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Nov 2009

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Featured in this issue Gestational diabetes C-reactive protein in risk assessment Smoking cessation Aspects of hypothyroidism Diabetes and breastfeeding Primary care role model for diabetic patients


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References: 1. Klein O. et al. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes, Obesity and Metabolism. 2007;9:290-299. 2. Philis-Tsimikas A et al. Comparison of Once-Daily Insulin Detemir with NPH Insulin Added to a Regimen of Oral Antidiabetic Drugs in Poorly Controlled Type 2 diabetes. Clinical Therapeutics. 2006;28(10):1569-1581. 3. Rosenstock J et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia. 2008;51:408-416.

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OBESITY IPIDAEMIA DYSL

ISSN 1811-6515

IN RESISTANC E INSUL

HYPERTENSION

DIABETES &

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Diabetes & vascular disease

S

E

V

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R DISEA

THE SOUTH AFRICAN JOURNAL OF

HYPER INSULINAEMIA

in association with the British Journal of Diabetes & Vascular Disease

THROMBOSI S HYP

ERGLYCAEMIA

VOLUME 6 NUMBER 4 • november 2009 www.diabetesjournal.co.za

Corresponding Editor PROF WF MOLLENTZE Head of the Department of Internal Medicine, University of the Free State, Bloemfontein Consulting Editors PROF J-C MBANYA PROF AJ BRINK National Editorial Board DR A AMOD Centre for Diabetes, Endocrinology and Metabolic Diseases, Life Healthcare, Chatsmed Gardens Hospital, Durban SR K BECKERT Diabetes Nurse, Paarl PROF F BONNICI Emeritus Professor, Faculty of Health Sciences, University of Cape Town and President of Diabetes South Africa PROF R DELPORT Department of Family Medicine, University of Pretoria

CONTENTS

Editorial

131

Gestational diabetes: time to act BD Kramer

134

C-reactive protein as a marker of cardiovascular risk. Chicken, egg or turkey? B Karet

139

Should we measure C-reactive protein in risk assessment? AJ Dalby

DR L DISTILLER Director of the Centre of Diabetes and Endocrinology, Houghton, Johannesburg

Review

DR F MOHAMED Department of Endocrinology, Grey’s Hospital, Pietermaritzburg

141

Smoking cessation 1: choosing the right pharmacotherapy for each patient

PROF CD POTGIETER Specialist Nephrologist, University of Pretoria and Jakaranda Hospital, Pretoria PROF K SLIWA Associate Professor of Medicine and Cardiology, Baragwanath Hospital, University of the Witwatersrand, Johannesburg PROF YK SEEDAT Emeritus Professor of Medicine and Honorary Research Associate, University of Natal, Durban International Editorial Board PROF IW CAMPBELL Physician, Victoria Hospital, Kircaldy, Scotland, UK PROF PJ GRANT Professor of Medicine and head of Academic Unit of Molecular Vascular Medicine, Faculty of Medicine and Health, University of Leeds; honorary consultant physician, United Leeds Teaching Hospitals NHS Trust, UK PROF J-C MBANYA Professor of Endocrinology, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Cameroon and President-Elect, International Diabetes Federation (2006−2009) PROF N POULTER Professor of Preventive Cardiovascular Medicine, Imperial College, School of Medicine, London, UK DR H PURCELL Senior Research Fellow in Cardiology, Royal Brompton National Heart and Lung Hospital, London, UK

P Aveyard, A Parsons, R Begh

143

Smoking cessation 2: nicotine replacement therapy – new tricks with old drugs P Aveyard, A Parsons, R Begh

149

Color profile: Generic CMYK printer profile Composite Default screen

Cardiovascular and diabetes aspects of hypothyroidism J Lazarus

Patient Information Leaflet

147

Starting on a statin to prevent heart and vascular disease and stroke

Diabetes Educator’s Focus

152

Diabetes and breastfeeding

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B Campbell Safety-Coated

156

R

Diabetes Personality A primary care role model for diabetic patients: Sr Sesi Ramonotsi

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Assistant Editor: Special Assignments JULIA AALBERS TEL: (021) 976-4378 FAX: 086 610 3395 e-mail: jaalbers@icon.co.za Production Editor SHAUNA GERMISHUIZEN TEL: (021) 785-7178 FAX: 086 628 1197 e-mail: shaunag@xsinet.co.za Editorial Assistant and Circulation ELSABÉ BURMEISTER TEL/FAX: (021) 976-8129 e-mail: elsabe@cvja.co.za Production Co-ordinator WENDY WEGENER TEL: (021) 976-4378 e-mail: wendy.icon@wol.co.za

The South African Journal of Diabetes and Vascular Disease is published four times a year for Clinics-Cardive Publishing Co. by Martingraphix and printed by Durbanville Commercial Printers. Articles in this Journal are sourced as per agreement with the British Journal of Diabetes and Vascular Disease

All correspondence to be directed to: THE EDITOR PO BOX 1013 DURBANVILLE 7551 or info@cvja.co.za TEL/FAX: (021) 976-8129 INT: 2721 976-8129

The opinions, data and statements that appear in any articles published in this journal are those of the contributors. The publisher, editors and members of the editorial board do not necessarily share the views expressed herein. Although every effort is made to ensure accuracy and avoid mistakes, no liability on the part of the publisher, editors, the editorial board or their agents or employees is accepted for the consequences of any inaccurate or misleading information.

EASD Watch

158

Update from the European Association for the Study of Diabetes, Vienna, 2009

IDF Watch

164

Update from the World Diabetes Congress, Montreal, 2009

Drug Trends in Diabetes

167

Efficient and safe glucose control in type 2 diabetes: new ADVANCE results from IDF

It is now possible to improve symptoms and prognosis in angina patients

Practical guidance on intensifying insulin therapy in type 2 diabetes using BIAsp 30

176

Diabetes News

Front cover photographs from left to right: This visual of C-reactive protein (CRP) relates to the expert review of CRP as a maker of cardiovascular risk (page 134) Diabetes personality in this issue is Sr Sesi Ramonotsi, who works at Pelanomi Hospital, Bloemfontein. Read more about her dedication to educating diabetic patients and be inspired. Picture by Deon Ellis Photography (page 156) Smoking is not a good lifestyle choice. Read how to stop, or help your patients who are at cardiovascular risk to stop smoking (pages 141 and 143) Color profile: Generic CMYK printer profile Composite Default screen

It's the shell that makes safer.

Safety-Coated R

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Each tablet contains Aspirin 81mg. Reg.No.: 29/2.7/0767 Pharmafrica (Pty) Ltd, 33 Hulbert Road, New Centre, Johannesburg 2001 Under licence from Goldshield Pharmaceuticals Ltd. U.K.

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

EDITORIAL

Gestational diabetes: time to act Brian D Kramer

G

 stational diabetes (GDM) is defined as any e glucose intolerance detected for the first time during pregnancy.1 Therefore this embraces a heterogeneous group of conditions categorised by any degree of hyperglycaemia, including type 1 diabetes (T1DM) and monogenic forms of diabetes. However, this is most often understood to mean a transient form of diabetes emerging during the second half of pregnancy and remitting post partum. Although this latter form of diabetes, including the attendant risk of producing large-for-gestational-age babies and conferring a higher risk of future maternal diabetes has long been recognised, it is only relatively recently that the true spectrum of risk associated with this has begun to emerge. Categorising a patient as having GDM has been the subject of controversy2 as, in common with other disorders, GDM is defined by measuring a single risk factor (under a variety of defined conditions). This risk factor is a continuous variable in the general population (in this case, glucose). This has graduated from an earlier statistical approach in which abnormality was accepted when values lay outside of two standard deviations of the mean, to the modern era when abnormal values have been defined in terms of the perceived risk that accrues from these (see HAPO study group).3,4 However, this remains a work in progress, so that as the risk associated with various levels of glucose intolerance becomes better understood, the definition is likely to become further refined. A further area of uncertainty relates to the numerous screening tests used by different prenatal clinics worldwide. Often designed as practical ways to identify patients in a particular clinical setting, these should not necessarily be equated with the diagnostic standards laid down by the World Health Organisation, which are required for epidemiological and other studies. For a review of these see Hough.5 The incidence of GDM has risen steadily over the last few decades.6,7 This may, in part, relate to a change in diagnostic criteria and/or to an increase in screening. However, studies performed in the USA and Australia point to a true increase in incidence across a spectrum of ethnic groups and at all maternal ages. For example, in northern California between 1991 and 2000, a rise in incidence of 3.7 to 6.6% was observed.8,9 The reasons for this increase have been

Correspondence to: Brian D Kramer Centre for Diabetes and Endocrinology Houghton, Johannesburg. Tel: +27 (0)11 712-6000 e-mail; brian@cdecentr.co.za S Afr J Diabetes Vasc Dis 2009; 6: 131–133.

VOLUME 6 NUMBER 4 • NOVEMBER 2009

Brian D. Kramer incompletely explored10 but may include an increase in the prevalence of pre-existing maternal obesity and other risk factors.11-13 Moreover, the increasing prevalence of type 2 diabetes (T2DM) in the background population of this age group may have lead to an increased rate of detection during pregnancy. More studies are needed in this area. All women experience a substantial change in insulin sensitivity during pregnancy. During early pregnancy, the change in sensitivity is variable and may be enhanced.14 This may promote maternal fat deposition. During the latter half of pregnancy, women develop a level of insulin resistance approximating the level encountered in a newly diagnosed type 2 diabetic. This is associated with a maternal state of catabolism as evidenced, for example, by raised triglycerides and free fatty acids, which are in turn available to the foetus. Maternal insulin-mediated glucose disposal worsens by 40 to 60% compared with pre-pregnancy, and insulin secretion increases by a factor of 250% to compensate for this.14 Abdominal muscle biopsies obtained at caesarian section suggest that a possible explanation for this at a cellular level relates to defective tyrosine phosphorylation of the transmembranal insulin receptor and a depleted level of IRS (insulin receptor substrate), an important link in the post-receptor chain of insulin signalling with which the insulin receptor interacts.14 These changes may reflect activation of alternative intracellular pathways leading to serine phosphorylation of the insulin receptor (which has the opposite effect to tyrosine phosphorylation), as well as enhanced degradation and depletion of IRS. These alternate pathways may encompass PKC, JNK and NFkB, which are activated by TNF-alpha and other cytokines, as well as the

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mTOR pathway, which is activated by the availability of excess nutrients as well as low levels of adiponectin. All of these changes have been observed during pregnancy.14 The panoply of elevated cytokines encountered during pregnancy is similar in pattern to that observed in obesity per se. Some are of maternal origin, but many are of placental origin.15 The view of the placenta as a simple selective barrier between maternal and foetal circulation is becoming redefined, with the recognition that it has an important regulatory role in the interaction between mother and foetus, with feedback mechanisms operating independently in both circulations. In addition to the putative effect of cytokines on maternal insulin sensitivity, traditional hormones of placental origin may also be involved, for example, human placental growth hormone.14 The immediate increase in insulin sensitivity post delivery points to the importance of the placental origin of the factors responsible for insulin resistance, but it remains unclear which these may be and how they may operate. It also remains unclear whether the mechanism for the insulin resistance during pregnancy is mediated by a mechanism that is the same as that which sets the stage for T2DM. Does insulin resistance account for GDM? Although the change in insulin sensitivity is quantitatively similar in GDM and normal pregnancy, women destined to develop GDM are more insulin resistant prior to pregnancy and are therefore more insulin resistant during pregnancy.16 Nevertheless, this is insufficient to allow for the development of GDM. Studies indicate that compared with normal pregnancy, insulin secretion in GDM is lower for all levels of insulin sensitivity, indicating the presence of a defect in beta-cell functioning.16,17 The nature and pathogenesis of the beta-cell defect remains to be elucidated but is believed to antedate the pregnancy and may reflect the changes in beta-cell function that are commonly encountered in association with insulin resistance. Equally important is that the beta-cell defect persists (and evolves) postpartum17 and virtually assures the mother will develop T2DM at a later stage. The maternal incidence of diabetes after having GDM is about 10% in the first three months after delivery and 10% per year thereafter.18 In this sense, GDM can be viewed simply as a phase in the evolution of T2DM. An important consideration arising from our current understanding of the pathogenesis of GDM is the question whether GDM and the subsequent progression to T2DM is preventable. To answer this, it is necessary at the inception to identify those at risk. As pointed out, the major factor determining the development of GDM in the face of the diminished insulin sensitivity encountered during pregnancy is an associated underlying beta-cell defect.16 This is not readily detectible prior to pregnancy but can be inferred as likely to be present in any patient with features of insulin resistance prior to pregnancy – including obesity. Such patients are candidates for pre-conception intervention aimed at preventing GDM and this would inevitably include lifestyle change as part of the approach. However, there is little that has been done in this area to date and it is unclear whether

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insulin sensitisers could be of value in this setting. Once GDM develops, any pre-existing beta-cell defect becomes manifest and the task is to prevent postpartum evolution to T2DM and, failing that, to detect it at an early stage so as to begin treatment. The potential to influence the development of subsequent T2DM using both lifestyle change as well as pharmacotherapy has been shown in the TRIPOD/PIPOD studies as well as in the DPP trial, which also recruited prior gestational diabetics.19 Early detection requires formal glucose tolerance tests at three months and then annually after delivery.20 These important follow-up tests are less frequently performed than is ideal. The risk that accrues to the pregnancy itself has also been the subject of uncertainty. Experience derived over a long period from pregnancy data in T1DM has taught us to expect poor outcomes such as macrosomia, prematurity and intrauterine diabetes, to mention only a few complications of pregnancy exacerbated by diabetes. However, whether the lesser degrees of asymptomatic hyperglycaemia associated with GDM carry a similar spectrum of risks, and whether treatment influences the outcome, is in the process of being belatedly answered by trials such as the ACHOIS and MIG studies.21,22 All of the data generated thus far suggest that GDM does matter and that lowering blood glucose levels improves outcome. This has led to significant policy shifts, with the implementation of universal testing for GDM in all pregnant women in some countries, as opposed to screening only designated high-risk individuals, with the inevitable loss of sensitivity that this implies. Most intriguing however is what happens to the infant born of a gestational diabetic. Long-term observational studies are in progress with a view to examining a variety of possible effects. At this early stage several important parameters have already become prominent – among these are body weight, glucose intolerance and blood pressure. Increased infant weight-for-gestational-age at birth is associated with maternal diabetes.23-26 Although these infants may loose excess weight rapidly after delivery, this is only temporary, and in some but not all cohorts studied, by the second year after birth they have become significantly heavier than infants born of non-diabetic mothers.27 This subsequent tendency to weight gain is observed even when the infant is not obese at birth. This relative degree of overweight at birth continues to track through puberty and beyond,22 such that obese babies born of diabetic mothers become obese adolescents, thereby assuming all the attendant risks associated with this. The mechanism accounting for these important developments remains speculative, but may reflect a resetting of the foetal adipo-insular axis, leading to insulin resistance and childhood adiposity.27 The key question of whether intervention to prevent or treat GDM decreases the risk for obese children (and adults) remains a tantalising one. Although genetic factors have received attention as a possible explanation for these developments in GDM offspring, the discordant development of siblings (Pima Indians) born either

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before or after the maternal development of diabetes attests to the importance of the intra-uterine metabolic milieu.27 The rate of impaired glucose tolerance (IGT) or T2DM in GDM offspring is a further cause for concern. In Pima Indians, an ethnic group with an excessively high risk for T2DM generally, the risk of T2DM is markedly increased in GDM offspring, with a grading of risk according to the severity of maternal glucose intolerance during pregnancy.27 By age five to 14 years, T2DM is present almost exclusively among the offspring of diabetic mothers.27 Similar observations are derived from the Chicago study which is ongoing and following the children through to adulthood. A recent report from this group indicates that at an average age of 12.3 years, offspring of diabetic mothers had a significantly higher prevalence of IGT (19.3 vs 2.5%) compared with age- and gender-matched controls.28 Again, sibling studies point to the intra-uterine environment being the major contributor to this, as opposed to genetic factors.27 Furthermore, this increased risk for IGT/T2DM also applies to the offspring of mothers with T1DM.27,28 Although it has not been conclusively shown that this early form of IGT/T2DM occurring in the young has the same underlying pathogenesis as T2DM in adults, it appears that both insulin resistance and a beta-cell defect need to coexist for this to develop. In experimental animals with no genetic tendency to diabetes, hyperglycaemia during pregnancy led to IGT with both impaired insulin action and secretion in the adult offspring.27 In adult Pima Indians with normal glucose tolerance, the acute insulin response was about 40% reduced in the offspring of mothers diabetic during pregnancy, compared with siblings born before the development of diabetes in the mother. Moreover, adult offspring of T1DM mothers also had a decreased insulin response.27 It therefore appears that hyperglycaemia during gestation may in some way programme the foetal pancreas, predisposing to subsequent impairment of insulin secretion. Arising from these observations are a number of conclusions. Among these are the importance of the intrauterine environment as a determinant of the adult phenotype and disease. Since this is potentially modifiable, studies are required to point us in the direction most likely to be useful and cost effective as regards strategies to prevent GDM and the subsequent downstream effects on mother and child. Worrisome is the increasing incidence of GDM, meaning that an increasing proportion of offspring are at risk to develop degrees of glucose intolerance, and by so doing will in turn expose their own offspring to the effects of an unfavourable intra-uterine environment, which will inevitably have a multiplier effect in future generations. This is a public health matter of prime importance and therefore input is required from concerned governments.

References 1. Proceedings of the 4th international workshop-conference on gestational diabetes mellitus. Diabetes Care 1998; 21(Suppl 2); B1–167.

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EDITORIAL

2. World Health Organisation. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Geneva: WHO, 1999 (WHO/ NCD/NCS/99.2). 3. Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycaemia and adverse pregnancy outcomes. N Engl J Med 2008; 358: 1991–2002. 4. HAPO study cooperative research group. Associations with neonatal anthropometrics. Diabetes 2009; 58: 453–459. 5. Hough GA. Interesting times. S Afr J Diabetes 2008; 1: 9–12. 6. Ferrara A. Increasing prevalence of gestational diabetes mellitus. A public health perspective. Diabetes Care 2007; 30(Suppl 2): S141–146. 7. Dabelea D, Snell-Bergeon JK, Hartsfield CL, et al. Increasing prevalence of GDM over time and by birth cohort. Kaiser Permanente of Colorado GDM screening program. Diabetes Care 2005; 28: 279–284. 8. Ferrara A, Kahn HS, Quesenberry CP, et al. An increase in the incidence of gestational diabetes mellitus: northern California 1991–2000. Obstet Gynecol 2004; 103: 526–533. 9. Ishak M, Petocz P. Gestational diabetes amongst Aboriginal Australians: prevalence, time trend, and comparison with non-Aboriginal Australians. Ethn Dis 2003; 13: 55–60. 10. Jovanovic L, Pettitt DJ. Gestational diabetes mellitus. J Am Med Assoc 2001; 286: 2516–2518. 11. Dempsey JC, Sorensen TK, Willimson MA, et al. Prospective study of GDM risk in relation to maternal recreational physical activity before and during pregnancy. Am J Epidemiol 2004; 159: 663–670. 12. Moses RG, Shand JL, Tapsell LC, et al. The recurrence of GDM; could dietary differences in fat intake be an explanation? Diabetes Care 1997; 20: 1647–1650. 13. England LJ, Levine RJ, Quan C, et al. Glucose tolerance and risk of GDM in nulliparous women who smoke during pregnancy. Am J Epidemiol 2004; 160: 1205–1213. 14. Barbour LA, McCurdy CE, Hernandez TL, et al. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care 2007; 30(Suppl 2): S112–S119. 15. Desoy G, Hauguel-De Mouzon S. The Human placenta in GDM. Diabetes Care 2007; 30(Suppl 2): S120–S126. 16. Buchanan TA, Xiang A, Kjos SL, et al. What is gestational diabetes? Diabetes Care 2007; 30(Suppl 2): S105–S111. 17. Homko C, et al. Insulin secretion during and after pregnancy in patients with GDM. J Clin Endocrinol Metab 2001; 86: 568–573. 18. Kim C, Newton KM, Knopp RH, et al. Gestational diabetes and the incidence of type 2 diabetes. Diabetes Care 2002; 25: 1862–1868. 19. Ratner RE. Prevention of type 2 diabetes in women with previous gestational diabetes. Diabetes Care 2007; 30(Suppl 2): S242–S245. 20. Kitzmiller JL, Dang-Kilduff L, Taslimi MM, et al. Gestational diabetes after delivery. Diabetes Care 2007; 30(Suppl 2): S225–235. 21. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of GDM on pregnancy outcomes. N Engl J Med 2005; 352: 2477–2486. 22. Rowan JA; MIG investigators. A trial in progress: gestational diabetes. Diabetes Care 2007; 39(Suppl 2): S214–S219. 23. Dunger DB, Petry CJ, Ong KK, et al.Genetics of size at birth. Diabetes Care 2007; 30(Suppl 2): S150–S155. 24. Pettitt DJ, Nelson RG, Saad MF, et al. Diabetes and obesity in the offspring of Pima Indian women with diabetes during pregnancy. Diabetes Care 1993; 16: 10–314. 25. Pettitt DJ, Baird HR, Aleck KA, et al. Excessive obesity in offspring of Pima Women with diabetes during pregnancy. N Engl J Med 1983; 308: 241–245. 26. Pettitt DJ, Bennett PH, Knowler WC, et al. Gestational diabetes and impaired glucose tolerance during pregnancy; long term effects on obesity and glucose tolerance in the offspring. Diabetes 1985; 34(Suppl 2): 119–122. 27. Dabelea D. The predisposition to obesity and diabetes in offspring of diabetic mothers. Diabetes Care 2007; 30(Suppl 2): S169–174. 28. Silverman BL,Metzger BE, Cho NH, et al. Impaired glucose tolerance in adolescent offspring of diabetic mothers: relationship to fetal hyperinsulinism. Diabetes Care 1995; 18: 611–617.

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TOPICAL REVIEW

SA JOURNAL OF DIABETES & VASCULAR DISEASE

C-reactive as as a marker of cardiovascular C-reactiveprotein protein a marker of risk. Chicken, eggrisk. or turkey? cardiovascular Chicken, egg or turkey? Brian Karet Brian Karet GPwSI Diabetes, Leylands Medical Centre, Heaton Bradford BD9 5PZ, UK.

S Afr J Diabetes Vasc Dis 2009; 6 1: 134–139 6

I

n 2006 cardiovascular disease (CVD) cost the UK £14.4 billion in health care costs alone, of which £3.2 billion was attributable to coronary heart disease (CHD). Social costs including employment and community care were estimated to have cost another £12 billion. In 2004, there were about 216,000 deaths from CVD, about half of which were from CHD. However, death rates from CHD have been falling. Between 1997 and 2006 death rates for men between 55 and 64 years of age fell by almost 50%1 and it seems that half of this reduction is due to improvements in the management of risk factors.2 Lifestyle and therapeutic interventions are available for the major risk factors for CVD, namely smoking, high blood pressure, dyslipidaemia, obesity and diabetes. Given the cost implications, how to focus these interventions on the most appropriate groups and individuals is a challenge for all health economies. Traditionally, multiple risk prediction algorithms have been used to predict the absolute and relative risk of CHD (and more recently CVD) over the next 10 years of an individual’s life. The original algorithms based on the Framingham data3 were informed by the relatively small but detailed Framingham Study of predominantly white middle-aged Americans.4 Inflammation as part of the process of endothelial instability has emerged as a key mediator of atherogenesis leading to clinically important CVD events.5 Of numerous inflammatory markers studied, Creactive protein (CRP) has emerged not just as a conveniently and relatively cheaply PCCJ 134

measured marker of CVD6,7 but also according to some, as a key intermediary in the development of vascular inflammation.8,9 Indeed CRP has even been promoted as a population-based screening tool,10 a point which has not escaped the avid attention of the lay press.11 This review will look at what CRP is and examine not just the worth of some of the research but also the usefulness and practicality of using CRP over and above the risk engines currently used in clinical practice.

