with hypoglycaemia per subject was 7.4%, with duration of hypoglycaemia ‡ 2 h on 23% of the nights with hypoglycaemia. A higher incidence of nocturnal hypoglycaemia over 12 months was associated with baseline lower HbA1c levels (p < 0.001) and occurrence of nocturnal hypoglycaemia during baseline blinded CGM use (p < 0.001). Frequency of nocturnal hypoglycaemia was not associated with age or insulin modality (insulin pump vs. MDI). Conclusions: Prolonged nocturnal hypoglycaemia is a relatively frequent event, especially in patients with lower HbA1c levels, without a significant difference between children and adults. • Comment: Recurrent episodes of hypoglycaemia, especially at young ages, may

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cause short- and long-term adverse effects on cognitive function, lead to hypoglycaemia unawareness, and be associated with significant emotional morbidity for the child and parents. Fear of hypoglycaemia, especially during the night, may compromise quality of life for the family, and jeopardise efforts for better metabolic control. The results of this study demonstrate the scope of the problem. Maybe the development of closedloop systems with the fine tuning of feedback control of insulin delivery based on real-time CGM data will help to minimise this problem.

CLOSED-LOOP STUDIES Suspended insulin infusion during overnight closed-loop glucose control in children and adolescents with type 1 diabetes D. Elleri,1,2 J. M. Allen,1,2 M. Nodale,2 M. E. Wilinska,1,2 C. L. Acerini,1 D. B. Dunger,1,2 R. Hovorka1,2 1 Department of Paediatrics and 2Institute of Metabolic Science, University of Cambridge, Cambridge, UK Diabet Med 2010; 27: 480–4 Background: Some physicians have expressed concern that an interruption of insulin delivery when hypoglycaemia is predicted during overnight closed-loop glucose control might result in hyperglycaemia. Methods: In seven young people aged 14.2 ± 2.1 years with T1D (duration 6.9 ± 4.0 years), insulin delivery was discontinued for 165 min [median interquartile range (IQR) 105–210] when hypoglycaemia was predicted. The prediction algorithm was based on the model predictive control approach. Results: Plasma glucose was 6.2 ± 3.2 mmol ⁄ l (mean ± SD) at the time insulin was suspended and reached a nadir of 5.2 ± 2.7 mmol ⁄ l after 60 min of insulin suspension. The lowest observed plasma glucose level was 3.0 mmol ⁄ l at 45 min after pump suspension. When insulin delivery resumed, mean plasma glucose was 6.4 ± 2.2 mmol ⁄ l and it peaked 60 min later at 7.9 ± 2.1 mmol ⁄ l. The maximum observed plasma glucose within 120 min of resuming the insulin was 11.6 mol ⁄ l. Conclusions: Suspension of insulin delivery during closed-loop glucose control was not associated with an increased risk of hyperglycaemia.

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• Comment: Although the number of subjects reported (seven) was small, useful data on the safety of discontinuing insulin in a closed-loop system was provided. Studies during the night, when young people are most apt to experience severe hypoglycaemia and when routine blood glucose testing is usually not done, are particularly important. Future studies should also report data on blood ketone monitoring.

Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial R. Hovorka,1,2 J. M. Allen,1,2 D. Elleri,1,2 L. J. Chassin,1,2 J. Harris,2 D. Xing,3 C. Kollman,3 T. Hovorka,1 A. M. Larsen,1 M. Nodale,1 A. De Palma,1 M. E. Wilinska,1,2 C. L. Acerini,1,2 D. B. Dunger1,2 1 Department of Paediatrics and 2Institute of Metabolic Science, University of Cambridge, Cambridge, UK, and 3Jaeb Center for Health Research, Tampa, FL, USA Lancet 2010; 375: 743–51 Background: Closed-loop systems link continuous glucose measurements to insulin delivery. The aim of this trial was to establish whether closed-loop insulin delivery could control overnight blood glucose in young people. Methods: Three randomised crossover studies were undertaken in 19 patients aged 5–18 years with T1D of duration 6.4 years (SD 4.0). They compared standard CSII and closed-loop delivery (n = 13; APCam01); closed-loop delivery after rapidly and slowly absorbed meals (n = 7; APCam02); and closed-loop delivery and standard treatment after exercise (n = 10; APCam03). Allocation was by computer-generated random code. Participants were masked to plasma and sensor glucose. In APCam01, investigators were masked to plasma glucose. During closedloop nights, glucose measurements were fed every 15 min into a control algorithm calculating rate of insulin infusion, and a nurse adjusted the insulin pump. During control nights, patients’ standard pump settings were applied. Primary outcomes were time for which plasma glucose concentration was 3.91–8.00 mmol ⁄ l or £ 3.90 mmol ⁄ l. Analysis was per protocol. Results: Seventeen patients were studied for 33 closed-loop and 21 continuous infusion nights. Primary outcomes did not differ significantly between treatment groups in APCam01 (12 analysed; target range, median

52%, IQR 43–83, closed-loop vs. 39%, IQR 15–51, standard treatment, p = 0.06; £ 3.90 mmol ⁄ l, 1%, IQR 0–7 vs. 2%, IQR 0– 41, p = 0.13), APCam02 (six analysed; target range, rapidly absorbed meal 53%, IQR 48–57 vs. slowly absorbed meal 55%, IQR 37–64, p = 0.97; £ 3.90 mmol ⁄ l, 0%, IQR 0–4 vs. 0%, IQR 0–0, p = 0.16) and APCam03 (nine analysed; target range 78%, IQR 60–92, closed-loop vs. 43%, IQR 25–65, control, p = 0.0245, not significant at corrected level; £ 3.90 mmol ⁄ l, 10%, IQR 2–15 vs. 6%, IQR 0–44, p = 0.27). A secondary analysis of data documented increased time in the target range (60%, IQR 51–88 vs. 40%, IQR 18–61; p = 0.0022) and reduced time for which glucose concentrations were £ 3.90 mmol ⁄ l (2.1%, IQR 0.0–10.0 vs. 4.1%, IQR 0.0–42.0; p = 0.0304). No events with plasma glucose concentration < 3.0 mmol ⁄ l were recorded during closed-loop delivery, compared with nine events during standard treatment. Conclusions: Closed-loop systems could reduce the risk of nocturnal hypoglycaemia in children and adolescents with T1D. • Comment: Although a small sample size (19 patients) and a conglomerate of three studies, this study demonstrates the usefulness of closed-loop systems overnight to reduce the risk of nocturnal hypoglycaemia and improve overall glycaemic control in youth. Interestingly, the data also show that glucose control with manual closed-loop delivery was not adversely affected by exercise or the consumption of rapidly and slowly absorbed meals. Improved sensing accuracy and more sophisticated applications to improve daytime control will provide a significant step toward developing a fully automatic closed-loop system.

