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THE SOUTH AFRICAN JOURNAL OF

Diabetes Vascular Disease OBESITY

LIPIDAEMIA DYS

IN RESISTANCE INSUL

HYPERTENSION

ETES & DIAB

V

AS

AR DISEASE

HYPER INSULINAEMIA THROMBOSIS

ERGLYCAE MIA

September 2011

HYP

Volume 8 Number 3

ATH EROSCLEROSIS

CUL

Featured in this issue HIV and diabetes Appraisal of the Consumer Protection Act Platelet volume with gestational diabetes mellitus Self-monitoring of blood glucose Help to quit smoking Cardiovascular protection in African patients


ISSN 1811-6515

THE SOUTH AFRICAN JOURNAL OF HYPE

RINSULINAEMIA

Diabetes & vascular disease VOLUME 8 NUMBER 3 • SEPTEMBER 2011 www.diabetesjournal.co.za

Corresponding Editor Dr L Lombard Netcare, Kuilsrivier Hospital, Cape Town 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

CONTENTS

Editorial

103

Cardiovascular protection in special populations L Lombard

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

Reviews

104

HIV and diabetes D Wilson

106

DR F MAHOMED Department of Endocrinology, Grey’s Hospital, Pietermaritzburg PROF WF MOLLENTZE Head of Department of Internal Medicine, University of the Free State, Bloemfontein 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

SM Taghavi, H Rokni, S Fatemi

Ethics Focus

108

An ethical and legal appraisal of the new South African consumer protection act in terms of diabetes care

Achieving Best Practice

109

Assessment of mean platelet volume of pregnant women with gestational diabetes mellitus and impaired glucose tolerance as a marker of future cardiovascular disease risk

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, International Diabetes Federation 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

Metformin decreases thyrotropin in overweight women with polycystic ovarian syndrome and hypothyroidism

A KöŞüŞ, N KöŞüŞ, M Duran, NO Turhan

Diabetes Educator’s Focus

113

Self-monitoring of blood glucose in type 2 diabetes: a current view L Lombard

Hands On

117

Helping people to quit smoking B Bostock-Cox


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

Prevention in Practice

121

Avoiding weight gain after stopping smoking S Baic

Diabetes Personality

125

Get the message of diabetes out there

ADA Watch

127

2011 Update from San Diego, USA

CDE Watch

133

2011 Update from the Centres for Diabetes Excellence

Diabetes News

136

Winners of the CDE awards for 2011

Journal Update

All correspondence to be directed to:

137

Cardiovascular protection in African patients, from the world literature

THE EDITOR PO BOX 1013 DURBANVILLE 7551 or info@cvja.co.za

Patient Leaflet

140

Aspirin in primary prevention of vascular events

Drug Trends in Diabetes

141

South Africa’s poor warfarin control raises questions of benefit above other anticoagulant therapies in atrial fibrillation

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. and printed by Tandym Print. Articles in this Journal are sourced as per agreement with the British Journal of Diabetes and Vascular Disease

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.

J Aalbers

142

Getting to the root of diabetes: the promise of liraglutide P Wagenaar

Front cover photographs from left to right: • Most diabetic patients die from cardiovascular consequences (page 103) • Self-monitoring of glucose is vital to the long-term health of diabetics (page 113) • Smoking cessation and weight loss are key lifestyle changes in diabetes (pages 117 and 121)


SA JOURNAL OF DIABETES & VASCULAR DISEASE

EDITORIAL

Cardiovascular protection in special populations LANDI LOMBARD

M

ost professionals reading this Journal will be struggling with the ever-increasing number of patients with diabetes who consult us daily. These days I seldom see patients without this challenging illness, which is probably more of a cardiovascular risk factor than a disease, as suggested by our Journal’s title. In this edition, the focus is on cardiovascular protection in special subgroups and includes some interesting articles. In a Medical Research Council (MRC)1 assessment of the burden of disease attributable to diabetes in South Africa, the research showed that 14% of ischaemic heart disease, 10% of stroke and 12% of hypertensive and renal disease is directly attributable to diabetes. The investigation used South African community studies on diabetes in various population groups to assess risk in terms of a World Health Organisation risk-assessment protocol. We also know that ischaemic heart disease, stroke, hypertension and renal disease are increasing in prevalence. Clinicians are aware that the presence of diabetes is regarded as a cardiovascular risk equivalent, ranking equally with smoking, hypertension and raised cholesterol levels, as has been shown by Steven Haffner et al.2,3 In a recent study of long-surviving patients with type 1 diabetes who had developed the metabolic syndrome, undertaken in Johannesburg at the CDE, intima–media thicknesses were used to assess their cardiovascular risk. This clinical study showed that those patients who developed features of the metabolic syndrome had greater carotid artery intima–media thicknesses as a result. By inference, they are at higher risk of atherosclerosis and possibly cardiovascular disease.4 Interestingly, a recent study5 on South Africans, regarding diet and cardiovascular health, has shown than the South African population has a better understanding of the cardiac risks of high cholesterol levels, high blood pressure and diabetes than of the risks related to being overweight. Obesity, however, is currently a worldwide crisis (including in South Africa) and will be followed by increasing diabetes and cardiovascular burden, overwhelming our healthcare capabilities. We need much more public education around the issue of overweight and obesity, and its role in adversely affecting cardiovascular health. In this issue, a review on HIV and diabetes by Wilson is long overdue and puts into perspective the complex interactions of the disease and the treatments used. It is unfortunate that the increasing diabetes risk in HIV patients is partially a reflection of our treatment success and increased drug availability/usage. Achieving Best Practice provides valuable practical advice on how to avoid weight gain during smoking cessation and focuses on lifestyle recommendations. It also discusses the value of nicotine replacement and pharmacotherapy. Also, in ADA Watch, our special report on the American Diabetes

Association meeting in June, intensive lifestyle and early intensive dietary interventions (page 130) show diabetes ‘remission’ in 11% of these overweight and obese patients. An interesting article from Turkey, assessing the future cardiovascular risk in pregnant women with gestational diabetes and impaired glucose tolerance, using mean platelet volume, provides useful information on current and future thrombosis risk. This is a novel concept and could become a measurable cardiovascular risk factor in the future (page 109). The risk of thrombosis takes us to the issue of aspirin treatment in diabetic patients, which is dealt with in the patient information leaflet. This has dramatically changed recently due to new data and is not as clear-cut as it was previously. For many years, all diabetic patients were put on aspirin therapy as primary prevention. However, recent research on aspirin in both Europe and Japan has shown that aspirin (81–162 mg daily) should be recommended for diabetic patients with a 10% and higher-decade risk for a cardiovascular event, while those below 5% should not be given a daily aspirin dose. Those in the 5–10%, 10-year risk group need to be individualised, and we will probably be doing more risk-score assessments in the future.6,7 As clinicians, we need to be alert to this nuance in aspirin usage and that the old approach of aspirin for all diabetics was too simplistic. Cardiovascular risk in diabetic patients also relates to glucose control and we hope the article on patient glucose self-monitoring will be of value to the diabetes care team. This discusses new developments and gives some guidance on glucose testing in type 2 diabetes. It includes international guidelines as well as individual views. I would like to end this editorial on a personal note, because this is my first edition as corresponding editor. I hope I can serve this journal and its growing number of readers as well as the previous editors did. I’m looking forward to an interesting journey, supported by an excellent team at the South African Journal of Diabetes and Vascular Disease.

References 1.

2.

3.

4.

5.

Correspondence to: Dr Landi Lombard Netcare Kuilsrivier Hospital, Cape Town Tel: +27 0(21) 900-6350 e-mail: lclombard@mweb.co.za S Afr J Diabetes Vasc Dis 2011; 8: 103

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6.

7.

Bradshaw D, Norman R, Lewin S, Cairncross E, et al. Estimating the burden of diseases attributable to diabetes in South Africa in 2000. S Afr Med J 2007; 97(8 Pt 2): 700–706. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339(4): 229--234. Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP. San Antonio Heart Study. National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation 2004; 110: 1251–1257. Distiller LA, Joffe BI, Brown V, Distiller GB. The effects of features of the metabolic syndrome on atherosclerotic risk in relatively long-surviving patients with type 1 diabetes. Metabol Syndr Relat Disorder 2010; 8(6): 539–543. Dolman RC, Stonehouse W, van’t Riet H, Badham J, Jerling JC. Beliefs of South Africans regarding food and cardiovascular health. Publ Hth Nutr 2008; 11(9): 946–954 De Berardis G, Sacco M, Strippoli GFM, Pellegrini F, Graziano G, Tognoni G, Nicolucci A. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials Br Med J 2009; 339: 4531 Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular disease in people with diabetes. Circulation 2010; 121(24): 26942701.

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HIV and diabetes DOUGLAS WILSON

S

outh Africa is a rapidly urbanising society and has high levels of obesity, with a burgeoning epidemic of type 2 diabetes.1,2 This phenomenon is occurring in the context of one of the worst HIV pandemics in the world, associated with extraordinarily high mortality in young adults.3,4 Antiretroviral therapy has transformed the management of HIV infection in South Africa, but as patients living with HIV gain weight and survive into middle age, they are at significant risk of developing type 2 diabetes.5 If not treated appropriately, patients living with both these chronic conditions develop serious target-organ damage, notably atherosclerosis, chronic renal impairment and peripheral neuropathy. Sight-threatening retinopathy, commonly affecting patients with diabetes, is usually caused by opportunistic infections (such as cytomegalovirus) in patients living with HIV and is best prevented by timely initiation of antiretroviral therapy. Antiretroviral therapy is associated with dyslipidaemia, lipodystrophy, insulin resistance and glucose intolerance.6 The underlying reasons for these observations remain to be fully elucidated, but persisting systemic inflammation may contribute to the development of the diabetic state.7 Lipodystrophy is associated with reduced levels of apidonectin, leptin, and abnormal growth hormone secretion.8-10 The intra-abdominal (visceral) fat accumulation component of lipodystrophy is particularly associated with insulin resistance and diabetes.11-13 Lipid abnormalities most often seen are elevated triglycerides, total cholesterol and low-density lipoprotein cholesterol, and low high-density lipoprotein cholesterol.14,15 Additionally, HIV infection causes endovascular inflammation. The commonest end result of these abnormalities is atherosclerosis, and patients with HIV infection and diabetes are at increased risk of myocardial infarction and stroke.16,17 The antiretroviral drugs most often associated with dyslipidaemias are stavudine, zidovudine, efavirenz, lopinavir/ritonavir and the ‘earlier’ protease inhibitors. Abacavir is associated with an increased risk of myocardial infarction. Those with a ‘cleaner’ lipid profile include lamivudine, emtricitabine, nevirapine, tenofovir and atazanavir. The approach to lipid abnormalities begins with dietary modification, followed by medication. Drug interactions between lipid-lowering drugs and antiretrovirals are common and consulting a web-based resource is helpful (e.g. www.hiv-druginteractions. org). In general, low-dose atorvastatin, pravastatin, the fibrates and niacin are safe to use with the protease inhibitors.18,19 Diagnosis of diabetes in HIV-infected patients follows established international guidelines, i.e. an HBA1c level of > 6.5%. The

management strategies are similar for HIV infection and diabetes. Lifestyle modification, healthy eating, exercise, support from family and friends, knowledge of the illness and medications, and scrupulous adherence to treatment regimens are fundamental to both conditions.20 Glucose intolerance is managed with diet and exercise, weight loss and metformin. There is a theoretical risk of lactic acidosis due to metformin but this does not preclude using metformin with standard antiretroviral drugs in patients with normal renal function. Pioglitazone has been shown to have beneficial effects in patients with antiretroviral-induced lipo-atrophy and could rationally be combined with metformin for the management of diabetes in HIVinfected patients taking antiretroviral therapy.21,22 Importantly, pioglitazone increases fracture risk in postmenopausal woman, and tenofovir reduces bone density. Measuring bone density in patients taking both drugs, with a view to preventing fractures should be considered. Exenatide has not been specifically studied in patients living with HIV. Subcutaneous insulin should be initiated as soon as it becomes apparent that diet, weight loss and oral agents are not achieving therapeutic goals (i.e. HBA1c level of < 7%).23 All patients with diabetes should receive aspirin, a statin and an ACE inhibitor or angiotensin receptor blocker (which also reduces the risk of HIV nephropathy).24 Glucose control should be monitored with home capillary blood testing and measurement of HBA1c levels. Interestingly, in patients on antiretroviral therapy, the HBA1c level may slightly underestimate the degree of glycaemia but the clinical relevance of this observation is uncertain.25 Type 1 diabetics are a challenging group of patients, who often become HIV infected during adolescence. Management of the two conditions is along established lines, but these patients need significant counselling and support to address high-risk behaviour, non-adherence to medications, and issues of sexuality and body image. The need for rigid adherence to both insulin therapy and antiretroviral therapy can be especially problematic for these patients.26

References 1.

2. 3.

4.

Correspondence to: Dr Douglas Wilson Department of Medicine, Edendale Hospital and University of KwaZulu-Natal, Pietermaritzburg Tel: +27 (0)33 395-4146 e-mail: wilsondpk@gmail.com S Afr J Diabetes Vasc Dis 2011; 8: 104–105

104

5.

6.

Kruger HS, Puoane T, Senekal M, van der Merwe MT. Obesity in South Africa: challenges for government and health professionals. Publ Hlth Nutr 2005; 8: 491–500. Idemyor V. Diabetes in sub-Saharan Africa: health care perspectives, challenges, and the economic burden of disease. J Natl Med Assoc 2010; 102: 650–653. Statistics South Africa. Mortality and causes of death in South Africa 2007: finding from death notification 2009. http://www.statssa.gov.za/publications/ statsdownload.asp?PPN=P0309.3&SCH=4507 National Department of Health, South Africa (2007) The national HIV and syphilis survey, South Africa. http://www.doh.gov.za/docs/reports/2007/hiv/part1.pdf Samaras K, Wand H, Law M, Emery S, Cooper D, Carr A. Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Foundation and Adult Treatment Panel III criteria: associations with insulin resistance, disturbed body fat compartmentalization, elevated C-reactive protein, and [corrected] hypoadiponectinemia. Diabetes Care 2007; 30: 113–119. Fisher SD, Miller TL, Lipshultz SE. Impact of HIV and highly active antiretroviral

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7.

8. 9.

10.

11.

12.

13.

14. 15.

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therapy on leukocyte adhesion molecules, arterial inflammation, dyslipidemia, and atherosclerosis. Atherosclerosis 2006; 185: 1–11. Brown TT, Tassiopoulos K, Bosch RJ, Shikuma C, McComsey GA. Association between systemic inflammation and incident diabetes in HIV-infected patients after initiation of antiretroviral therapy. Diabetes Care 2010; 33(10): 2244–2249. Sweeney LL, Brennan AM, Mantzoros CS. The role of adipokines in relation to HIV lipodystrophy. AIDS 2007, 21: 895–904. Tsiodras S, Perelas A, Wanke C, Mantzoros CS. The HIV-1/HAART associated metabolic syndrome - novel adipokines, molecular associations and therapeutic implications. J Infect 2010; 6: 101–113. Luo L, Zhang L, Tao M, Qiu Z, Xie J, Han Y, et al. Adiponectin and leptin levels in Chinese patients with HIV-related lipodystrophy: a 30-month prospective study. AIDS Res Hum Retroviruses. 2009; 25: 1265–1272. Moyle G, Moutschen M, Martínez E, Domingo P, Guaraldi G, Raffi F, et al. Epidemiology, assessment, and management of excess abdominal fat in persons with HIV infection. AIDS Rev. 2010; 12: 3-14. Mulligan K, Khatami H, Schwarz JM, Sakkas GK, DePaoli AM, Tai VW, et al. The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia. J Clin Endocrinol Metab 2009; 94: 1137–1144. Hansen BR, Haugaard SB, Jensen FK, Jensen JE, Andresen L, Iversen J, Andersen O. Long-term high-physiological-dose growth hormone reduces intra-abdominal fat in HIV-infected patients with a neutral effect on glucose metabolism. HIV Med 2010; 11: 266–275. Grunfeld C. Dyslipidemia and its treatment in HIV infection. Top HIV Med 2010; 18: 112–118. Julius H, Basu D, Ricci E, Wing J, Basu JK, Pocaterra D, Bonfanti P. The burden of metabolic diseases amongst HIV positive patients on HAART attending the Johannesburg Hospital. Curr HIV Res 2011 Jun 2. [Epub ahead of print] Carr A, Ory D. Does HIV cause cardiovascular disease? PLoS Med 2006; 3: e495–496.

17. DAD study group. Class of antiretroviral drugs and the risk of myocardial infarction. New Engl J Med 2007; 356: 1723–1735. 18. Tebas P, Zhang J, Hafner R, Tashima K, Shevitz A, Yarasheski K, et al. Peripheral and visceral fat changes following a treatment switch to a non-thymidine analogue or a nucleoside-sparing regimen in HIV-infected subjects with peripheral lipoatrophy: results of ACTG A5110. J Antimicrob Chemother 2009; 63: 998–1005. 19. Blanco F, San Román J, Vispo E, López M, Salto A, Abad V, Soriano V. Management of metabolic complications and cardiovascular risk in HIV-infected patients. AIDS Rev 2010; 12: 231–241. 20. Wohl DA, McComsey G, Tebas P, Brown TT, Glesby MJ, Reeds D, et al. Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis 2006; 43: 645–653. 21. Raboud JM, Diong C, Carr A, Grinspoon S, Mulligan K, Sutinen J, et al; Glitazone and Lipoatrophy Meta-Analysis Working Group. A meta-analysis of six placebocontrolled trials of thiazolidinedione therapy for HIV lipoatrophy. HIV Clin Trials 2010; 11: 39–50. 22. Sheth SH, Larson RJ. The efficacy and safety of insulin-sensitizing drugs in HIVassociated lipodystrophy syndrome: a meta-analysis of randomized trials. BMC Infect Dis. 2010; 10: 183. 23. Kim PS, Woods C, Georgoff P, Crum D, Rosenberg A, Smith M, Hadigan C. A1C underestimates glycemia in HIV infection. Diabetes Care 2009; 32: 1591–1593. 24. Kalayjian RC. The treatment of HIV-associated nephropathy. Adv Chronic Kidney Dis 2010; 17: 59–71. 25. Kim PS, Woods C, Georgoff P, Crum D, Rosenberg A, Smith M, Hadigan C. A1C underestimates glycemia in HIV infection. Diabetes Care 2009; 32: 1591–1593. 26. Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group, Sabin CA, Smith CJ, d’Arminio Monforte A, Battegay M, Gabiano C, Galli L, et al. Response to combination antiretroviral therapy: variation by age. AIDS 2008; 22: 1463–1473.