Dr Tin Evans/Science Photo Library

Introduction

What is CRP? CRP is a plasma protein produced in the liver that derives its name from its binding affinity to the C polysaccharide of pneumococcal cell walls.12 However, it has found usefulness as an easily measurable acute phase protein. Acute phase responses are seen in a variety of conditions ranging from inflammation to infection, tissue damage (such as myocardial infarction) and malignancy. Indeed CRP is used as a marker of disease activity in several rheumatological conditions and can reach levels several hundred times the base line level. It is, however, an entirely non-specific but clearly very sensitive marker in the range of conditions described. Atherosclerosis is also now widely regarded as a chronic inflammatory condition. CRP levels associated with atherosclerosis are, however, significantly lower than those seen in other conditions, typically 3-10 mg/L which many laboratories have previously regarded as being within the normal range. Despite its lack of specificity the promotion of CRP as a marker of CVD has progressed for two main reasons. Firstly,

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the introduction of commercially available assays, first developed in London, with high levels of sensitivity (hsCRP)7 and, secondly, a raft of data associating these marginal CRP levels with CVD both in detecting prevalent disease and predicting future events.13,14

How well is CRP linked with CVD? For over 70 years it has been noted that CRP rises after myocardial infarction15 and for over 20 years that persistently elevated CRP levels after an infarction were associated with a worse outcome.16 More recently and with the increased recognition of the importance of inflammation in unstable atherosclerotic lesions, several large observational trials noted that raised baseline levels of CRP in people with ischaemic heart disease were significantly predictive of future coronary events.17,18 It also seems this is true of people without known ischaemic heart disease19 although the odds ratios are relatively modest. Alongside all the observational studies have been a series of cytological papers 139 VOLUME 6 NUMBER 4 • NOVEMBER 2009


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• The association is unlikely to be causal • CRP may be useful in post MI patients to assess risk of complications • As a marker of cardiovascular risk, it is probably no better than Framingham based risk assessment tools

Figure 1. (A) Relationship between ABPI at inclusion and at 12 months and serum hsCRP at inclusion. The average ABPI at inclusion decreased from the low-CRP group to the high-CRP group (analysis of variance [ANOVA]; p trend = 0.001). (B) The average ABPI at 12 months’ follow-up also decreased from high to low baseline serum hsCRP (ANOVA; p trend = 0.001) B

.9

A

p=0.001 .8 p=0.078

p=0.001

.7

.6

.5 low CRP

intermediate CRP

high CRP

Average (95% CI) ABPI at 12 months, follow-up

• CRP is non specifically associated with inflammation and CVD

Average (95% CI) ABPI at inclusion

Key points

EDITORIAL

.9 p=0.001 .8

.7 p=0.012 .6

p=0.151

.5 low CRP

intermediate CRP

high CRP

Key: ABPI = ankle-brachial pressure index; hsCRP = highly sensitive C-reactive protein; CI = confidence interval Reproduced with permission from Vainas T, Stassen FR, de Graaf R et al. J Vasc Surg 2005: 42: 243-5124

Alongside all the observational studies have been a series of cytological papers suggesting CRP is not just a marker of atherosclerosis but it also plays a key role in the pathogenesis of CVD

140

suggesting CRP is not just a marker of atherosclerosis but also plays a key role in the pathogenesis of CVD,20,21,22 carotid artery plaques23 and peripheral vascular disease (Figure 1).24 It seems therefore that there is an observational association between CRP and CVD and that CRP is present in unstable plaques. However, is it possible that CRP is a totally non-specific marker in CVD as it is in other areas of disease and the correlations are fatuous?25 A relatively novel method of assessing association between observations and events is to use the method of Mendelian randomisation as developed by the Department of Social Medicine in Bristol.26 In the case of CRP, several genotypes exist which lead to statistically significant variations in the basal plasma CRP levels which should translate into different CVD risk, if indeed CRP is causally related to CVD. Also this model will exclude reverse causality, where nascent cardiovascular disease influences CRP levels rather than the reverse. When these genotypes were looked at in samples taken from participants in the British Women’s Health and Heart study by some of the original authors,27 they did not find a causal relationship between CRP and cardiovascular risk factors and by implication CVD. There is one other interesting observation which casts doubt on the causal relationship between CRP and CVD. It might be expected that those individuals with a family history of diabetes or CVD might have higher circulating CRP levels. In a study based on data from the large

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American National Health and Nutrition Examination Survey (NHANES 1999–2000) there was no independent association between family history and CRP.28

Does CRP add to existing multifactorial risk assessments? Elevated CRP levels are well known to be associated with a variety of cardiovascular risk factors including poor glycaemic control, obesity and hypertension and dyslipidaemia10,28 and the more markers of this cohort (known as the metabolic syndrome)29 presents the higher the CRP.30 Most currently used risk assessment tools are based on some or all of these risk factors. So how well does CRP enhance this information? Two main strains of information suggest that it is not particularly helpful: firstly, stands data from populations in both the Framingham Heart Study31 and the previously mentioned NHANES.32 The former prospective study, over eight years involving almost 4,500 asymptomatic men and women, showed raised CRP levels which indicated increased risk of CVD events, but there was no incremental advantage for CRP over an assessment of risk based on a combination of systolic blood pressure, total cholesterol/HDL ratio, diabetes and smoking. The latter paper retrospectively looked at over 15,000 patients from the NHANES III cohort, using similar conventional markers and also included ethnicity, BMI and levels of physical activity as a comparator to CRP. The conclusion was that elevated CRP levels were rare in the absence of conventional risk PCCJ

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Figure 2. Occurrence of a first coronary event within 10 years, estimated by Cox proportional hazards models in percentages. (A) Percentage estimated by a model with FRS adjusted for survey. (B) Percentage estimated for each of the FRS categories by a model with CRP (3 categories) adjusted for FRS (continuous) and survey. Probability values indicate significance status of CRP in the Cox model CRP

B 25

A 25 20

< 1 mg/L 1–3 mg/L > 3 mg/L

p=0.14

20 p=0.02

15 %

%

15

10

10

5

5

0

p=0.28

p=0.03

p=0.19

0 <6

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11–14 15–19

> 20

<6

6–10

11–14 15–19

> 20

Framingham estimate of 10 year risk (%)

Key: FRS = Framingham Risk Score; CRP = C-reactive protein Reproduced with permission from Koenig W, Lowel H, Baumert J, Meisinger C. Circulation 2004; 109: 1349-5338

factors and again the more risk factors, the higher the CRP. Secondly, the major British Women’s Health and Heart Study33 which was both prospective and predictive showed almost no independent association of CRP with CVD once all confounding factors had been excluded. It would seem therefore that although CRP is associated with cardiovascular events, its addition to established risk factor matrixes does not improve their ability to predict coronary events.34-36 The authors of the Framingham Study mentioned above31 come to the same conclusion for cardiovascular risk as a whole. Not surprisingly, the Harvard-based proponents of CRP have very recently responded with a large observational study designed to compare traditional cardiovascular risk prediction models with and without CRP supplementation.37 They do not quote odds ratios but use a “measure of fit” comparing predicted risk to observed risk. They note that while the measure of fit improved with the addition of CRP, the (area under the curve) AUC did not, and suggest that the AUC is not PCCJ 136

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actually suited to discriminate between risk predictors when they share significant odds ratios – i.e. they are all strong predictors. Clearly this essentially statistical discussion has some way to run and rather like the metabolic syndrome discussions is distilling into differing transatlantic perspectives.

Can CRP help in improving the risk stratification of people who may be incorrectly assigned? This is a different question from the one discussed above as different markers of risk may be more sensitive in different subgroups of the population. It does appear from two large studies based on the US Women’s Health Study previously quoted14 that although the addition of CRP does not improve risk prediction for women at low or high risk, in women in the 5% to 20% risk category about 20% were recategorised with the additional use of CRP. This appears also to be true in men who took part in the MONICA study in Germany38 where men with a 10-year Framingham score between 10% and 20% with elevated CRP levels were associated with additional risk (Figure 2). This was not true of men whose risk was lower than 10%. Even more data come from the well-respected Atherosclerosis Risk in Communities (ARIC) study where patients thought to be at low risk specifically because of low LDL levels were shown to be at increased risk where CRP levels were elevated.39 In 2003 a joint statement from the US Centers for Disease Control and Prevention and the American Heart Association (CDC/AHA) on markers of inflammation and cardiovascular disease looked to give a lead in this area in the face of a growing body of evidence and pressure in the lay press to have a mass screening programme. The statement noted that there were already inconsistencies in published data. Rather amazingly it specifically recommended against screening the entire adult population of the United States and supported the concept that CRP is best used to detect increased risk in those people whose conventional multivariable risk factor score gives a 10year risk between 10% and 20%.35 Despite comments from the Reykjavik group36 that this advice might be inappropriate, on balance and in the light of subsequent trial data, it appears the CDC/ADA advice still has validity.

What about other variables affecting CRP? In an “Expert Opinion” review of the clinical use of CRP10, Dr Paul Ridker from Harvard states that in most 141 VOLUME 6 NUMBER 4 • NOVEMBER 2009


TOPICAL REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE settings a single CRP assessment is adequate and suggests CRP measurements have low levels of variability. There are, however, significant published data at odds with these assertions. Firstly, there appears to be significant intra-subject variability over time with very low reliability levels especially in people under 40,40 with women having consistently lower levels than men. Other authors have found such a large intra-subject variability to make the number of repeat readings necessary impractical in a clinical setting.41 Not only does CRP seem to vary over time but it also appears to have a significant seasonal variation, being higher in the winter than in the summer.42 Most importantly of all there appears to be a huge ethnic diversity in baseline CRP measurements.43 Therefore it would appear that race, gender, seasonal and intra-subject variability challenge the usefulness of CRP as a clinical marker of CVD risk.

What happens if CRP is reduced?

As far as cardiovascular risk prediction is concerned there is little robust evidence that CRP is any better than the best multifactorial models we already have

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A variety of non-pharmacological actions known to reduce cardiovascular risk also reduce CRP, including weight loss, diet, exercise and stopping smoking. In addition statins which have a significant benefit for cardiovascular risk also markedly reduce CRP. It has been suggested that the degree of risk reduction by statins in some of the larger trials (CARE, AFCAPS/ TEXCAPS) is related to the level of CRP (i.e. the higher the CRP, the greater the risk reduction). Fibrates and aspirin also lower CRP but to a lesser extent although the cardiovascular benefit is much less obvious.10 COX2 inhibitors and other NSAIDs also reduce CRP but appear to increase cardiovascular risk.44,45 There are as yet sparse data supporting the concept that reduction of CRP independent from other known risk factors reduces CVD events.46

How useful is CRP in cardiovascular disease? As noted above, it is possible that CRP could be of use in the stratification of people at intermediate risk of CVD as assessed by conventional multi-factorial risk tools. The addition of CRP in these circumstances may persuade clinicians and patients to engage more enthusiastically in lifestyle modification and improve adherence to treatment regimens. As many of the risk factors for CVD cause elevation of CRP, it could also be used as a tool for assessing responses to treatment and this has already been done in the case of glitazone47 and statin drugs (Figure 3).48 Some numerically fixated patients may also be impressed by a falling number in a

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test to reflect their reduced CVD risk rather than looking at the scales or measuring their abdominal girth. One other possible clinical use has emerged for CRP and that is as a marker of myocardial infarction or death both in the short and longer term in people with established CVD.49,50 This avenue is interesting as it may allow clinicians to focus attention on those at particularly high risk of complications after cardiological procedures. Inevitably attention has focused on whether therapeutic interventions to reduce CRP will result in benefit in terms of CVD risk reduction. In a recent letter in Nature51 a group of researchers describe a drug that appeared to prevent the myocardial damage known to be caused by exogenous CRP in rats and suggest that therapeutic inhibition of CRP may be useful in containing the damage in acute myocardial infarction. They do admit somewhat disarmingly that the true physiological role of CRP is not known and that CRP inhibition is “unlikely to have adverse effects”. As production of CRP is part of the host response to inflammation, infection and trauma, suppressing it may lead to unexpected outcomes as happened in the recent unfortunate events in the trial using TGN 1412, in which healthy volunteers became very seriously unwell after an apparent ‘cytokine storm’ in response to the drug.52

Conclusion CRP is one of many inflammatory markers and the recent focus on its use and associations is in part due to the relative ease and low cost of the assay. In the UK the test costs about £2. However, as mentioned it is not particularly stable and needs to be interpreted cautiously in ethnically diverse populations. It appears to add little to conventional multifactorial risk stratification although may have a role in refining risk in some subgroups of people and assisting those caring for and treating people at very high risk of CVD. The true role of CRP in the pathogenesis of atherosclerosis is unclear which makes attempts to interfere with the host response seem premature. In respect of its involvement in CVD, although CRP is predominantly hepatically produced, some is generated from damaged endothelial cells but it is unclear whether this is a causal relationship, a result of significant plaque deterioration or merely an unassociated observation. In a recent paper looking at CRP antibodies, no independent association was found with atherosclerosis.53 As the CDC/ADA statement said three years ago, inflammatory markers and cardiovascular disease will PCCJ

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Figure 3. Comparison within each treatment for the median percent change from baseline to 12 weeks in hsCRP overall (grey bars) and for those > 2.0 mg/L (red bars) (n=141) -30.00

-27.3% p=0.002

-24.8% p<0.0001

-18.9% p=0.002

Median change (%)

-20.00

-16.0% p=0.04

-14.1% p=0.17

-15.9% p=0.10

-10.00

0.00

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Simvastatin

Combined

Treatment Key: hsCRP = highly sensitive C-reactive protein Reproduced with permission from Muhlestein JB, May HT, Jensen JR. J Am Coll Cardiol 2006; 48: 39640148

be a “fertile topic for investigations”. This continues to be true and CRP appears to be a useful and interesting clinical research tool with some narrow clinical applications. It may also give additional insight into the way that adipose tissue is involved in the evolution of atherosclerosis. However, as far as cardiovascular risk prediction is concerned, there is little robust evidence that CRP is any better than the best multifactorial models we already have. References 1. www.heartstats.org (accessed 25.8.08) 2. Unal B, Critchley JA, Capewell S. Explaining the decline in coronary heart disease mortality in England and Wales between 1981 and 2000 Circulation 2004; 109: 1101-07. 3. Wilson PW, D’Agostino RB, Levy D et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 1837-47. 4. Gordon T, Castelli WP, Hjortland MC et al. Predicting coronary heart disease in middle-aged and older people: The Framingham Study. JAMA 1977; 238: 497-99. 5. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115-26. 6. Lagrand WK, Visser CA, Hermens WY et al. C- reactive protein as a cardiovascular risk factor: more than just an epiphenomenon? Circulation 1999; 100: 96-102.

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7. Roberts WL, Moulton L, Law TC et al. Evaluation of nine automated highsensitivity C-reactive protein methods: implications for clinical and epidemiological applications. Part 2 Clin Chem 2001; 47: 418-25. 8. Pasceri V, Willerson TJ, Yeh ET. Direct pro-inflammatory effect of Creactive protein on human endothelial cells. Circulation 2000; 102: 2165-8. 9. Torzewski M, Rist C, Mortensen RF et al. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol 2000; 20: 2094-9. 10. Ridker PM. Clinical Application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107: 363-9. 11. New York Times. Predicting Heart Attacks (Editorial) 17.11.2002: pp A10. 12. Du Clos TW. Function of C-reactive protein. Ann Med 2000; 32: 274-8. 13. Zeiske AW, Tracy RP, McMahon CA et al. Elevated serum C-reactive protein levels and advanced atherosclerosis in youth. Arterioscler Thromb Vasc Biol 2005; 25: 1237-45. 14. Ridker PM, Rifai N, Rose L et al. Comparison of C-reactive protein and low density lipoprotein cholesterol levels in the prediction of first cardiovascular event. N Engl J Med 2002; 347: 1557-1565. 15. Pepys M. CRP or not CRP? That is the question. Arterioscler Thromb Vasc Biol 2005; 25: 1091-94. 16. de Beer FC, Hind CRK, Fox KM et al. Measurement of C-reactive protein concentration in myocardial ischaemia and infarction. Br Heart J 1982; 47: 239-43. 17. Thompson SG, Keinast J, Pyke SDM et al. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1997; 332: 635-41. 18. Haverkate F, Thompson SG, Pyke SDM et al. Production of C-reactive protein and the risk of coronary events in stable and unstable angina. Lancet 1997; 349: 462-466. 19. Ridker PM, Buring JE, Shih J et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98: 731-33. 20. Pasceri V, Willerson JT, Yeh ET. Direct pro-inflammatory effect of Creactive protein on human endothelial cells. Circulation 2000; 102: 2165-68. 21. Meuwissen M, van der Wal AC, Niessen HW et al. Co-localisation of intraplaque C-reactive protein, complement, oxidised low density lipoprotein and macrophages in table and unstable angina and acute myocardial infarction. J Clin Path 2006; 59: 196-201. 22. Zwatka TP, Hombach V, TorzewskiJ. C- reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 2001; 103: 1194-7. 23. Grupinski J, Turu MM, Martinez-Gonzalez J et al. Endogenous expression of C-reactive protein is increased in active (ulcerated non-complicated) human carotid artery plaques. Stroke 2006; 37: 1200-04. 24. Vainas T, Stassen FR, de Graaf R et al. C-reactive protein in peripheral artery disease: relation to severity of the disease and to future cardiovascular events. J Vasc Surg 2005; 42: 243-51. 25. Davey Smith G, Ebrahim S. Folate supplementation and cardiovascular disease. Lancet 2005; 366: 1679-1681. 26. Davey Smith G, Ebrahim S. What can mendelian randomisation tell us about modifiable behaviour and environmental exposures? BMJ 2005; 330: 1076-9. 27. Timpson NJ, Lawlor DA, Harbord RM et al. C-reactive protein and its role in the metabolic syndrome: mendelian randomisation study. Lancet 2005; 366: 1954-9.

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28. King DE, Mainhous AG 3rd, Buchanan TA, Pearson WS. C-reactive protein and glycemic control in adults with diabetes. Diabetes Care 2003; 26: 1535-9. 29. Magliano DJ, Shaw JE, Zimmet PZ. How to best define the metabolic syndrome. Ann Med 2006; 38: 34-41. 30. Santos A-C, Lopez C, Guimaraes JT, Barrou H. Central obesity as a major determinant of increased high-sensitivity C-reactive protein in metabolic syndrome. Int J Obesity 2005; 29: 1452-56. 31. Wilson PW, Nam B-H, Pencina M et al. C-reactive protein and the risk of cardiovascular disease in men and women from the Framingham Heart Study. Ann Int Med 2005; 165: 2473-78. 32. Miller M, Zhan M, Havas S. High attributable risk of elevated Creactive protein level to conventional coronary heart disease risk factors. Ann Int Med 2005; 165: 2063-68. 33. Lawlor DA, Smith GD, Rumley A et al. Associations of fibrinogen and C-reactive protein with prevalent and incident coronary heart disease are attenuated by adjustment for cardiovascular risk factors. The British Womenâ&#x20AC;&#x2122;s Health and Heart Study. J Thromb Haemost 2005; 93: 955-63. 34. Greenland P. When is a new prediction marker useful? Arch Int Med 2005; 165: 2454-56. 35. Pearson TA, Mensah GA, Alexander RW et al. Markers of inflammation and cardiovascular disease. Application to clinical and public health practice. A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107: 499-511. 36. Danesh J, Wheeler JG, Hirshfield GM et al. C-reactive protein and other circulatory markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350: 1387-97. 37. Cook NR, Burling JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Int Med 2006; 145: 21-29. 38. Koenig W, Lowel H, Baumert J, Meisinger C. C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort in southern Germany. Circulation 2004; 109: 1349-53. 39. Ballantyne CM, Hoogeveen RC, Bang H et al. Lipoprotein-associated phospholipase A2, high sensitivity C-reactive protein, and risk for incident coronary heart disease in middle aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation 2004; 109: 837-42. 40. Nasermoaddeli A, Sekine M, Kagamimori S. Intra-individual variability of high sensitivity C-reactive protein: age-related variations over time

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in Japanese subjects. Circ J 2006; 70: 559-563. 41. Campbell B, Badrick T, Flatman R, Kanowski D. Limited clinical utility of high-sensitivity C-reactive protein assay. Ann Clin Biochem 2002; 39: 85-8. 42. Sung KC. Seasonal variation of C-reactive protein in apparently healthy Koreans. Int J Cardiol 2006; 107: 338-42. 43. Anand SS, Razak F, Yi Q et al. C-reactive protein as a screening test for cardiovascular risk in a multi-ethnic population. Arterioscler Thromb Vasc Biol 2004: 24: 1509-15. 44. Bogatt P, Brophy JM, Noel M et al. Impact of prolonged cyclooxygenase-2 inhibitors on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein: a randomised placebo controlled trial. Circulation 2004; 110: 934-9. 45. Hermann M, Ruschitzka F. Coxibs, non-steroidal anti-inflammatory drugs and cardiovascular risk. Internal Med J 2006; 36: 308-19. 46. Lloyd-Jones DM, Liu K, Tian L, Greenland P. Narrative review. Assessment of C-reactive protein in risk prediction for cardiovascular disease. Ann Int Med 2006; 145: 35-42. 47. Qayyum R, Adomaityte J. Meta-analysis of the effect of thiozolodinediones on serum C-reactive protein levels. Am J Cardiol 2006; 97: 655-8. 48. Muhlestein JB, May HT, Jensen JR. The reduction of inflammatory biomarkers by statin, fibrate and combination therapy among diabetic patients with mixed dyslipidemia : The DIACOR ( Diabetes and Combined Lipid Therapy Regimen) Study. J Am Coll Cardiol 2006; 48: 396-401. 49. Goldberg A, Gruberg L, Roguin A. Pre-procedural C-reactive protein levels predict myocardial necrosis after successful coronary stenting in patients with stable angina. Am Heart J 2006; 151: 1265-70. 50. Linnemann B, Voigt W, Nobel W, Janka HV. C-reactive protein is a strong predictor of death in type 2 diabetes: associations with multiple factors of the metabolic syndrome. Exper Clin Endocr Diab 2006; 114: 127-34. 51. Pepys MB, Hirshfield GM, Tennent GA et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006; 440: 1217-21. 52. BBC. Drug Trial Man May Lose Fingers http://news.bbc. co.uk/1/hi/health/4914546.stm 16.04.06. 53. Rosenau B, Costenbader KH, Schur PH. C-reactive protein, anti-Creactive protein antibodies and clinical atherosclerosis. Vasc Med 2008; 13: 25-28.