Effectiveness of sensoraugmented insulin pump therapy in type 1 diabetes R. M. Bergenstal,1 W. V. Tamborlane,2 A. Ahmann,3 J. B. Buse,4 G. Dailey,5 S. N. Davis,6 C. Joyce,7 T. Peoples,8 B. A. Perkins,9 J. B. Welsh,8 S. M. Willi,10 M. A. Wood,11 for the STAR 3 Study Group 1 International Diabetes Center at Park Nicollet, Minneapolis, MN, USA, 2Yale University, New Haven, CT, USA, 3Oregon Health and Science University, Portland, OR, USA, 4University of North Carolina School of Medicine, Chapel Hill, NC, USA, 5Scripps Institute, La Jolla, CA, USA, 6University of Maryland School of Medicine, Baltimore, MD, USA, 7Memorial University of Newfoundland, Health Science Center, St John’s, NL, Canada, 8 Medtronic, Northridge, CA, USA, 9Toronto

General Hospital, Toronto, ON, Canada, 10 Children’s Hospital of Philadelphia, Philadelphia, PA, USA, and 11Helen DeVos Children’s Hospital, Grand Rapids, MI, USA N Engl J Med 2010; 363: 311–20 Background: Insulin pumps and CGM sensors represent technologies designed to assist patients with T1D in safely reaching glycaemic goals. Recent studies have suggested that patients who used sensor-augmented pump therapy with adherence to CGM had improved HbA1c levels without an increased rate of hypoglycaemia. The aim of this multicentre randomised controlled trial was to compare the efficacy of sensor-augmented pump therapy with that of a regimen of MDI in 485 patients (329 adults and 156 children) with inadequately controlled T1D for 1 year. Methods: Patients eligible for the study were those with T1D, aged 7–70 years, who had received MDI that included long-acting analogue insulin during the previous 3 months and who had glycated haemoglobin of 7.4–9.5%. Patients were randomly assigned to receive either sensor-augmented pump therapy or a regimen of MDI. Primary endpoint was the change from the baseline glycated haemoglobin level at 1 year. Results: At 1 year, the baseline mean glycated haemoglobin level (8.3% in both study groups) had decreased to 7.5% in the pump therapy group, compared with 8.1% in the MDI group (p < 0.001). In both adults and children in the pump therapy group, glycated haemoglobin levels fell rapidly from baseline to 3 months and remained lower than levels in the MDI group for the remainder of the study. An increased frequency of sensor use was associated with a greater reduction in glycated haemoglobin levels at 1 year. The proportion of patients who reached the glycated haemoglobin target was greater in the pump therapy group than in the MDI group, both in adults and children. The rate of severe hypoglycaemia in the pump therapy group did not differ significantly from that in the MDI group, and there was no significant weight gain in either group. Conclusions: In both adults and children with inadequately controlled T1D, sensoraugmented pump therapy resulted in significant improvement in glycated haemoglobin levels compared with injection therapy. A significantly greater proportion of both adults and children in the pump therapy group than in the MDI group reached the target glycated haemoglobin level, without increasing biochemical hypoglycaemia or the rate of severe hypoglycaemic events. • Comment: This trial demonstrated that nearly half the children in the pump therapy

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group reached the American Diabetes Association age-specific targets for glycated haemoglobin by the end of the study. In contrast to the findings in previous studies, this study suggested that the effects of the combined system were greater than what would be expected from the individual components alone. However, it did not evaluate the effect of insulin pump therapy alone vs. sensor-augmented pump therapy to determine the contribution of each component of the system. In patients with T1D, including children with suboptimal glycaemic control, the use of a sensor-augmented insulin pump can be considered to try to improve glycaemic control.

NEW THERAPIES IN TYPE 1 DIABETES Inflammatory markers are increased in youth with type 1 diabetes: the SEARCH case–control study J. K. Snell-Bergeon,1 N. A. West,1 E. J. Mayer-Davis,1 A. D. Liese,2 S. M. Marcovina,3 R. B. D’Agostino,4 R. F. Hamman,1 D. Dabelea1 1 Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA, 2Gillings School of Global Public Health and School of Medicine, University of North Carolina, Chapel Hill, Department of Epidemiology and Biostatistics and Center for Research in Nutrition and Health Disparities, NC, USA, 3Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, WA, USA, and 4University of South Carolina, Columbia, SC, and Wake Forest University School of Medicine, SC, USA J Clin Endocrinol Metab 2010; 95: 2868–76 Background: The objective of the study was to investigate the association of inflammation with obesity, hyperglycaemia and dyslipidaemia in youth with T1D. Methods: This was a cross-sectional study of youth with and without T1D. The patients were SEARCH case–control participants with T1D (n = 553; mean age 15 years, range 10– 22; median duration 2.7 years) and without diabetes (n = 215; mean age 15 years, range 10–22). The main outcome measures were interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), fibrinogen and leptin. Results: Inflammatory markers were evaluated by diabetes status, quartiles of glycated haemoglobin and obesity using multiple linear regression analyses, adjusted for age, sex, study

site, race ⁄ ethnicity, T1D duration, body mass index and pubertal status. Compared with controls, youth with T1D had higher IL-6 and fibrinogen levels at all levels of glycaemia and obesity, and hsCRP levels were significantly higher in youth with T1D in the top three quartiles of glycated haemoglobin (‡ 7.2%) and among normal-weight subjects. Leptin was lower in youth with poor glycaemic control. Higher hsCRP and fibrinogen were correlated with higher total and low-density lipoprotein cholesterol and apolipoprotein B in youth with T1D, whereas higher fibrinogen was correlated with higher low-density lipoprotein and apolipoprotein B in controls. Conclusions: T1D is characterised by excess inflammation, independent of adiposity and glycaemic control. Even T1D youth in good glycaemic control had higher levels of IL-6 and fibrinogen than controls. Elevated inflammatory markers were associated with an atherogenic lipid profile, which may contribute to accelerated atherosclerosis in youth with T1D. • Comment: Although elevated IL-6 and hsCRP levels have been shown previously in youth with T1D, the size of this study and the differences were impressive. One has to wonder at what stage intervention with antiinflammatory agents might be effective. Other than worrying about Reye’s syndrome, a trial of aspirin therapy would be of interest.

Etanercept treatment in children with new-onset type 1 diabetes: pilot randomised placebo-controlled, double-blind study L. Mastrandera,1,2 J. Yu,3 T. Behrens,1 J. Buchlis,1,2 C. Albini,1,2 S. Fourtner,1,2 T. Quattrin1,2 1 Department of Pediatrics, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA, 2Women and Children’s Hospital of Buffalo-Kaleida Health, Buffalo, NY, USA, and 3Department of Biostatistics, School of Public Health, University at Buffalo, Buffalo, NY, USA Diabetes Care 2009; 32: 1244–9 Background: TNF-a and other cytokines play a role in the autoimmune process leading to T1D. Etanercept (a recombinant soluble TNF-a receptor fusion protein) binds to TNF-a, clears it from the circulation, and blocks its biological activity. The aim of this study was to evaluate if Etanercept administration can prolong the partial remission period in children with newly diagnosed

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T1D.The end-points were percentage change from baseline of HbA1c, C-peptide AUC and insulin dosage. Methods: A randomised double-blind, placebo-controlled trial of 24 weeks included 18 patients with newly diagnosed diabetes (< 5.7 weeks) aged 7.8–18.2 years, with positive glutamic acid decarboxylase and ⁄ or insulin autoantibody and HbA1c > 6%, who were randomly assigned to receive either subcutaneous injection of Etanercept or placebo. Results: After 24 weeks, the HbA1c level was lower in the Etanercept group compared with the placebo (5.9% ± 0.5% vs. 6.98% ± 1.2%, p < 0.05). At week 24, there was an increase of 39% in the C-peptide AUC in the Etanercept group, whereas in the placebo group C-peptide AUC decreased by 20% (p < 0.05). The insulin dose decreased in the Etanercept group and increased in the placebo (p < 0.05). No severe adverse events were reported. Conclusions: This pilot study demonstrated that Etanercept may preserve b-cell function with an increase in endogenous insulin production, and better glycaemic control. • Comment: In the last decade a lot of studies about agents that may preserve the b-cell function have been published. Most of the agents have a significant effect on the immune system. Although the results of the present study sound promising, we need to remember that it is a small study of short duration, and larger studies are needed to confirm the efficacy and safety of Etanercept in the long term in newly diagnosed paediatric patients with T1D.