Commercial weight loss programmes offer clinically useful early intervention for obesity

T

he increasing prevalence of overweight and obesity requires effective approaches to weight loss in primary care and community settings. Obesity and its associated co-morbidities demand early intervention, as the high prevalence of obesity puts pressure on scarce healthcare resources. Weight loss of 5 to 10% is associated with clinically significant health benefits, including a reduction in risk factors for diabetes and cardiovascular disease. The efficacy of commercial weight-loss programmes has not been assessed in direct comparison with standard care in primary healthcare settings. Recent findings indicate that commercial programmes in partnership with primary-care providers are a robust intervention for obesity, with commercialprogramme participants losing twice as much weight. In a parallel group, non-blinded, randomised, controlled trial, 772 overweight and obese adults (with at least one other risk factor for obesity-related disease) were recruited by primary-care practices in Australia, Germany and the UK. Participants received either 12 months of standard care

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as per national treatment guidelines, or 12 months’ free membership to the commercial weight-loss programme ‘Weight Watchers’. Primary outcome was weight change over 12 months. Of the 377 participants assigned to the commercial programme, 230 completed the 12-month assessment. Of the 395 participants assigned to standard care, 214 completed the 12-month assessment. In all analyses, participants in the commercialprogramme group lost approximately twice as much weight as did those in the standard-care group. The mean weight change at 12 months was –5.1 kg for those in the commercial programme versus –2.2 kg for those receiving standard care. For those participants who completed the 12 months, mean weight loss was 6.7 kg in the commercial programme versus 3.3 kg is the standard-care group. Participants randomised to the commercial programme were also more than three times as likely to lose at least 5% of their body weight compared with those receiving standard care. The greater weight loss in participants assigned to the commercial programme was

accompanied by greater reductions in waist circumference and fat mass, which would be expected to reduce the risk for type 2 diabetes and cardiovascular disease. There was also the suggestion of greater improvements in glucose and lipid metabolism in the commercial programme participants. Weight Watchers promotes a hypo-energetic, balanced diet based on healthy eating principles, increased physical activity and group support. Participants are encouraged to achieve and maintain their self-selected weight-loss goals through weekly meetings encompassing a weigh-in and group discussion, behavioural counselling and motivation. Internet-based systems enable monitoring of food intake, activity and weight change, as well as access to community discussion boards, recipes and other information. 1.

Source: Jebb SA, Ahern AL, Olson AD, Aston LM, Holzapfel C, Stoll J, et al. Primary care referral to a commercial provider for weight loss treatment versus standard care: a randomised controlled trial. www.thelancet.com. Published online September 8, 2011 DOI: 10.1016/S0140-6736(11)61344-5.

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Metformin decreases thyrotropin in overweight women with polycystic ovarian syndrome and hypothyroidism SM Taghavi, H Rokni, S Fatemi Abstract

O

bjective: To assess the effect of metformin administration on thyroid function in overweight women with polycystic ovarian syndrome (PCOS). Methods: Twenty-seven overweight women with PCOS and hypothyroidism were selected. Fifteen patients (group I) were treated with metformin 1 500 mg/day for six months and 12 patients (group II) with placebo. Serum thyrotropin (TSH), free T3 and free T4 were measured at baseline and six months after the beginning of the study. Results: A significant decrease (p < 0.001) in TSH levels was observed in group I but not in group II subjects after six months of metformin treatment. No significant change in free T3 and free T4 was observed throughout the study in any group. Conclusion: In obese PCOS patients with primary hypothyroidism, metformin results in a significant fall and sometimes normalisation of TSH, without causing any reciprocal changes in other thyroid function parameters. Keywords: hypothyroidism, metformin, polycystic ovarian syndrome (PCOS), thyrotropin (TSH)

Introduction Polycystic ovarian syndrome (PCOS) is a common endocrinopathy occurring in five to seven per cent of women of reproductive age and primary hypothyroidism is also very prevalent in women and occurs more commonly in PCOS.1 Metformin has been used for the treatment of type 2 diabetes and PCOS for many years. Recently there have been some reports that metformin is able to influence thyroid function tests, mainly by a decrease in serum levels of thyrotropin (TSH).2 We evaluated the interplay between metformin and thyroid tests by following thyroid hormone levels in overweight PCOS patients with hypothyroidism after treatment with metformin or placebo.

Patients and methods This study was performed in 27 overweight women with PCOS and primary hypothyroidism. PCOS was diagnosed in accordance with the Rotterdam consensus diagnostic criteria. Hypothyroidism in all patients was subclinical and was diagnosed for the first time. Fifteen patients (group I) were treated with metformin 1 500 mg/ day for six months and 12 patients (group II) with placebo. The Correspondence to: S Morteza Taghavi Endocrine Research Center, Mashhad Medical University, Ahmad Abad Street, Ghaem Hospital, Mashhad, Iran. Email: taghaviMR@mums.ac.ir From: Diabetes Vasc Dis Res 2011; 8(1): 47–48 S Afr J Diabetes Vasc Dis 2011; 8: 106–107.

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patients did not receive any other medication for treatment of PCOS. Serum TSH, free T4 (FT4) and free T3 (FT3) were measured once at baseline and six months after the beginning of the study. All statistical analysis was performed using SPSS 14. Data are shown as mean ± standard deviation. Paired t-tests were used to analyse changes in thyroid function tests and BMI. P-values less than 0.05 were considered significant.

Results Clinical characteristics and thyroid function tests in the two groups of patients are summarised in Table 1. There was no significant difference between mean age and BMI in the two groups. Mean basal TSH levels decreased significantly in group I after six months of metformin treatment (p < 0.001). In five patients in this group (30%) serum TSH levels reached normal range. Mean basal TSH levels in patients in group II did not change significantly after placebo treatment. In one patient in this group, serum TSH levels reached normal range, which can be seen in the natural course of subclinical hypothyroidism.3 Serum FT4 and FT3 levels did not change significantly during the study in any group (Table 1).

Discussion These data show for the first time that metformin administration in overweight PCOS patients with primary subclinical hypothyroidism results in a significant fall in TSH levels. This is an important finding clinically, because hypothyroidism occurs in more than 10% of PCOS patients1 and metformin is a common prescription for them. There are several possible explanations for the TSH-reducing effect of metformin but they are speculative at the present time. A subtle increase in the gastrointestinal absorption of levothyroxin is the first possible mechanism, but a reduction in thyroid hormone levels was not reciprocal with TSH in patients with hypothyroidism treated with levothyroxin in initial case reports by Vigersky et al.4 This finding was also shown in another study by Cappelli et al. He also

Table 1. Clinical characteristics and thyroid function tests in two groups of patients (mean ± SD) Group I before treatment

Group I after treatment 28.59 ± 2.56

Group II before treatment

Group II after treatment

28.2 ± 2.2

27.96 ± 1.73

BMI (kg/m2)

29.7 ± 2.5

TSH (mIU/l)

7.78 ± 1.74

6.14 ± 2.47

8.02 ± 2.21

8.82 ± 2.89

FT4 (pg/ml)

16 ± 2.26

15.6 ± 2.45

15.8 ± 2.2

16.5 ± 3.8

FT3 (pg/ml)

4.8 ± 0.99

4.83 ± 1.26

4.6 ± 1.1

4.67 ± 1.28

Group 1: Fifteen patients treated with metformin 1 500 mg/day for six months Group 2: Twelve patients treated with placebo

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ruled out any influence of changes in body weight associated with metformin therapy on TSH levels.2 Our study also confirms these findings. Enhancement of inhibitory feedback of thyroid hormones on TSH secretion is another mechanism suggested by Cappelli et al.2 Induced constituent activation of the TSH receptor and increased dopaminergic tone has also had been suggested by Vigersky et al.4 Previous studies have suggested that there is a disruption of the neuroendocrine mechanisms in women with PCOS, mainly due to a deficiency in hypothalamic dopamine.5 Metformin administration improves endogenous hypothalamic dopaminergic tone, simultaneously with decreasing the insulin resistance in obese PCOS patients.6 The possibility that metformin administration decreases TSH levels by increasing dopamine in the hypothalamus may be the best explanation but needs to be fully elucidated by further studies. The main limitation of our study was the small number of patients. However, a significant decrease in TSH levels was observed in our patients.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conclusion

4.

In overweight PCOS patients with primary hypothyroidism, treatment with metformin resulted in a significant fall in TSH and in some cases improvement of hypothyroidism. We can begin treatment of obese PCOS patients with subclinical hypothyroidism with metformin and re-evaluate their thyroid function after six months.

5.

Conflict of interest statement The authors declare that they have no conflicts of interest. Acknowledgements This study was performed with the support of Mashhad Endocrine Research Center. All authors have contributed significantly and are in agreement with the content of the manuscript.

References 1.

2. 3.

6.

Janssen OE, Mehlmauer N, Hahn S, et al. High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. Eur J Endocrinol 2004; 150: 363–369. Cappelli C, Rotondi M, Pirola I, et al. TSH-lowering effect of metformin in type 2 diabetes. Diabetes Care 2009; 32: 1589–1590. Díez JJ, Iglesias P. Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab 2004; 89: 4890–4897. Vigersky RA, Filmore-Nassar A, Glass AR. Thyrotropin suppression by metformin. J Clin Endocrinol Metab 2006; 91: 225–227 Quigley ME, Rakoff JS, Yen SSC. Increased luteinizing hormone sensitivity to dopamine inhibition in polycystic ovary syndrome. J Clin Endocrinol Metab 1981; 52: 231–234. Ortega-González C, Cardoza L, Coutiño B, et al. Insulin sensitizing drugs increase the endogenous dopaminergic tone in obese insulin-resistant women with polycystic ovary syndrome. J Endocrinol 2005; 184: 233–239.

Newcomer to the South Africa pharmaceutical community Accord Healthcare, a newcomer to the South African pharmaceutical community, is an international generics producer of high-quality, affordable medicines. Currently, Accord Healthcare has over 1 100 product registrations worldwide across an extensive range of therapeutic classes, including endocrine, antidiabetic and cardiovascular products. Among the pipeline of products that are intended for the South African market, Accord Metformin 500- and 850-mg tablets are the first to be launched in the diabetes/cardiovascular arena. All medicines are packed according to international stand-

VOLUME 8 NUMBER 3 • SEPTEMBER 2011

ards and meet patient expectations in this regard. As per South African guidelines, metformin is indicated for the treatment of type 2 (non-insulin dependent) diabetes mellitus when diet has failed, and especially if the patient is overweight. Accord Metformin can be given alone as initial therapy, or in combination with a sulphonylurea and/or insulin. Accord Healthcare was established in 2001 as the marketing and distribution arm of Intas Pharmaceuticals Ltd. Other affiliates are Astron Research (research and development), Lamda (a clinical research organisa-

tion) and PV Solutions (a pharmacovigilance company). Highest quality manufacturing capabilities have regulatory approval from global bodies such as the FDA (USA), MHRA (United Kingdom), TGA (Australia), ANVISA (Brazil) and the MCC (South Africa). Over the last decade, Accord Healthcare has developed a reputation in all aspects of pharmaceuticals and continues to provide world-class quality, economical pricing and easy accessibility. For more information on Accord Healthcare, visit www.accord-healthcare.com

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An ethical and legal appraisal of the new South African Consumer Protection Act in terms of diabetes care An interview with Ms Elsabé Klinck, consultant in the medico-legal arena in South Africa S Afr J Diabetes Vasc Dis 2010: 8: 108

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o law has changed consumer rights as much as the new Consumer Protection Act. It has also created new liabilities for all in the supply chain of medicine and medical devices, including doctors, nurses and pharmacists. The way in which one communicates to consumers (patients) has become critical. The Act necessitates a complete review of all forms, brochures, notices, etc used in a healthcare facility or practice. There are also very specific duties relating to misunderstandings, and this law has changed the way in which informed consent must be obtained. What aspects of clinical practice are covered by the new Act? All equipment and goods (medicine) that are used in diabetes care are covered by the Act. The services provided (consultations, advice, the whole experience when at the doctor, etc) are also covered by the Act. The Medicines Control Council has asked for exemption for registered medicines from the Act but the outcome of this process is not known yet. Also, because medical devices are not registered, the services and medical devices used when providing healthcare fall under the act. The diabetes care team needs to inform patients on the general performance of the equipment that is being used, e.g. meters, blood pressure monitors. A note to this effect should be on the patient’s file: ‘I explained to the patient how to use the glucose meter and its reliability in common use’. Everyone in the supply chain is responsible for the delivery of unsafe goods, a product failure, defect or hazard in any goods, or inadequate instruction or warnings. One must always issue instructions and warnings to patients on how to safely and effectively use health goods. One must draw the patient’s attention to the brochure or leaflet that comes with a particular product, and encourage him/her to come back to you if he/she is uncertain about its purpose or use. Make a note that you have particularly educated the patient in this regard. If you do this, the buck is returned to the supplier and does not lie in your hands. How does this Act strengthen or alter Ethical Rule 23 of the Health Professions Council of South Africa? Ethical Rule 23 states that patients must know the treatment options available to them and understand why these treatments are indicated. Patients should be offered the best possible care that is cost-effective, provided that they exercise the choice of treatment and know what other options they have given up on. In the diabetes environment where there are expert guidelines available (such as SEMDSA), neglect to follow these guidelines could result in a medico-legal challenge and/or challenge under the Consumer Protection Act. An example is neglect to enforce

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recommendations such as annual evaluation of eyesight, examination of feet for pathology related to the diabetic condition and failure to up-titrate medication when HbA1c levels are not under control. Patients often have an unrealistic expectation of medical care. How do we deal with this in a way that complies with the Consumer Protection Act, yet keeps patients committed to the treatment we are prescribing? There is a specific requirement to inform patients as to the purpose and limitations of the treatment. There is also a specific requirement now to correct misapprehensions, such as if the patient believes in a particular homeopathic medicine. Prior to this Act, one could just ‘nod at this usage’. Now there is a clear responsibility to correct a misapprehension by saying and noting that you have warned the patient that the therapy being followed is not supported by thorough scientific research. What about the Consumer Protection Act and formularies? It is clear that formularies are possible, as cost effectiveness is a valid reason in terms of medical schemes’ legislation for limiting choice. However, formularies must be based on evidence. Also, switching between brands without alerting the consumer/patient to this is not ‘a fair option’. Both the Medicines Act and the Consumer Protection Act require of a patient to consent to a product substitution. The medical aid will need to offer the patient a choice to remain on his/her existing brand, but may require a co-payment if the patient would have been fine on the formulary treatment. In the event of failure of the formulary medicine, the nonformulary medicine required by the patient must then be available at no extra cost to the patient. The same goes if the patient experiences an adverse event on a formulary treatment. How does the process of adjudicating an infringement of the Consumer Act work? The consumer has access to the National Consumer Commission and to a tribunal in the event of a dispute. The Act is being widely advertised under the byline ‘I know my rights. Do you know yours?’ The Commission can be contacted at share call: 086 026 6786, fax: 086 151 5259, e-mail: ncc@thedti.gov.za. J Aalbers, Special Assignments Editor

References 1. 2. 3.

Consumer Protection Act, 2008. Medical Schemes Act, 1998 and the General Regulations thereto. Medicines and Related Substances Act, 1965.

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ACHIEVING BEST PRACTICE

Assessment of mean platelet volume of pregnant women wıth gestational diabetes mellitus and impaired glucose tolerance as a marker of future cardiovascular disease risk AyDIn KÖS¸üS¸, nerMIn KÖS¸üS¸, MÜzeyyen DUrAn, nIlGÜn ÖzTÜrK TUrHAn Abstract

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bjective: To assess the platelet count and mean platelet volume (MPV) of pregnant women with gestational diabetes mellitus (GDM) or gestational impaired glucose tolerance (GIGT) to find out whether GDM and GIGT are risk factors for future development of cardiovascular disease. Study design: A 50-g oral glucose load (OGL) was administered to all participants and haemotological parameters were studied at 24–28 gestational weeks. When plasma glucose ≥ 140 mg/dl (7.8 mmol/l) was measured following the OGL, a 100-g–3-h oral glucose tolerance test was undertaken. Results: A significant difference was observed for MPV values between the GDM and normal OGL groups. Conclusion: Presence of a high MPV in GDM could demonstrate an increase in the risk for current and future thrombotic complications. Keywords: cardiovascular disease risk, gestational diabetes, glucose intolerance, mean platelet volume

Introduction GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.1,2 GDM affects 1.2–14.3% of the pregnant population.1,2 GIGT is also a glycaemic disorder and is considered as a pre-diabetic state.3 Considering the GDM consequences of increased perinatal and maternal morbidity and mortality, in addition to long-term complications, its accurate identification and treatment is of utmost importance.4-6 More than 50% of GDM women will develop type 2 diabetes mellitus in their future life and women with a history of GIGT also have an increased risk of developing diabetes.7 Diabetes is an established risk factor for CVD; therefore, the subset of women with GDM who develop type 2 diabetes mellitus are at an increased risk of developing CVD in the future.8,9 Altered platelet morphology and function have been reported in patients with the metabolic syndrome, stroke and diabetes mellitus.10-14 MPV is a new and independent risk factor for atherothrombosis and CVD. Many studies have shown that Correspondence to: Dr Nermin Kös¸ üs¸ Department of Obstetrics and Gynaecology, Faculty of Medicine, Fatih University, Ankara, Turkey. Tel: +90 505 632 50 23 Fax: +90 312 221 32 76 or +90 312 409 88 86 e-mail: nerminkosus@gmail.com From: Br J Diabetes Vase Dis 2010; 10: 233–237 S Afr J Diabetes Vasc Dis 2011; 8: 109–112.