Should we measure C-reactive protein in risk assessment? Anthony J Dalby

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 his review, Karet presents a critical discussion of the n role of C-reactive protein (CRP) in the prediction of atherosclerotic cardiovascular disease (ASCVD). He points PCCJ

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scoring systems, certain studies have called this proposal into question, finding no relationship between the CRP level and the risk of ASCVD. In general, he finds support for the view that CRP does not add to the accuracy of the usual risk-prediction tools because elevations of CRP, occurring as they frequently do in conjunction with recognised risk factors, turn out to be too non-specific. More recent studies also support this view.1 Furthermore, because CRP is an acute-phase reactant that may be elevated in a wide variety of inflammatory conditions and may vary with time, gender and ethnic origin, its accuracy in predicting ASCVD is further compromised. We have yet to understand CRP’s role in the atherosclerotic process, whether it is an active participant in the development of atheromatous plaque, or a by-product of the inflammatory process initiated by the entry of low-density cholesterol into the arterial intima; so-called ‘reverse causality’ resulting in the elevation of its concentration. However, various observations suggest that individuals with low serum lipid levels and a raised CRP are at higher risk of developing the complications of ASCVD and that there is an interaction between the levels of CRP and the serum lipids that predicts higher risk.2 In the PROVE-IT study, it was shown that the greatest improvement in outcome was achieved when both LDL cholesterol and CRP levels were reduced during statin treatment following an acute coronary syndrome. Those authors found that although the statin treatment reduced both LDL cholesterol and CRP, the observed reductions in these two elements were unrelated to one another.3 Similar findings flowed from the more recent JUPITER study in which rosuvastatin was compared to placebo therapy in asymptomatic individuals who would not normally be identified as needing statin therapy, according to their lipid profile, but in whom the CRP level was elevated above 2 mg/l. In that group, statin therapy resulted in a small absolute (but proportionately large) reduction in the incidence of ASCVD. Once again, no correlation could be found between the magnitudes of LDL cholesterol and CRP reduction, although the effectiveness of statin therapy was greatest when both were reduced by treatment.4 Unfortunately, the JUPITER study cannot teach us when CRP should be used, but Correspondence to: Anthony J Dalby Cardiologist, Milpark Hospital, Johannesburg Tel: +27 (0) 11 726-7083 Fax: +27 (0) 11 726-6444 e-mail: ajd@hot.co.za S Afr J Diabetes Vasc Dis 2009; 6: 139–140.

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simply demonstrates the effect of rosuvastatin treatment in individuals selected according the trial’s inclusion criteria. How then should we assess ASCVD risk in our patients? Firstly, all the traditional risk factors should be assessed and submitted to analysis, employing one of the risk calculators, the Framingham score perhaps being the most widely known and applied in South Africa. However, it is vitally important to recognise that risk scoring applies only to individuals without evidence of ASCVD [ischaemic heart disease, cerebrovascular disease or peripheral vascular disease (PVD)] or type 2 diabetes mellitus, as these individuals require intensive secondary preventive treatment irrespective of their ‘risk score’. The most frequently encountered problem however is that of individuals with an intermediate risk score between 5 and 20%, which would not in itself indicate the need for intervention. They are most often middle-aged, female and have one or two moderately elevated risk factors. It is in this group that ancillary tests are most helpful in deciding how to proceed. In these instances one may incorporate factors such as an increased abdominal girth, evidence of renal dysfunction or proteinuria, dysglycaemia and/or elevated CRP into the estimation of risk. Other often fruitful indicators of the presence or absence of disease rather than the risk of disease include carotid and femoral ultrasound, which may reveal an increased intima– media thickness (IMT) or frank atheromatous plaque, and the ankle–brachial index as an indicator of PVD. While coronary atheroma is readily detectable by computed tomographic angiography (CTA), the cost of such studies does not recommend its use in the context of a general screening programme. Therefore, the answer to the question whether CRP should be measured during risk assessment is to use it judiciously in those asymptomatic individuals whose risk score indicates a borderline risk and in whom additional factors may swing the decision for or against pharmacotherapy administered in addition to lifestyle modification.

References 1. Melander O, Newton-Cheh C, Almgren P, et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. J Am Med Assoc 2009; 302: 49–57. 2. Ridker PM. High-sensitivity C-reactive protein. Potential adjunct for global risk assessment in primary prevention of cardiovascular disease. Circulation 2001; 103: 1813–1818. 3. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352: 20–28. 4. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: A prospective study of the JUPITER trial. Lancet 2009; 373: 1175–1182.

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Smoking cessation 1: choosing the right Smoking cessation 1: choosing the right pharmacotherapy for for eacheach patient pharmacotherapy patient Paul Amanda Parsons, Rachna Begh PaulAveyard, Aveyard, Amanda Parsons, Rachna BEGH National Institute of Health Research Career Scientist, UK Centre for Tobacco Control Studies, Primary Care Clinical Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

S Afr J Diabetes Vasc Dis 2009; 62: 141–142 d

M

ost smokers want to stop smoking and intend to stop at some point, according to crosssectional studies.1 Nearly half of all smokers expect not to be smoking in a year’s time, but only two to three in every hundred actually stop smoking permanently each year.2 It is widely recognised that healthcare professionals have an important role to play in helping patients to stop smoking, but what is the best way to achieve this? Although some characteristics of smokers predict success in smoking cessation, including genetic factors, it is not currently possible to use these to individualise choice of smoking cessation therapy. There is no strong evidence for matching therapy to enhance success. Despite this, we offer here some guidance for making sensible choices of pharmacotherapy, based mainly on clinical experience. In a second paper (see page 21), we look at optimising the use of nicotine replacement therapy. Further papers will continue to review optimal approaches for smoking cessation in subsequent issues of PCCJ.

Factors to consider in making choices about pharmacotherapy 1. Heaviness of smoking or tobacco dependence Almost all trials of pharmacotherapy have either specifically included only smokers of 10 or more cigarettes daily or enrolled mainly smokers smoking more than this. Consequently, the evidence for treating lighter (and therefore probably less dependent) smokers is scanty. This is important because one-quarter to one-third PCCJ

of smokers smoke less than this.3,4 There are two relevant trials of treating lighter smokers with nicotine replacement therapy (NRT) (gum and lozenge) that suggest, but do not provide strong evidence, that it would be effective in this group.5,6 Smokers who smoke fewer than 10 cigarettes per day experience troublesome urges to smoke on stopping and during most attempts to stop smoking.7 Also, providing NRT is safe because smokers can titrate the dose of acutely used forms of NRT.8 Consequently, a reasonable position is to provide acute forms of NRT to lighter smokers. There is no evidence that bupropion or varenicline would be effective or ineffective in this population of lighter smokers, so short-acting NRT is the treatment of choice. The US guidelines suggested no pharmacotherapy in this group,9 however, so an alternative strategy would be to support quitting and offer NRT as a rescue therapy should smokers be troubled by symptoms on abstinence. Heavy smokers, or more dependent smokers, can be judged clinically by the number of cigarettes they smoke per day (20 or more), smoking within half an hour of waking, or by exhaled carbon monoxide (above 20 parts per million). Such smokers can be treated as others, but with respect to NRT, should be prescribed combination NRT, which means using a patch plus an acute form of therapy. © iStockphoto.com/Palto

Introduction

2. In pregnancy There is no evidence that NRT is effective in pregnant women specifically, but the trials are too small to know whether or not it is as effective as in non-pregnant adults.10 The speed of nicotine metabolism increases by about 30% in pregnant women,11 which could impair the effectiveness of NRT. A reasonable position is to discuss use of NRT, ideally within the context of specialist support, and to use acute forms of NRT such as gum or inhaler or to take nicotine patches off at night to minimise exposure to the fetus. The same advice would apply to breastfeeding women. This guidance is supported by the National Institute for Health and Clinical Excellence (NICE).12 Other forms of pharmacotherapy are not generally used in pregnancy and their use is not supported by NICE,12 although bupropion is recommended by some experts if the alternative is smoking.13 Tricyclic antidepressants have been used extensively in pregnancy with no 19

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TOPICAL REVIEW REVIEW Key points: Drug choice for smoking cessation • The differences in effectiveness between pharmacotherapies is much less than the difference between treatment and no treatment. Some treatment is better than no treatment. • Nicotine replacement is safe for practically all smokers and is the treatment of choice if minimal supervision is likely, in pregnant smokers, and dependent adolescents. • Use the contra-indications and cautions and the past experience of the patient using medication to the pharmacotherapy to support the current quit attempt.

Although it is important to consider choice of pharmacotherapy, the main issue is ensuring that more smokers use pharmacotherapy to help them stop smoking

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evidence of harm and the British National Formulary advises use of such drugs if the clinician judges the balance of risks to be favourable. If a woman fails to stop with support and NRT, nortriptyline should be considered.

3. Adolescents There is no evidence that NRT is effective in adolescents, but there is also no reason to assume it would not be effective in supporting smoking cessation in carefully selected adolescents. It is licensed down to the age of 12 years and advised in selected individual cases where there is clear evidence of tobacco dependence.12 No other pharmacotherapies are licensed for use in people under 18 years. 4. General considerations It is, of course, imperative to take note of contraindications and cautions on the use of medication in determining choice of smoking cessation pharmacotherapy. However, assuming these do not constrain choices, other factors can play a role. Patients suffering from tobacco dependence have a low probability of ceasing tobacco use permanently on any single attempt to stop smoking.14 Most research shows that experience of having tried to stop previously increases the likelihood of achieving it on the current attempt. Patients often use different pharmacotherapies and their past experience of these is a useful guide to choice for the current occasion, in our experience. However, this has to be interpreted. It is common to hear patients say, ‘I used the nicotine patch and it did not work. Six months after stopping I started smoking again [long after the patch was stopped]’. It is important to be clear that it is the experience only while a person is using medication that gives information on which pharmacotherapy works. In the absence of personal experience, knowing whether behavioural support and clinical supervision will be provided or not is important. Given the warnings about supervision of the use of varenicline, and the need to observe for mood changes and measure blood pressure with bupropion, regular supervision of patients using these drugs is highly desirable. In addition, there is strong evidence that NRT is effective with no supervision of its use,15 evidence of which is lacking for bupropion and varenicline. Therefore, if no supervision is provided, NRT is the first-choice medication.

Conclusions Although it is important to consider choice of pharmacotherapy, the main issue is ensuring that more smokers use pharmacotherapy to help them stop smoking. In the UK, about half of quit attempts take place with no pharmacotherapy support at all. The main issue is to reduce this proportion. References 1. Hyland A, Borland R, Li Q et al. Individual-level predictors of cessation behaviours among participants in the International Tobacco Control (ITC) Four Country Survey. Tob Control 2006; 15(suppl 3): iii83-94, doi:10.1136/tc.2005.013516. 2. Taylor T, Lader D, Bryant A, Keyse L, Joloza MT. Smoking-related behaviour and attitudes, 2005. London: Office for National Statistics, 2006. www.statistics.gov.uk/downloads/theme_health/Smoking 2005.pdf 3. Taylor T, Lader D, Bryant A, Keyse L, Joloza MT. Smoking-related behaviour and attitudes, 2005. London: Office for National Statistics; 2006. 4. West R. Smoking and smoking cessation in England, 2006. http://aspsilverbackwebsites co uk/smokinginengland/Ref/paper4 pdf [ 2006 :[1-4] 5. Shiffman S. Nicotine lozenge efficacy in light smokers. Drug Alcohol Depend 2005; 77: 311-14, doi:10.1016/j.drugalcdep.2004.08.026. 6. Ahluwalia JS, Okuyemi K, Nollen N et al. The effects of nicotine gum and counseling among African American light smokers: a 2 x 2 factorial design. Addiction 2006; 101: 883-91, doi:10.1111/j.13600443.2006.01461.x. 7. DiFranza JR, Wellman RJ. A sensitization homeostasis model of nicotine craving, withdrawal, and tolerance: Integrating the clinical and basic science literature. Nicotine & Tobacco Research 2005; 7(1): 9-26, doi:10.1080/14622200412331328538. 8. Fagerstrom KO, Hughes JR. Nicotine concentrations with concurrent use of cigarettes and nicotine replacement: a review. Nicotine & Tobacco Research 2002. 9. Fiore MC, Jaen CR, Baker TB et al. Treating tobacco use and dependence: 2008 update. U S Department of Health and Human Services 2008; 1-256. 10. Fry-Smith A, Hyde C, Moore D, Roberts J, Sandercock J. Clinical and cost-effectiveness of nicotine replacement therapy for new licensed indications and combination therapy: a summary of best evidence. http://guidance nice org uk/page aspx?o=404383 [ 2007 [cited 2007 June 1]; 11. Dempsey D, Jacob 3rd P, Benowitz NL. Accelerated metabolism of nicotine and cotinine in pregnant smokers. J Pharmacol Exp Ther 2002; 301: 594-8, doi:10.1124/jpet.301.2.594. 12. National Institute for Health and Clinical Excellence. Guidance on smoking cessation. 2008. Ref Type: Report 13. Benowitz NL, Dempsey DA. Pharmacotherapy for smoking cessation during pregnancy. Nicotine & Tobacco Research 2004; 6(2 suppl 2): 189-202, doi:10.1080/14622200410001669169. 14. Hughes JR, Keely J, Naud S. Shape of the relapse curve and longterm abstinence among untreated smokers. Addiction 2004; 99(1): 29-38, doi:10.1111/j.1360-0443.2004.00540.x. 15. Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews: Reviews 2008 Issue 1 John Wiley & Sons, Ltd Chichester, UK DOI: 10 1002/14651858 CD000146 pub3 2008; (1).

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Smoking 2: nicotine replacement Smokingcessation cessation 2: nicotine replacement therapy tricks withwith old drugs therapy––new new tricks old drugs Paul Aveyard, Amanda Parsons, Rachna BEGH Paul Aveyard, Amanda Parsons, Rachna Begh National Institute of Health Research Career Scientist, UK Centre for Tobacco Control Studies, Primary Care Clinical Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

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ike Russell, who did much to create the current understanding of smoking as tobacco addiction said ‘smokers smoke for the nicotine but die from the tar’.1 If this is so, it should be possible to provide enough nicotine replacement and keep smokers satisfied and thus help them to stop. Years later, we now have evidence that nicotine replacement is effective, but nicotine replacement therapy is, from this perspective, surprisingly ineffective. In this piece, we examine how primary care physicians can help smokers get more from nicotine replacement therapy (NRT).

Reviewing the evidence Cochrane reviews provide exhaustive searches of the literature. The reviewers critically appraise the quality of the evidence and summarise the highest-quality evidence, typically in a meta-analysis. The Cochrane review of NRT for smoking cessation summarises 106 trials in which NRT is contrasted with no intervention or, more usually, with placebo.2 The rate ratio (RR) (95% confidence interval) for long-term abstinence is 1.58 (1.50 to 1.66). There are several types of NRT available and the evidence is insufficient to choose a single best product among these. The rate ratios for the individual products are: � 1.43 (95% CI: 1.33 to 1.53, 53 trials) for nicotine gum � 1.66 (95% CI: 1.53 to 1.81, 41 trials) for nicotine patch � 1.90 (95% CI: 1.36 to 2.67, 4 trials) for nicotine inhaler � 2.00 (95% CI: 1.63 to 2.45, 6 trials) for oral tablets/lozenges PCCJ

2.02 (95% CI: 1.49 to 3.73, 4 trials) for nicotine nasal spray. The effects were largely independent of the duration of therapy, the intensity of additional support provided, or the setting in which NRT was offered.

A question of dose

© iStockphoto.com/New Photo Service

Introduction

Most specialists in the treatment of tobacco dependence believe that smokers stopping smoking use either insufficient doses of NRT or use NRT for insufficient time to gain maximum benefit. However, the data from clinical trials to support these beliefs are surprisingly sparse. There is more evidence to support using higher doses of NRT than for prolonged courses. These data come from NRT gum trials, where heavily dependent smokers were randomised to either 4 mg or 2 mg gum, which were compared in four trials. For highly dependent smokers, the Cochrane review found a significant benefit of the higher dose, with a rate ratio (RR) of 1.85 (1.36 to 2.50). In low dependent or unselected smokers, there was no evidence for an effect (RR 0.77, 95% CI 0.49 to 1.21). For patch use, there is also evidence that higherthan-standard doses were more effective in smokers with higher dependence from the Cochrane review. These studies compared 44 or 42 mg patches to 22 or 21 mg 24-hour patches or 25 mg to 15 mg patches, both worn for 16 hours. The pooled estimate for the RR of 1.15 (1.01 to 1.30) provides some evidence for a modest effect of higher dose.

A further study looked at participants in a trial comparing nicotine lozenges with placebo lozenges.3 Participants were split into high- and low-lozenge use groups, based on their median use. Interestingly, participants who were high users were more dependent on nicotine at baseline, suggesting that nicotine dependence and withdrawal is a driver of use of lozenges. In participants using nicotine lozenges, the odds of successful smoking cessation increased by 10% for each extra lozenge consumed per day. There was no such effect in the placebo group. In fact, increased use of placebo lozenges was associated with a small, but statistically not significant, decrease in abstinence. This effect, if real, is probably due to greater need to consume lozenges, indicating worse withdrawal symptoms. However, it provides strong evidence to support clinicians’ efforts to boost adherence to NRT, which is notoriously poor for shortacting forms (see Boxes 1 and 2). 21

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Box 1 Practical advice on prescribing NRT

Box 2 Common myths about NRT

Nicotine patches • The patch dose on the packet gives the approximate dose absorbed over 16 or 24 hours. Patches of either duration deliver about 1 mg/hour and there is no evidence that one is better than the other. • The instructions for which patch dose to use vary between manufacturers for no good reason. Most experts would advise using the full-strength patch for anyone smoking within 30 minutes of waking or smoking 10 or more cigarettes per day. • Advise people to take the back off and waft patches in the air for 10 seconds before application to the skin - it helps them stick. • Put the patch on smooth hairless skin and use a different position each time. If it starts to come off, try micropore tape. • Skin reactions are fairly common (in response to the glue). Try swapping the patch to a different make, or use emollient and hydrocortisone 1% to manage the reaction.

• Nicotine is dangerous. Wrong: there is no evidence that nicotine causes or exacerbates cancer or heart disease. It may reduce placental blood flow so it might not be harmless in pregnant women, but this is uncertain. • Taking less NRT is a sign of recovery. Wrong: it is a risk factor for relapse. Patients need to be strongly encouraged that more is better. • Using NRT long-term means nothing has been gained. Dependence has been transferred. Wrong: there is no harm from long-term NRT and no reason to advise people to stop it. If necessary, it is much easier to stop long-term NRT use than cigarette smoking.

Other types of NRT • With acute forms of NRT, the main difficulty is getting patients to use sufficient. Specific instructions usually help such as ‘on the hour, every hour’. • Patients should be told to take NRT regularly but to use as much as is needed to keep urges at bay. The maximum doses in the summary of product characteristics reflect historic licensing terms and do not reflect safety limits. Smokers are adept at titrating nicotine doses and are unlikely to overdose. • All forms of NRT are unpleasant to use and, at best, neutral to the smoker. Patients need to be warned about this and told to persist, because they get less unpleasant over time, and they will appreciate the benefits. Practising using NRT before quitting is helpful. Patients using oral forms need to avoid swallowing too much saliva, which will cause heartburn or hiccups and other local irritation problems and greatly reduce the amount of nicotine absorbed. • The nasal spray is very aversive for many people on initial use. It provides the quickest delivery of nicotine and many people get to like it because of this. Patients need to be strongly encouraged to persist with it, practising before quitting. It is a good choice for more dependent smokers.

indirect comparison of studies with longer and shorter courses versus placebo. Only one study contrasted longer and shorter courses of NRT, where participants were randomised to either 28 weeks or 12 weeks of 15 mg/16-hour patches.4 This was a large trial and the RR for long-term abstinence was 1.05 (0.88 to 1.26). There is also no evidence from the Cochrane review that the widely used ‘step-down’ regimen are more effective than stopping NRT patches abruptly. However, patients like the step-down regimens and they are not harmful or more expensive than stopping abruptly so there is no reason to avoid this approach. Although there is no evidence from randomised trials that prolonged use of NRT is helpful, there are strong reasons to assume that it would be. This is based on observations of patients’ behaviour. Studies show that around one-quarter of successful quitters use NRT for a year or more, and those who are more dependent on nicotine are more likely to be long-term users.5,6 This is true of the short-acting forms of NRT but not of patches. In smokers randomised to placebo or NRT, very few if any carry this on long term, while those with active treatment are more likely to use it long term.7,8 Long-term use is associated with reduced weight gain on quitting.8 Long-term use of NRT does not represent transferred dependence. Psychiatric interviews with long-term users revealed no-one who met the criteria for dependence, unlike with cigarettes.9 A number of patients feel ashamed about the need to continue NRT in the long term. They need to be strongly reassured (see Box 2) and it is wise to continue to prescribe NRT with encouragement to keep on using it as long as is necessary to prevent people from smoking even one puff of a cigarette. However, there is no evidence from trials to

Approach to dose adjustment • It is much more common to find underdosing than overdosing. This is evidenced by urges to smoke and/or withdrawal symptoms. If suspected, increase the dose, explaining the rationale. • One protocol for smoking cessation suggests increasing the dose of NRT by using multiple patches if smoking is not totally stopped.16 We have used this with some success and no problems. • Nicotine overdose symptoms are unusual but include nausea, diarrhoea, and increased salivation.

What is the optimal duration of use? However, there is less evidence on the effects of increased duration of treatment with nicotine replacement. In the Cochrane review, there is no evidence that longer treatment courses were associated with better outcomes. This comparison rests on 22 144

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Figure 1. Blood cotinine concentrations prior to quitting and after quitting in abstinent smokers using a 15 mg/16-hour patch 600

Blood cotinine concentration (ng/ml)

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Starting patches before stopping smoking

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support long-term NRT use for all, so this should not be advocated strongly to all people trying to quit smoking.

Concordance with NRT patches is high in routine clinical practice, but it has an important disadvantage over other products in that the user is unable to use it to deal with smoking cues

Many clinicians and patients will be worried about the risk of overdose using both NRT patches and other forms of NRT, but most of these fears are groundless. Figure 1 is taken from a clinical trial of patients treated for tobacco dependence with a standard 15 mg/16-hour patch.10 We measured blood cotinine levels while people were still smoking and after stopping smoking. Cotinine is a breakdown product of nicotine that has a much longer half-life and gives a more accurate measure of nicotine consumption than blood nicotine itself. Such patients typically had lower blood cotinine levels when on a nicotine patch than when smoking. The only selection criteria for this trial were smokers of 10 or more cigarettes per day and wanting to stop smoking. In addition, there is very good evidence that smokers can tolerate high doses of nicotine providing they are administered slowly, as is the case with a patch.13

Use of combinations of different forms of NRT Concordance with NRT patches is high in routine clinical practice,10 but it has an important disadvantage over other products in that the user is unable to use it to deal with smoking cues. Smoking cues are objects, places, or mood states that have been characteristically associated with smoking in the life of the smoker. In someone attempting to stop smoking, these cues set up urges to smoke. Other forms of NRT can be taken when urges strike and can reduce the urge to smoke within 10 minutes.11 A sensible strategy is to combine a nicotine patch that delivers a reasonable dose of NRT and to prescribe an additional acute form of NRT (such as gum or sublingual tablet) to use when the need arises. This strategy has empirical support. The Cochrane review of NRT summarised the results of seven trials of combination NRT compared with single forms of NRT and found an RR of 1.35 (1.11 to 1.63). Consequently NICE guidance has recommended the use of combination NRT – particularly patch plus acute form.12 In these trials, where the strategy tested was patch plus acute form, it was usual that participants were advised to use a minimum dose of additional acute NRT with ad libitum or free use on top of that.