Effect of ingested interferon-a on b-cell function in children with new-onset type 1 diabetes K. I. Rother,1 R. J. Brown,1 M. M. Morales,2 E. Wright,1 Z. Duan,1 C. Kampbell,1 D. M. Harlan,1 P. R. Orlander,3 S. Brod,2 D. S. Hardin,4 J. Popovic,5 R. C. McEvoy6 1 National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA, 2 University of Texas Medical School, Department of Neurology, Houston, TX, USA, 3 University of Texas Medical School, Department of Internal Medicine, Houston, TX, USA, 4University of Texas Southwestern, Dallas, TX, USA, 5Children’s Mercy Hospital and Clinics, Kansas City, MI, USA, and 6St Paul Children’s Hospital, St Paul, MI, USA Diabetes Care 2009; 32: 1250–5 Background: Preservation of b-cell function is an important treatment goal in

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patients with T1D. Multiple clinical trials attempted to prevent progressive b-cell destruction after onset of T1D using immunosuppressive or immunomodulatory agents. The current trial evaluated the safety and efficacy of ingested hrINF-a to preserve b-cell function in newly diagnosed patients with T1D. Methods: A prospective randomised placebo-controlled, double-blind, multicentre, parallel group study of 128 patients aged 3–25 years with diabetes duration up to 6 weeks, without other significant concurrent illness, was carried out. Patients were randomly assigned to receive ingested hrINF-a at 5000 or 30,000 units or placebo once daily for 1 year. The primary outcome was the change in meal-stimulated C-peptide AUC from the beginning to the end of the study. A data safety review was performed. Results: Children treated with hrINF-a lost significantly less of their C-peptide secretion, especially those receiving the low dose (5000 units) in comparison with the placebo (29% ± 54% vs. 56% ± 29%, respectively, p = 0.028). There was no difference in the occurrence of adverse events among the three treatment groups. No difference was found among treatment groups for the decline in HbA1c from screening to 12 months. Conclusions: This study demonstrated that ingested hrINF-a was a safe medication, and a beneficial effect on b-cell function was observed after 1 year in the 5000-unit group. • Comment: Greater residual b-cell function lowers the risk of developing microvascular complications and markedly reduces the risk of hypoglycaemia (23). Preservation of residual endogenous insulin secretion is predicted to have a major impact on metabolic control in T1D patients. This study gives hope in par-

ticular for young patients because of its good safety profile, oral use, and beneficial effect on b-cell function. However, the long-term effects of hrINF-a in newly diagnosed T1D patients are still unknown, and further larger studies are needed to determine whether there is any sustained benefit without long-term safety issues.

References 1 The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86. 2 Shalitin S, Gil M, Nimri R, de Vries L, Gavan MY, Phillip M. Predictors of glycemic control in patients with type 1 diabetes commencing continuous subcutaneous insulin infusion therapy. Diabet Med 2010; 27: 339–47. 3 Cobry E, McFann K, Messer L et al. Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther 2010; 12: 173–7. 4 Pankowska E, Szypowska A, Lipka M, Szpotanska M, Blazik M, Groele L. Application of novel dual wave meal bolus and its impact on glycated hemoglobin A1C level in children with type 1 diabetes. Pediatr Diabetes 2009; 10: 298– 303. 5 Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. The effect of continuous glucose monitoring in well-controlled type 1 diabetes. Diabetes Care 2009; 32: 1378–83. 6 Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Effectiveness of continuous glucose monitoring in a clinical care environment. Evidence from the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF-CGM) Trial. Diabetes Care 2010; 33: 17–22. 7 Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Prolonged nocturnal hypoglycemia is common during 12 months of continuous glucose monitoring in children and adults with type 1 diabetes. Diabetes Care 2010; 33: 1004–8. 8 Elleri D, Allen JM, Nodale M et al. Suspended insulin infusion during overnight closed-loop glucose control in children and adolescents with type 1 diabetes. Diabet Med 2010; 27: 480–4. 9 Hovorka R, Allen JM, Elleri D et al. Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial. Lancet 2010; 375: 743–51.

10 Bergenstal RM, Tamborlane WV, Ahmann A et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med 2010; 363: 311–20. 11 Chase HP, Beck R, Tamborlane W et al. A randomized multicenter trial comparing the GlucoWatch Biographer with standard glucose monitoring in children with type 1 diabetes. Diabetes Care 2005; 28: 1101–6. 12 Hirsch IB, Abelseth J, Bode BW et al. Sensor-augmented insulin pump therapy: results of the first randomized treatto-target study. Diabetes Technol Ther 2008; 10: 377–83. 13 The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF-CGM) Study Group. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med 2008; 359: 1464–76. 14 Bequette BW. A critical assessment of algorithms and challenges in the development of a closed-loop artificial pancreas. Diabetes Technol Ther 2005; 7: 28–47. 15 Snell-Bergeon JK, West NA, Mayer-Davis EJ et al. Inflammatory markers are increased in youth with type 1 diabetes: the SEARCH case–control study. J Clin Endocrinol Metab 2010; 95: 2868–76. 16 Skyler JS, Greenbaum CJ, Lachin JM et al. Type 1 Diabetes TrialNet – an international collaborative clinical trials network. Ann NY Acad Sci 2008; 1150: 14–24. 17 Mastrandera L, Yu J, Behrens T et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized placebo-controlled, double-blind study. Diabetes Care 2009; 32: 1244–9. 18 Rother KI, Brown RJ, Morales MM et al. Effect of ingested interferon-a on b-cell function in children with new-onset type 1 diabetes. Diabetes Care 2009; 32: 1250–5. 19 Pan´kowska E, Błazik M, Dziechciarz P, Szypowska A, Szajewska H. Continuous subcutaneous insulin infusion vs. multiple daily injections in children with type 1 diabetes: a systematic review and meta-analysis of randomized control trials. Pediatr Diabetes 2009; 10: 52–8. 20 Weinzimer SA, Steil GM, Swan KL, Dziura J, Kurtz N, Tamborlane WV. Fully automated closed-loop insulin delivery versus semi automated hybrid control in pediatric patients with type 1 diabetes using an artificial pancreas. Diabetes Care 2008; 31: 934–9. 21 The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF-CGM) Study Group. JDRF randomized clinical trial to assess the efficacy of real-time continuous glucose monitoring in the management of type 1 diabetes: research design and methods. Diabetes Technol Ther 2008; 10: 310–21. 22 Cryer PE. Panting Lecture: Hypoglycemia: the limiting factor in the management of IDDM. Diabetes 1994; 43: 1378– 89. 23 Steffes MW, Sibley S, Jackson M, Thomas W. b-cell function and the development of diabetes-related complications in the Diabetes Control and Complications Trial. Diabetes Care 2003; 26: 832–6.

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Advanced Technologies and Treatments for Diabetes

Technology and the Human Factor Diabetes technology and the human factor A. Liberman,1 B. Buckingham,2 M. Phillip1 1

Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Stanford Medical Center, Stanford, CA, USA

2

When developing new technologies for human use the developer should take into consideration not only the efficacy and safety of the technology but also the desire and capabilities of the potential user. Any chronic disease is a challenge for both the patient and his ⁄ her caregivers. This statement is especially true in the case of patients with type 1 diabetes mellitus (T1DM) where adherence to therapy is crucial 24 hours a day 365 days a year. No vacation days are possible for the T1DM patient. It is therefore obvious why any new technology which is developed for helping patients cope with the disease should take into consideration the ‘human factor’ before, during and after the production process starts. There is no doubt that technology has changed the life of patients with T1DM in the last few decades, but despite the availability of new meters, new syringes, new sophisticated insulin pumps and continuous glucose sensors and communication tools, these technologies have not been well utilised by many patients. It is therefore important to understand why the technology is not always utilised and to find new ways to maximise use and benefits from the technology to as many patients as possible. The present chapter will review papers published in the last year where the patient’s ability or willingness was an important factor in the success of the technology. We will try to understand why insulin pumps, glucose sensors and self-monitoring of blood glucose (SMBG) are not used enough or appropriately, whether there is a specific group that finds it more difficult than others to adopt new technologies and what can be done to overcome that issue. For this chapter we chose articles from a Public Medicine review of the literature related to human factors affecting the outcome of studies and of user acceptance of continuous glucose monitoring, insulin infusion pump therapy. We also searched the literature in the field of psychology in order to accurately define the problems that the users of technology are facing (such as adherence, quality of life, motivations, executive functioning etc.) Those articles that had the most important contributions to understanding human factors as well as those highlighting the interface between technology and psychology, were chosen for this review, with emphasis on articles that provide insight into future studies and acceptance of emerging technologies for glycemic control.