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Abbreviations and acronyms CVD

cardiovascular disease

EDTA

ethylenediaminetetraacetic acid

GDM

gestational diabetes mellitus

GIGT

gestational impaired glucose tolerance

HSD

honestly significant difference

MI

myocardial infarction

MPV

mean platelet volume

NDDG

National Diabetes Data Group

OGL

oral glucose load

OGTT

oral glucose tolerance test

PDW

platelet distribution width

RBC

red blood cell

RDW

red cell distribution width

increased MPV is one of the risk factors for MI, cerebral ischaemia and transient ischaemic attacks.10-15 MPV is an important, simple, effortless and cost-effective measure that should be used for predicting the possibility of impending acute events like MI and cerebrovascular events.3,14-16 Patients with larger platelets can easily be identified during routine haematological examination and could possibly benefit from preventive treatment.17 In this study we aimed to assess the platelet count and MPV values of pregnant women with GDM or GIGT to find out whether GDM and GIGT are risk factors for future development of CVD.

Materials and methods The study was conducted at Fatih University, Department of Obstetrics and Gynecology, between September 2008 and December 2009. Cases diagnosed with anaemia, haemoglobinopathy, chronic inflammatory disease, renal failure, cyanotic congenital heart diseases, pre-existing diabetes mellitus, other chronic diseases and pre-eclampsia were excluded from the study. Informed consent was obtained from all selected subjects. A 50-g OGl was administered at 24–28 gestational weeks to all participants. When plasma glucose ≥ 140 mg/dl (7.8 mmol/l) was measured following the OGl, a 100-g–3-h OGTT was done. A fasting peripheral venous blood sample was obtained from all participants at the same time during OGTT. GDM was a plasma glucose level of ≥ 200 mg/dl (11.1 mmol/l) 1 h after a 50-g OGl or ≥ two abnormal plasma glucose values in a 3-h 100-g OGTT according to nDDG criteria (≥ 105 mg/dl [5.8 mmol/l] fasting, ≥ 190 mg/dl [10.6 mmol/l] at 1 h, ≥ 165 mg/dl [9.2 mmol/l] at 2 hours, or ≥ 145 mg/dl [8.1 mmol/l] at 3 h).18 Only one value abnormality in 100-g OGTT was accepted as GIGT.

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In all cases, haematological parameters (haemoglobin, haemotocrit, RBC and platelet count, MPV, RDW and PDW) were studied. Platelet count and MPV were performed as part of each full blood count. Samples were taken by antecubital venipuncture into tubes containing tripotassium EDTA. All samples were analysed on a Beckman/Coulter MAXM Hematology Analyzer (Beckman Coulter, CA, UsA) 2–6 h after collection, to minimise changes in platelet size. MPV reference range is determined as 7.8–11.0 fl. Strict quality-control procedures were adopted; Trilevel controls and external quality assurance programmes were used on a regular basis to ensure the accuracy and precision of the instrument. Data were analysed with the SPSS software version 13.0 for Windows (SPSS Inc., Chicago, Illinois, USA). Mean (± SD) were calculated for age and MPV for all three groups separately. Difference between the means of age, MPV and sex between the groups and within the groups were calculated by analysis of variance (ANOVA) using Tukey’s HSD test; p-values and 95% confidence intervals (CI) were also calculated. A p-value of ≤ 0.05 was taken as significant. The relationships between two continuous variables, platelet count and MPV were assessed by linear regression analysis. All tests were two-sided with a 0.05 significance level.

GDM groups, respectively. There were significant differences between the three groups in terms of OGl results (p < 0.001 for GDM versus GIGT, GDM versus normal OGl, GDM versus GIGT and GIGT versus normal OGl). When groups were compared for haematological parameters, RBC count, haemoglobin, haematocrit, RDW and PDW values were similar (Table 1). The mean platelet counts in non-diabetes, GIGT and GDM groups were 236 400, 241 100 and 253 200 thousand, respectively. Mean platelet counts were higher in normal OGl than in the GIGT group and in GIGT than in the GDM group. The statistical analysis showed, however, that there was no significant difference between the platelet counts of the three groups. The mean MPV values in the three groups were 8.19, 8.22 and 8.67 fl, in non-diabetic, GIGT and GDM groups, respectively. Although MPV values were higher in GDM than GIGT and GIGT than normal OGl groups, no significant differences were found between them with p-values of 0.099 and 0.987 respectively. The only significance was observed in MPV values of the GDM versus normal OGl group with a p-value of 0.007 (Table 1). In linear regression analysis an inverse relationship between platelet count and MPV levels was observed (p < 0.001, r = 0.105). Patients with high MPV values had a lower platelet count (Fig. 1).

Results

Discussion

A total of 318 patients fulfilling the selection criteria were selected and allocated to three groups. These included 239 (75.2%) normal OGl, 34 (10.6%) GIGT and 45 (14.2%) GDM groups. Mean age, gravity, parity and gestational age in three groups were similar (Table 1). The mean OGl results were 118.1 (6.6 mmol/l), 149.3 (8.3 mmol/l), 172.1 mg/dl (9.6 mmol/l) in the non-diabetic, GIGT and

GDM is a significant but frequently neglected problem for the future health of the mother. Women with a history of GDM have an 18–50% risk of developing type 2 diabetes mellitus within five years following pregnancy.19,20 Although this risk for future type 2 diabetes mellitus is well established for women with GDM, there have been few studies of this issue in women with lesser degrees of glucose intolerance in pregnancy.21-25 Research by Carr et al.26 on this subject showed that women with a history of GIGT have an increased risk of developing diabetes. In a recent study Vambergue et al.27 reported that GIGT was independently associated with glucose intolerance at 6.75 years postpartum, and cases with GIGT had an 4.57-fold increased risk compared with normal pregnant women.

Normal OGl

GIGT

GDM

Age (year)

29.6 ± 4.8

30.9 ± 6.2

31.2 ± 5.1

Gravidity (n)

2.2 ± 1.4

2.2 ± 1.2

2.3 ± 1.5

Parity (n)

0.9 ± 1.2

1.0 ± 1.0

1.0 ± 0.8

Gestational age (week)

25.7 ± 1.3

25.9 ± 1.1

25.6 ± 1.4

OGl (mg/dl) (mmol/l)

118.1 ± 23.5 (6.6 ± 1.3)

149.3 ± 18.9 (8.3 ± 1.1)

172.1 ± 27.9 (9.6 ± 1.6)

RBC (million)

4.18 ± 0.50

4.22 ± 0.40

4.25 ± 0.50

Haemoglobin (g/dl) (mmol/l)

11.9 ± 1.2 (7.4 ± 0.8)

12.4 ± 1.00 (7.4 ± 0.8)

12.0 ± 1.4 (7.5 ± 0.9)

Haematocrit (%)

35.3 ± 3.4

35.1 ± 2.8

34.3 ± 2.3

RDW (%)

13.8 ± 2.1

13.3 ± 1.4

13.4 ± 1.0

Platelet (n)

253.2 ± 68.0

241.1 ± 45.0

236.4 ± 59.3

MPV (fl)

8.19 ± 0.85

8.22 ± 0.97

8.67 ± 1.43*

PDW (%)

16.1 ± 1.5

16.2 ± 1.5

15.9 ± 2.0

* p < 0.05: statistically significant difference between normal OGl and GDM group. GDM = gestational diabetes mellitus; GIGT = gestational impaired glucose tolerance; MPV = mean platelet volume; OGl = oral glucose load; PDW = platelet distribution width; RBC = red blood cell; RDW = red cell distribution width.

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Fig. 1. Correlation between platelet count and mean platelet volume.

12.00

Mean platelet volume (fl)

Table 1. Demographic, haematological and biochemical results of groups

10.00

8.00

6.00 R Square Linear: 0.105

100.00

200.00

300.00 400.00 500.00 Platelet count (x1000)

600.00

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

Diabetes is an established risk factor for CVD; therefore, the subset of women with GDM who develop type 2 diabetes mellitus are at an increased risk of developing CVD in the future.8,9 It is uncertain, however, whether normoglycaemic women with a history of GDM or GIGT who do not develop type 2 diabetes mellitus later are also at increased risk of future CVD. Women with a history of GDM, although normoglycaemic after pregnancy, have increased insulin resistance and decreased endothelium-dependent vasodilation.28,29 Such data suggest that GDM may represent the transient unmasking of a latent metabolic syndrome that may become clinically apparent later in life as CVD. Vascular dysfunction is another independent risk factor for CVD and women with prior GDM may have impaired vascular function.30,31 In their study, Anastasiou et al.29 concluded that women with a history of GDM have impaired endothelial function as assessed by flow-mediated dilatation. Another study on this issue31 showed that women with prior GDM have impaired acetylcholine-induced skin vasodilatation after the postpartum period (2–4 years), assessed by laser Doppler flow, when compared with normal controls. The changed balance between prostacyclin and thromboxane observed in vessels of diabetic patients might serve as an explanation for the vascular modifications mentioned above.32 This imbalance between prostacyclin and thromboxane is responsible for hypercoagulability in diabetic patients and could result in foetal loss – one of the most important complications of GDM. Hypercoagulability and vascular dysfunction cause microthrombosis on placental bed vessels and placental infarctions. Consequently, this generates an impairment in the foetomaternal circulatory system, that results in low placental perfusion and finally in the loss of the foetus.33 Platelets play an important role in the integrity of normal homeostasis, and MPV is the indicator for their function.34 The large platelets contain more dense granules, are more potent than the smaller platelets, and are hence more thrombogenic.35-37 An increase in MPV has been documented in patients with metabolic syndrome, stroke and diabetes mellitus.36 Increased MPV is now emerging as an independent risk factor for thromboembolism and MI.13,14,38,39 Yin et al.40 compared platelet counts and MPV values for pregnant women with GDM in the last trimester with the values for healthy pregnant women. Women with GDM were found to have a lower platelet count on average and a higher MPV. Nevertheless, this finding was not statistically significant. Bozkurt et al.41 demonstrated that the MPV of their GDM group was significantly higher than the MPV of healthy pregnant women, but no statistically significant difference was observed in the platelet count between the GDM and normal pregnant women. Additionally, an inverse relationship was observed between platelet number and MPV. We found similar results to Bozkurt et al. GDM cases had a lower platelet count on average and a higher MPV. There was no difference between groups in terms of platelet count, but the MPV of our GDM group was significantly higher than the healthy group. An inverse relationship between platelet count and MPV levels was also observed. This knowledge may be important for prevention of thrombotic complications related to increased MPV in patients with GDM that can result in impairment in the foetomaternal circulatory system. Anticoagulant therapy such as low-dose aspirin may improve pregnancy outcome by blocking the action of cyclo-oxygenase in platelets, thereby inhibiting platelet thromboxane synthesis and preventing thrombosis of the placental vasculature.

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ACHIEVING BEST PRACTICE

Key messages MPV in pregnancy may: • indicate future CVD risk • improve follow up of women with GDM and GIGT.

There is a relationship between MPV values and blood glucose levels. MPV changes with alteration of blood glucose and can be used as an effective marker for blood glucose level.42 In a study group of 22 patients with diabetes mellitus, MPV values were found to be higher initially, but with the decrease of blood glucose, a significant decrease in MPV values was also observed.42 De Pablos-Velasco et al.43 showed that patients with GIGT had higher prevalence of certain cardiovascular risk factors than patients with normal glucose tolerance in a white population. In our study MPV was found to be increased in the GIGT group. Although this increase was not statistically significant, it may be an early sign of risk for future CVD.

Conclusion Glucose intolerance during pregnancy may be an early sign of metabolic disease later in life. Becoming pregnant is a good challenge for women to assess their metabolic state. Because pregnancy itself contains excessive metabolic changes, women who tolerate these changes successfully (healthy pregnant women) can be accepted as having a lower CVD risk for the future if no other risk factors are present. Women with GDM would be expected to be at greater risk of future CVD. Our findings suggest that GDM may serve as a marker of increased risk for future CVD. Another important finding in our study was the presence of higher MPV in GIGT than in normal OGl cases. This means that GIGT may be a risk factor for CVD also. Because MPV in GIGT was only slightly elevated and the increase not statistically significant, we concluded that the risk for MPV-related CVD and thromboembolism was not considerably elevated. The MPV value can contribute to improvement of follow up and management of GDM and GIGT. It may aid in decreasing the complications of glucose intolerance and insulin resistance through early realisation of future CVD risk. Further studies with larger series and long-term follow up of these cases are needed to confirm this evidence. Such evidence might lead women to take preventive measures now and in the future, such as lifestyle changes or prophylactic pharmacological interventions.

References 1. 2. 3.

4.

Hanna FW, Peters JR. Screening for gestational diabetes: past, present and future. Diabet Med 2002; 19: 351–58. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2003; 27: 88–90. Bock G, Dalla Man C, Campioni M, et al. Pathogenesis of pre-diabetes: mechanisms of fasting and postprandial hyperglycemia in people with impaired fasting glucose and/or impaired glucose tolerance. Diabetes 2006; 55: 3536–49. Jimenez-Moleon JJ, Bueno-Cavanillas A, Luna-Del-Castillo JD, et al. Prevalence of gestational diabetes mellitus: Variations related to screening strategy used. Eur J Endocrinol 2002; 146: 831–7.

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14.

15. 16. 17.

18. 19.

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Evans MJ. Diabetes and pregnancy: a review of pathology. Br J Diabetes Vasc Dis 2009; 9: 201–6. Lindsay RS. Gestational diabetes: causes and consequences. Br J Diabetes Vasc Dis 2009; 9: 27–31. Gabbe SG, Graves CR. Management of diabetes mellitus complicating pregnancy. Obstet Gynecol 2003; 102: 857–68. Khaw KT, Wareham N, Bingham S, et al. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the european prospective investigation into cancer in norfolk. Ann Intern Med 2004; 141: 413–20. Daviglus ML, Stamler J, Pirzada A, et al. Favorable cardiovascular risk profile in young women and long-term risk of cardiovascular and all-cause mortality. J Am Med Assoc 2004; 292: 1588–92. Khandekar MM, Khurana AS, Deshmukh SD, et al. Platelet volume indices in patients with coronary artery disease and acute myocardial infarction: an Indian scenario. J Clin Pathol 2006; 59: 146–9. Kiliçli-Camur N, Demirtunç R, Konuralp C, et al. Could mean platelet volume be a predictive marker for acute myocardial infarction? Med Sci Monit 2005; 11: 387–92. Chu SG, Becker RC, Berger PB, et al. Mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. J Thromb Haemost 2010; 8: 148–56. Nadar SK, Lip GY, Blann AD. Platelet morphology, soluble P selectin and platelet P selectin in acute ischaemic stroke. The West Birmingham Stroke Project. Thromb Haemost 2004; 92: 1342–8. McCabe DJ, Harrison P, Sidhu PS, et al. Circulating reticulated platelets in the early and late phases after ischaemic stroke and transient ischaemic attack. Br J Haematol 2004; 126: 861–9. O’Malley T, Langhorne P, Elton RA, Stewart C. Platelet size in stroke patients. Stroke 1995; 26: 995–9. Sharpe PC, Trinick T. Mean platelet volume in diabetes mellitus. Q J Med 1993; 6: 739–42. Khuwaja AK, Rafique G, White F, Azam SI. Macrovascular complications and their associated factors among persons with type 2 diabetes in Karachi, Pakistan: a multi-center study. J Pak Med Assoc 2004; 54: 60–6. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979; 28: 1039–57. Metzger BE, Cho NH, Roston SM, Radvany R. Pre-pregnancy weight and antepartum insulin secretion predict glucose tolerance five years after gestational diabetes mellitus. Diabetes Care 1993; 16: 1598–605.

It's the shell that makes safer.

Safety-Coated R

81mg The ORIGINAL low dose aspirin for optimum cardio-protection pH

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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.

20. Kaufmann RC, Schleyhahn FT, Huffman DG, Amankwah KS. Gestational diabetes diagnostic criteria: long-term maternal follow-up. Am J Obstet Gynecol 1995; 172: 621–5. 21. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002; 25: 1862–8. 22. Lee AJ, Hiscock RJ, Wein P, et al. Gestational diabetes mellitus: clinical predictors and long-term risk of developing type 2 diabetes. Diabetes Care 2007; 30: 878–83. 23. Löbner K, Knopff A, Baumgarten A, et al. Predictors of postpartum diabetes in women with gestational diabetes mellitus. Diabetes 2006; 55: 792–7. 24. Lauenborg J, Hansen T, Jensen DM, et al. Increasing incidence of diabetes after gestational diabetes: a long-term follow-up in a Danish population. Diabetes Care 2004; 27: 1194–9. 25. Weijers RN, Bekedam DJ. Relationship between gestational diabetes mellitus and type 2 diabetes: evidence of mitochondrial dysfunction. Clin Chem 2007; 53: 377–83. 26. Carr DB, Newton KM, Utzschneider KM, et al. Modestly elevated glucose levels during pregnancy are associated with a higher risk of future diabetes among women without gestational diabetes mellitus. Diabetes Care 2008; 31: 1037–9. 27. Vambergue A, Dognin C, Boulogne A, et al. Increasing incidence of abnormal glucose tolerance in women with prior abnormal glucose tolerance during pregnancy: DIAGEST 2 study. Diabet Med 2008; 25: 58–64. 28. Kousta E, Lawrence NJ, Godsland IF, et al. Insulin resistance and b-cell dysfunction in normoglycaemic European women with a history of gestational diabetes. Clin Endocrinol 2003; 59: 289–97. 29. Anastasiou E, Lekakis JP, Alevizaki M, et al. Impaired endothelium-dependent vasodilatation in women with previous gestational diabetes. Diabetes Care 1998; 21: 2111–5. 30. Weber T, Auer J, O’Rourke MF, et al. Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation 2004; 109: 184–9. 31. Hu J, Norman M, Wallensteen M, Gennser G. Increased large arterial stiffness and impaired acetylcholine induced skin vasodilatation in women with previous gestational diabetes mellitus. Br J Obstet Gynaecol 1998; 105: 1279–87. 32. Saldeen P, Olofsson P, Laurini RN. Structural, functional and circulatory placental changes associated with impaired glucose metabolism. Eur J Obstet Gynecol Reprod Biol 2002; 105: 136–42. 33. Alonso A, Soto I, Urgelles MF, et al. Acquired and inherited thrombophilia in women with unexplained fetal losses. Am J Obstet Gynecol 2002; 187: 1337–42. 34. Jakubowski JA, Thompson CB, Vaillancourt R, et al. Arachidonic acid metabolism by platelets of differing size. Br J Haematol 1983; 53: 503–11. 35. Chamberlain KG, Tong M, Chiu E, Penington DG. The relationship of human platelet density to platelet age: platelet population labeling by monoamine oxidase inhibition. Blood 1989; 73: 1218–25. 36. Pereira J, Cretney C, Aster RH. Variation of class I HlA antigen expression among platelet density cohorts: a possible index of platelet age? Blood 1988; 71: 516–9. 37. Martin J. The relationship between megakaryocyte ploidy and platelet volume. Blood Cells 1989; 15: 108–21. 38. Tavil Y, Sen N, Yazici HU, et al. Mean platelet volume in patients with metabolic syndrome and its relationship with coronary artery disease. Thromb Res 2007; 120: 245–50. 39. Boos CJ, Lip GY. Assessment of mean platelet volume in coronary artery disease: what does it mean? Thromb Res 2007; 120: 11–3. 40. Yin SM, Li YQ, Xie SF, et al. Study on the variation of platelet function in pregnancy induced hypertension and gestational diabetes mellitus. Zhongua Fu Chan Ke Za Zhi 2005; 40: 25–8. 41. Bozkurt N, Yilmaz E, Biri A, et al. The mean platelet volume in gestational diabetes. J Thromb Thrombolysis 2006; 22: 51–4. 42. Saigo K, Yasunaga M, Ryo R. Mean platelet volume in diabetics. Rinsha Byar 1992; 40: 215–7. 43. De Pablos-Velasco PL, Martinez Marin FJ, Rodriguez Perez F, et al. Prevalence and determinants of diabetes mellitus and glucose intolerance in a Canarian Caucasian population: comparison of the 1997 ADA and the 1995 WHO criteria: the Guia study. Diabet Med 2001; 18: 235–41.