One other strategy for using NRT patches is to start them two weeks before a person stops smoking. The Cochrane review included three studies that contrasted nicotine patch two weeks prior to quitting to patch only after abstinence, as is standard. The RR was 1.79 (1.17 to 2.72). A more recent review included a further study, producing an OR of 2.17 (1.46 to 3.22).14 Use of a nicotine patch prior to abstinence is not specifically licensed. However, in the UK, the unhelpful warnings about not smoking while on the patch have been removed in the past few years. This pre-quit patch strategy is not yet routinely advocated in any national guidelines, but should be considered in smokers who have had trouble stopping previously despite optimal use of NRT. Together with changes in labelling of NRT products, several short-acting forms of NRT are now licensed for cutting down smoking with a view to achieving abstinence in the longer term. These licences are based on trials that enrolled smokers who did not want to stop in the next month but who were prepared to cut down. A review and meta-analysis of these studies showed that smokers who, if asked by a doctor ‘do you want to stop smoking?’ would answer ‘no’ can be helped to stop by gradual smoking reduction with the aid of NRT. The RR is 2.06 (1.34–3.15) and the treatment appears cost-effective by UK standards, with a cost/quality-adjusted life year of £1,600 to £8,000.15

Conclusions NRT will remain an important part of treatment plans for tobacco dependence. Using NRT before quitting might enhance efficacy and using a combination of 23

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nicotine patch plus top-up NRT is now advised in guidelines for many smokers and is more effective than using a single form alone. References 1. Russell MA. Low-tar medium nicotine cigarettes: A new approach to safer smoking. Br Med J (Clin Res Ed) 1976; 1: 1430-3. 2. Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews: Reviews 2008 Issue 1 John Wiley & Sons, Ltd Chichester, UK, doi:10 1002/14651858 CD000146 pub3 2008;(1). 3. Shiffman S. Use of more nicotine lozenges leads to better success in quitting smoking. Addiction 2007; 102: 809-14, doi:10.1111/j. 1360-0443.2007.01791.x. 4. Tonnesen P, Paoletti P, Gustavsson G, Russell MA, Saracci R, Gulsvik AA. Higher dosage nicotine patches increase one-year smoking cessation rates: Results from the European CEASE trial. European Respiratory Journal 1999; 13: 238-46, doi:10.1034/j.1399-3003.1999.13b04.x. 5. Hajek P, Jackson P, Belcher M. Long-term use of nicotine chewing gum. Occurrence, determinants, and effect on weight gain. JAMA 1988; 260: 1593-6, doi:10.1001/jama.260.11.1593. 6. Hajek P, McRobbie H, Gillison F. Dependence potential of nicotine replacement treatments: effects of product type, patient characteristics, and cost to user. Prev Med 2007; 44: 230-4, doi:10. 1016/j.ypmed.2006.10.005. 7. Hughes JR, Gust SW, Keenan R, Fenwick JW, Skoog K, Higgins ST. Long-term use of nicotine vs placebo gum. Arch Intern Med 1991;

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151: 1993-8, doi:10.1001/archinte.151.10.1993. 8. Sutherland G, Stapleton JA, Russell MA et al. Randomised controlled trial of nasal nicotine spray in smoking cessation. Lancet 1992; 340: 324-9, doi:10.1016/0140-6736(92)91403-U. 9. Hughes JR, Adams EH, Franzon MA, Maguire MK, Guary J. A prospective study of off-label use of, abuse of, and dependence on nicotine inhaler. Tob Control 2005; 14: 49-54, doi:10.1136/tc.2004.008367. 10. Aveyard P, Brown K, Saunders C et al. A randomised controlled trial of weekly versus basic smoking cessation support in primary care. Thorax 2007; 62: 898-903, doi:10.1136/thx.2006.071837. 11. Shiffman S, Shadel WG, Niaura R et al. Efficacy of acute administration of nicotine gum in relief of cue-provoked cigarette craving. Psychopharmacology (Berl) 2003; 166: 343-50. 12. National Institute for Health and Clinical Excellence. Guidance on smoking cessation. 2008. Ref Type: Report 13. Fagerstrom KO, Hughes JR. Nicotine concentrations with concurrent use of cigarettes and nicotine replacement: a review. Nicotine & Tobacco Research 2002. 14. Shiffman S, Ferguson SG. Nicotine patch therapy prior to quitting smoking: a meta-analysis. Addiction 2008; 103: 557-63, doi:10. 1111/j.1360-0443.2008.02138.x. 15. Wang D, Connock M, Barton PM, Fry-Smith A, Aveyard P, Moore D. ‘Cut down to quit’ with nicotine replacement therapies (NRT) in smoking cessation: a systematic review if effectiveness and economic analysis. Health Technol Assess 2008; 12(2). 16. Bittoun R. A combination nicotine replacement therapy (NRT) algorithm for hard-to-treat smokers. Journal of Smoking Cessation 2006; 1(1): 3-6, doi:10.1375/jsc.1.1.3.

Clinical notes from 2009 EASD by attending clinician Dr Ahmed, ADVANCE Isipingo Hospital,NOTICE Natal FOR YOUR DIARY Liraglutide efficacy extends over two years

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lycaemic control in type mic episodes with liraglutide tide dosage groups, compared 0.0002). 2 diabetes was better versus glimepiride.’ Frid was with 1.60 with glimepiride and The actual mean HbA1c levels maintained with iraglutide than reporting on results from a six- 0.16 for metformin alone. for the five treatment groups RY CARE CARDIOVASCULAR SOCIETY ANNUAL SCIENTIFIC MEETING AND AGM with the sulfonylurea drug, month randomised, doubleAlso, liraglutide was asso- at the end of two years were: glimepiride, over two years and blind, placebo-controlled trial ciated with weight loss and • liraglutide 0.6 mg plus methad a better side-effect profile. called LEAD-2, followed by an shrinking waist circumference, formin: 7.74% Among patients taking 1.8 18-month open-label exten- whereas patients taking the • liraglutide 1.2 mg plus metformin: 7.44% mg/day of liraglutide, 31% sion. His report covered 780 sulfonyurea gained weight and achieved HbA1c levels below patients entering the extension, their bellies expanded. Mean • liraglutide 1.8 mg plus metout of about who partici- weight losses from baseline of formin: 7.38% after two years, compared nicians, 7% GPs, practice nurses, managers and875 commissioners with only 23.5% of those on pated in the blinded portion. 2.07 to 3.03 kg were seen in • glimepiride plus metformin: 7.49% Patients in the study had a the liraglutide groups at study glimepiride at 4 mg/day (p < 0.0001), reported Anders Frid, mean HbA1c level of 8.3% at end, unrelated to dosage. • metformin alone: 8.12%. ST MD of Oresund diabetes RD team baseline. All received metformin Patients on glimepiride gained However, Frid reported no data and Lund University of Malmo, and the study included a group 0.7 kg (p = 0.0001 relative to on more rare side effects such as cancer, concerns over which Sweden. Patients taking two who received that drug alone. all liraglutide groups). Overall, Frid reported, the appear to have blocked the lower doses of liraglutide, Among those patients, only which has not been approved 10.8% had HbA1c levels below odds ratio for meeting the drug’s USA approval. In April, in the USA, met the 7% target 7% at the end of two years. three major goals of treatment: an FDA advisory committee A more dramatic advantage HbA1c less than 7%, no weight agreed that animal data linking at about the same rate as the for liraglutide over glimepiride gain and no hypoglycaemic liraglutide to thyroid tumours glimepiride group. ‘We have proved the non- was in the rate of hypoglycae- episodes during the two years could apply to humans, inferiority,’ he said, ‘with mic episodes. The annual rate was 4.9 for liraglutide versus although clinical studies had sustained weight loss and for these episodes was 0.15 per glimepiride and 3.8 for liraglu- not identified any special risk. markedly fewer hypoglycae- patient in each of the liraglu- tide versus metformin alone (p Reviewed by Dr DF Zaleznik tion please contact Diane Newman at office@pccs.org.uk, continued on page 155

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Patient information leaflet

Keep and Copy Series STARTING ON A STATIN TO PREVENT HEART AND VASCULAR DISEASE AND STROKE

S Afr J Diabetes Vasc Dis 2009; 6: 147.

WHAT IS THIS PILL FOR? Statins are a treatment to lower your cholesterol level. Cholesterol is a type of fat, or lipid, found in your blood.

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WHY AM I BEING ADVISED TO TAKE IT? Lower cholesterol levels have been shown to reduce your chance of having a heart attack or stroke in the future. This is because high levels of cholesterol can ‘fur up’ your blood vessels, increasing the risk of a blood clot forming, which can lead to a heart attack or stroke. Based on your current level of risk, you are likely to benefit from lowering your cholesterol. WHAT IS A HEALTHY CHOLESTEROL LEVEL? A cholesterol level of 5 mmol/l or less is good, with levels of 4 mmol/l or less being ideal. However, there are different types of cholesterol and the ratio of ‘good’ cholesterol (HDL cholesterol, which helps to remove cholesterol from your blood) to ‘bad’ cholesterol (LDL cholesterol, which ‘furs up’ your blood vessels) is also important. WHAT DOSE SHOULD I TAKE? The dose of statin prescribed will depend on your cholesterol level. If you are experiencing high cholesterol levels (> 5–6 mmol/l), then your doctor may choose to prescribe a more powerful statin, which will lower your cholesterol more efficiently. Rosuvastatin is the most powerful of the new statins. Your doctor will probably start you on a low dose of rosuvastatin and gradually increase your dose but not more than once every two to four weeks. WHEN SHOULD I TAKE IT? Some cholesterol comes from your food but it is important to realise that your body also makes its own cholesterol in your liver. Most of this cholesterol is made at nighttime, so you may get more benefit if you take your tablet at nighttime too. Talk to your doctor, nurse or pharmacist if you think this may be difficult for any reason. HOW WILL I KNOW IT IS WORKING? Studies have shown that statins reduce the risk of heart attacks and strokes. For this reason, there is no need to have a routine blood test to check your lipid levels once you have started on your tablet. However your liver function will be tested at three and 12 months to ensure that

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the drug is suiting you. HOW LONG SHOULD I TAKE IT FOR? Your cholesterol level will be lowered by taking the tablets. If you stop taking them, your cholesterol will rise again. For this reason, we advise that you should keep taking the tablets for as long as possible, and ideally, for life. WHAT COMMON SIDE EFFECTS MIGHT I EXPECT? Side effects from statins are surprisingly rare. However, all drugs have side effects – even ‘dummy’ pills used in medical trials have been shown to cause side effects in some people, so it is not always the tablet that is to blame. With statins, rare side effects include muscle or joint pains, lack of energy, constipation and indigestion and you should let your doctor, nurse or pharmacist know if these occur. It is important to remember, however, that the likely benefits from statins are greater than the risks, for the majority of people. WHAT IF I DECIDE THAT I DO NOT WANT TO TAKE THESE PILLS? Your doctor or nurse will have advised you to take these tablets because you are likely to benefit from reducing your risk of a heart attack or stroke. High cholesterol does not make you feel unwell so it can sometimes be difficult to understand why you should take a tablet for the rest of your life. Nonetheless, it is worth remembering that huge medical trials have proven the benefit of these pills in reducing the risk of heart attack or stroke. IS THERE AN ALTERNATIVE? You can – and should – try to eat healthily and reduce your overall fat intake. Taking regular exercise such as walking can raise your ‘good’ cholesterol. You should also try to loose weight if you need to. Taking statins will add to these changes. Mildly raised cholesterol can be improved by diet and exercise but studies show that statins will lower the levels further. CAN MY CHOLESTEROL GO TOO LOW? Statins have been used for more than 30 years and no significant longterm problems have been shown in any of the trials. Recent trials have looked at lowering cholesterol levels to 3 mmol/l or less and, overall, it seems the lower the level, the less the risk of heart attacks and strokes. Source: Medline Plus and British Journal of Primary Care Nursing.

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Cardiovascular and diabetes aspects of hypothyroidism JOHN LAZARUS

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y pothyroidism is common in adults and the prevalence of sub-clinical hypothyroidism is high in women, with various studies showing a range of 4 to 21% (average 7–10%) frequency in the population. ‘The incidence of thyroid disease increases with age and impacts on cholesterol levels’, said Prof John Lazarus at a recent CME meeting hosted by Merck Serono. ‘We see a mean serum total cholesterol increase with increasing thyroid-stimulating hormone (TSH) levels.’ Prof Lazarus cited the following key findings from the Colorado Thyroid Disease Prevalence study undertaken by Canaris et al among a population of visitors to a health fair, and published in the Archives of Internal Medicine.1 • Most patients with thyroid dysfunction have sub-clinical hypothyroidism (above 5 mIU/l, but below 10 mIU/l), which raises a clinical conundrum in respect of treatment. • Of patients on thyroid medication, only 60% are in the normal TSH range. • Thyroid disease often goes undiagnosed. The Framingham study of cardiovasular risk2 showed that 13.6% of American women older than 60 years had TSH levels above 10 mIU/l, whereas the prevalence of raised TSH in the male population in this study was 5.7%. Prof Lazarus advised physicians to test for thyroid peroxidase (TPO) antibodies as well as TSH when investigating for hypothyroidism because in true hypothyroidism (where the TSH level is > 10 mIU/l), TPO antibodies will also be present. ‘These antibodies are often associated with type 1 diabetes and occur more commonly in type 2 diabetes than in the general population. If TPO antibodies are present, lower levels of TSH are indicative of hypothyroidism’, Prof Lazarus noted. Various factors play a role in the development of thyroid disease. These include smoking, stress, female hormones, iodine and selenium, drugs, irradiation, infections, allergies and pregnancy. Hypothyroidism presents with a wide range of clinical features, including fatigue, forgetfulness, moodiness,

Correspondence to: John Lazarus Centre for Endocrine and Diabetes Sciences, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK Tel: +44 2920 744326 Fax: +44 2920 744326 e-mail: lazarus@cf.ac.uk S Afr J Diabetes Vasc Dis 2009; 6: 149–150.

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John Lazarus

depression, hair loss, dry skin, puffy eyes, deepening of the voice, persistent dry throat, infertility and menstrual irregularities. Of particular concern, when it comes to heart disease, are weight gain, elevated cholesterol and a slowed heartbeat. The most common treatment prescribed for thyroid disease is levothyroxine, a synthetic form of the thyroid hormone, thyroxine. ‘Seventeen billion tablets are prescribed per year’, said Prof Lazarus. ‘It’s important that there is a wide enough dosage range so that the dose can be personalised for the individual patient. Scored tablets that can be broken in half are an advantage in providing an appropriate dosage.’ He pointed out that levothyroxine is a very reliable drug, but that it has a narrow therapeutic ratio. Under- and over-replacement are common and both can have serious negative consequences. Too much thyroxine is associated with increased cardiovascular morbidity and mortality, atrial fibrillation and worsening ischaemic heart disease. Too little is associated with elevated cholesterol levels. ‘In optimising the dose, we also have to consider the possibility of poor absorption and interaction with food and other drugs.’ In the Cardiovascular Health study,3 more than 300 thyroid hormone users over the age of 65 years were identified and classified into low TSH (< 0.45 mIU/l), euthyroid (0.45–4.5 mIU/l) and high TSH (> 4.5 mIU/l) categories. The presence of diabetes was associated with both low and high TSH levels,

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Practical clinical guidance to therapy with levothyroxine (Euthyrox²) • Where hypothyroidism is diagnosed, introduce 100 µg/day of levothyroxine and monitor TSH levels six weeks to two months later. If TSH is too high, a lower dose can be introduced without harm to the patient.

indicating a need to assess these patients more frequently. There is debate about whether or not to introduce thyroxine replacement in patients with sub-clinical hypothyroidism, but Prof Lazarus believes the available evidence suggests that these patients should be treated. ‘Potential benefits include prevention of progression to overt hypothyroidism, improved lipid and cardiovascular risk profiles and improved cognitive and psychiatric symptoms.’ He notes that the co-existence of heart disease and thyroid disease is common. ‘Women with sub-clinical hypothyroidism (mild thyroid failure with elevated TSH below 10 mIU/l and normal free thyroid hormone values) have a greater prevalence of aortic atherosclerosis and myocardial infarction. It has also been suggested that sub-clinical hypothyroidism is a particular risk factor for myocardial infarction in elderly women. However, not all studies are confirmatory in this regard, making the epidemiology difficult. That said, there is no doubt that overt hypothyroidism is a definite cardiovascular

Take-home message When to have a raised index of suspicion for the presence of hypothyroidism: • in female patients with symptoms • in women with type 1 diabetes • in both men and women with type 2 diabetes with sudden loss of glucose control • in men with raised cholesterol and a family history of thyroid disease.

risk factor.’ Prof Lazarus concluded by underscoring that undiagnosed hypothyroidism is a serious public health problem. ‘It is common, it often goes undetected and may be associated with serious adverse health outcomes.’

References 1. Canaris GJ, Tape TG, Smith LM, Nickol DR, Wigton RS. The Colorado Thyroid Disease Prevalence study. Arch Int Med 2000; 160: 526–534. 2. Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P. The aging thyroid: thyroid deficiency in the Framingham study. Arch Int Med 1985; 145: 1386–1388. 3. Somwaru LL, Arnols AM, Joshi N, Fried LP, Cappola AR. High frequency of and factors associated with tyroid hormone over-replacement and under-replacement in men and women aged 65 and older. J Clin Endocrin Metab 2009; 94(4): 1342–1345.

More local news from the IDF conference

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r Areti Philotheou chaired the main session on diabetes in youth, with much-appreciated, heart-felt messages about the plight of children in the developing world. Dr Philotheou was one of the ani-

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mated discussants, part of a very select psychopedagogic quartet, expounding for two hours to an enthralled audience what a Socratic dialogue on patient empowerment is all about. She also had the

honour – a South African first – of being nominated by the IDF Board of Management as co-chair of the IDF Task Force on Children and Adolescents in order to work with IDF, ISPAD and WHO on worldwide pro-

grammes to stop the scourge of early deaths and disabilities, still so common in young people with diabetes.

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Diabetes Educator’s Focus DIABETES AND BREASTFEEDING Correspondence to: Brenda Campbell Registered nurse, registered midwife, International board-certified Lactation consultant Netcare Parklane Hospital, Johannesburg Tel: +27 (0)11 480-4119 Fax: +27 (0)11 643-2141 e-mail: brendac@parklane.netcare.co.za

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h is article is based on a paper presented at the 11th Centre for Diabetes Education Postgraduate Forum in Diabetes Management held from 8–10 August, 2009 in Johannesburg.

S Afr J Diabetes Vasc Dis 2009; 6: 152–155.

Introduction Worldwide, the race is finally on in earnest to meet the millennium development goals. Child survival is the key strategy. It has been shown that 13% of all deaths in children under five years old could be averted by successful breastfeeding alone.1 Other key interventions such as early mother–infant contact and skin-toskin care can also save millions of lives. New research continues to stress the value of breastfeeding, yet there are many mothers who choose to formula feed their babies. At present, formula feeding is known to have serious implications for child health, and problems are experienced with the milk powder and the water being used, as well as the feeding bottles. It is also now widely accepted that it is more important for a diabetic mother to breastfeed than for any other mother – in fact the word ‘antidiabetogenic’ is now being used in association with diabetes and breastfeeding. Diabetic women can and do successfully breastfeed their babies, and research shows that they are as likely to choose to breastfeed as non-diabetic mothers. However, because of the added risks and difficulties, such as obesity and the high number of operative deliveries, many of these mothers require expert assistance and ongoing postnatal follow up and support in order to successfully initiate and sustain breastfeeding. Diabetic mothers benefit greatly from the involvement of a dedicated multidisciplinary team approach. The services of a qualified and experienced lactation consultant should be included in this team. Breastfeeding has also been shown to have considerable benefits with regard to decreasing obesity in infancy, childhood and later life. It therefore has the potential to contribute to breaking the cycle of over-

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weight and diabetes, which may occur among the offspring of diabetic mothers. Reasons for mothers with diabetes to breastfeed Breastfeeding has numerous advantages for mothers with diabetes and for their babies. These mothers have lower insulin requirements and better control of their blood glucose while breastfeeding. They also have lower plasma glucose levels and improved glucose metabolism. Their daily insulin requirements are generally much lower than when they are not breastfeeding. The mother’s diabetes may actually improve during lactation (i.e. breastfeeding is antidiabetogenic). Breastfeeding may also protect healthy mothers from developing type 2 diabetes. In a large study of 150 000 nurses in the USA, each year of lifetime breastfeeding lowered a woman’s risk of contracting type 2 diabetes by 15%. This protection lasted for 15 years after the woman’s last birth.2,3 Mothers with gestational diabetes who do not breastfeed their babies are twice as likely to develop type 2 diabetes postpartum.4 Reasons for babies of DIABETIC mothers to breastfeed Several studies have linked the occurrence of type 1 diabetes with the early use of infant formula. Researchers believe that the protein found in cow’s milk might sensitise the immune system in vulnerable babies, leading to an increased risk of type 1 diabetes. Further research in this regard is ongoing at present and results are expected later this year.3 Breastfed babies of diabetic mothers may have a lower risk of developing diabetes themselves. The in-

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Diabetes Educator’s Focus sulin in breast milk may help prevent diabetes from developing in susceptible children. Other data suggest that breastfeeding protects children from obesity and type 2 diabetes. A systematic review found that being breastfed was linked with a 40% decrease in the risk of type 2 diabetes later in life, and with lower serum glucose and insulin concentrations in infancy. A dose-response protective association was also found in youths of all ethnic categories in the study, who had been breastfed as babies.7 Maternal obesity Maternal obesity is associated with increased risk of gestational diabetes (GDM) and a higher lifetime risk of type 2 diabetes. Obesity is common among women with GDM and their babies are exposed to adverse intrauterine conditions as well as a genetic and environmental disposition towards being overweight. Maternal obesity is now accepted as the leading cause of high-risk pregnancy in the developed world, with studies from America, Australia and the United Kingdom showing high incidences in this regard. Problems experienced by overweight mothers include: polycystic ovarian syndrome, infertility, difficulties with conception and complications with pregnancy, increased maternal and neonatal adverse outcomes (including prematurity, macrosomia and an increase in all forms of infant malformations). All of these problems also result in increased costs of obstetric care, and complications and difficulties with breastfeeding. Research shows that clinicians at present do not manage obese women differently from normal-weight patients. Wherever possible, a sincere attempt should be made to get obese women to loose weight before falling pregnant. Considerable effort needs to be made worldwide to stem this tide of negative events. Infant, childhood and adolescent obesity The birth weight of full-term singletons has increased by 116 g on average over the last 30 years. There is increasing evidence that breastfeeding has a protective effect against obesity in later life. Several studies have shown that 37% of those who were never breastfed were overweight. Exclusive breastfeeding has been revealed to be an independent preventative of childhood overweight. The prevalence of childhood overweight decreases with increased duration of breastfeeding in infancy. The risk of childhood overweight may be reduced by 40 to 50% when the breastfeeding duration is more than three months. Women with diabetes can and do breastfeed Women with diabetes can breastfeed successfully, and as noted, it is even more important for both these mothers and their babies, than for any other mother–baby dyad.