CONTINUOUS GLUCOSE SENSORS Validation of measures of satisfaction with and impact of continuous and conventional glucose monitoring Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group Diabetes Technol Ther 2010; 12: 679–84 Background: The evaluation of patientreported outcomes (such as the impact of the technology and satisfaction with the

technology) is important in clinical trials of continuous glucose monitoring (CGM). The DirecNet study group had previously developed a CGM Satisfaction Scale (CGM-SAT) along with a Glucose Monitoring Survey (GMS). These scales were used in this larger Juvenile Diabetes Research Foundation randomised clinical trial (JDRF-RCT) of CGM to validate the measures and assess the impact of CGM. Methods: The CGM-SAT (a 44-item scale) was used by 224 patients and102 parents to grade their experience with CGM over the previous 6 months in the JDRF-RCT, and the

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Correspondence to: Moshe Phillip, The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Tel.: +972-3-9253731 Fax: +972-3-9253836 Email: mosheph@post.tau.ac.il Disclosures:. BB is on the advisory boards of Medtronic Minimed, NovoNordisk, BD, GluMetrics, Unomedical, Animas, and Biodel. He receives research support from Medtronic Minimed, Abbott diabetes care, and Biodel. He was a principal investigator in the JDRF randomized clinical trial of continuous glucose monitoring, and in DirecNet studies, and both groups had articles reviewed in this chapter. AL has no conflict of interest. MP’s institution received research grant support, with receipt of travel and accommodation expenses in some cases, from Medtronic and Dexcom. MP is a consultant for Animas, Medtronic and Bayer; and is a member of Scientific advisory boards for CGM3 Ltd., D-Medical and Physical Logic. Endorsed by the International Conference on ATTD organized by Kenes International.

GMS (a 22-item scale) was used by 447 patients and 221 parents to grade the blood glucose monitoring system they were using (SMBG alone or with CGM) at baseline and at 6 months. Results: The authors found that the alpha coefficient for all respondents was 0.94 for the CGM-SAT and 0.84 for the GMS at baseline and 6 months. Parent–youth agreement was 0.52 for the CGM-SAT at 6 months and 0.24 and 0.20 for the GMS at baseline and 6 months, respectively, for the Standard Care Group. The authors report that test–retest reliability of the GMS at 6 months for con-

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trols was r = 0.76 for adult patients, 0.63 for paediatric patients and 0.43 for parents. As to GMS, there were two issues that were apparent: glucose control and social complications, accounting for 28% and 9% of variance, respectively. Factor analysis isolated measurement factors for the CGM-SAT labelled benefits of CGM and hassles of CGM, accounting for 33% and 9% of variance, respectively. Conclusions: The authors found that both CGM-SAT and GMS were reliable and valid measures of patient-reported CGM outcomes. The present results supported several psychometric properties of the CGM-SAT and GMS, including internal reliability (both), parent–youth agreement (CGM-SAT and, to a lesser degree, GMS), and test–retest reliability (GMS). The relatively low estimates of parent–youth agreement on the GMS suggest that parents and youths should complete this measure separately and that parental proxy responses for youths’ perspectives of CGM are not valid.

Continuous glucose monitoring in youth with type 1 diabetes: 12-month follow-up of the Juvenile Diabetes Research Foundation continuous glucose monitoring randomised trial H. P. Chase,1 R. W. Beck,2 D. Xing,2 W. V. Tamborlane,3 J. Coffey,4 L. A. Fox,5 B. Ives,3 J. Keady,6 C. Kollman,2 L. Laffel,6 K. J. Ruedy2 1 Barbara Davis Center, Denver, CO, USA, 2 Jaeb Center for Health Research, Tampa, FL, USA, 3Yale University, New Haven, CT, USA, 4 University of Iowa, Iowa City, IA, USA, 5 Nemours Children’s Clinic, Jacksonville, FL, USA, and 6Joslin Diabetes Center, Boston, MA, USA Diabetes Technol Ther 2010; 12: 507–15 Background: The use of CGM in children and adolescents is not well defined. The authors have examined the use of CGM over a 12-month period in adolescents with TIDM. Methods: Eighty subjects 8–17 years old with T1DM and baseline HbA1c ‡ 7.0% used CGM as part of a 6-month randomised trial and subsequent 6-month extension study. Outcomes included frequency of CGM use, HbA1c levels, rate of severe hypoglycaemia, and a CGM satisfaction scale. Results: In all, 95% of the patients were using CGM after 6 months (median use

5.5 days per week) compared with 84% after 12 months (median use 4.0 days per week). Patients using CGM ‡ 6 days per week in month 12 (n = 17) had substantially greater improvement from baseline in HbA1c than the patients using CGM <6 days per week in month 12 (p < 0.001). They also reported greater satisfaction with CGM use (p = 0.001). The incidence of severe hypoglycaemic events was low during the 12 months of the study. Conclusions: In adolescents with T1DM, the frequency of using CGM decreases over time. Patients who use the device for most of the week can have substantial improvement in glycaemic control. • Comment: In their discussion the authors point out that both patients and parents of patients who used CGM ‡ 6 days a week had similarly favourable views of the benefits of CGM as it relates to improving their understanding. Less than 1% of all phone calls were related to algorithm-related issues, yet the educators thought the algorithm guidelines were the most difficult teaching point. Other difficult teaching points were lag time, issues with sensor insertions, and technical and troubleshooting issues and management of glycaemic control. In contrast, the patients and families who used CGM less frequently had less positive views regarding the hassles and burdens of using these devices. This difference is clearly pointed out in the responses to the CGM satisfaction scale where the group using the CGM <6 days a week described their experience with the CGM as ‘harder or more complicated than expected’, ‘hard to get working right’, ‘makes it harder to sleep’, ‘shows more ‘‘glitches’’ and ‘‘bugs’’ than it should’ and ‘is more trouble than it’s worth’. In conclusion the authors state: ‘The results of this study suggest that for CGM to achieve more widespread and consistent use in pediatrics, future generations of the devices will need to be simpler to use, less painful to insert, and more accurate and reliable with fewer false alarms, especially at night. However, at this time, even the current state of CGM technologies offers unprecedented opportunities to improve glycemic control and reduce the occurrence of hypoglycemia if the devices are used on a near-daily basis.’ There are continuing improvements in CGM technology which will improve the human interface with these devices, but it is important to provide realistic expectations and ongoing education and emotional support for children and adolescents embarking on using this technology. This paper by Chase et al. provides empirical evidence of the well-known problem of

decreased adherence and satisfaction in diabetes management during adolescence (1,2). The results showed that adolescents did not use the CGM as much as the pre-pubertal children in this study, showed less satisfaction from it and eventually failed to achieve the study A1c targets. According to the CGM satisfaction scale results there was a difference between satisfied patients and non-satisfied in both subscales: the benefit and the hassle caused by the CGM. However, the difference was greater in the hassle subscale. In other words, adolescent patients were indeed less satisfied than children but they could understand the benefits of CGM use. What they could not accept was the trouble and the burden caused by the CGM (e.g. ‘has been harder or more complicated than expected’, ‘is too hard to get working right’). This finding brings into mind a very common experience in clinical practice. During the childhood period the parents mostly accept the dependent nature of the diabetes management. As a result they are willingly to accept the responsibility of being deeply involved in their child’s coping efforts including solving technical difficulties and keeping a daily routine. However, when the child is entering adolescence the parents often change their attitudes toward this issue and start expecting their child to manage his ⁄ her diabetes in an independent manner like an adult whether he ⁄ she has mentally matured or not. On the other hand, parents are fearful that their child will not take adequate care of himself or herself and therefore compromise health and wellbeing. The adolescent is also confused because one of the tasks of the adolescent period is to achieve independence from parents but with diabetes the task becomes more difficult. Parents should be guided to coordinate their expectations with the children’s actual psychological state and abilities and to give them as much help as they need.