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Diabetes Educator’s Focus

Correspondence to: Dr Landi Lombard Netcare Kuilsrivier Hospital, Cape Town Tel: +27 0(21) 900-6350 e-mail: lclombard@mweb.co.za S Afr J Diabetes Vasc Dis 2011: 8: 113– 116

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SELF-MONITORING OF BLOOD GLUCOSE IN TYPE 2 DIABETES: A CURRENT VIEW

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elf-monitoring of blood glucose (SMBG) is often be a daily practice in the patient’s management of his/ her diabetes, and the readings are used by healthcare professionals to monitor the progress of both type 1 and type 2 diabetes patients. In type 1 diabetes, where patients need multiple daily injections, there is no doubt that daily self-monitoring is essential to manage their diabetes.1,2 In type 2 diabetes, although it is often used, SMBG is a lot more controversial. It contributes significantly to the cost of managing the diabetes because of the expense of the equipment and the ongoing cost of the strips. Healthcare budgets worldwide are under huge pressure and healthcare professionals must economise on the healthcare budget where possible. It is therefore important to know whether SMBG is a sensible expenditure in the management of type 2 diabetes, particularly in non-insulin-dependent patients. Several studies have shown no benefit with SMBG,3-5 whereas others suggest the contrary.6-8 As recently as 2008, publications in the British Medical Journal (ESMON4 and DiGEM5 trials) did not support the use of SMBG in type 2 diabetes. Both trials concluded that there was no benefit in control as measured by HbA1c levels and there was a concomitant decrease in quality of life. The conclusion was that SMBG is not recommended in non-insulin-dependent type 2 diabetics. Many randomised, controlled trials have been done; some supported SMBG and others showed that it was not cost effective. Many of these studies were small in sample size and had significant issues with compliance with protocol. The quality of these studies was often poor and patient

intervention was too infrequent, which made the interpretation of these results difficult. Larger meta-analyses have been published,9-15 which were identified from retrospective PubMed searches, but SMBG was done in only a third of these cases.16 Dextrostix, used for the estimation of blood glucose levels, was first developed in 196417 and was fairly inaccurate, with no monitoring device to give readings. In the 1980s, the first blood glucose-monitoring device was developed, and since then, dozens of companies make these devices, which are small and accurate and contribute to the management of diabetes. In South Africa, blood glucose testing contributes significantly to the cost of managing diabetes in both the private and public sectors. However, there is no doubt that improved diabetes control is associated with fewer complications; and we should aim for optimal blood glucose control. This has been supported by large trials such as the UKPDS,18,19 the Kumamoto trial in type 2 diabetics,20 and the DCCT1 and EDIC21 trials in type 1 diabetes. In a re-analysis of the DCCT22 by Lachin et al. in 2008, it was established that glycaemic exposure, as measured by HbA1c levels, explained most of the benefits of control due to therapy for type 1 diabetes. They could explain 95% of the microvascular complications of retinopathy and nephropathy by the differences in HbA1c levels in the two groups. HbA1c levels also explained 92% of the complications of peripheral neuropathy. However, HbA1c levels are not a good reflection of macrovascular risk.23 In order to assess an individual patient’s risk of complications, HbA1c level is not necessarily a good indicator of long-term

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Table 1. IDF 2009 guidelines: recommendations for SMBG use in noninsulin-treated diabetes

Table 3. National Institute of Health and Clinical Excellence (NICE) guidelines.

1. SMBG should be used only when individuals with diabetes (and/or their care-givers) and/or their healthcare providers have the knowledge, skills and willingness to incorporate SMBG monitoring and therapy adjustment into their diabetes care plan in order to attain agreed treatment goals.

Recommends SMBG for patients: • on intensified insulin therapy • on basal and premixed insulin • with T2DM on diet/oral agents in case of special circumstances of: – newly diagnosed diabetes – acute illness – therapy modification – pregnancy – unexplained or unnoticed hypoglycaemia – coronary artery disease – neuropathy

2. SMBG should be considered at the time of diagnosis to enhance the understanding of diabetes as part of their education and to facilitate timely treatment initiation and titration optimisation. 3. SMBG should also be considered as part of ongoing diabetes selfmanagement education to assist people with diabetes to better understand their disease and provide a means to actively and effectively participate in its control and treatment, modifying behavioural and pharmacological interventions as needed, in consultation with their healthcare provider. 4. SMBG protocols (intensity and frequency) should be individualised to address each individual’s specific educational, behavioural, clinical and provider requirements for data on glycaemic patterns and monitor impact of therapeutic decision making. 5. The purpose(s) for performing SMBG and using SMBG data should be agreed between the person with diabetes and the healthcare provider. These agreed upon purposes/goals and actual review of SMBG data should be documented. 6. SMBG use requires an easy procedure for patients to regularly monitor the performance and accuracy of their glucose meter.

risk. Both genetic factors and blood glucose variability play important roles.24,25,32 In 2010, three publications contributed to our knowledge on SMBG. The Bonomo et al. trial25 in 273 patients showed an improvement in glycaemic control, measured by HbA1c level, when the patients were compliant with the intensive SMBG strategy. Although general compliance was not that Table 2. Consensus on the frequency and timing of SMBG testing by treatment. Treatment

Frequency

Intensified insulin

4–8 tests per day

• • • •

Conventional insulin

2–4 tests per day

• Primarily pre-prandial • Postprandial 1–2 times every day • Nocturnal once weekly or fortnightly

Oral glucoselowering

6–8 tests per week

• Equal pre- and postprandial tests • Infrequent testing should be done in pairs (pre + postprandial) • 7-point monitoring over a single day once per week or month

Newlydiagnosed T2DM

3–5 tests per week

• To improve patient awareness and compliance to lifestyle modification and treatment

Gestational dabetes

4–8 tests per day

• High frequency recommended during pregnancy • Postprandial testing performed at 1 hour postprandial

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Timing Primarily pre-prandial and bedtime 7–10 tests per week postprandial Nocturnal once per week Should follow ISPAD guidelines if aged < 18 years

good, there was still a benefit shown. It was also noticed that glycaemic control could be improved by SMBG if there was a good understanding of testing and interpretation by both the patient and healthcare professional. The Duran et al. trial26 confirmed that SMBG was of benefit in 161 newly diagnosed type 2 diabetics who were observed for one year. SMBG is now recommended for all newly diagnosed type 2 diabetic by the International Diabetes Federation (IDF).28 The Kemph trial was a 12-week lifestyle intervention study, which showed glucometabolic improvements of 0.3%, as measured by HbA1c levels, with SMBG and structured lifestyle interventions.27 The IDF published guidelines in 2009 for SMBG in type 2 diabetes and made clear recommendations regarding its use.28 These are summarised in Table 1.28 The European consensus statement on the frequency and timing of SMBG in type 2 diabetes is summarised in Table 2.29 This can be compared to the NICE guidelines from the UK, which are summarised in Table 3.30 In February 2011, the STeP (Structure Testing Program) study on 483 patients was published in Diabetes Care.33 The aim was to assess blood glucose testing in poorly controlled non-insulin-treated type 2 diabetics. Both patients and physicians participated in a collaborative programme to gather, interpret and appropriately use structured SMBG data. The patients were followed for 12 months and the primary endpoint was change in HbA1c levels at 12 months. STeP was a two-arm prospective, randomised trial in 34 primary-care practices in the United States on 483 noninsulin-treated type 2 diabetics. It was important to note that the sites were randomised, not the individual patients. There were two groups; the active control group (ACG) had usual care with quarterly physician visits. Point-of-care HbA1c monitoring was done, and SMBG was freely available. A structured testing group (STG) received the same care as the ACG, but also used the Accu-Check 360 degree View blood glucose analysis system. The results were analysed both as intention-to-treat (ITT) and as a per-protocol analysis. The ITT analysis included all patients

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Fig. 1. Intention-to-treat (ITT) analysis: Change in mean HbA1c over 12 months in patients with non-insulin-treated type 2 diabetes, according to randomisation group.

who had a baseline visit and one additional visit (n = 483). It showed 0.3% improvement in the STG versus the ACG (p = 0.04), which was a statically significant improvement (Fig. 1). When this analysis was repeated in the per-protocol analysis (n = 291), including all patients who were more than 80% adherent to the study protocol, the HbA1c difference was 0.5% in favour of the STG (p = 0.0025) (Fig. 2). As in many of the other SMBG studies, the dropout rate of patients in the perprotocol analysis compared to the ITT analysis was noted. The STG group had earlier changes made to their treatment, as well as earlier initiation of insulin (Fig. 3). It is interesting to note that the STG, doing seven-point profiles for three consecutive days, used fewer strips than the ACG in the ITT analysis. General well being and depression scores were analysed and found to have improved from the beginning of the study in both groups, but more so in the STG. The STeP results were therefore contrary to the results of the DiGEM5 and ESMON4 trials published in 2007 and 2008, respectively. The STeP study is one of the best thus far on SMBG in non-insulin-treated type 2 diabetes and confirms with little doubt the benefit of SMBG. The difference was that there

Fig. 3. Intent-to-treat analysis: Comparison of the number of patients who received treatment change at month 1 by study group.

was clear-cut analysis of the SMBG results and changes were made appropriately, confirming the notion that testing without analysis and action is futile. Where cost is concerned, it is important to check whether patients use the prescribed strips, and health professionals should download the results from the glucose-monitoring devices. In my opinion, glucose-monitoring devices without the option of downloading the data should not be used. Most of the devices are very accurate and there is a wide variety available. There is also a large variation in the cost of strips. It is important when using SMBG to vary the time of testing, particularly if good values are confirmed, for example, on fasting results. Then pre-lunch and pre-supper values should also be checked. Table 4 gives recommendations regarding testing frequency in type 2 diabetics on different treatment regimes and the predicted number of strips used. One can see that there is variation in the recommended usage and the number of strips used, so the frequency of testing should be individualised. HbA1c level may also influence frequency of testing, and patients with good glycaemic control on recurrent testTable 4. Recommendation for test frequency as done in my own practice.

Fig. 2. Per-protocol (PP) analysis: Change in mean HbA1c over 12 months in patients with non-insulin treated type 2 diabetes.

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Treatment

Tests per day

Strips per month

Intensive insulin

Three times

100

Premix insulin

Twice

50

Basal insulin

Once or less, vary

25

Combination orals

Once or less, vary

25

Low-risk orals*

None if HbA1c < 6.5% or twice per week

0–12

*Metformin or DDP-IV inhibitor or the combination.

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ing and HbA1c could test less frequently than patients who are not at target.

7. 8.

Conclusion There is no doubt that most type 2 diabetes patients should be doing SMBG. It is important for health professionals to train their patients in the use of the equipment and interpretation of the results. This self-empowerment of type 2 diabetics is critical. With the increase in incidence of diabetes worldwide, healthcare professionals need to empower patients to monitor themselves. The results of SMBG should be downloaded and discussed with the patient on each visit to the healthcare professional. Remember that HbA1c testing is done to detect poor glycaemic control and should be carried out at least twice a year on all diabetes patients, but SMBG should be available to help improve glycaemic control and assess changes that should be made to the medication. References 1.

2. 3. 4.

5.

6.

9. 10. 11. 12. 13. 14. 15. 16.

The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–986. Evans JM, Newton RW, Ruta DA, MacDonald TM, Stevenson RJ, Morris AD. Frequency of blood glucose monitoring in relation to glycaemic control: observational study with diabetes database. Br Med J 1999; 319: 83–86. Davidson MB, Castellanos M, Kain D, Duran P. The effect of self monitoring of blood glucose concentrations on glycated hemoglobin levels in diabetic patients not taking insulin: a blinded, randomized trial. Am J Med 2005; 118(4): 422–425 O’Kane MJ, Bunting B, Copeland M, Coates VE, ESMON study group. Efficacy of self monitoring of blood glucose in patients with newly diagnosed type 2 diabetes (ESMON study): randomised controlled trial. Br Med J 2008; 336(7654): 1174– 1177. Farmer A, Wade A, Goyder E, Yudkin P, French D, Craven A, et al. Impact of self monitoring of blood glucose in the management of patients with non-insulin treated diabetes: open parallel group randomised trial. Br Med J 2007; 335(7611): 132. Guerci B, Drouin P, Grangé V, et al. ASIA group. Self-monitoring of blood glucose significantly improves metabolic control in patients with type 2 diabetes mellitus: the Auto-Surveillance Intervention Active (ASIA) study. Diabetes Metab 2003; 29: 587–594.

17. 18.

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20. 21. 22. 23. 24. 25. 26.

It's the shell that makes

27. 28. 29.

safer. 30.

31.

Safety-Coated R

81mg The ORIGINAL low dose aspirin for optimum cardio-protection pH

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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.

32. 33.

Schwedes U, Siebolds M, Mertes G, SMBG study group. Meal-related structured self-monitoring of blood glucose: effect on diabetes control in non-insulin-treated type 2 diabetic patients. Diabetes Care 2002; 25: 1928–1932. Barnett AH, Krentz AJ, Strojek K, et al. The efficacy of self-monitoring of blood glucose in the management of patients with type 2 diabetes treated with a gliclazide modified release-based regimen. A multicentre, randomized, parallelgroup, 6-month evaluation (DINAMIC 1 study). Diabetes Obes Metab 2008; 10: 1239–1247. McAndrew L, Schneider SH, Burns E, Leventhal H. Does patient blood glucose monitoring improve diabetes control? A systematic review of the literature. Diabetes Educ 2007; 33(6): 991–1011. Sarol JN Jr, Nicodemus NA Jr, Tan KM, Grava MB. Self-monitoring of blood glucose as part of a multi-component therapy among non-insulin requiring type 2 diabetes patients: a meta-analysis (1966–2004). Curr Med Res Opin 2005; 21(2): 173–184. Jansen JP. Self-monitoring of glucose in type 2 diabetes mellitus: a Bayesian metaanalysis of direct and indirect comparisons. Curr Med Res Opin 2006; 22(4): 671– 681. Welschen LM, Bloemendal E, Nijpels G, Dekker JM, Heine RJ, Stalman WA, Bouter LM. Self-monitoring of blood glucose in patients with type 2 diabetes who are not using insulin: a systematic review. Diabetes Care 2005; 28(6): 1510–1517. Kempf K, Neukirchen W, Martin S, Kolb H. Self-monitoring of blood glucose in type 2 diabetes: a new look at published trials. Diabetologia 2008; 51(4): 686–688. Poolsup N, Suksomboon, N, Jiamsathit W. Systematic review of the benefits of self-monitoring of blood glucose on glycemic control in type 2 diabetes patients. Diabetes Technol Ther 2008; 10(Suppl 1): S51–66. Towfigh A, Romanova M, Weinreb JE, Munjas B, Suttorp MJ, Zhou A, Shekelle PG. Self-monitoring of blood glucose levels in patients with type 2 diabetes mellitus not taking insulin: a meta-analysis. Am J Manag Care 2008; 14(7): 468–475. Klonoff DC, Bergenstal R, Blonde LS, et al. Consensus report of the coalition for clinical research-self-monitoring of blood glucose. J Diabetes Sci Technol 2008; 2(6): 1030–1053. Cohen SL, Legg S, Bird R. A bedside method of blood-glucose estimation. Lancet 1964; 2(7365): 883–884. UK Prospective Diabetes study (UKPDS) group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–853. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. Br Med J 2000; 321: 405–412. Brownlee M, Hirsch IB. Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications. J Am Med Assoc 2006; 295:1707–1708. Epidemiology of Diabetes interventions and complications reserach group (EDIC): Diabetes Care 1999; 22: 99–111. Lachin JM, Genuth S, Nathan DM, Zinman B, Rutledge BN. The effect of glycemic exposure on the risk of microvascular complications in the Diabetes Control and Complications Trial – revisited. Diabetes 2008; 57: 995–1001. Kilpatrick ES, Rigby AS, Atkin SL. Mean blood glucose compared with HbA1c in the prediction of cardiovascular disease in type 1. Diabetologia 2008; 51: 365–371. Kilpatrick ES, Rigby AS, Atkin SL. The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care 2006; 29: 1486– 1490. Bonomo K, De Salve A, Fiora E, Mularoni E, Massucco P, Poy P, et al. Evaluation of a simple policy for pre- and post-prandial blood glucose self-monitoring in people with type 2 diabetes not on insulin. Diabetes Res Clin Prac 2010; 87: 246–251. Duran a, Martin N, Runkle I, Perez N, Abad R, Fernandez M, et al. Benefits of SMBG in the management of new-onset T2DM: The St. Carlos Study, a prospective RCT J Diabetes 2010; 2: 203–211. Kempf K, Kruse J, Martin NS. ROSSO-in-praxi: a self-monitoring of blood glucosestructured 12-week lifestyle intervention significantly improves glucometabolic control of patients with T2DM. Diabetes Technol Therapeut 2010; 12(7): 2010. IDF Clinical Guidelines task force for type 2 diabetes 2009. www.idf.org. Schnell O, et al. on behalf of the European Expert Consensus Panel (Munich 2009) Consensus Statement on Self Monitoring of Blood Glucose in Diabetes. A European Perspective. Diabetes, Stoffwechsel und Herz 2009; 18: 285–289. National Institute for Health and Clinical Excellence. Type 2 diabetes: the management of type 2 diabetes. NICE clinical guideline 66. [cited 2008 November 17]; Available from: http://www.nice.org.uk/Guidance/CG66/NiceGuidance/pdf/English. The Diabetes Control and Complications trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study research group: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643–2653. Brownlee M, Hirsch IB. Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications. J Am Med Assoc 2006; 295: 1707–1708. Polonsky WH, Lawrence F, Shickman CH, et al. Structured self-monitoring of blood glucose significantly reduces A1C levels in poorly controlled, non-insulin-treated type 2 diabetes. Diabetes Care 2011; 34(2): 262–267.