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In a recent study, the majority of women with type 1 diabetes successfully initiated breastfeeding. The prevalence of breastfeeding in this group at four months was comparable to that in the overall maternal population. A higher education level and previous experience with breastfeeding were independent predictors of exclusive breastfeeding at four months.8 However women with diabetes do have significantly more breastfeeding complications and difficulties. They are more likely to develop preeclampsia, have induced labour and deliver by caesarean section. Their babies are more likely to be very large and to be delivered early.3 In addition, mothers who are overweight are more than twice as likely to be unsuccessful with breastfeeding as women of normal weight.9 Therefore mothers with obesity-related type 2 diabetes may well have trouble with early breastfeeding. Obese women also have a slower prolactin response in the first few days postpartum.10 Problems with initiation of lactation Insulin plays a central role in initiating and maintaining milk production. This may partly explain why mothers with diabetes are usually slower to produce milk in the early days.3 Many have a delay of about two to four days’ duration in lactogenesis 2, however by day seven, the milk supply is normally unaffected. This may also be related to the stability of their diabetes and their insulin regimen immediately postpartum. Anxious mothers or those in pain secrete only small amounts of the hormone oxytocin. Oxytocin is essential for breastfeeding. It assists in transporting milk from the milk-producing cells in the breast to the areola and nipple area, from where the infant can extract it. Other stress also interferes with oxytocin production and as a result these mothers produce less milk. Medical problems often keep mothers and babies apart in the first hours and days after birth, leading to fewer chances to breastfeed and a higher likelihood that these babies may receive early exposure to infant formula. Advances in diabetes control, especially during pregnancy, have decreased the risk of surgical intervention and prematurity, however these factors potentially contribute to breastfeeding problems. It is therefore vital that these mothers get good antenatal education on breastfeeding and significantly more support and assistance following the birth, in order to successfully initiate lactation. This assistance is most effectively delivered when breastfeeding management is placed in the hands of experienced and competent international board-certified lactation consultants (an allied healthcare field which is now steadily growing in South Africa). Considering the wealth of information and research now available, we should be offering all mothers with diabetes the services of a Lactation consultant.

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Diabetes Educator’s Focus Policies and practices The World Health Organisation recommends exclusive breastfeeding for the first six months, followed by the continuation of breastfeeding for up to two years and beyond while appropriate complementary foods are being introduced. The ‘Ten steps to successful breastfeeding’ (A World Health Organisation guideline) outlines the interventions that birthing facilities should be implementing in order to help all mothers succeed with the initiation of breastfeeding. Policies and protocols for mothers with diabetes need to follow these guidelines as closely as possible in order to give mothers the best possible chance of success. Care of the mother The diabetic mother needs to be educated about her own care as a breastfeeding mother. She needs to know what to expect: • She will have lower plasma glucose levels due to improved glucose metabolism • Her daily insulin requirement will generally be much lower • She is therefore improving her glycaemic control while she is nourishing her baby • Use of a personal blood glucose monitor is essential. Urine testing is not recommended because lactose is excreted in the urine in the later stages of pregnancy and during lactation if the mother has an over-supply of milk. The mother’s diet Producing milk requires substantial amounts of energy, and in type 1 diabetes, unless a mother knows and understands this concept, her blood glucose levels may drop precipitously.3 It is important that the kilojoule intake is sufficient to prevent excessive metabolism of fat stores, as this can lead to the production of ketones. This can be monitored by testing the urine. The amount of extra energy required for synthesis of milk will depend on the mother’s body weight, any changes in her metabolic efficiency and the control of her diabetes. Initially, approximately 2 100 to 3 360 additional kilojoules of carbohydrates per day will be required. She also needs extra carbohydrates daily to maintain the quantity of lactose in breast milk. The mother will need regular meals and nourishing snacks to maintain her blood glucose levels. It is most important for the mother to eat before breastfeeds, as the oxytocin rush which occurs during the let-down reflex can cause a drop in blood glucose levels. Gestational diabetes may often be controlled by diet alone in the postpartum period. Mothers should satisfy their hunger with a

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healthy range of acceptable foods. Breast refusal or the alteration of the mother’s nutritional intake can be hazardous. Slow, leisurely weaning is recommended. Breastfeeding guidelines Diabetes does not affect the mother’s ability to lactate. Her milk lactose, protein and fat content are within the normal range. Frequent feeding helps to keep the mother’s blood glucose levels stable. Mothers need good antenatal education. They should also choose a breastfeeding support facility for the delivery of their baby. Early skinto-skin contact and initiation of lactation within the first hour is critically important, and should be attempted whenever possible. The mother and baby should be kept together 24 hours a day if possible. All mothers should be given special assistance with positioning and latching their babies as this is particularly important in order to avoid nipple damage, mastitis and thrush, which are more common in diabetic mothers. Should these conditions occur, they require early, vigorous intervention and treatment. Any difficulties with latching in mother or baby need prompt specialist attention. Mothers also require special assistance with initiation of their milk supply should the mother and baby be separated or either one be ill. The use of bottles, teats and pacifiers should be avoided wherever possible, as well as the use of infant formula and oral glucose water. Mothers should also be well educated about breast filling before leaving the birthing facility, as this can be a difficult phase for many mothers. It is absolutely vital to refer these mothers to a well-recognised and established breastfeeding support group for good ongoing assistance and support (it is preferable for this to be a continuation of hospital care). Community-based breastfeeding support organisations such as the La Leche League may also play a role. Special care of the baby The baby of a diabetic mother may be at risk of developing hypoglycaemia soon after birth. Frequent blood glucose monitoring may be necessary initially. Feeds in the first 12 hours are particularly crucial. Additional spoons of expressed colostrum can be most useful if the baby is not suckling well as yet. If necessary, additional fluids intravenously or by spoon, cup or bottle may be given. Babies of diabetic mothers are more likely to be premature and have respiratory distress and jaundice and therefore be in special care, which may lead to a delay in establishing lactation. Conclusion Breastfeeding is of great benefit to both mothers who suffer from diabetes, and to their babies. It is also a comfort to many of these mothers,

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Diabetes Educator’s Focus and they report feeling a sense of well being while breastfeeding. With so many advantages to be gained, the extra effort that may be needed to establish and manage breastfeeding in mothers with diabetes is very worthwhile and rewarding. Acknowledgements I thank the team and presenters of the GOLD09 online conference for lactation consultants (Health e-Learning). Michael Brown assisted with the literature search. I also acknowledge the many mothers from whom we learn.

References 1. Jones G, Steketee RW, Bhutta ZA, Morris SS, Bellagio child study group. How many deaths can we prevent this year? Lancet 2003; 362(9377): 65–71. 2. Stuebe AM, Rich-Edwards JW, Willett WC, Manson JE, Michels KB. Duration of lactation and incidence of type 2 diabetes. J Am Med Assoc 2005; 294(20): 2601– 2610. 3. Stuebe AM. Breastfeeding and diabetes. Special benefits. Diabetes Voice 2007;

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52(1): 26–29. 4. Kjos S, Henry O, Lee R, Buchanan T, Mishell D. The effect of lactation on glucose and lipid metabolism in women with recent gestational diabetes. J Am Diet Assoc 1993; 98(6): 642–648. 5. Odeleye OE, de Courten M, Pettitt DJ, Ravussin E. Fasting hyperinsulinaemia is a predictor of increased body weight gain and obesity in Pima Indian children. Diabetes 1997; 46(8): 1341–1345. 6. Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. Does breastfeeding influence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. Am J Clin Nutr 2006; 84(5): 1043–1054. 7. Maah DM, Snively BM, Beyer J, Imperatore G, Bell R, Mayer-Davis EJ, et al. Birth weight (corrected) and elevated albumin to creatine ratio in youth with diabetes: the SEARCH for Diabetes in Youth study. Pediatr Nephrol 2008; 23(12): 2255–2260. E-pub 2008 Jul 8. Erratum in: Pediatr Nephrol 2009; 24(1): 221. 8. Stage E, Nørgård H, Damm P, Mathiesen E. Long-term breast-feeding in women with type 1 diabetes. Diabetes Care 2006; 29(4): 771–774. 9. Hilson JA, Rasmussen KM, Kjolhede CL. Maternal obesity and breast-feeding success in a rural population of white women. Am J Clin Nutr 1997; 66(6): 1371– 1378. Erratum in: Am J Clin Nutr 1998; 67(3): 494. 10. Kugyelka JG, Rasmussen KM, Frongillo EA. Maternal obesity is negatively associated with breastfeeding success among Hispanic but not Black women. J Nutr 2004; 134(7): 1746–1753.

continued from page 146

Clinical notes from 2009 EASD by attending clinician Dr Ahmed, Isipingo Hospital, Natal Phase III data look good for novel diabetes drug

A

 n investigational drug targeting an insulin-independent pathway in type 2 diabetes produced early and substantial reductions in blood glucose and body weight in a phase III, randomised, placebocontrolled trial. After 24 weeks of treatment, glycated haemoglobin levels declined from 0.7 to 0.8% with dapagliflozin, an inhibitor of renal sodium glucose co-transporter 2 (SGLT2), compared to a decline of 0.3% among patients in a placebo group, according to Cliff Bailey of Aston University in Birmingham. Patients receiving the drug also lost 3 to 4 kg of body weight, as opposed to less than 2 kg with placebo.

SGLT2 is a key molecule in the re-absorption of glucose in the kidneys, from where it is returned to the blood circulation. Inhibiting it forces the kidneys to excrete glucose in the urine instead, thereby lowering blood glucose levels. Dapagliflozin was the first SGLT2 inhibitor to reach clinical testing and is now the first for which phase III data have been reported. In the current trial, 546 patients with type 2 diabetes, poorly controlled with metformin, were randomised to three doses of dapagliflozin (2.5, 5 or 10 mg once daily) or placebo, in addition to their previous doses of metformin. Mean Hb1c level at baseline was 8.1% and mean met-

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formin doses ranged from about 1 800 to 1 900 mg daily in the four groups. About 25% of each dapagliflozin group had at least a 5% decrease in body weight, compared with 6% of the placebo group who lost that much, Bailey said. He also reported on a variety of other outcomes, all expressed as mean change from baseline: • diastolic blood pressure: –2.1 to 5.1 mmHg for dapagliflozin, –0.1 mmHg for placebo (p not reported) • fasting plasma glucose: –17.8 to –23.5 mg/dl for dapagliflozin, –6.0 mg/dl for placebo (p < 0.05). Bailey said that orthostatic hypotension was not increased with the drug, despite the

decreases in blood pressure, nor were there any differences between the dapagliflozin and placebo groups in the incidence of hypoglycaemic episodes. Some increases were seen in female genital infections, with up to 13% of patients on dapagliflozin affected, compared with 5% of the placebo group. John Buse, MD of the University of North Carolina commented that the HbA1c reduction was relatively modest but the weight loss and lack of other major adverse effects were in dapagliflozin’s favour. Other phase III trials of the drug are underway. Reviewed by Dr DF Zaleznik

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Diabetes Personality A PRIMARY CARE ROLE MODEL FOR DIABETIC PATIENTS S Afr J Diabetes Vasc Dis 2009; 6: 156–157. Sr Sesi Ramonotsi Chief professional nurse, Heidedal Community Health Centre, Bloemfontein

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r oviding quality care for diabetes mellitus patients in a resource-poor primary healthcare setting is fraught with challenges. But that doesn’t stop dedicated, caring professionals like Sr Sesi Ramonotsi from doing everything possible to ensure that her patients get the best possible care at all times. Sr Ramonotsi is chief professional nurse at Heidedal Community Health Centre in Bloemfontein. She admits that when she first entered the nursing field it was just a job, but by the time she had completed her nursing studies in 1983, she was passionate about caring for patients. Over the years, her work has encompassed many areas of adult curative health, including maternal health and anti-retroviral medicine. When she was assigned to the Centre’s diabetes clinic in 1999, she had no strong feelings about endocrinology, but an environment she describes as a ‘happy clinic’ quickly made her new assignment an attractive one. Sr Ramonotsi and her team are responsible for screening patients for diabetes, educating, advising

Sr Ramonotsi tests a patient’s blood sugar levels.

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and treating them and, if necessary, referring them on. ‘We do all the usual tests, such as urine dipstick, fingerprick, and weight and body mass index measurements’, she says. Based on the results of these tests, Sr Ramonotsi is in the front line when it comes to having to tell someone they’re diabetic. ‘Usually, they go straight into denial, as the diagnosis brings a lot of fear. It’s very important to reassure them that diabetes is not a death sentence. I see myself as a role model in this regard. I’m a diabetic and I’ll say to them, “Look at me. I have diabetes. I’m still here and I’m still working!” Once the patient has accepted the diagnosis and been reassured, the next step is to make sure he/she understands the disease and where the problem is – specifically that diabetes is not just about sugar. I use posters of human physiology to show them where the pancreas is and explain how its dysfunction causes their diabetes.’ The next challenge is to introduce treatment and ensure patient compliance. Sr Ramonotsi, like most professionals who work with diabetics, encounters a lot of resistance, especially when it comes to insulin injections. ‘Some patients just don’t want to take medicine’, she says, pointing out that some prefer to use ‘natural alternatives’ like Aloe Extra, which not only have no proven value, but can interact harmfully with allopathic medicines. However, she takes great satisfaction in watching patients become more aware and more compliant, thanks to her efforts. ‘All my patients have my telephone number and can call me at any time. When I get calls from patients asking questions about their glucometer readings and the doses of medicine they need to take, I know that they understand their condition and are now committed to doing what’s necessary to control it.’ Sr Ramonotsi gets many phone calls. She estimates

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Sr Ramonotsi focuses on helping patients maintain a normal body weight.

that her clinic serves over 2 000 patients, some of whom come from as far afield as Thaba Nchu and Ladybrand. Dealing with the numbers is challenge enough, but the clinic’s lack of resources means that often there isn’t enough medication for all. She feels that it’s important too, always to keep in mind that many of these patients are extremely poor or unemployed, and consequently have psychosocial issues in addition to their diabetes. ‘One of the saddest situations is when these people apply for government grants and fail to get them’, she says. She also laments the fact that financial constraints don’t allow for routine HbA1c assessment and that patients need to be referred to higher levels for this. Asked about job satisfaction, Sr Ramonotsi takes great pride in the trust her patients show her and the confidence they have in her care of them. ‘If I’m off duty or on night shift, they’re always unhappy that I’m not there and let me know about it afterwards. When referred upward, some have even been known to communicate my advice by saying, “My doctor told me this”.’ She feels a sense of achievement when she sees

Teaching patients how to monitor their own glucose levels is vital to good glucose control.

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Insulin administration techniques need to be explained to the patients.

patients become compliant with treatment and consequently experience an improved health status. ‘It’s an ongoing struggle, but my patients’ trust in me inspires me to go on’, she says. It’s not only patients who have given Sr Ramonotsi and her team the thumbs up. Once a week, medical students from the University of the Free State visit the clinic to learn more about screening, diagnosing and treating diabetes. ‘We get lots of positive feedback from them, and they’re impressed by how organised and efficient we are, despite all the challenges we face.’ Sr Ramonotsi doesn’t believe in resting on her laurels, either. Despite her heavy and demanding workload she also tries to attend as many lectures and conferences as she can to keep abreast of new developments in diabetes care. ‘I’m just sorry that financial constraints prevent me from attending more than I do’, she concludes. All photographs by Deon Ellis Photography.

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EASD WATCH SUMMARIES

2009 UPDATE FROM VIENNA, AUSTRIA European Association for the Study of Diabetes Contributors: Dr D Blom, Dr EH Du Raan, Dr TE Kinvig

Cardiovascular disease and hypoglycaemia risk according to cognitive function in people with type 2 diabetes: ADVANCE study In the ADVANCE study, cognitive dysfunction was an independent predictor of cardiovascular outcome as well as of total mortality. Severe cognitive dysfunction was also positively linked to severe hypoglycaemia. The benefits of blood pressure lowering and intensive glycaemic control were unaffected by baseline cognitive function. These findings were presented by Dr de Galan from the University of Nijmegen at session 25 (abstract 146) of the 2009 EASD in Vienna on behalf of the ADVANCE investigators. The ADVANCE study enrolled type 2 diabetic patients at high vascular risk. The interventions were blood pressure control with perindopril plus indapamide or placebo, and tight glucose control with gliclazide MR versus standard glucose control. The main results of the study have been published previously. In the current analysis, patients were stratified with a baseline Mini Mental State examination (MMSE) into normal cognitive function (MMSE 28–30; 8 689 patients), mild cognitive impairment (MMSE 24–27; 2 231 patients) and severe cognitive dysfunction (MMSE < 24; 212 patients). Patients with cognitive dysfunction were older, more likely to be female, had more cardiovascular disease and poorer glycaemic control as assessed by HbAIc. Both mild and severe cognitive dysfunction was associated with worse clinical outcomes. The multiple-adjusted hazard ratio for mild cognitive dysfunction was 1.27 (95% CI: 1.11–1.46) for major cardiovascular events, 1.41 (95% CI: 1.16–1.71) for cardiovascular death, and 1.34 (95% CI: 1.15–1.55) for all-cause mortality. Severe hypoglycaemia requiring assistance from a bystander was more common in patients with severe cognitive dysfunction but the rate of hypoglycaemia was unaffected by mild cognitive

29 September – 2 October 2009

dysfunction. The beneficial effect of tight blood pressure and glycaemic control was not affected by cognitive functioning. Although the MMSE is a relatively crude measure of cognitive function, this study once again highlights the high prevalence of cognitive dysfunction in patients with type 2 diabetes. Mild cognitive dysfunction is often not clinically recognised, but is, as this study clearly shows, a powerful predictor of outcome. This is at least in part because cognitive dysfunction marks severe and longstanding disease. Patients with cognitive dysfunction are also less likely to cope with complex therapeutic interventions such as intensive insulin treatment with self-titration and the higher rate of hypoglycaemia in those with severe cognitive dysfunction therefore does not come as a surprise. The authors did not present any data on cognitive outcome at this session (data awaited) but the question whether intensive blood pressure and glycaemic control is associated with better cognitive outcomes

is clearly highly relevant. On this topic, Dr Yamanoto from Tokyo’s Women’s University presented an intriguing report at the same session, on a lifestyle intervention (diet and exercise) in elderly subjects with previously undiagnosed and untreated diabetes or impaired glucose tolerance, which showed clear improvements in several measures of cognitive functioning. These patients all had relatively mild hyperglycaemia and very few were treated with hypoglycaemic drugs. Although lifestyle interventions are often difficult to implement they may benefit patients in unexpected ways. Dr D Blom, University of Cape Town

Diabetes and pregnancy: determinants of neonatal and maternal complications: HAPO study The Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study was a purely observational study performed in 15

TABLE OF CONTENTS Cardiovascular disease and hypoglycaemia risk according to cognitive function in people with type 2 diabetes: ADVANCE study����������������������������������158 Diabetes and pregnancy: determinants of neonatal and maternal complications: HAPO study�����������������������������������������158 Melatonin: good morning to an unexpected culprit in type 2 diabetes���������159 Novel therapies for type 2 diabetes mellitus�������������������������������������������������160 Pregnancy outcomes in women with hyperinsulinaemia and impaired glucose tolerance prophylactically treated with metformin: a case–control study��������160 To amputate or not?�������������������������������161

Diabetes education and management���161 Diabetes in childhood�����������������������������161 Paradigms in metabolic disease������������161 Cholesterol absorption decreases after Roux-en-Y gastric bypass but not after gastric banding������������������������������������162 Colesevelam HCl improves glucose metabolism and increases plasma glucagonlike peptide 1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP) concentrations in subjects with type 2 DM���������������������������������������������162 Hepatic steatosis does not result in hepatic insulin resistance in subjects with familial hypobetalipoproteinaemia�������������163

Independent report compiled with financial support from Sanofi Aventis for healthcare professionals in Southern Africa 158

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centres in nine countries across the world, excluding Africa, to assess maternal and foetal outcomes at different levels of glycaemia. This study was published in the N Engl J Med 2008; 358(19): 1991–2002. HAPO demonstrated risk at levels not conventionally considered to be diabetes and therefore brings into question our current recommendations for the management of pregnant women. Dr M Hod (Diabetes and Pregnancy, Thursday 1 October 2009) discussed the study at length with respect to the fact that this was an observational study and that the recommendations are based on pregnancy outcome data. The 25 505 patients underwent a 75-g oral glucose tolerance test (OGTT) – data remained blinded if patients had a fasting glucose of 5.8 mmol/l or less or a two-hour value of 11.1 mmol/l. A total of 23 316 patients were followed up. The primary outcomes were macrosomia, caesaerian section, elevated C-peptide indicating neonatal hyperinsulinaemia and neonatal hypoglycaemia. Secondary outcomes were delivery prior to 37 weeks, shoulder dystocia or birth injury, admission to the neonatal ICU, neonatal jaundice and pre-eclampsia. There were no obvious thresholds at which risks increased and there was a continuous relationship with fasting, one- and two-hour glucose measurements with both the primary and secondary outcomes. A fasting blood glucose (FBG) < 4.4 mmol/l accounted for 50% of the study population and resulted in a 7% incidence of large-for-gestational-age (LGA) babies; whereas an FBG of > 5.0 mmol/l was evident in 11.9% of the study population and resulted in 17.6% LGA babies. Therefore an FBG of < 4.4 mmol/l would significantly decrease the risk of LGA babies and the consequent implications with respect to birth injuries and future risk for type 2 diabetes in the offspring. Should we use only the FBG level? Dr Hod suggested that the one- and two-hour blood glucose values added a further 5.7 and 2.1% detection to the single fasting glucose level. The new recommendations have yet to be finalised and will be discussed with a number of groups, including the WHO, prior to publication. Although this study was not conducted in any African centres, correcting for ethnicity showed no change across the data, suggesting applicability to our population. As a result of this study, which looked solely at pregnancy outcomes, the likely intervention thresholds

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based on a 75-g OGTT at 24–28/40 weeks’ gestation (or earlier if there is a previous history) could be as low as 5.1 mmol/l for fasting blood glucose levels, 10 mmol/l for one-hour and 8.5 mmol/l for two-hour levels. The cost implications could be enormous. Prior to institution of new guidelines, the recommendation should be that any overweight or obese woman considering pregnancy is intensively counselled regarding the risks of dysglycaemia to the mother and the proposed infant. Dr TE Kinvig, private practice, Cape Town