Educating families on real-time continuous glucose monitoring – the DirecNet Navigator pilot study experience L. Messer, K. Ruedy, D. Xing, J. Coffey, K. Englert, K. Caswell, B. Ives Diabetes Research in Children Network (DirecNet) Study Group, Tampa, FL, USA The Diabetes Educator 2009; 35: l24–35 Background: The aim was to describe the process of educating families and children

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with type 1 diabetes on real-time continuous glucose monitoring (RT-CGM) and to compare training of patients using continuous subcutaneous insulin infusion (CSII) vs. those using multiple daily injections (MDI). Methods: Patients with CSII (n = 30) and with MDI (n = 27) were educated using the Navigator RT-CGM in a clinical trial. Time spent with families for visits and calls was tracked and compared between patient groups. The Diabetes Research in Children Network (DirecNet) educators were surveyed to assess the time intensive and difficult educational concepts related to CGM. Results: Of the MDI families, an average of 9.6 h was spent on protocol-prescribed visits and calls and 2 h on participant-initiated contacts over 3 months. MDI families required an average of 5.4 more phone contacts over 3 months than CSII families. According to the DirecNet educators, lag time and calibrations were the most crucial teaching concepts for successful RT-CGM use. The most time was spent on teaching technical aspects, troubleshooting and insulin dosing. The most unanticipated difficulties were skin irritation and problems with adherence of the sensor. Conclusion: Educators who teach RTCGM should emphasise lag time, calibration and technical device training, and sensor insertion. Follow-up focus should include insulin dosing adjustments and skin issues. The time and effort required to introduce RT-CGM provided an opportunity for the diabetes educators to re-emphasise good diabetes care practices and promote autonomy to patients and families. • Comment: This is the first published study which provides an estimate for the amount of time required to initiate (about 80 min at the introduction of CGM) and follow patients on CGM. At each follow-up visit about 7 min was spent on device teaching, 15 min on CGM data review and 15 min on other diabetes management issues. This was a DirecNet study which also provided their algorithms (3) for diabetes management which required about 30 min at the initial visit, and then 5 min reviewing in follow-up visits. Most phone calls between visits were about devicerelated issues, and it was of interest that patients on MDI therapy had about twice the number of phone calls compared with patients on CSII therapy. This can be explained by the fact that MDI families had less experience with technical devices related to diabetes. For most MDI families this was also their first exposure to wearing a device attached to their skin. Many educators commented about the difference between CSII and MDI families in the educator survey. The following is an example of the responses: ‘The

MDI patients are not used to taking extra doses of insulin, and they were challenged to make more [insulin] corrections, such as after school. Usually, they would just wait until dinner.’ It could be suggested that MDI participants were less accustomed to making insulin management changes on their own and the consequences of those changes were more traumatic (i.e. taking additional injections). Practically speaking, there was a larger psychological cost to MDI patients vs. CSII patients pertaining to dosing adjustments. Perhaps the most unexpected difficulty for both CSII and MDI patients involved the magnitude of skin issues related to CGM use. During the 476 scheduled phone calls and completed visits, 306 reports of skin and sensor issues occurred. Primary concerns included sensors not adhering to the skin and rashes from the tape.

The effect of continuous glucose monitoring in wellcontrolled type 1 diabetes Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group Diabetes Care 2009; 32: 1378–83 Background: The aim of this study was to examine the potential benefits of CGM which have not been assessed. The management of both adults and children with well-controlled type 1 diabetes was considered. Methods: A total of 129 adults and children with well-controlled type 1 diabetes (age range 8–69 years) and A1c < 7.0% were assigned randomly to be treated either with continuous or standard glucose monitoring for a period of 26 weeks. The main study outcomes were duration with glucose level of £ 70 mg ⁄ dl, the level of A1c and severe hypoglycaemic events. Results: It was found after 26 weeks that biochemical hypoglycaemia (£ 70 mg ⁄ dl) was less frequent in the CGM group than in the control group but without a statistically significant difference. Median time with a glucose level £ 60 mg ⁄ dl and time out of range (£ 70 or ‡ 180 mg ⁄ dl) were significantly lower in the CGM group than in the control group (p = 0.05 and p = 0.003, respectively). There was a significant treatment group difference favouring the CGM group in mean A1c at 26 weeks adjusted for baseline (p < 0.001). Severe hypoglycaemic events occurred in about 10% of patients in both groups. Four outcome measures combining A1c and hypoglycaemia data significantly favoured the CGM group in comparison with the control group.

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Conclusions: This study demonstrated that most outcomes, including those combining A1c and hypoglycaemia, favoured the CGM group. It seems that CGM has potential benefits for well-controlled type 1 diabetes patients.

Factors predictive of use and of benefit from continuous glucose monitoring in type 1 diabetes Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group Diabetes Care 2009; 32: 1947–53 Background: This study tried to evaluate what factors would predict a successful use of CGM among paediatric and adult patients with well-treated type 1 diabetes. Methods: The 232 participants that were randomly assigned to the CGM group (165 with baseline A1c ‡ 7.0% and 67 with A1c < 7.0%) were asked to use the device on a daily basis. The associations of baseline factors and early CGM use with its use ‡ 6 days per week in the sixth month and with change in A1c from baseline to 6 months were evaluated. Results: After 6 months, only baseline factors of age ‡ 25 years (p < 0.001) and more frequent self-reported pre-study blood glucose meter measurements per day (p < 0.001) were found to be associated with greater use of CGM. Use of the device and the percentage of CGM glucose values of 71–180 mg ⁄ dl during the first month were predictive of CGM use in month 6 (p < 0.001 and p = 0.002, respectively). More frequent CGM use was associated with a greater reduction in A1c after 6 months (p < 0.001) in all age groups. Conclusions: After a period of 6 months, adults with type 1 diabetes who were intensively treated were more likely to show a near-daily CGM use than paediatric patients. In all age groups near-daily CGM use was associated with a similar reduction in A1c. Frequency of blood glucose meter monitoring and initial CGM use may help predict the likelihood of long-term CGM benefit in intensively treated type 1 diabetes patients of all ages. • Comment: Previously published randomised clinical trials of CGM had enrolled subjects with A1c > 7% because lowering of A1c was the primary outcome of interest (4–6). The first study described herewith was conducted to determine if CGM would provide benefit to well-controlled children and adolescents who had already achieved an A1c < 7.0%. After 6 months of CGM use the area under the curve for CGM readings

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< 70 mg ⁄ dl was 0.26 in the CGM group and 0.49 in the control group (p < 0.03) and 88% of the CGM group maintained an A1c < 7%, whereas A1c drifted up in the control group and only 63% were able to maintain an A1c < 7% (p < 0.001). This was the first randomised trial to demonstrate that CGM can be of benefit to persons who have already achieved an excellent A1c. The second paper examines whether there were factors that could predict which subjects would show good adherence to using a CGM. After adjusting for age, the only significant factor was the number of self-reported blood glucose tests, which probably reflects that these subjects were more engaged in their diabetes self-management. It is of interest that, after adjusting for age, the subjects’ duration of diabetes, education level, household income, history of recent severe hypoglycaemia, fear of hypoglycaemia or type of insulin treatment (MDI or pump) had no predictive value for their subsequent frequency of CGM use. The problem of compliance and adherence is one of the central issues that medical and rehabilitation psychology is dealing with. Several models and therapy methods have been developed to address this problem, e.g. the trans-theoretical model of health behaviour change, which offers a framework of motivating non-adherent patients by referring to motivation as a state and not as a trait (7–9). The most interesting finding is that children and adolescents are less likely to maintain daily uses of CGM even in a study environment where the sensors are free of charge and special support for the participants is available. This raises the question about the benefits of CGM in populations which are generally less adherent to chronic therapy such as children and adolescents in routine life (outside of study). The results of the present study encourage the diabetes team to search for ways to better understand the human factor that prevents patients from using new and effective technologies in treating chronic diseases especially among children and adolescents.