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Hands on HELPING PEOPLE TO QUIT SMOKING

Bev Bostock-Cox Nurse Practitioner, Walsgrave Health Centre, Coventry Clinical Lecturer, Education for Health, Warwick

H

elping people who smoke to quit is one of the most important steps we can take in reducing their risk of cardiovascular disease, in addition to reducing the other harms caused by smoking.

From: the British Journal of Primary Care Nursing S Afr J Diabetes Vasc Dis 2011: 8: 117– 120

Key points: helping people to quit smoking • Include smoking cessation advice at every opportunity, not just when asked • Smokers are four times more likely to quit when given ongoing support combined with pharmacological interventions • Match the pharmacological intervention to the patient’s needs, bearing in mind previous attempts to quit and cost effectiveness • NRT is available in several different forms and may also be prescribed in ‘patch plus top-up’ form where indicated • Mood changes are a side effect of stopping smoking. Studies with varenicline show no increase in risk of suicidal behaviour

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‘Smoking kills’. This is just one of the health warnings on cigarette packets these days, although there are others, telling the buyer that ‘smoking can cause a slow and painful death’, ‘clogs arteries causing heart attacks and strokes’, ‘reduces sperm count’ and ‘harms your unborn baby’. Nobody can be left in any doubt as to the harmful effects of smoking in the face of the barrage of warnings around today. As well as respiratory and cardiovascular diseases, other conditions associated with smoking include eye conditions such as macular degeneration and cataracts, gastric problems such as peptic ulcers, and reproductive problems including sub-fertility, increased risk of spontaneous abortion and low birthweight babies. In 1948, around 65% of the population were cigarette smokers. This figure dropped to 55% in 1970 and has continued to fall, so that only about one in five adults now smokes, according to latest figures. The level is higher in manual workers, offering one explanation for the link between deprivation and premature mortality. Nonetheless, around three out of four smokers are keen to quit at any given time and the surgery is

often the first point of contact when they decide to take the first step on the road to becoming an ex-smoker. So what can we do to help people to quit? HELPING PEOPLE TO QUIT It is important to include smoking cessation advice at any given opportunity, not just when a patient asks for it. Advice should be offered in a non-judgemental way, so that even if the person is not ready to quit now they will realise that they can approach you when the time is right. Guidelines recommend giving brief advice about how to quit and the services that are available to potential quitters, such as the NHS Stop Smoking service, including local smoking cessation groups. Offering brief advice has been shown to be effective in helping smokers to quit. Smokers are four times more likely to quit if they are given ongoing support, combined with pharmacological interventions such as nicotine replacement therapy (NRT). Data on smoking habits and the giving of advice on quitting should also be recorded for all patients aged 16 and over for the Quality and Outcomes Framework (QOF).

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The most effective method of quitting combines support to help people change their behaviour, together with pharmacological interventions such as NRT, bupropion and varenicline. The Department of Health advises that all of these methods should be made available to patients, matching each intervention to their individual needs by bearing in mind previous attempts to quit, the amount they currently smoke and the cost (including the cost-efficiency) of each intervention. Research has shown that simple advice will help one in 40 people quit smoking. Using NRT on top of this will increase the quit rate to one in 20. Other interventions such as bupropion or varenicline will mean that the numbers needed to treat (ie the number of people who are treated for one person to quit smoking) are 15 and eight, respectively. ACHIEVING BEHAVIOURAL CHANGE Clear guidance on helping smokers to quit is available from the Department of Health and the National Institute for Health and Clinical Excellence (NICE), amongst other organisations (see More Information). The model of change as described by Prochaska and Diclemente has been used to explore many types of behavioural change including smoking cessation and can be helpful in looking at the processes involved. The model explains the importance of recognising where any individual stands within the cycle of change, from pre-contemplation to contemplation, preparation, action, maintenance and relapse. Entry to and exit from the cycle can occur at any stage. Importantly, relapse is recognised as being a normal part of the cycle of change – which fits with real-life experience as, on average, smokers take four or more attempts before they manage to quit for good. Coping with relapse should, therefore, be included in any discussion with smokers about quitting. Explaining that each relapse brings the patient closer to success next time should go some way to helping to prevent them becoming demoralised. PHARMACOLOGICAL INTERVENTIONS Nicotine replacement therapy NRT is available on prescription or can be bought over the counter in supermarkets and chemists. NRT products have been licensed for use in the UK since the early 1980s. They have been shown to be very safe and it is useful to note that their use is much safer than continued use of nicotine from cigarettes. They deliver a steady dose of nicotine to the patient while preventing exposure to the other hazardous substances found in cigarette smoke if the person had otherwise continued to smoke. NRT can be delivered by a variety of systems including patches, gum, lozenges and inhalators, among others. In heavy smokers, or those who have failed to quit previously, NRT can also be used as combinations of products, specifically using patches to deliver a background dose of nico-

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Smoking and lung cancer trends over time

What are the stages in achieving behavioural changes?

Key initial advice to give on smoking cessation The five As approach can be useful when offering initial advice: • Ask about smoking and record smoking status • Advise patients of the health benefits of quitting • Assess willingness to stop • Assist smokers who are keen to stop to choose the best method for them • Arrange support, follow-up and monitor progress (Further information: www.smokefree.nhs.uk/resources)

tine while using back-up methods such as gum, lozenges or the inhalator to provide short extra bursts of nicotine during cravings. It is generally recommended that patients use NRT for up to 12 weeks and that the dose of nicotine is slowly reduced over this period, leading to eventual withdrawal from treatment. However, it is important to remember that NRT is much safer than smoking so it is better to maintain the patient on NRT for longer if necessary than for them to return to smoking. NRT is licensed for use in smokers aged 12 years and over, and is also licensed

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CASE STUDY: LIAM, 24 SMOKING HISTORY AND MOTIVATION TO QUIT Liam started smoking 10 years ago. He smokes 20-30 per day. He attends the surgery saying that he wants to quit because he simply cannot afford cigarettes since he lost his job. ASSESSMENT Liam seems to be well-motivated but you could use the 5 As tool to assess him further. If he seems keen to proceed with his quit attempt you could choose to work with him yourself or you could refer him to the local smoking cessation team. RECOMMENDED ACTION As well as providing ongoing support to make behavioural changes, you could prescribe NRT for Liam, using patches with or without ‘back-up’ NRT in the form of gum, for example. If saving money is a priority for Liam, you could use the Department of Health’s smoking cost calculator that will allow him to calculate how much money he will save by quitting his smoking habit (http://smokefree. nhs.uk/quittools/cost-calculator/). Liam may like to use the Smokefree website to enable him to take a more interactive approach to quitting.

CASE STUDY: ARTHUR, 68 SMOKING HISTORY AND MOTIVATION TO QUIT Arthur’s wife recently tried to give up smoking but was not successful. However, this has spurred Arthur on to give it a go and he is feeling quite competitive! He smokes 15–20 cigarettes per day. ASSESSMENT It might be an idea to encourage Arthur’s wife to have another attempt at quitting as they are both more likely to succeed with each other’s support. It is important to discuss with Arthur any previous attempts he has made to quit, including why these were unsuccessful – this may help him to identify and avoid any future stumbling blocks. RECOMMENDED ACTION Arthur is likely to benefit from NRT in patch or other form, depending on his personal preferences. As always, ongoing support should be provided.

for people with a history of cardiovascular disease and for women during pregnancy. Nicotine is a vasoconstrictor, which is why caution was advised in the past when using NRT in those at high risk of acute cardiovascular events; however, as previously stated, NRT is far preferable than continued cigarette smoking. As with all drugs, NRT is better avoided in pregnancy, but is safer than continued smoking; NRT is therefore licensed for use in pregnancy, although shorter-acting products, if appropriate to the patient’s needs, may be better in order to minimise foetal exposure.

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CASE STUDY: ALISON, 44 SMOKING HISTORY AND MOTIVATION TO QUIT Alison smokes 30 cigarettes a day. She also has a family history of early cardiovascular disease. A recent appointment for a cardiovascular risk assessment showed that her risk was 8% over the next 10 years, which is much higher than the average risk for someone her age and sex, of only 1%. She has decided that she would like to stop smoking to reduce her cardiovascular risk. She has tried several times before but has always gone back to smoking after a few weeks, despite using NRT. ASSESSMENT Alison has been frightened by her younger brother’s recent hospital admission with an acute coronary syndrome. He was also a smoker but has quit since his event. She is very motivated to quit but is mindful of her previous failures and fears that she cannot risk another failed attempt. RECOMMENDED ACTION In view of this, and after careful discussion of the options available, Alison decided to try varenicline. She is aware that nausea may be a side-effect but has decided that this may help her to avoid the snacking and weight gain that has accompanied previous quit attempts, and which she admits may have been a key reason for her going back to smoking in the past. You agree to continue to monitor her progress over the next 12 weeks.

Bupropion Bupropion (Zyban) is a prescription-only drug. It is available as a 150-mg tablet, which was originally developed as a treatment for depression but was discovered to be very effective as a smoking cessation drug. The usual dosing regimen for bupropion is 150 mg daily for six days, followed by 150 mg twice daily for the next two months. It takes one to two weeks to take effect so it is recommended that patients start taking the drug while they are still smoking and stop smoking in the second week of taking the tablets. Side effects include a dry mouth and sleep disturbance (although these may also be side effects of quitting smoking) and nausea in some people. Bupropion also seems to increase the risk of fits so should not be given to people who may already be at increased risk such as those with epilepsy or a previous history of seizures. Varenicline Varenicline (Champix) is also available only on prescription but is not licensed for use in pregnancy or in people under 18. It can be prescribed initially as a starter pack, which allows the patient to uptitrate the dose over the first two weeks of use, reducing the risk, of side effects. The main side effect is nausea, although this tends to subside with ongoing use.

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Reports of psychiatric changes in patients taking varenicline have been exaggerated by the media. However, it is known that smoking cessation itself may lead to mood changes and exacerbations of underlying mental health problems, so patients taking this drug (and arguably any other drug used to support smoking cessation) should be advised about the need to report any changes in mood or behaviour, including increased levels of agitation and/or depression. Any cause for concern should lead to discontinuation of the product. SUMMING UP In summary, smoking continues to be a major challenge to improving public health and primary care clinicians are in a key position when it comes to providing advice and support to patients during the quit process. The chances of quitting successfully are significantly increased when a combination of behavioural changes and pharmacological interventions are used. Decisions about the type of interventions used should be made in line with guidance from the Department of Health and NICE but should focus primarily on the individual needs of the patient concerned. The effort is well worthwhile in terms of the health benefits you will help your patient to gain by stopping smoking for good.

more information Key references • Cancer Research UK: smoking statistics available from http://info.cancerresearchuk.org/cancerstats/types/lung/smoking/index. htm#percent • Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews, 2007 Issue 1. Art No: CD006103. DOI: 10.1002/14651858.CD006103.pub2. • DiClemente, Carlo C.; Prochaska James O, et al. The process of smoking cessation: An analysis of precontemplation, contemplation, and preparation stages of change. Journal of Consulting and Clinical Psychology 1991; 59(2): 295-304. Resources • ASH Action on Smoking and Health www.ash.org.uk • Department of Health website www.dh.gov.uk • Education for Health – www.educationforhealth.org – for a distance learning course on smoking cessation • NHS Quit Kit available from http://smokefree.nhs.uk/quit-tools/ • NICE website www.nice.org.uk • Quitline – helps smokers to stop www.quit.org.uk Publications • Percival J. You can stop smoking. Virgin Books. 2007 (for patients) • Percival J. Helping people to stop smoking. Mims for Nurses Pocket Guide Haymarket Medical Media Ltd, London. 2009 (for nurses)

News from the European Society of Cardiology It’s official – chocolate linked to heart health

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igh levels of chocolate consumption might be associated with a one-third reduction in the risk of developing heart disease, finds a study published on bmj.com recently. The findings confirm results of existing studies that generally agree on a potential beneficial link between chocolate consumption and heart health. However, the authors stress that further studies are needed to test whether chocolate actually causes this reduction or if it can be explained by some other unmeasured (cofounding) factor. The World Health Organisation predicts that by 2030, nearly 23.6 million people will die from heart disease. However, lifestyle and diet are key factors in preventing heart diease, says the article. A number of recent studies have shown that eating chocolate has a positive influence on human health due to its antioxidant and anti-inflammatory properties. This includes

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reducing blood pressure and improving insulin sensitivity (a stage in the development of diabetes). However, the evidence on how eating chocolate affects your heart still remains unclear. So, Dr Oscar Franco and colleagues from the University of Cambridge carried out a large-scale review of the existing evidence to evaluate the effects of eating chocolate on cardiovascular events such as heart attack and stroke. They analysed the results of seven studies, involving over 100 000 participants with and without existing heart disease. For each study, they compared the group with the highest chocolate consumption against the group with the lowest consumption. Differences in study design and quality were also taken into account to minimise bias. Five studies reported a beneficial link between higher levels of chocolate consumption and the risk of cardiovascular

events. They found that the ‘highest levels of chocolate consumption were associated with a 37% reduction in cardiovascular disease and a 29% reduction in stroke compared with lowest levels’. No significant reduction was found in relation to heart failure. The studies did not differentiate between dark and milk chocolate and included consumption of chocolate bars, drinks, biscuits and deserts. The authors say the findings need to be interpreted with caution, in particular because commercially available chocolate is very calorific (around 500 calories for every 100 grams) and eating too much of it could lead to weight gain, risk of diabetes and heart disease. However, they conclude that given the health benefits of eating chocolate, initiatives to reduce the current fat and sugar content in most chocolate products should be explored.

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Prevention in Practice Sue Baic Senior Teaching Fellow in Nutrition and Public Health, Department of Exercise, Nutrition and Health Sciences, University of Bristol From: the British Journal of Primary Care Nursing S Afr J Diabetes Vasc Dis 2011: 8: 121– 123

Key Points: controlling weight gain in ex-smokers • Concern about potential weight gain is a common reason that people give for failing to stop smoking • Efforts to limit weight gain can play an important role in helping people to quit • Health professionals in health promotion are well placed to offer interventions to help immediate and long-term weight management in smokers trying to quit • Useful techniques include: interventions to improve dietary intake and behaviours, efforts to increase physical activity and pharmacological treatments

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AVOIDING WEIGHT GAIN AFTER STOPPING SMOKING

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topping smoking is associated with considerable health benefits and large numbers of smokers want to quit. However, concern about weight gain is one of the reasons people often give for not being able to quit smoking. It often reinforces the decision to continue smoking, particularly in women and young people who may mistakenly believe that smoking is an effective way to control their weight. Even if an individual successfully quits smoking, weight gain can often be the factor that causes relapse. What can we do to help? Smokers try to quit the habit once every two to three years, on average. Health professionals involved in health promotion can help people to make the most of these opportunities by exploring – and overcoming – barriers to quitting. This might usefully include helping people to understand the reasons for weight gain and to consider the relative risks of a small amount of weight gain compared with continuing to smoke. It is also helpful to support people in effective strategies for limiting any weight increase on quitting smoking and helping them to lose any weight gained. HOW MUCH WEIGHT DO EX-SMOKERS GAIN? The amount of weight gained after quitting smoking is highly variable. An American study looked at weight change over 10 years in 760 adults, including some who stopped smoking during this time. The average weight increase due to smoking cessation was 2.8 kg for men and 3.8 kg for women, after controlling for other variables. However, major weight gain – defined as more than 13 kg – occurred in around 10% of men and 13% of women. Those most susceptible to weight gain were younger adults, people with a lower education level and those who had smoked more than 15 cigarettes per day. It’s worth noting that this research was carried out before the higher levels of obesity prevalence we see today. More recent studies suggest substantial numbers of quitters gain more than 5% of their initial body weight, with an average increase of 7 kg over longerterm follow-up. For most people this weight gain does

not appear to negate the health benefits from stopping smoking, but it may be a health concern for those who are already overweight or obese, or for those particularly concerned with body weight issues. WHY DO EX-SMOKERS GAIN WEIGHT? A variety of physiological and behavioural mechanisms have been proposed to account for the changes in energy balance that follow smoking cessation. Nicotine can depress appetite and food intake. Smoking also provides the smoker with a substitute activity for eating and snacking. Smoking can also serve as a marker of

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the end of a meal. Rather than taking a second helping or having dessert, smokers may be more likely to stop eating and have a cigarette. After quitting, the urge to smoke can be frequent and uncomfortable, so food is often used as a replacement. Recent research suggests that the pleasurable and rewarding value of food may increase in certain susceptible individuals following smoking cessation. Food intake studies show that average energy intake increases by 250–300 kcal per day after smoking cessation. However, there is disagreement in the literature as to whether additional food intake is sufficient to account for the observed weight gain and it is widely believed that other factors are important. Nicotine appears to increase the resting metabolic rate and so increases energy expenditure. Metabolic studies have shown that smoking 24 cigarettes a day increases energy expenditure by around 200 kcals. Similar studies have shown reductions in resting metabolic rate of around 16% in females after 30 days of smoking cessation. However, it is important to note that not all studies have found such marked effects on metabolism and the importance is under debate. Other proposals for explaining weight gain following smoking cessation include changes in fat oxidation and adipose tissue enzyme activity and reductions in the production of chemicals associated with appetite control in individuals with underlying genetic susceptibility. For a comprehensive review of the subject area see the further information section at the end of this article. WHAT CAN EX-SMOKERS DO TO LIMIT WEIGHT GAIN? Use of nicotine replacement therapy (NRT) and other pharmacotherapies NRT is a way of partially and temporarily replacing some of the nicotine provided by cigarettes, so it can ease the withdrawal symptoms and help during the transition to complete abstinence. Nicotine gums, transdermal patches, inhalers, sublingual microtablets or lozenges, and nasal sprays can be bought over the counter and are also available on prescription. A recently updated Cochrane Review including more than 130 trials concluded that all forms of NRT were able to increase the rate of quitting smoking by around 50–70% compared to placebo. The likelihood of staying stopped for more than six months is also increased when a smoker uses NRT according to the directions. It is useful to dispel some of the myths and misunderstandings about the use of NRT. This might include educating patients about who can use these therapies, the correct way to use them, the recommended duration for use, their relative safety and side effects, and fear of addiction, which sometimes prevent effective use (http://www.smokefree.gov/docs/ MythsaboutNRTFactSheet.pdf). Individuals also benefit from personal advice on which type or combinations of NRT are best suited to their level and style of smoking.