Melatonin: good morning to an unexpected culprit in type 2 diabetes This is a new area of interest and was probably included in the programme as a result of three articles that appeared in the journal Nature Genetics in January 2009. The aim of this particular talk was to provide the background for the subsequent two talks, which were more specific to diabetes and gave a superb overview of the current understanding of melatonin – ‘the hormone of darkness’. Basic science of circadian rhythms, melatonin and melatonin receptors Humans have a near 24-hour physiological rhythm, which is synchronised by the light– dark cycle, according to Dr D Weaver. In the absence of vision, rhythmicity persists but is no longer regulated by the light– dark cycle. Blind people or those kept in low-light situations are found to have a longer than 24-hour rhythm. This rhythm will persist, however the period of inactivity will shift and no longer coincide with the light and dark. This is a phase shift. The circadian rhythm is synchronised by specialised retinal cells containing melanopsin. The entire cycle is regulated by the master clock – the suprachiasmatic nucleus in the hypothalamus. This alters neural, behavioural and physiological processes via a number of pathways, including melatonin and glucocorticoids. Sources of melatonin include the pineal gland, the gut and the retina. Melatonin secretion is highest at night, but the impact that it has on the physiology of the organism is species dependent. Melatonin effects are co-ordinated via receptors MT1 and MT2 – otherwise known as Mel 1a (MTNR1A) and Mel 1b (MTNR1B), respectively. MT1 receptors appear to be more highly expressed and localised, but there may be distinct or over-

lapping functions of the two receptors. Pancreatic melatonin receptors: from fiction to function Melatonin effects on the β-cells of the pancreas occur via MT1 and MT2 receptors, reported Dr E Mühlbauer. This German group has investigated the effects of melatonin on the pancreas. They have elucidated the actions of melatonin at the two receptors; the effects are mediated via G-protein-coupled receptors and involve cAMP and IP3 for MT1, and cGMP for MT2. Therefore activation of MT1 receptors can result in decreased and increased insulin production, respectively, depending on the mechanism of activation. The circadian rhythm that melatonin imposes on insulin secretion appears to be altered in type 2 diabetes mellitus, but the exact pathway is not clear. The circadian rhythm of insulin secretion persists in MT1 receptor knock-out mice, but there may be a phase shift. What is apparent is that serum insulin is reduced in the knock-out mice but the insulin gene expression is increased, causing blood glucose levels to increase. The GK rat model of type 2 diabetes shows increased glucose and insulin levels and expression of MT1 and MT2 receptors, but decreased levels of melatonin. Studies suggest that there is increased expression of MT1 and MT2 receptors in patients with type 2 diabetes mellitus compared to normoglycaemic patients. Streptozotocin-induced type 1 diabetes in rats results in a completely different picture with increased glucose, arylakylamine N-acetyltransferase (AANAT) and melatonin levels, and decreased insulin levels. It is unclear whether oral melatonin in the doses used for the management of sleep disorders manipulates insulin levels. The genetics of the melatonin receptor 1B in type 2 diabetes Dr Valeriya Lyssenko from Sweden discussed an MT2 receptor polymorphism which is associated with an increased risk of type 2 diabetes mellitus and IFG but not IGT. The polymorphism is associated with impaired insulin secretion demonstrated by increased proinsulin/insulin ratios in these β-cells. This MT2 receptor polymorphism appears to be associated with sleep disorders in some men. Variant-containing cells incubated with melatonin showed suppression of insulin secretion. If oral melatonin inhibits glucose-stimulated insulin secretion, is there a role for

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melatonin as a future antidiabetic agent? It has been recognised for a long time that there is a link between sleep and diabetes, but the prospect that this may be mediated by melatonin is exciting. This seminar was very provocative in terms of the physiology and the possible link with type 2 diabetes, but I think that we are still a long way from prescribing melatonin as a treatment for type 2 diabetes. Dr TE Kinvig, private practice, Cape Town

Novel therapies for type 2 diabetes mellitus: Treatment with VI-0521 (phentermine and topiramate) leads to one-year durable glycaemic benefit and weight loss in subjects with type 2 diabetes mellitus The aim of this study, presented by Dr WT Garvey, University of Alabama, Birmingham, USA (Abstract 173), was to demonstrate the persistence of the cardiovascular and metabolic benefits of this once-daily combination drug in a group of type 2 diabetic patients who had previously completed 28 weeks of therapy with this drug. Significant weight loss and statistically significant reductions in HbA1c and blood glucose levels, in addition to lowering of blood pressure and lipids, have been demonstrated. The subjects were patients who agreed to continue with their randomised treatment following on a completed 28-week double-blind, placebo-controlled trial to evaluate VI-0521. The drug was assessed over a total of 56 weeks and the primary endpoint was change in HbA1c from baseline (week 0) to week 56. There were 75 patients on active treatment – phentermine 15 mg and topiramate 92 mg. Phentermine was included to enhance cognition and alertness and hopefully counteract any possible adverse effects of the topiramate, although this dose is approximately 25% of the usual therapeutic dose. Phentermine has not been associated with pulmonopathy or valvulopathy. The placebo group contained 55 patients. The patient cohort was fairly representative of clinical patients. There was a 69% predominance of women, 59% Hispanic/Latin and 11% black subjects; mean baseline weight was 96 kg, and the BMI ranged from 27–45 kg/m2. Patients all had type 2 diabetes, mean HbA1c level was 8.7%, and fasting glucose was 9.6 mmol/l. At baseline 11% were drug naïve, 28%

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were on monotherapy and the remainder of the patients were on two or more oral medications for their diabetes. Patients with depression and on antidepressants were included, and active management of the diabetes occurred in both groups – in other words therapy was not frozen. All subjects were counselled about lifestyle and dietary modification for the duration of the 56-week study. The reduction in HbA1c levels in the placebo arm was 1.13% and in the treatment arm 1.67%, i.e. an overall reduction of 0.54% in the treatment group. Thirty-two per cent of the treated subjects achieved an HbA1c of < 6.5% compared to 16% in the placebo group. Interestingly, the placebo-treated patients required an increase in their antidiabetic medication whereas the subjects managed with VI-0521 had a net reduction in antidiabetic medication. Fasting glucose levels dropped by 2.42 mmol/l compared to 1.42 mmol/l in the placebo group. VI-0521-treated subjects lost 9.4% of their baseline body weight compared to 2.7% in the placebo group – this translates to 6.7% reduction in body weight with a 0.5% reduction in HbA1c levels for the subjects on VI-052. There were no treatment-related serious adverse events and the only drug discontinuation occurred in the VI-0521-treated group. Adverse events were mild to moderate and occurred at lower rates in the second study. Study participants completing treatment were above 90% in both groups. This compares favourably in terms of weight loss, HbA1c reduction and tolerability with the other drugs presented in these oral presentations. These included two studies with dapagliflozin (an SGLT2 inhibitor, resulting in decreased renal absorption of glucose from the proximal convoluted tubules) as add-on to metformin only and metformin, insulin, and occasionally TZD therapy, Colesevelam HCl, a bile acid sequestrant, and INCB13739, an 11βHSD inhibitor which inhibits the catalysis of cortisone to cortisol. The nature of the diabetes epidemic has led to a dramatic expansion in the classes of drugs available for treatment as well as the novel therapies targeting alternative processes of insulin and glucose homeostasis. All these drugs are in the early stages of development and still need extensive investigation before they will be available for use in our patients. Dr TE Kinvig, private practice, Cape Town

Pregnancy outcomes in women with hyperinsulinaemia and impaired glucose tolerance, prophylactically treated with metformin: a case–control study This study, by Drs KN Todorova-Ananieva, EI Kononova and AL Emin at the High-Risk Pregnancy Department, Specialised Hospital of Obstetrics and Gynaecology, Sofia, and the Clinical Institute of Reproductive Medicine, Pleven, Bulgaria (Abstract 101) was performed on women who had had at least one previous miscarriage and no known previous glucose intolerance. They were investigated and if they were glucose intolerant or diabetic, they were started on metformin. The women treated with metformin during their pregnancies had improved metabolic markers and reduced spontaneous miscarriage rates when compared to the women not on metformin. This study was an evaluation of the neonatal and maternal effects of metformin use in pregnant women with a previous failed pregnancy and no previous known history of glucose intolerance. This study was conducted in 66 pregnant women. It was a prospective one-year case–control study performed in women with subsequent pregnancy, subjected to an OGTT at 12 and 36 weeks’ gestation. Investigations included glucose and immunoreactive insulin levels at 0, 60 and 120 min. The use of metformin was based on the results of the initial OGTT. Group 1 included 21 women with normal insulin and glucose values; group 2 included 24 women with hyperinsulinaemia and impaired glucose tolerance (IGT); while group 3 included 21 women with hyperinsulinaemia and gestational diabetes mellitus (GDM). There were no significant differences between the groups in mean values for age of patient and BMI. The blood glucose values between patients in groups 1 and 3 were significantly different, being higher in the group with GDM. The stimulated insulin levels in patients in groups 2 and 3 were higher initially and the BMI in late pregnancy was significantly lower in group 1 (normal OGTT). The levels of blood glucose were lowest in patients in group 2 when assessed later in pregnancy. The levels of insulin in group 2 and 3 patients were lowest in the treatment groups in later pregnancy, than in the non-treated normal OGTT group; and statistically lower when compared to the same insulin levels in these patients in early pregnancy. No

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maternal or foetal complications were attributable to the metformin. The birth weights were not statistically different in the three groups. No comment was made on the foetal fat mass in the three groups. The rate of spontaneous abortion for the entire study population was 13.6% (9/66), the majority of these occurred in the group of patients who did not receive metformin – 6/21, 28.5%. Although a number of studies have suggested that the use of metformin in pregnancy is safe and may reduce the risk of spontaneous abortion in patients with PCOS, hyperinsulinaemia and previous pregnancy loss, the ADA do not recommend the routine use of metformin in pregnancy until further randomised, controlled trials are available. The Metformin Use in Gestational Diabetes study (MiG) conducted in Australasia and published in the N Engl J Med in May 2008 only addressed the use of metformin from 20 to 33 weeks’ gestation until delivery. This did not demonstrate any adverse foetal or maternal events – but is not helpful with regard to the population group in the Bulgarian study. Further studies are therefore required in the patient population as well as the group with previous gestational diabetes. Note that the dose used in the Bulgarian study was 250 mg tds, which is a substantially lower dose than most other studies – 1 500–2 550 mg daily in divided doses. Studies therefore need to consider the appropriate dose of metformin. Dr TE Kinvig, private practice, Cape Town

To amputate or not? In this oral presentation by ME Edmonds of the Diabetic Foot Clinic, Kings College, London Hospital, the reported levels of osteoprotegerin were raised in diabetic peripheral neuropathy and were correlated with peripheral arterial calcification. Fortyfive patients with diabetic neuropathy, 88 without neuropathy and 22 healthy controls were studied. All patients had palpable foot pulses. Neuropathy was assessed by measuring vibration perception threshold at the apex of the hallux. Thirty-eight patients were assessed for the presence of peripheral arterial calcification on foot and ankle X-rays. Osteoprotegerin levels were measured using ELISA. The outcome was raised serum OPG levels in both type 1 and type 2 diabetic patients with neuropathy. Furthermore,

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serum OPG was significantly correlated with peripheral neuropathy and peripheral arterial calcification. Dr EH Du Raan, Endocrine Unit, Universitas Academic Hospital, Bloemfontein

Diabetes education and management Motivational enhancement therapy (MET) with cognitive behavioural therapy (CBT) to treat type 1 diabetes improved glycaemic control by producing a 0.5% reduction in HbA1c levels at 12 months, but this beneficial effect was not maintained at 36 months, according to K Ismail, Psychological Medicine, Institute of Psychiatry, London. The 1 659 patients were screened from eight diabetes centres in London and Manchester, and 507 patients were found to be eligible for the study. The baseline sample consisted of 344 adults with type 1 diabetes, with HbA1c levels between 8.2 and 15% and without complications or severe co-morbid disease. They had been randomised to either nurse-delivered MET, MET plus CBT or usual diabetes care. The main outcome was the 36-month change in HbA1c levels. In the analysis, the mean baseline HbA1c level was 9.37% and the mean 36-month level was 8.72%, representing an average decrease in HbA1c values of 0.65% from baseline to 36 months, but not between MET versus usual care. The groups were very similar at 36 months. The effectiveness of MET plus CBT at 12 months had disappeared at 36 months. Dr EH Du Raan, Endocrine Unit, Universitas Academic Hospital, Bloemfontein

Diabetes in childhood Metabolic control during the first year of contracting type 1 diabetes (T1 DM) predicts HbA1c levels during adulthood, reported RW Holl, Epidemiology, University of Ulm, Germany. The importance of metabolic control is well established in type 1 diabetes. Most studies address patients in a cross-sectional manner, rather than following patients longitudinally over prolonged periods of time. The question is whether tracking of metabolic control is present in patients with T1 DM of paediatric onset, and followed continuously over the pubertal period until adulthood. Up to March 2009, 41 797 patients with T1 DM of paediatric onset (< 15 years)

were included in the database. The mean time of follow up was 6 ± 0.4 years. HbA1c levels during the first year of diabetes averaged 6.99% compared to 8.35 ± 0.02% during adulthood. In the whole group, after adjustment for age at onset, diabetes duration, insulin therapy and BMI during adulthood, gender, migration background and treatment centre, HbA1c level during the first year of diabetes was a strong predictor of HbA1c level during adulthood. This study provides convincing evidence for long-term tracking of metabolic control. Early focus on metabolic control, even during the first months of diabetes onset is important. Alternatively, disease heterogeneity or different personal traits in diabetes management might be responsible for the long-term stability of HbA1c levels in individual patients with paediatric diabetes onset, despite the considerable variability observed during puberty. Dr EH Du Raan, Endocrine Unit, Universitas Academic Hospital, Bloemfontein

Paradigms in metabolic disease Adipose tissue is directly targeted and initiated by bacterial lipopolysaccharide (LPS) at the early onset of high-fat diet-induced metabolic disease, said E Luche of France. It has recently been shown in the mouse and in humans that a fat-enriched diet (HFD) increased plasma lipopolysaccharide concentrations in the blood and was responsible for the low-tone inflammation observed during metabolic diseases. This mechanism depended on the LPS receptor CD 14 and targeted the adipose tissue, since CD 14 knock-out mice did not develop obesity in response to HFD. In response to a one-month LPS infusion, the adipose cell number was increased and the cells were smaller, suggesting an increased precursor proliferation. It was determined that all precursor populations were increased, including pre-adipocytes, macrophages and pre-endothelial cells. In vitro LPS stimulation increased the proliferation of cell types isolated from the stroma vascular fraction of wild-type but not CD 14 adipose depots. Conversely, in vitro, the LPS treatment reduced the adipose cell differentiation process, assessed by lipid accumulation, and the expression of adipogenic markers from wild-type but not from CD 14 knock-out precursors. It was shown that LPS, which originates from intestinal microflora, could directly

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trigger the adipose depot by a CD 14-dependant mechanism to initiate the proliferation of adipose tissue precursors. Dr EH Du Raan, Endocrine Unit, Universitas Academic Hospital, Bloemfontein

Cholesterol absorption decreases after Roux-en-Y gastric bypass but not after gastric banding Bariatric surgery improves multiple metabolic parameters including serum lipids. Not all bariatric procedures achieve the same degree of lipid lowering, and Roux-en-Y gastric bypass (RYGB) lowers lipids more effectively than gastric banding (GB). Cholesterol absorption decreases after Rouxen-Y bypass but not after gastric banding. Dr JA Pihlajamäki from the University of Kuipo in Finland presented this data at session 16 (Abstract 93). Bariatric surgery is the most effective treatment we have for obesity and diabetes and is being performed with increasing frequency. Bariatric surgery has profound effects on glucose metabolism but lipid metabolism is altered as well, albeit to a lesser extent. Relatively little is known on a mechanistic level about the lipid effects of bariatric surgery. Patients with obesity or insulin resistance are known to have increased cholesterol synthesis and decreased absorption compared to lean controls. This balance is shifted to decreased synthesis and increased absorption following weight loss. GB is a purely restrictive procedure while RYGB causes malabsorption in addition to restricting food intake. The authors studied 55 obese patients who underwent either RYGB (29) or GB (26). The surgical procedure was not assigned randomly and was chosen by the bariatric team responsible for the patient. Patients were studied at baseline and one year following surgery. The cholesterol synthetic precursors lathosterol, cholestenol and desmosterol were measured as markers of cholesterol synthesis, and cholesterol absorption was assessed by measuring plant sterols (campesterol, sitosterol and avenasterol). These plant sterols are not synthesised by humans but are taken up from the diet proportionally to cholesterol absorption. RYGB caused more profound weight loss than GB and was associated with greater reductions in total cholesterol, triglycerides and LDL-C than GB. Cholesterol synthetic markers decreased by 10–25%

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in all patients irrespective of the type of operation, as would be expected following weight loss. However, the expected increase in cholesterol absorption was only seen following GB, with an 18% increase in the sitosterol/cholesterol ratio, whereas RYGB was associated with a 22% decrease in this ratio. This difference remained significant after adjusting for the greater reduction in BMI and insulin resistance following RYGB. Serum sitosterol was positively correlated with the change in cholesterol, suggesting that decreased cholesterol absorption is one of the mechanisms that mediates the reduction of serum cholesterol following bariatric surgery. This is one of the first studies to examine lipid metabolism on a mechanistic level following bariatric surgery. It clearly shows that decreased cholesterol absorption following RYGB is at least in part, the mechanism responsible for lowering cholesterol postoperatively. A full understanding of lipid metabolism following bariatric surgery will require more detailed studies, including turnover studies. This study highlights that not all bariatric procedures have equivalent metabolic effects and that these differences should be considered when recommending a specific procedure to patients. Dr D Blom, University of Cape Town

Colesevelam HCl improves glucose metabolism and increases plasma glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) concentrations in subjects with type 2 DM Colesevelam, a novel bile acid sequestrant, was originally developed as a lipid-lowering agent but was recently licensed for use as a hypoglycaemic agent by the FDA. This study shows for the first time that the glucose-lowering effect of Colesevelam may at least in part be mediated by increased levels of the incretins GLP-1 and GIP. Dr C Beysen from KineMed Inc in Emeryville presented the results of this mechanistic study at session 29 (abstract 171). The modest glucose-lowering effects of bile acid sequestrants have been known for many years, having first been shown for cholestyramine. However, cholestyramine use declined rapidly after the discovery of statins, which are much more effective and have much greater tolerability, and the above observation was all but forgotten. Colesevelam is a specifically engineered bile

acid sequestrant that has far fewer gastrointestinal side effects than cholestyramine and is a useful additional agent in patients with residual LDL hypercholesterolaemia despite maximum tolerable statin therapy. In patients with type 2 diabetes it can lower HbA1c levels by about 0.6–0.7%. The mechanism of glucose lowering was unknown. The authors randomly assigned 60 subjects with type 2 DM to 12 weeks of Colesevelam (3.75 g/d) or placebo in a 1:1 fashion. Fasting endogenous glucose production, gluconeogenesis, glycogenolysis and plasma glucose clearance were measured at baseline and at 12 weeks both in the fasted state and following a mixed-meal challenge, using stable isotope infusions of appropriate substrates. Additionally plasma glucose, insulin, glucagon, GLP-1 and GIP were also measured. HbA1c levels were reduced by 0.62% at 12 weeks in the Colesevelam group. Colesevelam increased patients’ fasting total GLP-1 level, postprandial total GLP-1 area under the curve (AUC) (+ 2 267 ± 750 pmol/l per 300 min) and postprandial GIP AUC (+ 3 850 ± 857 pmol/l per 300 min) compared to placebo. All these changes were statistically significant. Plasma glucose clearance increased significantly from baseline in the Colesevelam-treated group but remained unchanged with placebo. There was no change from baseline in endogenous glucose production and glycogenolysis with Colesevelam whereas these parameters increased in the placebo group. There were no differences in fasting insulin, postprandial insulin, glucagon and fasting GIP levels and absolute gluconeogenesis between the groups. The glucose-lowering effect of Colesevelam is therefore mediated at least in part by enhanced incretin secretion. Incretin therapy, using either incretin analogues or DPP-IV inhibitors, is a promising new approach in the management of type 2 DM. The effect of Colesevelam on incretin levels is somewhat unexpected and further research will be required to characterise this effect in more detail and understand the underlying molecular mechanisms. Currently, Colesevelam may be an attractive therapeutic option in patients with type 2 DM with elevated LDL-C despite statin therapy, and an HbA1c level that is modestly (0.5%) above target, as it may address both problems with a single agent. Dr D Blom, University of Cape Town

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Hepatic steatosis does not result in hepatic insulin resistance in subjects with familial hypobetalipoproteinaemia Familial hypobetalipoproteinaemia is characterised by severe hepatic steatosis but in a detailed metabolic study of these patients, there was no evidence of hepatic insulin resistance. These findings were presented at session 31 (abstract 184) by Dr NM Lammers of the Academic Medical Centre in Amsterdam. There is a strong positive correlation between hepatic steatosis and hepatic insulin resistance as well as whole-body insulin resistance. However, many questions regarding the mechanisms of hepatic fat accumulation and the molecular links to hepatic insulin resistance remain to be resolved. Hepatic insulin resistance is not found in all animal models of hepatic steatosis, suggesting that excess hepatic fat does not inevitably cause hepatic insulin resistance. One of the best-known animal models of hepatic steatosis without hepatic insulin resistance is the mitochondrial triacylglycerol transfer protein (MTP)-deficient rat. MTP transfers lipids onto nascent lipopro-

Insulin Glargine 2 4 - h o u r b a s a l c o v e r a g e . D a y a f t e r d a y.

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teins and MTP deficiency is associated with severe hepatic steatosis due to the inability to export lipids from the liver. Human MTP deficiency causes abetalipoproteinaemia but this is an exceedingly rare disorder. The authors of this paper therefore studied hepatic insulin sensitivity in a related disorder known as familial hypobetalipoproteinaemia (FHBL), which in its homozygous state is also associated with severe hepatic steatosis. The molecular defect in FHBL is in apolipoprotein B100 (apoB) and mutations in both alleles are associated with severe hypolipidaemia and marked hepatic steatosis due to failure of hepatic lipid export. Eight patients with FHBL and eight controls matched for height, weight, age, body mass index, waist–hip ratio and physical activity were studied. Hepatic fat and intramyocellular fat were measured using MRI spectroscopy. Hepatic insulin sensitivity, peripheral insulin sensitivity and endogenous glucose production were measured in the fasting state using a two-step hyperinsulinaemic euglycaemic clamp technique with infusion of stable isotopes as tracers. Patients with FHBL had much higher hepatic fat levels (27%) than the controls (5%). There was no difference in intramyo-

cellular triglyceride content between the two groups. None of the measures of glucose metabolism or insulin sensitivity, both at the hepatic or peripheral level, differed between the two groups. The authors of this paper are to be congratulated for managing to find and enroll eight patients with FHBL in this very detailed and elegant metabolic study. This study conclusively shows that excess hepatic fat in humans is not per se sufficient to cause hepatic and peripheral insulin resistance. Clearly, much remains to be learnt about hepatic fat and insulin resistance. The mechanism by which hepatic fat accumulates may be more important than the sheer presence of hepatic fat. MTP inhibition can lower lipids powerfully and MTP inhibitors are currently being studied as additional lipid-lowering agents for patients with severe hyperlipidaemia (e.g. homozygous familial hypercholesterolaemia) insufficiently responsive to conventional lipid-lowering therapy. MTP-inhibitor therapy is often accompanied by an increase in hepatic fat and this study provides some reassurance that this increase in hepatic fat will not inevitably lead to hepatic insulin resistance. Dr D Blom, University of Cape Town

Insulin Glulisine The speed you need. When you need it.