Effectiveness of sensoraugmented insulin pump therapy in type 1 diabetes R. M. Bergenstal,1 W. V. Tamborlane,2 A. Ahmann,3 J. B. Buse,4 G. Dailey,5 S. N. Davis,6 C. Joyce,7 T. Peoples,8 B. A. Perkins,9 J. B. Welsh,8 S. M. Willi,10 M. A. Wood,11 for the STAR 3 Study Group 1 International Diabetes Center at Park Nicollet, MI, USA, 2Yale University, New Haven, CT, USA, 3Oregon Health and Science

University, Portland, OR, USA, 4University of North Carolina School of Medicine, Chapel Hill, NC, USA, 5Scripps Institute, La Jolla, CA, USA, 6University of Maryland School of Medicine, Baltimore, MD, USA, 7Memorial University of Newfoundland, Health Science Center, St John’s, NL, Canada, 8Medtronic, Northridge, CA, USA, 9Toronto General Hospital, Toronto, ON, Canada, 10Children’s Hospital of Philadelphia, Philadelphia, PA, USA, and 11Helen DeVos Children’s Hospital, Grand Rapids, MI, USA N Engl J Med 2010; 363: 311–20 Background: Recently developed technologies for the treatment of T1DM include pumps and pumps with glucose sensors. Methods: In this multicentre, randomised, controlled trial, the efficacy of sensor-augmented pump therapy (pump therapy) was compared with a regimen of multiple daily insulin injections (injection therapy) during 1 year in 485 patients (329 adults and 156 children) with uncontrolled type 1 diabetes. The primary end-point was the change in HbA1c from the baseline. Results: After 1 year, the baseline mean HbA1c (8.3% in both study groups) had decreased to 7.5% in the pump therapy group, compared with 8.1% in the injection therapy group (p < 0.001). The proportion of patients who reached the HbA1c target (< 7%) was greater in the pump therapy group than in the injection therapy group, without a significant difference in the rate of severe hypoglycaemia between the groups. Conclusions: In all uncontrolled type 1 diabetes patients, sensor-augmented pump therapy resulted in significant improvement in HbA1c levels, compared with injection therapy. A significantly greater proportion of patients in the pump therapy group than in the injection therapy group reached the target HbA1c level. • Comment: This paper tested the difference between the diabetes management of children and adolescents (as well as adults) with type 1 diabetes using the sensor-augmented insulin pump therapy vs. insulin injections. This is one of the first randomised trials to demonstrate a significant improvement in glucose control for adolescents as well as adults. One of the most striking findings was the very low rate of severe hypoglycaemic events in both adults and children. The adolescents had 9.0 severe hypoglycaemic events per 100 patient-years compared with adolescents in the Diabetes Control and Complications Trial (DCCT) who had 85.7 events per 100 patient-years in the intensive group; in the DCCT the mean A1c was 8.1% compared

with 7.9% in STAR 3. There is still work to be done in the children and adolescent age groups since in these groups there was a constant incline towards 8% at the end of the year. Furthermore, although there was significant improvement among the sensor pump group, over 55% of the children in this group did not achieve the targets recommended by the American Diabetes Association (A1c < 8% between the ages of 6 and 12 years and A1c < 7.5% among adolescents between the ages of 13 and 19 years). These results suggest that in certain subpopulations diabetes may not be the patient’s first priority. These are the patients who may most benefit from closed-loop therapy. It is also possible that the appropriate psychosocial support during implementation of these therapies may improve subject acceptance and use of the technology. Other factors such as sports and activities in this age group which make sensor and pump wear more difficult may also be playing a role in user acceptance, as well as the importance of peer acceptance in adolescence and the effect that wearing sensors and pumps may have on body image.

Psychosocial factors associated with use of continuous glucose monitoring M. D. Ritholz,1–3 A. Atakov-Castillo,1 M. Beste,1 E. A. Beverly,1,2 A. Leighton,1 K. Weinger,1,2 H. Wolpert1,2,4 1 Joslin Diabetes Center, 2Harvard Medical School, 3Children’s Hospital, and 4Beth Israel Deaconess Medical Center, Boston, MA, USA Diabet Med 2010; 27: 1060–5 Background: To identify psychosocial factors correlated with the use of CGM by adults with type 1 diabetes. Methods: Twenty adult patients with a mean diabetes duration of 25 ± 19 years followed in the multicentre JDRF Continuous Glucose Monitoring Trial were divided into three groups: HbA1c responders (who demonstrated an improvement in HbA1c with CGM, baseline HbA1c ‡ 7.0% with a reduction in HbA1c ‡ 0.5%), hypoglycaemia responders (baseline HbA1c < 7.0%, with a decreased time < 3.9 mmol ⁄ l while remaining within target HbA1c) and HbA1c nonresponders (baseline HbA1c ‡ 7.0%, with HbA1c reduction < 0.5%). Subjects participated in interviews focusing on their psychosocial experiences with CGM. Results: Major features that differentiated responders (both the HbA1c and hypoglycaemia groups) from non-responders were as

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follows: (i) coping with frustrations – responders used self-controlled rather than emotions-based coping when faced with CGM frustrations; (ii) use of information – responders used retrospective pattern analysis in glycaemic management; (iii) ‘significant other’ ⁄ spousal involvement – responders endorsed interest, encouragement and participation by their loved ones. Both responders and non-responders expressed body image concerns when wearing the monitoring devices. Conclusions: This study emphasises the significance of coping skills, retrospective data review and involvement in the effective management of CGM. These data can help to improve patient selection and guidance in the use of this new technology. • Comment: This is one of a few studies that examined directly the positive psychosocial factors associated with the use of CGM. Although this study examined an adult population it also included adolescents aged 15–18 (being a qualitative study there was not enough data differentiating the adolescents’ subgroup). Two factors found to be related to diabetes management (coping with frustrations and use of information) may be associated with executive functioning which is crucial from the neuropsychological developmental point of view. The ability to plan ahead, organise, use flexible thinking and deal with frustrations is associated with prefrontal cortex functioning and ADHD problems in children and youth. Treating this problem independently might help to improve diabetes management (10,11). One can assume that the importance of psychosocial factors that were found to be significant for adults such as emotion regulation and social support will be even more important among children and adolescents.

CONTINUOUS SUBCUTANEOUS GLUCOSE INFUSION – INSULIN PUMPS Predictors of glycaemic control in patients with type 1 diabetes commencing continuous subcutaneous insulin infusion therapy S. Shalitin,1 M. Gil,1 R. Nimri,1 L. de Vries,1 M. Y. Gavan,1 M. Phillip1 1 Institute of Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Copyright Journal compilation ª 2010 Diabetes UK

Diabet Med 2010; 27: 339–47 Background: Patients with type 1 diabetes who changed their diabetes management into a CSII regimen were examined in order to identify variables that predict glycaemic control, and to improve patient selection for this treatment. Methods: The notes of 421 type 1 diabetic patients aged 2.6–39.8 years who initiated CSII treatment and used it for ‡ 1 year were reviewed. At pump initiation, the mean age was 15.9 ± 7.2 years, mean diabetes duration 6.4 ± 5.8 years. Mean time of CSII use was 4.1 ± 2.1 years. Good glycaemic control was defined by HbA1c stratified by age (American Diabetes Association target levels). Improvement in glycaemic control was defined as a reduction of ‡ 0.5% in HbA1c from baseline. The change in the rate of severe hypoglycaemic or diabetic ketoacidosis events was also determined. Results: A significant sustained decrease in HbA1c was observed with CSII for an average of 6 years, without increased rates of hypoglycaemia. Achievement of target HbA1c was significantly associated with the following parameters at pump initiation: lower HbA1c (p < 0.001), younger age (< 12 years), shorter diabetes duration (p < 0.001) and more frequent daily self-monitoring of blood glucose (p < 0.01). Improved glycogenic control was associated with longer CSII use (p = 0.032) and higher HbA1c at CSII initiation (p < 0.001). Conclusions: Patients with a high HbA1c who changed to CSII therapy demonstrated a sustained decrease in HbA1c and improved glycaemic control. Young age, frequent selfmonitoring of blood glucose and lower HbA1c at pump initiation were identified as predictors of achieving glycaemic targets with CSII. • Comment: In this study, the authors found that patients who switched into CSII therapy showed better results in their diabetes management. However, several demographic and behavioural variables such as young age, the frequency of blood tests and low level of HbA1c were identified as predictors for good management, suggesting that adherence to treatment is still playing a major role in achieving glycaemic targets with CSII. The findings of the present paper also encourage the diabetes team providers to consider switching patients to CSII use at an early age and soon after diagnosis, especially if they are compliant with their present therapy. This study raises the question of the selection criteria for insulin pump treatment. The main question in this subject is whether the approach should be constructing a proto-

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col which will evaluate the suitability of a patient to insulin pump from a multi-professional perspective and will include only patients who are very high functioning (12), or, on the other hand, whether the selection criteria should be more permissive and the main effort of the team would focus on assisting the patient and his ⁄ her family to adapt to insulin pump management in the best way they can.