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Table 1. Effective behavioural techniques for weight management during smoking cessation • Keeping a diary to monitor lifestyle behaviour changes • Monitoring progress and giving self-rewards for achieving short- and longterm goals to reinforce changes • Effectively dealing with triggers to eat and with high-risk situations • Coping with relapse • Seeking support and encouragement • Learning to cope with stress and problem-solving in ways other than eating or smoking • Changing eating behaviour – sitting down to eat at a table, slowing rate of eating • Adopting a non-smoking activity to signal the end of a meal, such as taking a walk, brushing teeth, washing dishes or sucking a mint

Effective non-nicotine pharmacological treatments for smoking cessation include bupropion SR, which modulates levels of neurotransmitters in the brain, and varenicline, which is a nicotine receptor partial agonist. Not only do these agents increase the chances of effective smoking cessation, they seem to have at least short-term effects in limiting associated weight gain. They seem to be particularly effective in people who have been shown to increase food intake after stopping smoking. The effects have been shown to be modest over the long term once treatment has stopped. Nevertheless, they may be worthwhile if weight gain is at least delayed until the ex-smoker feels better able to consider additional lifestyle changes to address weight gain. Behavioural solutions Individually tailored behavioural interventions, including some of the techniques of cognitive behavioural therapy (CBT), are effective in improving smoking abstinence and reducing associated weight gain (see Table 1). Benefits of these approaches have been shown both at end of treatment programmes and in longer-term follow up. Behavioural techniques are also effective in weight management. Many self-help resources are available for health professionals and patients (see http://www.bdaweightwise.com/going.html). DIETARY INTERVENTIONS Unsurprisingly, generalised and non-tailored dietary advice on its own is not very effective for achieving weight control in ex-smokers or in the general population. In contrast, individualised dietary advice tailored to food preferences, particularly when used in conjunction with other interventions, may be effective. Surveys of the dietary habits of people who are successful in losing weight – whether ex-smokers or non-smokers – show that effective strategies include eating regular meals, taking smaller portions, avoiding extreme diets, eating a diet low in fat and high in fruit, vegetables and whole grains, and restricting alcohol (see Table 2). These recommenda-

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Table 2. Effective dietary strategies for weight management during or after smoking cessation • Eat regular meals, including breakfast. Skipping meals is not effective in helping lose weight • Take smaller portions, especially of high-fat /high-sugar foods. Using a smaller plate can help • Avoid unduly restrictive or nutritionally imbalanced diets as they are generally ineffective in the long term and can be harmful • A maximum weekly rate of loss of 0.5–1 kg is a realistic target • Very low-calorie diets may be helpful for short-term use in obese patients under clinical supervision • Eat a low-fat diet consistent with general healthy eating advice, with plenty of fruit and vegetables and wholegrain, starchy foods • A range of flexible approaches to reducing energy intake may help. Consider using meal replacements or commercial slimming groups that meet good practice standards. • Restrict alcohol intake. Not only is it high in calories it can be a trigger to smoking or overeating. Drink plenty of low-calorie fluids

tions are now incorporated into the NICE guidelines on successful weight management. Even if an individual does not intend to lose weight, advice on a healthy diet can have other health benefits, particularly as research shows that many smokers have less healthy diets than non-smokers. Snacking can be a particular risk for the ex-smoker. Keeping a healthy range of snacks handy can be useful when the temptation to nibble kicks in (see Table 3). Restricting access to high-fat, high-sugar foods and high-calorie snacks in the house may be helpful. Sugar-free gum or mints can be useful. Nuts are high in calories but eating a few unshelled peanuts or pistachios with a drink – instead of smoking a cigarette – will keep a person’s hands busy, and the process of removing the shell slows down how much is eaten. INCREASING PHYSICAL ACTIVITY Increasing physical activity has been shown to be useful in controlling weight in non-smokers. Exercise may provide an ex-smoker with an alternative activity and interest that may help them cope with nicotine withdrawal. It may also help offset the decrease in metabolic rate associated with smoking cessation. There is little evidence that interventions to increase physical activity are associated with reduced weight gain during the period of giving up smoking. However, measures to increase physical activity as part of smoking cessation programmes may help to limit weight gain over the long term. Advice should take into account a person’s current level of fitness as many smokers are less active than non-smokers. SUMMING UP Efforts to limit weight gain can play an important role in helping people

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Table 3. Ideas for healthy snacks • Raw vegetable batons, such as carrot or celery sticks, cherry tomatoes, mange tout, baby corn, cucumber slices, red pepper, broccoli or cauliflower florets. Try serving with a low-fat dip such as salsa or tzatziki • Fresh fruit – whole or chopped, frozen grapes • Plain popcorn or pretzels • A small handful of unshelled nuts, seeds, olives or dried fruit • Yoghurt (low-fat plain or low-sugar versions) • Bread sticks, oatcakes, rice cakes or crispbreads • A sachet of low-calorie hot chocolate drinks or low-calorie soup • Sugar-free jelly

to quit smoking and to remain ex-smokers. Interventions designed to improve dietary intake and behaviours, efforts to increase physical activity and the use of pharmacological treatments can all help in immediate and long-term weight management in smokers who are trying to quit. They may be particularly important in people for whom weight gain has been an issue in previous attempts to stop smoking. Health professionals working in health promotion are well placed to help patients understand the reasons for weight gain after smoking cessation and to help them see the risk of weight gain compared to continuing to smoke. They can help people find ways to limit weight gain and help with weight loss when they stop smoking as part of optimising their health.

more information • Filozof C, Pinilla MCF, Fernandez Cruz A. Smoking cessation and weight gain. Obesity Reviews 2004; 5: 95-103 • National Institute for Health and Clinical Excellence, 2006. Brief interventions and referral for smoking cessation in primary care and other settings. http://guidance. nice.org.uk/PH1/Guidance/pdf/English • National Institute for Health and Clinical Excellence, 2006. Obesity. Guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children www.nice.org.uk/nicemedia/pdf/CG43quickrefguide2.pdf • Parsons AC, Shraim M, Inglis J et al. Interventions for preventing weight gain after smoking cessation. Cochrane Database of Systematic Reviews 1 CD006219, 2009 Useful resources • Pharmacological help with smoking cessation http://www.smokefree.gov/docs/ MythsaboutNRTFactSheet.pdf • http://www.patient.co.uk/health/Smoking-Nicotine-Replacement-Therapy.htm • http://www.patient.co.uk/health/Smoking-Helping-to-Stop-with-Bupropion.htm • Weight management and healthy eating http://www.bdaweightwise.com/index.html

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A leading partner in the field of diabetic research www.servier.com

1011/2/DMR/A/1

GLICLAZIDE MODIFIED RELEASE

For full prescribing information, refer to package insert approved by the medical regulatory authority. DIAMICRON 速 MR 30mg Tablets. Gliclazide 30mg. Reg. No. 35/21.2/0178. Each DIAMICRON Modified Release 30mg tablet contains 30mg Gliclazide. PHARMACOLOGICAL CL ASSIFICATION A21.2 Oral Hypoglycaemics. DIAGLUCIDE 速 MR 30mg Tablets. Gliclazide 30mg. Reg. No. 38/21.2/0223. Each DIAGLUCIDE 速 Modified Release 30mg tablet contains 30mg Gliclazide. Reg. No.38/21.2/0223. PHARMACOLOGICAL CL ASSIFICATION A21.2 Oral Hypoglycaemics. PRODUCT REGISTRATION NUMBER 35/21.2/0178. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: SERVIER L ABORATORIES SOUTH AFRICA (Pty) Ltd. Reg. No. 72/14307/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. Tel: +27(0) 861 700 900. Fax: +27(0)11 525 3401. BIOGARAN SA (Pty) Ltd. Reg. No. 2001/011749/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. Tel: +27(0)11 525 3448. Fax: +27(0) 866 465 144.


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Diabetes Personality GET THE MESSAGE OF DIABETES OUT THERE S Afr J Diabetes Vasc Dis 2011: 8: 125 – 126

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nce a nurse, always a nurse! This is the deeply felt view of Sr Kamaretha Beckert. She took some years off to raise her family before embarking on a new career 12 or 13 years ago, as a diabetes nurse educator (DNE) based in Paarl, Western Cape. She and her colleague, Dr Nickie Bernard, recently won the 2011 Servier Award for Community Involvement in Diabetes for their passionate commitment to diabetes care and education. ‘He is a wonderful and supportive colleague and we feel honoured to have been recognised with this award’, she says. ‘Sometimes as we push and pull, we wonder whether we’re really getting there. This underscores the importance of what we’re doing and motivates us to further our efforts.’ It was Dr Bernard who was instrumental in Sr Beckert becoming a DNE. When she wanted to get back into nursing, he asked her to help run a diabetes clinic. After training at the Centre for Diabetes and

Sr Beckert addressing diabetic children at an introduction and training camp.

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Endocrinology (CDE), she worked at the clinic for a number of years before branching out as an independent. ‘I wanted to be able to offer my services in the public sector as well’, she recalls. ‘It’s important to me to make a real difference in the community and I felt I needed a bigger scope than just working for one group of doctors in the private sector.’ Her work takes her to Stellenbosch and Worcester, as well as Paarl. She visits hospitals, where she works with patients; she runs support groups for type 2 diabetes patients and even lectures at a Wellington centre that trains home-based nurses, equipping them with the knowledge to deliver optimal care. When a patient is referred to her, she makes use of an educational tool called BodyLink to educate them about what diabetes is. ‘To be able to take control of something, you first need to understand it’, she says. ‘I approach the condition holistically, explaining its complications and its treatment. I make sure patients understand the importance of diet and exercise in managing diabetes, along with the role of medication. When indicated, I guide them through the process of initiating insulin. All this needs to be done slowly, carefully and sensitively, as newly diagnosed patients are often

Sr Kamaretha Beckert and Dr Nickie Bernard receiving their Servier Award for Community Involvement in Diabetes at the recent CDE congress.

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Sr Beckert and Dr Bernard with some of the teenagers at a youth leaders’ training camp.

absolutely devastated to find out they have diabetes. I underscore, however, that with the right tools – in the form of knowledge and medication – diabetes can be controlled, and that it is a condition rather than an illness.’ Diabetes Awareness Week, which takes place during the week of 14 November each year, offers Sr Beckert a platform to reach 200 to 400 individuals per day, of whom approximately 20% are newly diagnosed diabetics. ‘I’m committed to promoting awareness of diabetes and the importance of going for screening’, she says. To this end she also gives talks at schools and hands out a bookmark-like card that lists the warning signs of diabetes. There was a case of one little girl who took the card home and asked her mother, ‘is this what’s wrong with me?’ ‘When she came to my practice, she had a blood glucose reading of 28 mmol/l. She essentially diagnosed herself, because she had been given the knowledge to do so’, says Sr Beckert. Being a DNE is a vocation that comes with both rewards and challenges. Major challenges include a constant shortage of support staff and lack of funding in the face of an ever-growing diabetic population. ‘But these are outweighed by the rewards of being able to make a meaningful difference in patients’ lives, supporting them as best I can to make the changes necessary to manage and take ownership of their condition.’ Sr Beckert has a particular passion for children and for the past nine years has run a diabetes camp that draws children from further afield than her usual area of practice. She recalls an especially rewarding case of a child from Vredendal on the west coast, whose family didn’t want him to go to hospital. She and Dr Bernard worked with him and, with a basal-bolus regimen, lowered his HbA1c level from 11.9 to 9%. The introduction of an insulin pump lowered this still further to 6.2%. During this period, the patient also lost 14 kg. ‘It was a wonderful experience to watch this plump 10-year-old become a fit and well-controlled person with diabetes. Today he is a mentor and youth

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Treating children with diabetes as normal children is essential in teaching them that this is a condition, not an illness. They are then able to manage it better.

leader at the camps, using his own experience to help other children with diabetes to achieve similar results.’ A nine-month-old from Heidelberg was another memorable paediatric case for Sr Beckert. ‘Today, he is seven years old, his diabetes is controlled and he has never been back in hospital. This testifies to what is achievable – but it requires a team approach, involving nurses, doctors and dieticians, as well as the support of the child’s parents and teachers. It’s important to make sure that the latter are informed and empowered to support the child with diabetes.’ ‘We need to get the message out there when it comes to diabetes awareness’, she concludes. ‘I always encourage the people to whom I speak, to tell two other people. If each of these in turn tells two more, the multiplication effect of this will ensure that we succeed.’ ‘As a medical professional, it is a privilege to work daily with and serve men, woman and children, the pinnacle of God’s creation.’ Peter Wagenaar, Gauteng correspondent

Two diabetic children who, with help from Sr Beckert, have managed to control their diabetes.

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ADA WATCH

ADA WATCH SUMMARIES

2011 UPDATE FROM SAN DIEGO, USA American Diabetes Association Contributor: J Aalbers

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24–29 June 2011 48

EPIDEMIOLOGY African data still sparse on FPG trends and prevalence of diabetes: Lancet symposium at ADA An immense global investigation has been done on the changes in mean fasting plasma glucose (FPG) levels since 1980 and the prevalence of diabetes in adults, including data on 199 countries and territories. Data were obtained from surveys on health examinations and published epidemiological studies covering 370 countryyears and 2.7 million participants. Mean FPG and its uncertainty were calculated by age, country and year, according to the quality of data available. Sub-Saharan Africa was divided into four regions: Central, East, West and southern Africa (Botswana, Lesotho, Namibia, South Africa, Swaziland and Zimbabwe). The paucity of published data on Africa is shown in the map. Only four articles are cited for South Africa covering a sample size of 3 000 peoples (Levitt 1993, Mollentze 1995, Motala 2008, Omar 1993). No published data were found for Central Africa, although East and West Africa had more studies than southern Africa. The study developed a model, which was tested against countries with sufficient data (and withholding the data), comparing the predictive model with actual data. This modelling, according to the authors, did well and holds validity for countries/ regions with insufficient data. The bottom line is that incidences of glycaemia and diabetes are rising globally, driven by population growth and ageing, and by increasing age-specific prevalence. The mean FPG level in 2008 was lowest in sub-Saharan Africa (mainly estimated), east and south-east Asia, and high-income Asia-Pacific countries. The global age-standarised mean FPG levels in 2008 were 5.50 mmol/l for men and 5.42 mmol/l for women. The agestandarised adult diabetes prevalence was

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9.8% in men and 9.2% in women in 2008, up from 8.3 and 7.5%, respectively, in 1980.

A1chieve: type 2 diabetes study in rapidly growing, developing countries

Source: Danaei G, et al. National regional and global trends in fasting plasma glucose and diabetes prevalence since 1980. Lancet. Published online 25/6/2011:DOI: 10.1016/50140-6736(11)60679-X.

Baseline data on 66 726 people with type 2 diabetes across Asia, Africa, Europe and Latin America have shown that up to 80% of patients have complications, and HbA1c levels are poorly controlled. The average blood sugar level was 9.5% before initia-

TABLE OF CONTENTS EPIDEMIOLOGY African data still sparse on FPG trends and prevalence of diabetes: Lancet symposium at ADA�������������������������������������������������������������� 127 A1chieve: type 2 diabetes study in rapidly growing, developing countries����������������� 127 SOUTH AFRICAN CONTRIBUTIONS NAVIGATOR trial provides clinical setting predictors for type 2 diabetes, including black patients����������������������������������������������������� 128 CDE study sheds additional light on diabetic retinopathy risk in African patients���������������������� 128

PATHOPHYSIOLOGY OF TYPE 1 DIABETES Glycaemic control and incidence of heart failure in young type 1 diabetes patients������������� 129 PHARMACOLOGICAL TREATMENT OF DIABETES New ultra long-acting insulin: insulin degludec matches insulin glargine in both type 1 and type 2 diabetes patients, with less hypoglycaemia���������� 129 Insulin addition to GLP-1 receptor agonist (GLP-1RA) therapy in type 2 diabetes������������������ 129 Metformin still at core of first-line treatment for type 2 diabetes in focus on older patients�������������������������������������������������������������� 129

Identifying patients at high risk of sight-threatening diabetic retinopathy: the CDE database (2001–2009)�������������������������������� 128

Once-weekly exenatide shows continued benefits at 18 months in Duration-3 study���������� 130

TG/HDL-C ratio fails to identify insulin resistance in overweight black women worldwide���������������������������������������������������������� 128

Early intensive dietary intervention improves glycaemic control in type 2 diabetes�������������������� 130

Glucose uptake by myocytes more sensitive to fatty acids than adipocytes������������������������������ 128

Insulin glargine less effective in women?���������������� 130

Look Ahead Lifestyle trial: four-year data���������������� 130 Brief highlights from the oral poster sessions���������� 130

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tion of the study insulins in this prospective, multi-centre, open-label study of insulin analogues, run by Novo Nordisk. The A1chieve study is aimed at evaluating effectiveness and adverse events of premix (biphasic insulin) and mealtime (insulin aspart) insulin analogues in routine clinical-practice treatment of type 2 diabetes. In the baseline data, up to 75% of participants enlisted had cardiovascular disease. Up to 84% had other diabetic complications, such as kidney disease, retinopathy, foot ulcers and neuropathy. At the time of study entry, around 9% of patients had not received any glucose-lowering medication despite their HbA1c levels being above 10%. Those on oral antidiabetic medication had duration of diabetes of 5.9 years in South Asia and 10.4 years in Latin America. Despite their poor glucose control, they were not yet receiving insulin therapy. Prof Phillip Home, Professor of Diabetes Medicine in Newcastle, UK noted that this indicates the often-experienced delay of initiating insulin therapy. These baseline data from developing environments contrast with the UKPDS (49) study, which has shown that by six years’ duration of type 2 diabetes, 50% of patients should be on insulin therapy to keep HbA1c levels within the 7% target range. Source: A1CHIEVE study baseline data, ADA congress 2011.