SCHEDULING STATUS: S3 PROPRIETARY NAME AND DOSAGE FORM: APIDRATM solution for injection. COMPOSITION: 1 ml contains 3,5 mg insulin glulisine, corresponding to 100 U human insulin. REGISTRATION NUMBER: A38/21.1/0506 NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: sanofi-aventis south africa (pty) ltd, 2 Bond Street, Midrand, 1685. Reg. No. 1996/10381/07. SCHEDULING STATUS: S3 PROPRIETARY NAME (and dosage form): LANTUS ® (solution for injection). COMPOSITION: Each ml of the solution for injection contains 3.64 mg of the active ingredient insulin glargine, corresponding to 100 U human insulin. REGISTRATION NUMBER: 34/21.1/0248. NAME AND BUSINESS ADDRESS OF THE APPLICANT: sanofi-aventis south africa (pty) ltd, 2 Bond Street, Midrand, 1685. Reg. No. 1996/10381/07. APPLICANT: sanofi-aventis south africa (pty) ltd, 2 Bond Street, Midrand, 1685. Reg. No. 1996/10381/07.

ZA.GLA.09.04.13

Save these dates 10–13 Feb 26–28 Feb 12–14 March 26–29 March 9 April 10–12 April 13–16 May

3rd International conference on advanced technologies and treatment for diabetes Novo Nordisk physician’s update 1st International (ADDC) Abu Dhabi diabetes congress International cardiology and diabetes meeting Novo Nordisk meeting at SEMDSA SEMDSA 3rd World congress on controversies to consensus in diabetes, obesity and hypertension (CODHy)

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Basel, Switzerland Johannesburg, South Africa Abu Dhabi, United Arab Emirates Cape Town, South Africa Durban, South Africa Durban, South Africa Prague, Czech Republic

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IDF WATCH SUMMARIES

2009 UPDATE FROM MONTREAL World Diabetes Congress presented by the International Diabetes Federation Contributors: Prof WF Mollentze, J Aalbers

Spotlight on the developing world Prof Jean Claude Mbanya from Cameroon is the new president of the International Diabetes Federation (IDF). After his introduction, Prof Mbanya gave an encouraging and motivating speech, where he clearly stated that if we want to address the global burden of diabetes, we must address it in all countries worldwide, including the third world. While we witness a diabetes epidemic in the westernised world with its abundance of medicines, we forget about the hardship of patients in third-world countries who don’t have appropriate access to healthcare, education and drugs. Patients die in a hyper- or hypoglycaemic condition because of lack of insulin or food. Prof Mbanya said that his aim while president is to start changing this. With this, he introduced a new area, which is to start raising awareness and improving cooperation worldwide to address the global burden of diabetes.

Glucose-lowering agents and risk of malignancy An increased risk for the development of malignancy has emerged as yet another long-term complication of type 2 diabetes. Dr Edwin Gale reviewed this hitherto understudied and under-reported but real phenomenon. As emerging therapies for the management of type 2 diabetes bring new hope for longer survival and improved quality of life, the threat of increased risk of dying from a malignancy is becoming a new reality. Cancer of the pancreas is the most commonly occurring malignancy in patients with diabetes, followed by cancer of the ovary, stomach, bladder, colon and endometrium, whereas the prevalence of prostate cancer in men with diabetes is decreasing. It is unclear whether the increased risk of malignancy is due to type 2 diabetes itself, the kind of therapy used, or the phenotype associated with type 2 diabetes. In this regard, obesity, insulin resistance, insulin,

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IGF-1, hyperglycaemia or other metabolic abnormalities should all be considered in the pathogenesis of cancer in patients with type 2 diabetes. An association between diabetes and cancer does not equal causality, and confounding factors may also play a part. It is also of note that the use of metformin is associated with a decreased risk of being diagnosed with malignancy. Clinical trials are currently underway to examine the efficacy of metformin as an anti-cancer agent. The statistical methods used in the German study that suggested an increased risk of malignancy with the use of insulin glargine were also critically evaluated. Dr Gerstein (USA) emphasised that the German database was an administrative database and that the results should be interpreted as hypothesis generating and not hypothesis testing. All the speakers in this symposium concluded that much more research needs to be done in order to better explain the statistical association between diabetes and cancer.

Haemoglobin A1c as a diagnostic test for diabetes? The debate is no longer whether haemoglobin A1c should replace the measurement of plasma glucose (fasting or two-hour post 75-g load) as the preferred diagnostic test for diabetes, but rather when. This is the opinion of Dr David Sachs, clinical chemist from the Brigham and Women’s Hospital

October 2009

and Harvard Medical School, Boston. Judging by the low mean of 6.0% of all HbA1c tests requested in his hospital, doctors have already been doing so for some time, according to a recent survey (the diabetic patients in that hospital are apparently not that well controlled). Since 2003, the considerable improvement in the accuracy of the HbA1c assay has paved the way for a committee appointed by the American Diabetes Association to suggest that HbA1c tests may now be a better means to diagnose diabetes than the measurement of plasma glucose levels. Apart from its accuracy, it is now also clear that HbA1c levels correlate well with blood glucose concentrations. It must, however, be kept in mind that HbA1c levels may be influenced by haemoglobin variants such as HbS, C and others. The variability of HbA1c values on repeated testing in the same individual is below 2%, which is similar to the interindividual variation. Interestingly, in white subjects, the mean HbA1c concentration is 0.4% lower than that in Afro-Americans, and it increases by 0.03% per year as a person ages. Variation in the lifespan of red blood cells, which is difficult to measure accurately, may also affect HbA1c levels in normoglycaemic subjects. For example, the mean HbA1c concentration in patients with haemolytic anaemia is much lower compared to that in normal individuals. A recent blood transfusion also renders the results of the HbA1c assay inaccurate.

TABLE OF CONTENTS Spotlight on the developing world��������164 Glucose-lowering agents and risk of malignancy�������������������������������������������164 Haemoglobin A1c as a diagnostic test for diabetes?�����������������������������������������������164 The role of beta-cell mass and function in the pathogenesis of type 2 diabetes����165

Where are we regarding the PPAR-agonists 10 years on?���������������������������������165 Progress in foot care�������������������������������165 New IDF study reveals that people in developing countries pay more for diabetes care and have poorer health results����������������������������������������������������166

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The merits of replacing plasma glucose estimation with the measurement of HbA1c levels to diagnose diabetes mellitus was also addressed by a World Health Organisation (WHO) committee tasked with revising its classification and diagnostic criteria. The recommendations of the committee are still being withheld by the WHO ‘police’. Prof Sir George Alberti briefly reviewed the pros and cons of switching the approach. The most important pros include the fact that HbA1c is stable, it provides a time-average of blood glucose concentrations, patients do not have to prepare for the test, it is reproducible, and fasting is not required. The cons are: a standardised test is required, it is expensive, it is not freely available especially in developing countries, the test is not accurate in patients with anaemia or in the presence of a haemoglobinopathy, quality assurance schemes are lacking, few data are available, and the cut-off point is uncertain. Prof Alberti stressed that the WHO needs to be cognisant of the needs of all healthcare systems worldwide and hinted that the status quo may be maintained. The classification of diabetes on the other hand may have to change to accommodate the growing prevalence of type 2 diabetes in children and adolescents, as well the fast-growing list of genetic mutations associated with diabetes. The unfortunate category ‘pre-diabetes’ (formerly including impaired glucose tolerance and impaired fasting glucose) is expected to be renamed ‘intermediate hyperglycaemia’ according to Prof Alberti.

The role of beta-cell mass and function in the pathogenesis of type 2 diabetes Dr Peter Butler challenged the view that type 2 diabetes is the end result of longstanding insulin resistance. In the majority of insulin-resistant individuals, islet betacells successfully respond by increasing insulin secretion – the so-called appropriate response. In a minority of subjects, the response is inappropriate, resulting in type 2 diabetes. The mechanism behind this inappropriate response is possibly due to a loss of beta-cell mass due to accumulation of insulin amyloid polypeptide (IAPP). Animal data show that dysglycaemia develops when approximately 50% of beta-cell mass has been lost. The critical loss of beta-cells is accompanied by a decrease in hepatic insulin clearance, which buffers the

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IDF WATCH

decrease in insulin secretion. The loss in beta-cell function is most likely due to the production of toxic IAPP oligomeric precursors disrupting mitochondrial function, resulting in apoptosis of the beta-cells. Dr Butler presented evidence that beta-cells can regenerate but the net effect is a decrease in beta-cell mass due to a mismatch between apoptosis and regeneration. He also showed data that the regeneration of beta-cells is accompanied by an increase in the replication of pancreatic ductal cells, which may possibly explain the increased incidence of chronic pancreatitis and carcinoma of the pancreas in obese patients and in patients with type 2 diabetes. It is a matter of concern that GLP-1-based therapy is also associated with chronic pancreatitis and ductal hyperplasia. The opposite has been noted in metformintreated subjects.

Where are we regarding the PPARagonists 10 years on? ‘We are only at the beginning’ responded Dr B Staels from the Institut de Lille, France. Because of their wide range of actions on glucose homeostasis, lipid metabolism and vascular inflammation, the peroxisome proliferator-activated receptors (PPARs) remain ideal targets for the development of new drugs. Despite the initial promise, there is little outcome data demonstrating a cardiovascular benefit of thiazolidenedione (TZD) use. The increase in cardiac ischaemic events associated with the use of rosiglitazone, as revealed by the meta-analysis reported by Nissen and Wolski, could not be confirmed by longer-term studies, explained Dr Leiter from Toronto. A closer look at the results of the RECORD study showed that the predictors of heart failure associated with the use of rosiglitazone include age over 60 years, a waist circumference above 104 cm and an increased urinary albumin:creatinine ratio. Rosiglitazone should not be used in patients with symptoms of or who have developed heart failure, said Prof BeckNielsen from Odense, Denmark. The observation in the RECORD study that after 5.5 years of use of rosiglitazone, an increase in fracture rates became apparent came as no surprise to Prof Ian Reid, osteoporosis expert from Australia. Evidence was produced in 2002 that PPAR gamma agonists in in vitro studies promoted adipogenesis, whereas osteoblastogenesis was inhibited. Prof Reid cal-

culated from published study results that the number needed to harm (fracture risk) ranged from 21 to 55 patients. An increased fracture risk is therefore an issue with the use of thiazolidediones. Prof Reid recommended that fracture risk should be thoroughly assessed in patients where TZD treatment is contemplated. Should fracture risk be increased, another agent should be selected or measures should be taken to protect the bone.

Progress in foot care A history of foot ulceration is a marker of increased risk of mortality among persons with diabetes, was the finding of Dr M Iverson and colleagues from Norway. Their study included 1 339 patients with diabetes without a history of foot ulcers, 155 subjects with a history of foot ulceration, and 63 632 non-diabetic persons, followed for 10 years. During this period, 49% of patients with diabetes and a history of foot ulceration died, compared to 35% with diabetes and without a history of foot ulceration, and 11% of the control group without diabetes. The adjusted hazard risk (HR) for mortality in diabetics with a history of foot ulceration was more than double that of non-diabetic subjects (HR = 2.29) while a HR of 1.38 was found for diabetics without a history of foot ulceration. The authors concluded that their study underlined the importance of organising future healthcare services with follow-up routines that allow for optimal patient care and monitoring of persons with diabetic foot ulceration. The use of autologous platelet gel as an adjunct to good standards of care enhances wound healing in diabetic patients suffering from deep chronic foot ulcers, said Dr S Clavel from Le Creusot, France. Good standards of wound care include surgical debridement where indicated, infection control, medical management of co-morbidities and off-loading measures. Wounds must be free of infection, and bone sequestrants must be removed if present. This group reported complete wound healing in 77 of the 91 patients after only one application, and in almost all patients after several applications. Proper wound care and patience were key to their success. The IDF’s Step-by-Step foot-care programme is gaining popularity in many resource-poor settings. Dr Z Abbas and colleagues have introduced this training programme, with success in 14 health

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districts in Tanzania. The main objectives of the programme are to train healthcare professionals in diabetic foot management, reduce rates of foot complications by education and the early detection and prompt and appropriate treatment, and develop an infrastructure for support and service development. Also inherent in this programme is data collection to monitor secular trends in amputation rates. The annual amputation rate among referrals was 18% before the introduction of the programme. Dr Abbas showed that the upward trend in the amputation rate was reversed following the introduction of the training programme. Their data suggested improved foot ulcer management at a regional level. The Step-by-Step foot programme is also systematically being introduced into the Western Pacific region as well as the Caribbean. Dr S Kono from Hanoi, Vietnam presented data from seven Asian countries comprising 309 patients hospitalised with a new foot ulcer. Risk factors for foot ulceration as well as clinical characteristics of patients differed widely across the region. Some of the common features included relatively young age and short duration of diabetes, late presentation, trauma, and a high amputation rate, ranging from 17 to 61%. Dr Kono emphasised that increased awareness of diabetic foot problems, reduction in tobacco use, screening for high-risk patients, improved skills in the management of diabetic foot ulcers and the implementation of clinical guidelines were all essential steps to prevent diabetic foot ulcers and to reduce the amputation rate. Dr K Bakker from the Netherlands who spearheaded the introduction of the Step-by-Step programme in five Caribbean islands explained the logistics involved in the process, as well as funding issues. One of the difficulties is to get local health authorities involved.

New IDF study reveals that people in developing countries pay more for diabetes care and have poorer health results Type 2 diabetes is often seen as a condi-

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tion affecting older, unproductive adults in wealthy countries. However, the reality is that 70% of people with diabetes now live in low- and middle-income countries, and the economic impact of diabetes is much greater in poorer countries. Yet the majority of the spending, 90% of all medical expenditures for diabetes care, is made in the United States, Canada, the countries of Western Europe, and other wealthy countries. This is the conclusion of the most comprehensive investigation on the economic impact of diabetes ever to be conducted in low- and middle-income countries. The new data from the IDF came from researchers in five African countries (South Africa, Cameroon, Kenya, Mali and Tanzania) who interviewed 2 300 men and women with type 2 diabetes and an additional 2 300 of their neighbours who did not have diabetes. The studies revealed that people with diabetes have roughly three times the rates of heart disease, stroke, kidney disease and heart failure as their otherwise similar neighbours. People with diabetes also have more tuberculosis, HIV/AIDS and malaria. All these diseases lead to very high out-of-pocket medical expenses and lost income due to complications such as blindness, paralysis, amputation, pain, cognitive deficits, and other disabling problems. One out of six of the people interviewed said that they could not work at all because of their health, one of three said they could not work as much they wanted to, and 3% said that they had to work more than they wanted to, to cover their medical expenses. One of five reported that they were not able to buy much-needed food because of medical expenses, and more than half said they could not buy all the medicines they needed. Perhaps the most surprising findings were that 15% of the family members had quit work to care for a family member with diabetes, 20% had to cut back on work and 15% had to work more to contribute to the cost of medicines and care for a family member with diabetes. The result of this, according to Jonathan Betz Brown, PhD, chairman of the IDF Task Force on Health

Economics and of the Kaiser Permanente Center for Health Research, the global study leader, is that ‘children are kept out of school and deprived of food, families lose farms and businesses, and women and girls are forced to stay home and care for parents. In the end, these family tragedies add up to a less-educated and smaller workforce, greater social disorganisation and slower economic growth’. ‘You might think that the best way to help children in Africa would be to ignore chronic illnesses such as diabetes’, said the African study leader and IDF vice president, Dr Kaushik Ramaiya, of Shree Hindu Mandal Hospital in Dar es Salaam, Tanzania, ‘but in developing countries, children’s lives and prospects depend on the survival and strength of their parents and grandparents. When a father is fired because of a stroke, or a mother cannot raise crops and animals, or cook because of blindness or an amputation, the entire family can find themselves homeless and pulled into dire poverty.’ Findings from the African study show that people with diabetes on the continent have many more medical problems than healthy people of comparable age and gender, are much less able to function physically and work, are more frequent and more intensive users of medical care and drain precious economic resources from their family and society. The lead investigators in each study were recruited locally and all enjoy international reputations for their research. IDF President Prof Jean Claude Mbanya led the study in Cameroon, Dr Eva Njenga in Kenya, Mr Stephane Besançon in Mali, Dr Paul Rheeder in South Africa and Dr Kaushik Ramaiya in Tanzania. Other studies are underway in 17 cities in China, in Kazakhstan and in three countries in Central America. These are preliminary results and the data continue to be analysed. Final results will be published at a later stage. This report was compiled by WF Mollentze, consulting editor of the South African Journal of Diabetes & Vascular Disease and Julia Aalbers, assistant editor.

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DRUG TRENDS

Drug Trends Efficient and safe glucose control in type 2 diabetes: new ADVANCE results from IDF

T

 e ADVANCE study on h glucose lowering in type 2 diabetes patients continues to add to clinicians’ understanding on the benefits of using a pragmatic and incremental approach to lowering glucose levels in these patients. In this study, a gliclazide MR-based treatment regimen was shown to be both safe and efficient. New data from the glucoselowering arm of ADVANCE (Action in Diabetes and VAscular disease perindopril and Diamicron-MR Controlled Evaluation), presented at the International Diabetes Federation (IDF) congress in Montreal, Canada, recently, showed that this gliclazide MR-based treatment provided equal benefits across a broad range of patients in different clinical settings.1 Prof John Chalmers of the George Institute for International Health, Australia, presented the results of new analyses from the ADVANCE study, which evaluated the risk of clinical outcomes and the effects of intensive glucose control according to baseline

and follow-up clinical characteristics of the 11 140 patients included in the study. ‘In terms of the efficacy of glucose-lowering in the ADVANCE study, it is important to note that more than 80% of these patients reached the target of an HbA1c level ≤ 7%. Additionally, as the IDF recommends an even lower HbA1c level of ≤ 6.5%, it is interesting to note that this glicliazide MRbased approach with incremental therapy was able to reach this target in more than 60% of patients’, Prof Chalmers said in an interview with the South African Journal of Diabetes and Vascular Disease in Montreal (table 1). Glucose lowering, as measured by reductions in HbA1c levels, occurred in all patients irrespective of age, duration of diabetes, gender, body mass index (BMI) or baseline HbA1c levels, and also irrespective of the initial glucose-lowering treatment. In this context, it is interesting to note that only 9% of patients were not on glucose-lowering therapy at the outset of the study; 61% were

on metformin (74% at the end of the study) and 64% were on other sulphonylureas at baseline and were then switched to the gliclazide MR therapy. ‘The renal and micro-vascular benefits were seen across all sub-groups, and the safety profile, with very little incidence of hypoglycaemia, was also consistent across these groups of patients’, Prof Chalmers stressed. ‘These efficient and safe results were achieved in lean or obese patients, in all age groups, whether diabetes was of short or long duration, and regardless of the HbA1c levels at baseline’ (figures 1, 2). The annual rate of events of major hypoglycaemia in the intensive arm of the ADVANCE study was much less than in either the ACCORD or VADT (Veteran’s Administration Diabetes Trial) studies (figure 3), despite the clinical similarities of the definitions of major

Prof Chalmers hypoglycaemic events in these three studies. ‘It is increasingly clear that the graduated incremental regimen using the gliclazide MR-based approach was uniformly successful in getting HbA1c levels to target safely’, Prof Chalmers stressed. ‘In our regimen it could take two to three years to reach maximum intensity of HbA1c-measured

Figure 1. Baseline characteristics.

Table 1. Proportions of patients achieving HbA1c targets at the end of follow up.

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glucose control, whereas in the ACCORD study, the regimen aimed to reach target HbA1c levels within months of entering the study.’ The successful aspects of ADVANCE, a modern, intensive trial, are highlighted in comparison with the Framingham and UKPDS predictive models.2 ‘When we applied the Framingham or UKPDS risk equations to the ADVANCE patients and their experienced level of cardiovascular disease, these risk models overestimated the occurrence of cardiovascular events two- to three-fold. We have now developed an ADVANCE risk model for predicting major cardiovascular disease in patients with type 2 diabetes who are being managed according to contemporary therapeutic regimens’, Prof Chalmers said. ‘Although not yet published, we have chosen 10 important variables that are available in most clinical settings, for example, baseline glucose values instead of HbA1c levels to predict level of risk’, Prof Chalmers noted. ‘These results, showing the non-applicability of the UKPDS model emphasise the progress over the last five to 15 years. The cardiovascular risk in type 2 diabetes patients has certainly come down with increased use of statins and improved hypertension management. Even lifestyle has improved, with reduced smoking levels seen in patients in the ADVANCE study (14% at baseline, 8% at the

SA JOURNAL OF DIABETES & VASCULAR DISEASE

end of follow up), compared to the 20% of smokers in the UKPDS study’, Prof Chalmers commented. While the ADVANCE study showed a statistically non-significant reduction in macrovascular events in the intensively treated group, the ADVANCE-ON follow-up study is well underway. ‘We are hoping to track 100% of the ADVANCE patients in normal clinical practice over the next five years to see if macrovascular benefits materialise, as they did in the long-term follow up of the UKPDS study’, Prof Chalmers concluded.

probability of cardiovascular events in a multi-national contemporary population with diabetes. IDF Abstract 0.0198, 2009 congress. 3. Kengne AP, Patel A, Colagiuri S,

Heller S, Hamet P, Marre M, et al. Derivation of the ADVANCE models for predicting the risk of major cardiovascular disease in people with diabetes. IDF Abstract 0.0199, 2009 congress.

Figure 2. Changes in HbA1c levels.

1. Chalmers J, Zoungas S, Ninomiya T, et al. New results from ADVANCE. IDF congress invited talk, 22 October 2009. Montreal, Canada. 2. Kengne AP, Patel A, Colagiuri S, Heller S, Hamet P, Marre M, et al. Predictive accuracy of the Framingham and UKPDS risk equations in estimating the

Figure 3. Weight gain at the end of follow up.

continued on page 170

Book giveaway Congratulations to Sr Henrieke Fagan who won the September book giveaway for The Complete Nutritional Solution to Diabetes by Ria Catiscas.