Sociodemographic and psychosocial factors associated with continuous subcutaneous insulin infusion in adolescents with type 1 diabetes S. Cortina,1,3 D. R. Repaske,2,3 K. K. Hood1,3 1 Center for Adherence and Self-Management, Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA, 2Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA, and 3Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA Pediatr Diabetes 2010; 11: 337–44 Copyright ª 2010 John Wiley & Sons A ⁄ S Background: The relation between sociodemographic factors and psychosocial adjustment to CSII use among adolescents with type 1 diabetes was evaluated. Methods: A total of 150 adolescents with type 1 diabetes and their caregivers completed measures of general psychological functioning, diabetes functioning and stressful life events. Blood glucose monitoring frequency and glycaemic control were also assessed. Results: A large proportion of the variance in CSII use was associated with sociodemographic, diabetes-specific and psychosocial variables. CSII use was significantly correlated with higher frequency of blood glucose monitoring and having private insurance, and was also associated with adolescent and caregiver reports of sharing of responsibilities around diabetes management and negative affect regarding blood glucose monitoring. Conclusions: Adolescents using CSII were significantly different from their counterparts using MDI in insurance status, diabetes management behaviour, and family functioning related to diabetes. • Comment: This is another cross-sectional, non-randomised study comparing pump users to non-users. The differences observed in the groups (higher socioeconomic status in pump users) may reflect that it was easier for them to obtain insurance coverage, and the differ-

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ences in family functioning may reflect that caregivers were more inclined to prescribe pump therapy to better functioning families. For many years clinicians have been searching for a key variable that would determine the success of a given therapy for chronic diseases such as diabetes. The paper has constructed an ecological system model which creates equilibrium between inner and external circles of the patient’s diabetes management – specific psychological, CSII mastering skills, familial and family environment–sociodemographic characteristics and stressful life events factors, suggesting that helping the patient to improve his ⁄ her diabetes management should include not just the psychological aspects of the individual but also his ⁄ her close as well as his ⁄ her remote environment. Results suggest that an understanding of the sociodemographic and psychosocial factors may assist in predicting the treatment effectiveness.

Is insulin pump therapy better than injection for adolescents with diabetes? Y. P. Wu,2 M. M. Graves,1 M. C. Roberts,1 A. C. Mitchell2 1 Clinical Child Psychology Program, University of Kansas, Lawrence, KS, USA, and 2 Tallahassee Memorial Hospital Diabetes Center, Tallahassee, FL, USA Diabetes Res Clin Pract 1010; 89: 121–5 Background: CSII therapy is frequently used as an alternative to MDI in the management of paediatric type 1 diabetes. The purpose of the current study was to examine whether there are different medical and psychosocial results for adolescents using MDI vs. CSII as experienced in a routine clinical environment. Methods: Adolescents participating in the study and their parents completed questionnaires assessing quality of life and parenting stress. A1c levels were obtained from the medical files. Results: Metabolic and psychosocial outcomes did not differ significantly between adolescents using CSII and those treated with MDI. Higher parental stress was associated with older child’s age, lower quality of life and higher A1c levels. Conclusions: Physicians might present this information to parents and their adolescent children along with the potential advantages and disadvantages of each insulin regimen therapy. • Comment: This non-randomised cross-sectional study confirms other randomised trials in paediatrics, suggesting that there is no sig-

nificant difference between adolescents using CSII and adolescents using MDI in their A1c levels. According to the authors the similar medical and psychosocial outcomes associated with MDI and CSII may be due in part to advances in MDI therapy. However, the parental stress level significantly correlated with lower quality of life and higher A1c levels, suggesting that the choice of MDI vs. CSII may be only one of many factors that affect an adolescent’s diabetes-related medical and psychosocial outcomes. As the authors put it ‘there is no universal ‘‘best choice’’ for an insulin regimen (pump versus MDI). Instead, physicians might help families consider the advantages and disadvantages of both insulin regimens.’

Factors associated with increased risk of insulin pump discontinuation in paediatric patients with type 1 diabetes L. de Vries, Y. Grushka, Y. Lebenthal, S. Shalitin, M. Phillip Institute of Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel Pediatr Diabetes 2010 Aug 15 [Epub ahead of print] Background: The aim of this study was to find the rate of and predictors for insulin pump discontinuation among children and adolescents with type 1 diabetes. Methods: Medical chart review of 530 type 1 diabetes patients who started pump therapy revealed that 11.3% had discontinued pump use after 3 days to 5 years; of these 9.1% discontinued pump use at least 3 months after initiation. Data were retrieved from the files of these patients and from those of 100 randomly assigned pump-treated patients. Results: The pump discontinuation group had a significantly higher proportion of females (75% vs. 46%, p = 0.001) and patients older than 10 years (93.8% vs. 80%, p = 0.03) compared with the reference group. No significant difference was found between groups in age at diagnosis, pubertal stage, anthropometric data, duration of diabetes at pump initiation, rate of severe hypoglycaemic and ketoacidosis episodes, number of daily insulin injections and blood glucose measurements before pump treatment. At pump initiation and at the last follow-up visit, HbA1c was significantly higher in patients discontinuing pump therapy than in the controls. Conclusions: Almost 90% of the cohort maintained CSII therapy. Factors correlated

to higher risk of pump discontinuation were female gender, age > 10 years and poor metabolic control at pump initiation. These patients could be assisted by intensified support that may serve to maximise compliance with pump therapy.

Discontinuation of insulin pump treatment in children, adolescents, and young adults. A multicentre analysis based on the DPV database in Germany and Austria S. E. Hofer,1 B. Heidtmann,2 K. Raile,3 E. Fro¨ohlich-Reiterer,4 E. Lilienthal,5 M. A. Berghaeuser,6 R. W. Holl,7 and the German working group for insulin pump treatment in pediatric patients 1 Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria, 2Childrens Hospital, Wilhemstift, Hamburg, Germany, 3 Department of Pediatrics, Charite, Berlin, Germany, 4Department of Pediatrics, Medical University of Graz, Graz, Austria, 5Department of Pediatrics, Ruhr University of Bochum, Bochum, Germany, 6Department of Pediatrics, University of Mu¨nster, Mu¨nster, Germany, and 7 Department of Epidemiology, University of Ulm, Ulm, Germany Pediatr Diabetes 2010; 11: 116–21 Background: This survey checked the discontinuation rate of insulin pump treatment in the paediatric and young adult age groups. Methods: All pump users among the participating centres in the prospective multicentre Diabetes Patient Verlausdokumentation (DPV) (electronic diabetes patient documentation system) documented since 1995 were included in this analysis. Results: From a total number of 11,710 patients with type 1 diabetes treated with insulin pumps, 463 patients (4%) switched from insulin pump treatment to MDI. In the group who stopped pump treatment, the mean duration of pump therapy was 1.7 ± 0.06 years, and 60.5% of the patients were female. The discontinuation rate was lowest in the age group < 5 years (0.1%), followed by the groups aged 5–10 years (0.3%) and 15–20 years (0.8%), with the highest rate of discontinuation in the group aged 10– 15 years (2%). Conclusions: The discontinuation rate of insulin pump therapy was relatively low (4%). Younger age at the time of pump initiation was a predictor of a lower discontinuation rate. The highest rate was seen in adolescents aged 10–15 years. Girls stopped

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insulin pump treatment more often than boys. • Comment: These studies are important since they are focusing on trying to understand the reasons for discontinuation of CSII therapy among type 1 diabetic patients who were already using the pump. The cost of the pump is one of the main obstacles in many countries for the use of this technology. These two papers from different geographic locations and cultures both show that although switching to CSII therapy may be a good choice for most of the patients there is a segment of patients who encounter some difficulties during this process. The studies reveal some specific characteristics of this segment and point out that female patients who are older than 10 are prone to pump discontinuation. In other words, one may say that this study focuses on female adolescents as a high risk group. These findings are consistent with past studies showing that ‘the majority of the patients in the CSII-discontinuation group were girls, and in puberty’ (12). There may be several possible explanations for this result. First, carrying the device on the body might raise body image issues and cause negative feelings of shame and embarrassment. These feelings may be amplified by the possible presence of social anxiety disorder which is common in adolescence and among females. Second, the adolescent girl might feel that connecting to the insulin pump will interrupt the experience of independence and autonomy. Experience which is crucial to identity formation in this developmental period. The results of these two studies suggest that there is a need for further examination of the psychosocial characteristics that designate this group.

Attitudes towards insulin pump therapy among adolescents and young people S. Seereiner,1 K. Neeser,2 C. Weber,2 K. Schreiber,3 W. Habacher,1 I. Rakovac,1 P. Beck,1 L. Schmidt,1 T. R. Pieber1 1 Joanneum Research, Graz, Austria, 2 Institute for Medical Informatics and Biostatistics, Basel, Switzerland, and 3Isoplan Market Research, Saarbru¨cken, Germany Diabetes Technol Ther 2010; 12: 89–94 Background: This study examined reasons for discontinuation of CSII and investigated general attitudes towards CSII therapy among young patients with type 1 diabetes. Methods: A questionnaire was developed using a focus group of young people with diabetes. It was then used to survey a random

sample of adolescents and young people identified by physicians specialising in diabetes care and participating in a voluntary quality improvement initiative in Germany. Results: Eighty-eight patients participated in the survey (22 never used the pump, 20 had formerly used the pump, and 46 were using the pump at that time, with an average age of 20–22 years). Patients who never used the pump had a significantly shorter diabetes duration and had undergone their first diabetes education more recently. Current pump users were significantly younger at the time of the first diabetes education. No significant differences were found between patients concerning where they obtained information about the condition and treatment options. Social and psychological factors were prominent as reasons both for reluctance to try the pump therapy and for discontinuing therapy. Technical problems as a disadvantage of the pump were less likely to be named. Physicians confirmed that discipline and compliance were essential prerequisites for this therapy and supported findings that patients discontinuing pump therapy at their own request tend to do so for non-clinical reasons. Conclusions: Although the insulin pump has been generally accepted by patients for its technical reliability, clinical disadvantages relating to the use of the pump and more commonly social and psychological factors were named as the reason for patients being reluctant to try this therapy or discontinuing use of it. • Comment: This study specifically questioned former pump users about their reasons for discontinuing pump therapy and provides some insight into why adolescent females are more likely to stop CSII therapy. Females found the pump a constant reminder of their diabetes, and thought the pump was more visible and more annoying. In general, former pump users found the pump to be more bothersome during activities and considered the pump to feel like a foreign body, and that catheter insertions were more unpleasant than injections. When asked what would be the preconditions for resuming pump therapy, the most common precondition was an improvement of the catheter, followed by improved handling of the pump (smaller size, water resistance, decreased noise) and integration of glucose measurements with the pump. This emphasises that the human interface of catheters, tapes and wearing devices is critical. It also emphasises the important role of social and psychological factors in the process of trying or discontinuing use of pump therapy. In fact, the study suggests that one cannot predict the probability of pump therapy success without considering social and psycho-

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logical factors. The study emphasises that the dialogue with the patient should not be restricted only to attempts to understand the patient’s mental and emotional representations of his or her body that may influence his ⁄ her adherence to insulin pump therapy, but also consider the concrete physical challenges and the place of body issues that they have to cope with.

GLUCOSE CONTROL Type 1 diabetes among adolescents. Reduced diabetes self-care caused by social fear and fear of hypoglycaemia A. M. Di Battista, T. A. Hart, L. Greco, J. Gloizer Department of Psychology, School of Behavioural Science, University of Melbourne, Victoria, Australia The Diabetes Educator 2009; 35: 465–75 Background: The aim of this study was to investigate the correlations between social anxiety and adherence to diabetes self-management and quality of life, and to evaluate what the effects of fear of hypoglycaemia are on these associations in adolescents with type 1 diabetes. Methods: Adolescents with type 1 diabetes were recruited during clinic visits at two international centres. Participants filled in a questionnaire on social anxiety, behavioural adherence to the diabetes self-management regimen, quality of life, fear of hypoglycaemia, and recent HbA1c level. Results: Seventy-six adolescents participated in the study. Social anxiety levels were not statistically different between genders. In boys, social anxiety was associated with worse diet and insulin injection adherence. Social anxiety was positively correlated with poor quality of life in both genders. Fear of hypoglycaemia mediates the relationship between social anxiety and insulin adherence in boys. Conclusions: Social anxiety may interfere with behavioural adherence and quality of life among adolescents with type 1 diabetes. Screening and treatment of social anxiety may result in better adherence and increased quality of life. • Comment: The rationale for this study were the evidence-based studies that showed that fear of hypoglycaemia involves not only the fear of the negative acute health consequences of an episode, but also the fear of social reprisal for behavioural, motor and cognitive changes that occur during an epi-

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sode. In addition, social anxiety has a very high prevalence among adolescents and recent literature suggests that perceptions of peer reactions are important in predicting adolescent adherence to type 1 diabetes regimens. This study suggests that although social anxiety may affect the diabetes-related quality of life in both genders (which may cause depression), it affects only the adherence of the boys. The authors have taken a broad perspective from a contextual point of view on the issue of fear of hypoglycaemia by associating it with the issue of social anxiety which has a very high prevalence among adolescents and has some very clear developmental characteristics. By doing so the authors remind us that the coping efforts and difficulties of the patient should be seen as part of an integrated whole that contains the patient’s life events and general psychological strengths and weaknesses and not only his ⁄ her specific attitudes toward his ⁄ her diabetes management. The process of identifying the main issues that patients and their families are dealing with and the information they need to cope with has of course some important medical as well as economic aspects. However, it also has a very important psychological aspect

which is stated in the title of this paper, which emphasises that the essence of the process is to educate and to communicate with the patients and their families in order to initiate psychological change that will create a process of empowerment. Another important aspect of this issue is that the educators should be able to evaluate the level of understanding of the patient and his ⁄ her family. The evaluation process will of course include cognitive understanding but also emotional factors such as fear of technology, psychological strengths and weaknesses such as the ability to adjust and dealing with frustration and motivation for change (7–9).

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1 Moreland EC, Tovar A, Zuehlke JB, Butler DA, Milaszewski K, Laffel LM. The impact of physiological, therapeutic and psychosocial variables on glycemic control in youth with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2004; 17: 1533–44. 2 Svoren BM, Volkening LK, Butler DA, Moreland EC, Anderson BJ, Laffel LM. Temporal trends in the treatment of pediatric type 1 diabetes and impact on acute outcomes. J Pediatr 2007; 150: 279–85. 3 Buckingham B, Xing D, Weinzimer S et al. Use of the DirecNet Applied Treatment Algorithm (DATA) for diabe-

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ª 2011 Blackwell Publishing Ltd Int J Clin Pract, February 2011, 65 (Suppl. 170), 83–90


ATTD 2010 Yearbook