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MORE WITH

DIAMICRON MR ADVANCE

the largest, prospective study ever in 11 140 Type 2 diabetic patients 2,3 Diamicron MR* achieved HbA1c levels of 6.5%1 Diamicron MR* reduces serious diabetic complications 1 Diamicron MR* significantly reduces renal events by 21% & macroalbuminuria by 30% 1

DIAMICRON MR 30mg Tablets. Gliclazide 30mg. Reg. No. 35/21.2/0178. Each DIAMICRON Modified Release 30mg tablet contains 30mg Gliclazide. INDICATIONS In Type 2 diabetic patients, in association with dietary measures, life-style changes and exercise, when dietary measures and life style alone are not sufficient to control blood glucose. CONTRA-INDICATIONS Hypersensitivity to gliclazide or to any of the excipients, other sulphonylureas or sulphonamides; type 1 diabetes; diabetic pre-coma, diabetic keto-acidosis; severe renal or hepatic insufficiency; children. Do not use in lactation, as safety in lactation has not been established. Do not use in pregnancy, as safety in pregnancy has not been established. WARNINGS The administration of oral hypoglycaemics may be associated with increased cardiovascular mortality, as compared to treatment with diet alone or diet with insulin. DOSAGE AND DIRECTIONS FOR USE For adult use only. The daily dose may vary between 1 and 4 tablets per day i.e. from 30 to 120 mg taken as a single daily dose. The initial recommended dose is 30 mg once daily, taken with breakfast. The dosage can be increased progressively to 60, 90 or 120 mg daily by successive increments, respecting an interval of at least one month between each increment, except in patients whose blood glucose has not decreased after 15 days of treatment. In this case, it is possible to propose a dosage increase at the end of the second week of treatment. The daily dose should not exceed 120 mg. SIDE EFFECTS AND SPECIAL PRECAUTIONS Dizziness, weakness, paraesthesia, sensitivity reactions with fever, eosinophilic jaundice, headache and hypoglycaemia. In the event of meals being taken at irregular intervals and more particularly in the case of missed meals, treatment with DIAMICRON MR 30mg may lead to hypoglycaemia. Possible symptoms of hypoglycaemia may include headache, intense hunger, nausea, vomiting, lassitude, drowsiness, sleep disturbances, agitation, aggressiveness, diminished concentration, visual and speech disturbances, delirium, convulsions and coma. Effects on ability to drive and use machines: patients should be made aware of the symptoms of hypoglycaemia and should be careful when driving, or operating machinery. PHARMACOLOGICAL CLASSIFICATION A21.2 Oral Hypoglycaemics. PRODUCT REGISTRATION NUMBER 35/21.2/0178. FURTHER INFORMATION Servier Laboratories South Africa (Pty) Ltd. Reg. No. 72/14307/07 Devcon park, 7 Autumn St, Rivonia, 2191 For a complete list of side effects, special precautions and interactions, please consult the full package insert of DIAMICRON MR 30mg. References: 1. ADVANCE Collaborative Group. N Eng J Med. - On-line. 2. Study rationale and design of ADVANCE. Diabetologia 2001; 44: 1118-1120. 3. ADVANCE patient recruitment and characteristics of the study population at baseline. Diabetes Med 2005;22: 882-888.* DIAMICRON MR based strategy.

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continued from page 168

Comments from attending South African experts Prof WF Mollentze, Head of the Department of Internal Medicine, University of the Free State, Bloemfontein The ADVANCE study yielded another unexpected benefit, namely the development of a more accurate risk engine to predict cardiovascular disease. The predictive accuracy of the Framingham and UKPDS risk equations fell short when applied to the ADVANCE study population. The risk of major cardiovascular disease was overestimated by 170% using the two Framingham risk equations, while the risk of major coronary heart disease (CHD) was

overestimated by 289%. The UKPDS risk equation overestimated the risk of major CHD by 198%. Both the Framingham and UKPDS risk equations also overestimated the risk of major cerebrovascular events. After an average of five years of follow up in the ADVANCE trial, 473 major cardiovascular events were recorded in the initial cohort of 11 140 patients. More than 20 variables were investigated for their predictive value of cardiovascular disease. Of these, only the following were found to be significant predictors: age at diagnosis, known duration of diabetes, gender, pulse pressure, treated

hypertension, atrial fibrillation, diabetic retino-pathy, HbA1c levels, albumin/creatinine ratio and non-HDL cholesterol at baseline. The ADVANCE risk engine now awaits validation in other populations. Prof Chalmers remarked that the most likely explanation for the failure of the Framingham equations to accurately predict cardiovascular events in the ADVANCE study population is the fact that the Framingham population was non-diabetic and older. The reasons for the failure of the UKPDS risk equation to predict cardiovascular events accurately, on the other hand, are most likely due to

the fact that diabetes and the accompanying risk factors are treated more aggressively today than they were three decades ago. The widespread use of statins during the last decade may have made a significant contribution to delaying or preventing cardiovascular disease in the ADVANCE study population. Dr Larry Distiller, Centre for Diabetes and Endocrinology, Johannesburg I am looking forward to the availability of a new risk engine as it is indeed time the UKPDS risk engine is updated.

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EQUISWEET WITH SUCRALOSE: ALL-ROUND SWEET TREAT bloodstream from the gut. There are a number of foods that can help lower cholesterol when consumed on a regular basis, such as oats and soya. However no food or food ingredient is more effective than 25 g per day of Flora proactiv for lowering cholesterol. Flora entered a partnership with the World Heart Federation in 2003 to promote heart health awareness and strives to continue the cause. Visit: www.diabetesjournal.co.za to view the video on the mechanism of action of plant sterols.

A growing number of doctors and consumers are seeking an aspartame-free low-kilojoule sweetener that doesn’t compromise on taste. EquiSweet with sucralose provides just that, and is ideal for slimmers, diabetics and health and wellness enthusiasts alike. Sucralose has received a stamp of approval from the USA Food and Drug Administration as well as from authorities in more than 80 other countries, including South Africa. It is derived from sugar but the body does not recognise it as a source of energy. Sucralose is kilojoule free, it has no impact on blood glucose levels and no bitter aftertaste. Sucralose maintains its sweetness under high heat, and due to its excellent taste, it can be used in a wide range of foods and beverages. EquiSweet with sucralose is available in supermarkets and select pharmacies. Huletts’ comprehensive range

of sweetening solutions includes both nutritive and non-nutritive sweeteners. Another product that is receiving glowing reviews is SUGAlite, a baking blend that can be used to replace sugar gram for gram in virtually any recipe. SUGAlite lowers the glycaemic index (GI), as well as the total fat and kilojoules in the final baked product, while still providing a delicious sweet taste and a golden brown glow.

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DRUG TRENDS

Advertorial It is now possible to improve symptoms and prognosis in angina patients

C

 ronary artery disease o (CAD) remains the leading cause of mortality and morbidity worldwide. Ischaemic heart disease, together with stroke and congestive heart failure, account for at least 80% of the burden of cardiovascular disease (CVD) in both high- and low-income regions.1 Although HIV/AIDS-related diseases are the leading cause of death in South Africa, CVD is second, and it is the number one killer in those over the age of 30.1 Despite recent advances, mainly in terms of secondary prevention, chronic CAD remains a major public health concern and its management continues to pose a serious challenge to contemporary cardiology. But do we actually see patients with angina in daily practice? An analysis of the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine, GITS) trial followed the clinical course of patients with isolated angina.2 Three in 10 patients with angina seen in clinical practice had isolated angina, two had angina despite previous revascularisation, and five had angina after previous myocardial infarction (MI), heart failure or stroke. This study also demonstrated that patients with isolated angina had low rates of death and major cardiovascular events, and that there were no major differences in event rates between the mentioned sub-groups. Angina is therefore highly prevalent in clinical practice and these patients have a

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relatively long survival, which makes addressing the morbidity aspect of angina very important. Of equal importance is improving cardiovascular outcomes in these patients despite a relatively good prognosis, and this sentiment is echoed by the 2006 European Society of Cardiology guidelines on the management of stable angina pectoris, which state that treatment modalities for angina need to address both morbidity and mortality.3 The debilitating nature of angina and the limitations of currently available treatments have prompted the development of a new class of drug, namely the sino-atrial node If inhibitor ivabradine, which addresses both morbidity and mortality. We briefly examine below whether commonly used anti-anginal drugs address symptoms and outcomes in patients with angina, and how they do so.

Anti-anginal drugs: effect on symptoms An informal Medline search was done to evaluate comparative studies of beta-blockers (BBs) and calcium channel blockers (CCBs) in patients with angina. From the review of this data, it would appear that there is little (if any) difference between CCBs and BBs in terms of their effect on relief of symptoms in patients with angina. Angina as a healthcare priority is reflected in the fact that very few trials in this review had more than 100 patients and follow up was generally

less than two months. A meta-analysis was done of trials comparing single antianginal agents with combinations, to establish whether combining anti-anginal agents would give superior symptom relief in patients with angina.4 It was found that combining a CCB and a BB only supplied superior symptomatic relief at the peak of drug activity (six hours), and not at the trough of drug activity. With more robust data, ivabradine (Coralan®) as a single anti-anginal agent has demonstrated anti-anginal efficacy in more than 10 000 angina patients: in different angina patient groups, in clinical practice, versus BBs, versus CCBs, in combination with BBs, and in the long term.5-11 In patients already receiving BBs for angina, the addition of ivabradine resulted in a significant improvement in exercise tolerance and angina symptoms. Furthermore the effective relief of symptoms does not come at the clinical cost (fatigue, impotence, oedema, etc) associated with BBs and CCBs.

Anti-anginal treatment: effect on cardiovascular outcomes Contrary to popular belief, data on commonly used antianginal agents such as BBs and CCBs for the reduction of mortality and MI in angina patients do not exist. The reason for this misconception is the extrapolation of mortality data from trials on heart failure and post-MI patients to patients with angina (table 1). Ivabradine, in an analysis of 1 500 patients with limiting angina, in the BEAUTIfUL trial, demonstrated a reduction in the risk for the composite primary endpoints (MI, cardiovascular death and heart failure) by 24% and MI by 42% (figure 1). Even more impressive was the ‘numbers needed to treat’ of 28 for the primary endpoint and 37 for the reduction in MI.12 Note that these results were demonstrated in all the angina patients irrespective of their heart rates. This was the first time that any anti-anginal treatment had been proven to reduce hard endpoints such as MI in angina patients. For the first time, there is an

Table 1. Outcome data for anti-anginal agents in angina patients Medication

Study/outcomes

Beta-blockers

No data on stable angina Evidence in post MI and congestive heart failure Note: older trials had less use of ACEIs and statins

Calcium channel blockers

ACTION (stable angina) Nifedipine did not reduce the primary endpoint in the overall population Only coronary angiography and CABG reduced No effect on MI or mortality

Nitrates

No prognostic data in stable CAD patients

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Figure 1. Coralan reduces risk for the primary composite endpoint and myocardial infarction in all patients with symptomatic ischaemia (angina).

anti-anginal, ivabradine, which addresses both treatment objectives in angina treatment: it relieves the symptoms of angina and improves the prognosis. This is achieved with ivabradine alone or in combination with older anti-anginal agents and results in significantly improved quality of life for these patients. 1. Statistics South Africa 2006. Mortality and causes of death in South Africa, 2003 and 2004. Findings from death notification. Statistical release no P03039.3 Pretoria: Statistics South Africa. 2. Poole-Wilson P, Voko Z, Kirwan BA, de Brouwer S, Dunselman PH, Lubsen J, ACTION investigators. Clinical course of isolated stable angina due to coronary heart disease. Eur Heart J 2007 28; 1928–1935. 3. Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F, et al, Task force on the

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management of stable angina pectoris of the European Society of Cardiology; ESC Committee for Practice Guidelines (CPG), et al. Guidelines on the management of stable angina pectoris. Eur Heart J. 2006; 27(11): 1341–81. Epub 2006 May 30. 4. Klein WW, Jackson G, Tavazzi L. Efficacy of montherapy compared with combined antianginal drugs in the treatment of chronic stable angina pectoris: a metaanalysis. Coron Artery Dis 2002; 13(8): 427–436. 5. Borer JS, Fox K, Jaillon P, Lerebours G, Ivabradine investigators group. Antianginal and anti-ischemic effect of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation 2003; 107(6): 817– 823. 6. Koester R, et al. Herbsttagung der Deutsche Gesellschaft fur Kardiologie- Herz- und Kreislauf- forschung und 19.

Jahrestagung der Arbeitsgruppe Herzschrittmacher und Arrhythmie vom 09. Bis 11.10.2008 in Hamburg. Clin Res Cardiol 2008; 97(Suppl 2): 1464. 7. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K, INITIATIVE investigators. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005; 26(23): 2529–2536. Epub 2005 Oct 7. 8. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs 2007; 67(3): 393–405. 9. Tardif JC, Ponikowski P, Kahan T, ASSOCIATE study investigators. Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving betablocker therapy: a 4-month,

randomized, placebo-controlled trial. Eur Heart J 2009; 3(5): 540–548. Epub 2009 Jan 9. 10. Lopez-Bescos L, Filipova S, Martos R. Long-term safety and efficacy of ivabradine in patients with chronic stable angina. Cardiology 2007; 108(4): 387– 396. Epub 2007 Sept 21. 11. Tendera M, Borer JS, Tardif JC. Efficacy of I(f) inhibition with ivabradine in different subpopulations with stable angina pectoris. Cardiology 2009; 114(2) : 116–125. Epub 2009 May 26. 12. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R, BEAUTIFUL investigators. Relationship between ivabradine treatment and cardiovasular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with liniting angina: a subgroup analysis of the randomised, controlled BEAUTIfUL trial. Eur Heart J 2009 ; 30(19): 2337–2345. Epub 2009 Aug 31 (doi:10.1093/eurheart/ ehp358).

VOLUME 6 NUMBER 4 • NOVEMBER 2009


DRUG TRENDS

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Practical guidance on intensifying insulin therapy in type 2 diabetes using BIAsp 30

T

 e recently released conh sensus guidelines prepared by endocrinologists from the UK, the USA, Europe and the developing world (India, China and Turkey), focusing on how to introduce BIAsp 30 when intensifying insulin therapy in type 2 diabetes, fills an important gap in clinical guidelines.1 The international expert panel met at a Novo Nordisk-sponsored symposium in October last year with the specific purpose of providing practical guidance to general and specialist practitioners. The panel developed treatment algorithms to help physicians who wish to intensify insulin therapy in their patients with type 2 diabetes, from basal insulin once (OD) or twice daily (BID) to BIAsp 30 BID, and from BIAsp 30 once or twice daily to BIAsp 30 twice or three times daily (TID). The algorithms were developed with reference to published clinical trials and in the light of the experts’ own experience in treating patients whose glycaemic control was inadequate on their current insulin therapy (once/twice daily).

Patients on basal insulin requiring intensification of therapy A simple algorithm for switching patients from OD or BID basal insulin (analogue or human) to BIAsp 30 BID is shown in figure 1. Regardless of the basal regimen, if a patient has an HbA1c level higher than 8.0%, he/she should be transferred to BIAsp 30 BID. If the HbA1c level is moderately elevated (between 7.0 and 8.0%) but the fasting plasma glucose (FPG) value is within the normal range (4–6 mmol/l), the suboptimal overall glycaemia is probably caused by elevated postprandial glucose (PPG) levels, and the patient should be transferred to BIAsp 30 BID, as it provides prandial coverage as well. If, however, the HbA1c level is between 7.0 and 8.0%, and the FPG value is higher than 6 mmol/l, the existing basal insulin dose(s) can be titrated further until the patient achieves a FPG level below 6 mmol/l. If recurrent hypoglycaemia limits uptitration of the basal dose, or the daily dose reaches 0.5 U/kg (insulin units per kg body

Figure 1. A simple algorithm for the intensification of basal insulin therapy once daily (OD) or twice daily (BID) (analogue or human) to biphasic insulin aspart 30/70 (BIAsp 30) BID. FPG, fasting plasma glucose (amended from reference 1).

Basal insulin OD or BID

Hba1c 7–8% FPG > 6 mmol/l (FPG > 110 mg/dl)

Titrate basal insulin to achieve FPG < 6 mmol/l (FPG < 110 mmg/dl)

174

weight), switching to BIAsp 30 BID can be considered. When switching a patient from basal insulin OD or BID to BIAsp 30 BID, the points in table 1 provide some practical guidance.

Intensification of therapy with BIAsp 30 The algorithm for intensifying therapy from BIAsp 30 OD or BID to BIAsp 30 BID or TID is shown in figure 2. If a patient receiving BIAsp 30 OD or BID has a FPG value (with or without pre-dinner blood glucose measurement) within the normal range (4–6 mmol/l), but an HbA1c level higher than 7.0%, the suboptimal overall glycaemia is probably caused by elevated PPG

levels after a meal not covered by BIAsp 30. Then he/she should be transferred to BIAsp 30 BID or TID (i.e. the addition of one daily injection). If, however, the FPG level (with or without pre-dinner blood glucose measurement) is higher than 6 mmol/l, the existing BIAsp 30 dose(s) (OD or BID) should be titrated until the patient achieves a FPG value below 6 mmol/l. If, while doing so, hypoglycaemia occurs, the patient should be intensified to BIAsp 30 BID or TID (i.e. the addition of one daily injection). 1. Unnikrishnan AG, Tibaldi J, Hadley-Brown M, et al. Int J Clin Pract doi: 10.1111/j.17421241.2009.02192.x

Table 1. Practical guidance for switching from basal insulin OD or BID to BIAsp 30 BID • • • • • • •

Total dose transfer (1:1) to BIAsp 30 Split the dose 50:50 pre-breakfast and pre-dinner Titrate the dose, preferably once a week Discontinue sulffonylureas (SUs) Continue metformin Consider discontinuing thiazolidinediones (TZDs) as per local guidelines and practice Administer BIAsp 30 just before meals.

Figure 2. A simple algorithm for intensifying therapy from biphasic insulin aspart 30/70 (BIAsp 30) once (OD) or twice daily (BID) to BIAsp 30 twice or three times daily (TID). FPG, fasting plasma glucose; BG, blood glucose.

BIAsp 30 OD (pre dinner or BIAsp 30 BID)

HbA1c > 8.0% FPG: 4–6 mmol/l (FPG: 73–110 mg/dl)

Switch to BIAsp 30 BID

FPG and/or pre dinner BG: 4–6 mmol/l (73–110 mg/dl)

FPG and/or pre dinner BG: > 6 mmol/l (110 mg/dl)

HbA1c > 7.0%

Titrate BIAsp 30 OD or BID to achieve FPG and/or pre dinner BG < 6 mmol/l (110 mg/dl) If hypoglycaemia occurs

Switch to BIAsp 30 BID or TID

VOLUME 6 NUMBER 4 • NOVEMBER 2009


DIABETES NEWS

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Diabetes News Latest diabetes figures paint a grim global picture

T

 e International Diabetes h Federation (IDF) released new data recently showing that a staggering 285 million people worldwide have diabetes. The latest figures from the IDF Diabetes Atlas indicate that people in low- and middle-income countries (LMCs) are bearing the brunt of the epidemic, and that the disease is affecting far more people of working age than previously believed. In 1985, the best data available suggested that 30 million people had diabetes worldwide. Fast forward 15 years and the numbers were revised to just over 150 million. Today, less than 10 years on, the new figures, launched at the 20th World Diabetes congress in Montreal, Canada, put the number closer to 300 million, with more than half aged between 20 and 60 years. The IDF predicts that, if the current rate of growth continues unchecked, the total number will exceed 435 million in 2030 – many more people than the current population of North America. Prof Jean Claude Mbanya, president of the International Diabetes Federation voiced concern: ‘The data from the latest edition of the IDF Diabetes Atlas show that the epidemic is out of control. We are losing ground in the struggle to contain diabe-

tes. No country is immune and no country is fully equipped to repel this common enemy.’ Type 1 diabetes cannot be prevented. It is an autoimmune disease in which the body destroys its own insulin-producing cells. People with type 1 diabetes require daily injections of insulin to survive. The majority of all diabetes is type 2 diabetes (85–95%), which in many cases can be prevented. People with type 2 diabetes cannot effectively use the insulin they produce, but can often manage their condition through exercise and diet, although many go on to require medication, including insulin, to properly control blood glucose levels. It is estimated that 60% or more of type 2 diabetes could be prevented. Both type 1 and type 2 diabetes represent a serious health threat. Diabetes claims four million lives every year and is a leading cause of blindness, kidney failure, heart attack, stroke and amputation. Diabetes now affects 7% of the world’s adult population. The regions with the highest comparative prevalence rates are North America, where 10.2% of the adult population have diabetes, followed by the Middle East and North Africa region with 9.3%. The regions with the

Figure 1. Deaths attributable to diabetes as percentage of all deaths (20–79 years) by region, 2010.

N America/Canada SE Asia Mid East/N Africa Europe W Pacific SACA Africa

176

highest number of people living with diabetes are the western Pacific, where some 77 million people have diabetes and South East Asia with 59 million. India is the country with the most people with diabetes, with a current figure of 50.8 million, followed by China with 43.2 million. Behind them the United States (26.8 million), the Russian Federation (9.6 million), Brazil (7.6 million), Germany (7.5 million), Pakistan (7.1 million), Japan (7.1 million), Indonesia (7 million) and Mexico (6.8 million). When it comes to the percentage of the adult population living with diabetes, the new data reveal the devastating impact of diabetes across the Gulf region, where five of the Gulf states are among the top 10 countries affected. The Pacific island nation of Nauru has the world’s highest rate of diabetes, with almost a third of its adult population (30.9%) living with the disease. It is followed by the United Arab Emirates (18.7%), Saudi Arabia (16.8%), Mauritius (16.2%), Bahrain (15.4%), Reunion (15.3%), Kuwait (14.6%), Oman (13.4%), Tonga (13.4%) and Malaysia (11.6%). Figure 1 shows the number of deaths in 2010 per region. Diabetes has become a development issue. In the LMCs, it threatens health and economic prosperity. The IDF predicts that diabetes will cost the world economy at least US$376 billion in 2010, or 11.6% of the total world healthcare expenditure. By 2030, this number is projected to exceed US$490 billion. More than 80% of diabetes spending is in the world’s richest countries and not in the poorer countries, where over 70% of people with diabetes now live. The United States accounts

for $198 billion or 52.7% of the total diabetes spending worldwide. India, which has the largest diabetes population, spends US$2.8 billion or 1% of the global total. In most LMCs, people with diabetes must pay for their care out of their own pockets because public medical services and insurance are lacking. The diagnosis of diabetes in a low- or middle-income country can often drag entire families into poverty. ‘The world needs to invest in integrated health systems that can diagnose, treat, manage and prevent diabetes’, said Prof Nigel Unwin, who leads the team of experts behind the IDF Diabetes Atlas. ‘Governments also need to invest in actions outside the formal health sector, particularly in promoting healthier diets and physical activity, to reduce obesity and the risk of type 2 diabetes. Without effective prevention, diabetes will overwhelm health systems and hinder economic growth.’ Integrating plans for the prevention of diabetes into national health systems and policy frameworks is an important part of the response. The IDF warns that many health systems worldwide are not yet equipped to handle the extent of the diabetes threat, and that failure to take action will have serious consequences. ‘The epidemic represents nothing short of a global health emergency’, said IDF President Mbanya. ‘It is alarming that world leaders stand by while the diabetes fuse slowly burns. The serious impact on families, countries and economies continues with little resistance. Governments, aid agencies and the international community must take concerted action to defuse the threat now, before the diabetes time bomb explodes.’

VOLUME 6 NUMBER 4 • NOVEMBER 2009


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References: 1. Klein O. et al. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes, Obesity and Metabolism. 2007;9:290-299. 2. Philis-Tsimikas A et al. Comparison of Once-Daily Insulin Detemir with NPH Insulin Added to a Regimen of Oral Antidiabetic Drugs in Poorly Controlled Type 2 diabetes. Clinical Therapeutics. 2006;28(10):1569-1581. 3. Rosenstock J et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia. 2008;51:408-416.

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Featured in this issue Gestational diabetes C-reactive protein in risk assessment Smoking cessation Aspects of hypothyroidism Diabetes and breastfeeding Primary care role model for diabetic patients

SAJDVD Volume 6, Issue 4  

Gestational diabetes C-reactive protein in risk assessment Smoking cessation Aspects of hypothyroidism Diabetes and breastfeeding Primary ca...

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