SOUTH AFRICAN CONTRIBUTIONS NAVIGATOR trial provides clinical setting predictors for type 2 diabetes, including black patients The NAVIGATOR trial results of patients with impaired glucose tolerance (IGT) and cardiovascular disease (CVD) (or risk factors for CVD) were evaluated to determine hazard ratios for later development of type 2 diabetes (T2DM). In the NAVIGATOR study over a five-year period, 35% of patients developed type 2 diabetes. In this guided audio-tour poster, the only South African poster in this section, Dr Naomi Levitt and her co-workers’ contribution to this study is noted. Baseline data from the NAVIGATOR trial were used to develop a multivariate Cox proportional hazards model to estimate the risk of developing type 2 diabetes. Factors included were age, region, race, family history of T2DM, prior history of CVD, BMI,

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systolic blood pressure, and fasting glucose/ two-hour glucose, HbA1c and platelet/B haemoglobin levels. These factors provided better predictive value at the determined hazard ratio than other available international models such as the San Antonio Heart Study model and the FINRISK score. The value of the NAVIGATOR model is that it uses variables available in an everyday clinical setting and can be used globally to estimate future risk of type 2 diabetes in high-risk populations, including black/African communities. Source: Abstract No 1301 – poster. Estimating diabetes risk in patients with IGT and CVD or risk factors for CVD. ADA 2011 congress.

CDE study sheds additional light on diabetic retinopathy risk in African patients In this extensive database of 5 565 patients attending the CDE Centre in Johannesburg, who underwent diabetic retinopathy assessment using a Canon non-mydriate camera without mydriasis, the majority (70%) had no diabetic retinopathy. Those with diabetic retinopathy were more likely to be of non-white ethnicity (33.9 vs 26.3%), and hypertensives using ACE inhibitors, with fewer on aspirin. The presence of diabetic retinopathy was independently associated with increased duration of diabetes, non-white ethnicity [indigenous African 1.4 ocular risk compared to Caucasians (1), Asians (1.6) and mixed-race ancestry (3.3)]. This study emphasises the importance of the evaluation of diabetic retinopathy in vulnerable African, Asian and mixed-race patients in South Africa. Source: Abstract 2138 – poster. Chowdhury SR, Thomas RL, Distiller L, Brown V, Kramer BD, Luzio SD, Owens DR. ADA 2011 congress.

Identifying patients at high risk of sight-threatening diabetic retinopathy: the CDE database (2001–2009) Increased duration of diabetes, a higher HbA1c level at presentation to the centre and mixed-race ethnicity, were independently associated with the development of sight-threatening diabetic retinopathy (STDR). Over the eight-year period, 12% of the more than 5 000 patients developed background diabetic retinopathy, 1.2% developed STDR and only one subject developed proliferative diabetic retinopathy.

This centre ensures annual diabetic retinopathy screening as a standard feature of its diabetes care. In less well-resourced clinics, the identification of patients at higher risk of diabetic retinopathy can help to ensure that these vulnerable patients receive additional care, education, and efforts to improve diabetes control to reduce microvascular complications. Source: Abstract No 2134 – poster. Thomas RL, Chowdhury SR, Distiller LA, et al. Development of diabetic retinopathy in subjects attending a diabetes and endocrinology clinic in Johannesburg, South Africa.

TG/HDL-C ratio fails to identify insulin resistance in overweight black women worldwide In this interesting study of insulin resistance in overweight women of African descent from South Africa, West Africa (Jamaica) and America, the value of the triglyceride/ high-density lipoprotein cholesterol (TG/ HDL-C) ratio was assessed as a tool to identify insulin resistance. Contrasting the correlative value of this ratio in white South African women, the ratio was shown to be predictive in all women when the BMI was less than 25 kg/ m2. However when the BMI was above this level, the TG/HDL-C did not correlate with HOMA-IR in African women whether they were African-American, South African or West African. It did however still retain its ability to identify white women with insulin resistance, irrespective of their being overweight. There is a need to develop an alternative diagnostic tool that can be correlated with insulin resistance in overweight African women worldwide. Source: Abstract No 2501 – poster. Knight MG, Goedeke JH, Marshall K, et al. TG/HDL-C ratio fails to identify insulin resistance in overweight women of African descent worldwide.

Glucose uptake by myocytes more sensitive to fatty acids than adipocytes In a laboratory-based study from Stellenbosch University and the Faculty of Health Science, Natal, myocytes and adipocytes were exposed to fatty acids, and insulin-stimulated glucose metabolism was observed in these cell lines. The study showed that myocytes were especially sensitive to fatty acid exposure, particularly at higher glucose concentrations, and both glucose uptake

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and utilisation was reduced in these cells. The effect on the adipocyte was less evident. Source: Abstract 2552 – poster. Mazibuko SE, Muller CJF, Pheiffer C, Opoku A, Louw J. The in vitro effects of saturated and unsaturated fatty acids on insulin stimulated glucose metabolism of myocytes and adipocytes.

PATHOPHYSIOLOGY OF TYPE 1 DIABETES Glycaemic control and incidence of heart failure in young type 1 diabetes patients In patients with poor glucose control (HbA1c ≥ 10.5%), the risk of heart failure was four times higher than in patients with very good control (HbA1c < 6.5%). Risk of heart failure increased with age and duration of diabetes, and each 1% increase in HbA1c level resulted in a 30% higher risk of heart failure during follow up. This data comes from a Swedish registry of more than 20 000 patients with a mean age of 38.6 years. In the follow-up period of nine years, 3% of patients were admitted to hospital with a primary or secondary diagnosis of heart failure. This is the first cohort-based study determining the incidence of heart failure in type 1 diabetes patients only, although the UKPDS indicated a similar rate of heart failure (3%) in type 2 diabetes patients over 10 years. In comparison with Swedish figures for heart failure rates in male non-diabetics, the presence of poorly controlled type 1 diabetes leads to a similar event rate 20 years earlier (41–45 years) than in their non-diabetic counterparts. Patients 55 to 64 years of age have an event rate of 2.1 per 1 000 personyears. Source: Lancet/ADA Symposium and Lind M, et al. Glycaemic control and incidence of heart failure in 20 985 patients with type 1 diabetes: an observational study. Publish online. June 25 2011. DOI:10.1016/501406736(11)60471-6.

PHARMACOLOGICAL TREATMENT OF DIABETES New ultra long-acting insulin: insulin degludec matches insulin glargine in both type 1 and type 2 diabetes patients, with less hypoglycaemia1 A new insulin formulation, insulin degludec, under development by Novo Nordisk,

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lowers glucose levels with significantly less hypoglycaemia than insulin glargine. This study was a two-phase, 52-week clinical trial conducted first in type 1 diabetes patients, and second, in type 2 diabetes subjects. The studies were designed as treat-totarget studies, i.e. aiming to reach similar glycaemic targets with both insulin formats. Similar reductions in HbA1c levels were achieved with both insulins; 0.4% reduction in HbA1c in type 1 diabetes patients and 1.2% in type 2 diabetes subjects. In type 2 diabetes patients, there were significantly fewer hypoglycaemic events with insulin degludec compared to those given insulin glargine (11.1 vs 13.6 episodes/ patient year; p = 0.0359). Importantly, rates of nocturnal hypoglycaemia were much lower with insulin degludec compared to insulin glargine in both type 1 and 2 diabetes patients. A separate study presented in the latebreaking session2 showed the flexibility of usage of insulin degludec, which can be given at different times from day to day in patients with type 2 diabetes. Even when given at 40-hour intervals, overall glycaemic control was not affected nor did risk of hypoglycaemia increase. In this study of insulin degludec usage, the insulin was given once daily at greaterthan-daily intervals by alternating morning and evening injections from day to day. Reductions in HbA1c levels with this usage strategy were similar to those with insulin glargine. Sources: 1. Garber A. Insulin degludec improves long-term glycaemic control with less nocturnal hypoglycaemia compared with insulin glargine: 1-year results from randomised basal-bolus trial in patients with type 2 diabetes. NN 1250-3582. Heller S. Insulin degludec improves long-term glycaemic control with less nocturnal hypoglycaemia compared with insulin glargine: 1-year results from randomised basalbolus trial in patients with type 1 diabetes. NN 12503583. 2. Meneghini L. Flexible once daily dosing of insulin degludec does not compromise glycaemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes. NN 1250-3668.

Insulin addition to GLP-1 receptor agonist (GLP-1RA) therapy in type 2 diabetes There are very few data available on insulin therapy added to the therapy of patients with type 2 diabetes who are on GLP-1 receptor agonists and metformin; although there is a significant body of evidence

related to the value of GLP-1RAs added to insulin therapy in this condition. This study evaluated the efficacy and safety of liraglutide 1.8 mg added to metformin, followed by insulin detemir titrated from 10 mg/kg for those whose HbA1c level was still above 7%. After 12 weeks of treatment with liraglutide plus metformin, 61% of patients reached the target HbA1c level of less than 7%, and lost 4.4 kg of body weight. Continuing for a further 26 weeks, patients who received insulin detemir lowered their HbA1c levels by a further 0.5%. Those who remained on only liraglutide and metformin achieved stable HbA1c levels without further increase in this period of time. The addition of insulin increased the percentage of patients achieving an HbA1c level of less than 7%, from 17 to 43%; more than doubling those who reached targeted glucose control. Of interest to clinicians is that patients maintained their weight loss despite the addition of insulin detemir. Source: Abstract No 0276 – oral presentation. Rosenstock J, de Vreis JH, Seufert J, et al. Pharmacological treatment of diabetes. A new type 2 diabetes treatment paradigm: Sequential addition of liraglutide to metformin and then insulin detemir.

Metformin still at core of first-line treatment for type 2 diabetes in focus on older patients Sulfonylurea (SU) therapies have been associated with the potential for increased risk of cardiovascular disease (CVD), but remain a commonly used antihyperglycaemic medication, particularly in the elderly. This retrospective cohort study examined the potential association between initial monotherapy with SU or metformin (MET) and subsequent CVD in older patients with T2DM. A cohort of patients who were ≥ 65 years old with T2DM, and had received their first prescription of SU or MET monotherapy between 2003 and 2007 and remained on it for at least 90 days, were selected from the electronic medical record database. Patients also had to have had no antihyperglycaemic treatment and CVD events [ischaemic heart disease (IHD), myocardial infarction, stroke, transient ischaemic attack and peripheral arterial disease] within the prior year (baseline) and also have had at least two years of follow up after the first treatment.

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Logistic regression evaluated the likelihood of having a CVD event. Cox regression estimated time to first CVD event. Differences in baseline characteristics (demographics, clinical and laboratory measures, and co-morbidities) were controlled for using propensity score matching (PSM). Overall, 8 502 patients were included, with 4 251 per group. Mean age was 75 years and 49% were males. While controlling for differences in baseline characteristics using PSM, patients who initiated with SU had a significantly higher (p < 0.001) incidence of CVD events (12.4%) compared to those initiated with MET after two years of follow up. The difference was mainly driven by the increased incidence of IHD with SU (7.2%) compared to MET (5.5%) (p = 0.002). The likelihood of having a CVD event was higher in patients initiated with SU than with MET (95% CI = 1.08–1.41; p = 0.002). SU use was also associated with shorter time to first CVD event compared to MET (95% CI = 1.03–1.28; p = 0.004) Source: Abstract 0038 – oral presentation. Fu AZ, Qiu Y, Davies MJ, Engel SS. Risk of cardiovascular disease associated with sulfonylurea or metformin use in older patients with type 2 diabetes.

Once-weekly exenatide shows continued benefits at 18 months in Duration-3 study Type 2 diabetes patients treated with onceweekly exenatide continued to experience improved glycaemic control, sustained weight loss and fewer hypoglycaemic events than patients treated with glargine. This benefit was seen when exenatide or glargine was added to metformin monotherapy treatment or to therapy with metformin and suphonylurea. Importantly, discontinuations did not differ between patients receiving exenatide or glargine, although diarrhoea, nausea and vomiting, and injection site nodules occurred more frequently with exenatide treatment. In this period, to maintain HbA1c levels below 7%, insulin glargine dosage increased from 31.1 (SE 1.4) IU at 26 weeks to 34.8 IU at 84 weeks. Between-therapy benefit of 4.5- to 5-kg weight loss was seen with exenatide compared to glargine. Overall incidence of minor hypoglycaemic events was significantly less in the exenatide group compared to glargine,

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regardless of whether the patient was on monotherapy with metformin or metformin plus sulphonylurea therapy. Source: Abstract 0277 – oral presentation. Diamant M, Van Gaal L, Stranks S, Guerci B, Macconell L, Trautmann M. Duration-3: Efficacy of exenatide once weekly (EOW) and insulin glargine QD (IG) after 84 weeks in patients with type 2 diabetes (T2D).

Insulin glargine less effective in women? A pooled evaluation of nine clinical trials assessed the impact of gender on HbA1c levels, insulin dose and incidence of hypoglycaemia in type 2 diabetes patients treated with insulin glargine compared to other oral-therapy antidiabetic agents and other insulins (NPH, Premix, Lispro) and diet. While insulin glargine produced greater mean HbA1c reductions at week 24 versus competitors, women had smaller reductions in HbA1c levels and were less likely to reach glycaemic goals despite higher insulin doses and greater frequency of hypoglycaemic events. Source: Abstract 2264 – publish only. McGill JB, Vlajnic A, Knutsen PG, Recklein C, Rimler MS, Fisher SJ. Effect of gender outcomes in patients with T2D treated with insulin glargine vs competitors.

Early intensive dietary intervention improves glycaemic control in type 2 diabetes Early intensive dietary intervention with a dietary consultation and follow up every six months improves glycaemic control, while the addition of promotion of physical activity did not achieve any further benefit. The Early Activity in Diabetes (Early ACTD) trial set out to investigate whether increased physical activity would have effects on glycaemia over and above the dietary intervention. The study included some 600 patients, and a control group receiving usual care consisted of 100 patients. Over the 12-month period, glycaemic control worsened in the standard-care group, while HbA1c levels improved in the diet group and the diet-plus-activity group. There was less use of antidiabetic drugs and an improvement in body weight and insulin resistance in the intervention groups. Blood pressure was similar across all three groups. Source: Andrew RC, et al. Lancet symposium and ADA and published in the Lancet, online – DOI:10.1016/ S0140-6736(11) 60442-X.

Look Ahead Lifestyle trial: four-year data Look Ahead, a 13-year trial in the USA of overweight and obese patients with type 2 diabetes, has shown at year four that the intensive lifestyle-intervention group was not able to sustain the benefits achieved at the end of the first year. However, there was some good news in the severely obese group who initially lost 9% of their body weight, but were able at year four to still show a 5% weight loss. This weight gain was similar to that seen in the less obese patients. This trial has enrolled 5 000 patients and is funded by the National Institute of Health. Eight-year data is currently being collected. Severely obese patients are normally excluded from type 2 diabetes trials, so these data are important and offer a useful alternative to bariatric surgery. Importantly, the trial showed a 10% or greater weight loss at four years, and nearly 50% of those who lost 10% at year one sustained this weight loss to the end of year four. A significant number of patients (11%) also achieved complete reversal of their diabetes and were able to stop taking medication at year four (8%). This compares to only 3% in the standard-intervention group. Source: Look Ahead Symposium. ADA 2011.

Brief highlights from the oral poster sessions • Major depression independently predicted increased mortality from macrovascular events in the ACCORD trial [Abstract 0048-OR]. • HbA1c level misclassifies patients in a Veterans Administration study of mainly black (male) patients [Abstract 0042-OR]. • Resting energy expenditure is suppressed equally by large weight loss compared to bariatric surgery [Abstract 0055-OR]. • Diet soft drinks are not free of consequences and frequent use of these drinks is associated with increased weight circumference and visceral obesity [Abstract 0062-OR]. • Basal insulin treatment immediately following renal transplantation effectively prevents new-onset diabetes by providing beta-cell rest [Abstract 0072-OR]. • Elevated uric acid level may still be shown to be an important therapeutic

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target in order to reduce complications of type 1 diabetes [Abstract 0080-OR]. • Higher vitamin D status is associated with a lower risk of diabetes in the Diabetes Prevention Program (DPP) [Abstract 0117-OR]. • Lifestyle changes and metformin therapy reduce the biomarkers of inflammation, endothelial function and coagulation but these effects are influenced by age, gender and ethnicity [Abstract 0119-OR]. • Flaxseed, a good source of omega-3 fatty acids and viscous fibre, decreases glucose and improves glycaemic control

ADA WATCH

in individuals with pre-diabetes, according to a randomised, controlled study [Abstract 0122-OR]. • The Diabetes Prevention Trial – Type 1 Risk Score (DPTRS) is useful for identifying normoglycaemic children at high risk of developing type 1 diabetes [Abstract 0158-OR]. • Diffusion tensor imaging (DTI) has shown changes in the structure of the white matter of the brain in young children with type 1 diabetes [Abstract 0162-OR]. • Fenofibrate-induced impairment in renal function seen in the ACCORD trial of

type 2 diabetes patients is reversible after 50 days off the drug [Abstract 0368-OR]. • Analysis of the five-year data from the ACCORD trial shows that exposure to any insulin was not associated with increased risk of cancer-related outcomes. This is hypothesis-generating data [Abstract 0365-OR]. • Higher baseline 25(OH)D vitamin D independently predicted better betacell function and lower area-under-thecurve (AUC) glucose in patients at higher risk of developing diabetes [Abstract 0325-OR].

Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. PO Box 783155, Sandton, 2146. Tel: (011) 202 0500 Fax: (011) 807 7989 NN/DUO/4145/07/10/VER1

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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 速 (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


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CDE WATCH

CDE WATCH SUMMARIES

2011 UPDATE FROM THE CENTRES FOR DIABETES EXCELLENCE 22–24 July 2011

CDE annual meeting Contributor: J Aalbers

This annual meeting, the 13th CDE postgraduate forum, was held in East London and attended by about 400 delegates representing CDE centres around the country. In his comments, Prof Pankaj Joshi, chairing the first academic session noted the need for the CDE branches to extend their expertise to other healthcare professionals, clinics and patients outside the CDE. ‘The majority of patients with diabetes in South Africa are being treated outside the CDE network. We, as CDE, must think about outreach programmes to clinics in rural areas and engage with these communities to assist with the local health crisis in obesity and diabetes’, he said.

Evidence-based approaches in diabetes care We must remember the ‘grey’ between the black and white of evidence-based medicine when we treat individual patients Dr Paula Diab, Diabetologist, Johannesburg

First symposium on injection technique held in South Africa Sponsored by Lilly and BD Medical’s Diabetes Care Division, this workshop was led by Dr Anders Frid, head of the Endocrinology Clinic, Skane University Hospital, Malmo, Sweden. He presented a global view of injection techniques, based on research from 27 countries and their experts in the TITAN initiative (third Injection Technique workshop, 2009), which updated data from 10 years earlier (both BD-sponsored studies). Using CT scans and MRIs showing insulin distribution following injection, important trends in good clinical practice are emerging. Aspects of significance are:

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• There is a trend to shorter needles all over the world and the 12.5-mm needle could become obsolete, as there is no real medical reason for its use. • Skin thickness is the same in all patients and varies only between 1.5 and 3 mm regardless of the gender, age, body weight or race of the individual. • If you pinch the skin fold, you can always provide a good site for injection at a 90° angle to the surface of the skin fold. • Lipodystrophy has not decreased in incidence over the past 10 years and ongoing patient education is required, despite the broad-based improvement in needles and pens. • One in five patients forget the advice given by the nurse educator/sister when initiating insulin therapy, so do include regular reminders in your patients’ education support programmes. • Intramuscular injection of long-acting analogues must be avoided due to the risk of severe hypoglycaemia. • For rapid-acting analogues, injection into fat tissue is preferable but not

essential as absorption rates are similar from fat tissue and resting muscle. • Intramuscular injection of NPH should be avoided since rapid absorption and serious hypoglycaemia can result. • Premixed insulins – regular/NPH mix – should be given in the abdomen to increase speed of absorption of short-acting insulin. Any mix of NPH should be given in the thigh/buttock in the evening as this leads to slower absorption and lower risk of nocturnal hypoglycaemia. • Site rotation is vital and nurse-led inspection is the best way of identifying poor injection techniques. Remember, bariatric surgery offers remission, not cure – the underlying β-cell dysfunction remains Dr Laura Blacking, Johannesburg Additional reading: New injection recommendations for patients with diabetes. Diabetes Metab 2010; 36(2): S1–S29.

TABLE OF CONTENTS First symposium on injection technique held in South Africa............................................................... 133 Treating the untreatable type 2 patient................................................................................................. 134 Sanofi-Aventis recognises excellence in clinical care at CDE centres in South Africa.......................... 134 Metformin – discovered, lost and rediscovered..................................................................................... 134 Haemochromatosis and diabetes............................................................................................................ 135 Fear and diabetes..................................................................................................................................... 135 The changing gut microbiome: is it killing us?...................................................................................... 135

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Treating the untreatable type 2 patient Dr L Distiller, CDE Houghton and honorary visiting professor, University of Cardiff School of Medicine A small sub-group of type 2 diabetes patients are severely insulin resistant. Severe insulin resistance is defined as an insulin requirement of more than 200 units per 24 hours for more than two consecutive days (or alternatively, a dose of > 3 U (2U)/kg body weight). There are many causes of this syndrome, including severe infection or steroid use; endocrinopathies such as Cushingâ&#x20AC;&#x2122;s, Werner and HAIR-AN syndromes; genetic defects of the insulin receptor gene (type A syndrome, lephrechaunism, Rabson-Mendenhall syndrome); and insulin receptor antibodies. However, these are all rare. For practical purposes, in the majority of these patients, severe insulin resistance is associated with obesity and type 2 diabetes. Once the obvious causes of high insulin usage have been excluded, such as lifestyle issues, poor injection technique, and not using the prescribed insulin dosages, these patients present with a very difficult treatment conundrum. Most of these patients have inadequate glycaemic control despite massive doses of insulin. Providing adequate

amounts of insulin can be logistically difficult because of the large volumes needed per injection. This often results in injection site problems. In addition, the absorption rate of insulin is reduced with high-volume doses. Theoretically, several options are available in the treatment of these patients. While the majority of them will already be on metformin, the addition of another insulin sensitiser such as pioglitazone could be considered. However, this may result in only a marginal reduction in insulin dose and may promote further weight gain. The addition of a DPP-4 inhibitor has also been suggested. While this might cause a reduction in HbA1c levels by up to 0.8% and have no effect on weight, the effect on insulin doses is minimal. Although GLP-1 agonists are not registered for use with insulin, there is evidence that their use may not only result in some weight reduction, but also in a reduction in insulin dosage of up to 10%. However, no studies have been undertaken in the severely insulin resistant and neither the weight reduction not the reduction in insulin dosage seems to be sustained for more than a year. Bariatric surgery may be a therapeutic option for the obese, severely insulin-resistant patient. Although there is some anecdotal evidence for this form of therapy in these patients, no studies have been undertaken.

Sanofi-Aventis recognises excellence in clinical care at CDE centres in South Africa The Sanofi-Aventis Insuman award went to Dr Bruno Pauly.

There is a need for a study of bariatric surgery for the morbidly obese in South Africa Dr Ray Moore, Durban Overall, the most effective way of treating these patients appears to be with the use of highly concentrated insulin in the form of U-500 regular human insulin. Using this formulation will result in much smaller volumes per injection, less dayto-day variation in absorption and less absorption variation from different injection sites than with U-100 regular or NPH insulin. More importantly, the peak and duration of action of U-500 approaches that of human NPH insulin. It can therefore often be used as a twice-daily injection. While no prospective studies have been done to confirm the efficacy of this approach, a number of small retrospective analyses of the use of U-500 insulin in the severely insulin-resistant patient have been reported, with extremely good results. In conclusion, the use of U-500 regular insulin is probably the safest and most conservative option for the treatment of these patients. Bariatric surgery may be considered as an alternative provided the patient is fit enough, wants this option and can afford it, bearing in mind that there are no outcomes studies in the severely insulinresistant patient. The efficacy/role of a GLP-1 analogue added to insulin in severely insulin-resistant patients has not yet been adequately evaluated, but the combination of U-500 insulin and a GLP-1 analogue may prove to be the best approach. These patients with severe insulin resistance are being missed during the stepped-up care of diabetes. This may well be an opportunity for early exenatide use Dr Adri Kok

The Sanofi-Aventis award for the centre with the best glycaemic control, and comprising sponsorship to the 2012 ADA meeting in Philadelphia, went to Dr Jacques van Staden from George.

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Metformin â&#x20AC;&#x201C; discovered, lost and rediscovered Dr Gregory Hough, Port Elizabeth

The Sanofi-Aventis award for good clinical practice, and comprising sponsorship to the 2012 ADA meeting in Philadelphia, went to Dr Louis Minders from the Bluff, Durban.

In a challenging talk on metformin, Dr Hough noted its discovery in the 1920s, its loss to diabetes as the newly discovered insulin took front stage, its resurrection in 1958 in the UK, and its approval for use in type 2 diabetes in the United States in 1994.

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Metformin’s discovery predated an understanding of how it works. Its primary mechanism of action is now known to be related to its actions at a mitochondrial level through activation of protein kinases. An important practical aspect to remember is metformin’s slow onset of action, with maximum effects taking two weeks. ‘Also, if you care about your patient’s well-being, use only the extended-release formulation of metformin’. Metformin is not a first-line therapy in polycystic ovarian syndrome (PCOS), Dr Hough believes. ‘In the 113 randomised clinical trials of metformin used in this condition, very little evidence emerged to support its use in endometrial protection. In my view, it is a useful second-line therapy when other treatments to achieve pregnancy are not tolerated or are not wanted by the patient. Its use in patients with POS who are dysglycaemic and diabetic is warranted in the interests of improving glycaemic control’, Dr Hough said. There is a significant lower risk of cancer mortality in patients receiving metformin Dr Gregory Hough

Haemochromatosis and diabetes Prof Peter Jacobs and Lucille Wood, Cape Town Familial haemochromatosis associated with diabetes, cirrhosis, joint pathology and porphyria represent diverse genetically determined syndromes requiring specialist haemotologist evaluation and management. Once thought of as a single entity and treated by venesection until plasma ferritin levels are at the lower limit of normal, current understanding of the molecular pathophysiology has elucidated aspects of this approach. In suspected cases of iron accumulation, once secondary causes such as acute inflammation have been excluded, genetic testing is needed, with interventions based

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CDE WATCH

on the precise mutations present. Liverfunction and ferritin tests, radiological imaging with liver biopsy, and response to therapeutic phlebotomy underpin clinical decision-making. While venesection is central to avoiding the late complications that range from diabetes to cardiovascular disease, the process cannot be arbitrary, as evidence is emerging that as stores are depleted, there is activation of the regulatory pathways and enhanced iron absorption, resulting in increasing need for phlebotomy. In this situation, hepcidin levels provide a better measure of when to stop red cell removal than plasma ferritin levels. ‘Aside from a specialist endocrinologist, the cardiologist and rheumatologist should also be involved in the care of these patients’, Dr Jacobs concluded.

is frequently due to anxiety/fear. 3. RE-FOCUS: our brains are wired to overattend to disaster. Refocus on what has been achieved. 4. RE-ENGAGE: engage with patients about their upside, their achievements, and desires of their life. 5. RE-FRAME: emphasise the solutions to problems by cognitive reflection not emotional introspection on the problem itself. Obesity is a systemic inflammatory disorder Dr David Segal, CDE Johannesburg and Witwatersrand

The changing gut microbiome: is it killing us? Dr David Segal, Johannesburg

Fear and diabetes Dr Rayan S Pillay, Dot Shuttleworth Centre, Durban Dr Pillay was a representative of the Cardiff graduates who dedicated this lecture to the late Dr Majopela Mhlakaza, a fellow student. ‘Fear is the static that prevents me from hearing myself’ – Samuel Butler Fear is a factor that may well interfere with patients’ retention of information about their diabetes. Using research that focuses on assessing increased blood flow, and evaluated by sophisticated imaging techniques, the role of the amygdala nuclei has emerged as the guard dog for fear in the human brain. ‘Unconscious fear exists in our patients and we need to re-regulate their anxiety levels’, Dr Pillay noted. We can do this by a simple process of interaction with our patients, aimed at increasing their feeling of being SAFER. 1. Use the technique of RE-SOLVE: focus on what we can control about the disease, not on what we cannot control. 2. RE-ASSESS: continually emphasise the positive, as the patient’s inattentiveness

In a journey to examine childhood obesity differently and in the context of the increase in both type 1 and type 2 diabetes, Dr David Segal, paediatric endocrinologist with academic commitments at Wits University Medical Faculty and also in private practice at CDE, Parktown, explored the available medical literature and interpreted new data to provide concepts for clinical intervention. He targeted two main features of modern obesity. The first is neuro-economics or the cost–benefit of obtaining food. Secondly, he noted the consequences of increased fat and carbohydrate intake, which are challenging the β-cell and altering the gut microbiota so that food transition and absorption is modified. ‘While genetic studies have added to our knowledge of the gene control of appetite, satiety and feedback mechanisms, they have failed to give us a practical option to control obesity’, he said. The field of neuro-economics applied to food calculates the price-cost in energy expended, and the risk and effort to procure the food that we eat, and relates it to demand, which is ever present as appetite, and supply, which in urban areas is plentiful at the nearest supermarket.

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Diabetes News Winners of the CDE awards for 2011

A

nnually, the CDE congress, together with leading pharmaceutical companies, acknowledge those specialists who excel in their different categories with the Clinical Excellence Awards. The South African Journal of Diabetes and Vascular Disease congratulates the winners and we feature a few of them, with some of the activities.

Sr Maureen Barnard from George won the Lifescan Annual Travel Award for the diabetes educator showing the best personal and professional development and growth during the past year. The prize is either a travel grant towards an international diabetes-related congress to the value R 30 000 or full sponsorship for the Glamorgan Diploma. She did not attend, and colleague Dr Jacques van Staden accepted it on her behalf from JosĂŠ da Fonseca, product manager of HCP, LifeScan.

Sr Belinda Nortje won the Novo Nordisk Award for the top diabetes educator, which consists of sponsorship to the 2012 FEND meeting and a floating trophy. She accepted her award from David Broomfield, head of Marketing, Novo Nordisk.

Dr Betsie Kloppers from Hatfield, Pretoria won the Novo Nordisk Award for the best CDE centre. The prize is sponsorship to the 2012 EASD meeting in Berlin and a floating trophy.

Bayer captivated the doctors with their African stand as the CDE was held on Africa day.

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JOURNAL UPDATE

Journal Update

Cardiovascular protection in African patients, from the world literature Hypertension: a risk factor in vascular surgery The aim of this study was to determine risk factors associated with intermediate and long-term mortality in South African vascular surgical patients. Two risk factors identified in the South African National Burden of Disease study were associated with mortality: a ‘western lifestyle’ and the presence of associated risk factors such as hypertension and diabetes. This is in contrast to European and American populations where hypertension and diabetes are not important risk factors. In this study, hypertension was the only predictor of intermediate and long-term survival following vascular surgery in the South African setting. A cohort of 283 vascular surgical patients over the age of 39 years, admitted for both elective and emergency vascular surgery at Inkosi Albert Luthuli Central Hospital, were included in this study. All patients survived the surgical procedure and were discharged from hospital. Subsequent hospital clinic visits or hospital admissions were identified; and for those patients not returning, contact was made with the patient and/or next of kin. Demographic data associated with perioperative cardiac risk, as well as intra-hospital and all-cause mortality were extracted for all patients. Data collection on clinical risk factors included: history of ischaemic heart disease, history of congestive heart failure, diabetes, serum creatinine > 180 μmol/l, history of cerebrovascular accident, age, gender, history of smoking, and history of hypertension. Determination of predictors of intermediate and long-term survival are important, as these may identify patients who require further aggressive risk-factor modification, therapy and increased surveillance postoperatively. The prevalence of clinical risk predictors in South African vascular patients was similar to or higher than those reported in European vascular patients. In contrast to developed-world observations, peri-operative clinical risk indices were not associated with intermediate and long-term survival in South African vascular surgical patients. Hypertension was the only predictor of intermediate and long-term survival. It appears that traditional public health

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issues are more predictive of mortality for South African vascular surgical patients. Source: Biccard BM, Nepaul S. Risk factors associated with intermediate and long-term mortality following vascular surgery in South African patients. Cardiovasc J Afr 2010; 21(5): 263–267. PubMed PMID: 20972514.

A hidden burden of sub-clinical heart disease in obese urban African females This study seeks to quantify the burden of clinically overt and sub-clinical heart disease and cardiovascular risk factors relative to other conditions in urban Africans seeking primary healthcare. Considering the large pool of hypertensives and latent diabetics in the Soweto population, the identification of atrisk patients is being overlooked in the primary-care model. Risk factor profiling and referral for advanced investigation reveal a hidden burden of sub-clinical heart disease; the vulnerable patient being the African female, obese, with hypertension and latent diabetes. Data were collected on 1 311 consecutive patients attending two primary-care clinics in Soweto over a six-month period. A standardised programme of participant assessment included: self-reported cultural and socio-demographic profiling, risk factor profiling (family history of diabetes and heart disease, smoking, random blood glucose levels) and anthropometric profiles. Clinical assessment encompassed average seated systolic and diastolic blood pressure, heart rate and a physical examination for signs and symptoms of potential heart disease. A 12-lead ECG was performed. Prior and current diagnoses and pharmacological therapy for prevention or treatment of cardiovascular disease were recorded. The contribution of diagnosed forms of heart disease on case burden was small, at fewer than one in 100 patients (even though one in three were hypertensive). When suspicious cases were deferred for more definitive assessment, the case burden rose to three in 100 patients. Cardiovascular disease was evident in 4.9% of cases, in which gender bias for risk factors was evident. Females were more likely to have a history of hypertension, be obese and display symptoms suggestive of heart disease. Males were more likely to

smoke and exhibit higher blood pressure in hypertension. The prevalence of diagnosed type 2 diabetes was relatively low at 3.4%; however, 9.8% of patients had random blood glucose levels > 7.0 mmol/l, placing them at risk of metabolic disorders. Obese women were 2.0-fold more likely to record high blood glucose and systolic blood pressure than obese males. Males were 2.6-fold more likely to have an ECG abnormality than females. African women with high levels of obesity, hypertension and potentially latent diabetes were found to be particularly vulnerable to heart disease. This study highlights the central importance of assessment of cardiovascular risk and the implementation of proactive prevention and treatment campaigns to reduce non-communicable forms of disease in urban areas. Enhanced primary-care prevention may truncate the potential epidemic of heart disease related to hypertension and metabolic disorders. Source: Stewart S, Carrington MJ, Pretorius S, Ogah OS, Blauwet L, Antras-Ferry J, Sliwa K. Elevated risk factors but low burden of heart disease in urban African primary care patients: A fundamental role for primary prevention. Int J Cardiol 2011, Feb 23. [Epub ahead of print] PubMed PMID: 21353319.

Legacy of foetal and infant undernutrition in Nigerian adults: increased hypertension and impaired glucose tolerance A growing body of evidence suggests that increased susceptibility to chronic diseases in adulthood has a developmental basis originating in foetal life. Epidemiological studies from high-income countries have linked under-nutrition in foetal life with increased burden of non-communicable diseases in later life. This study examined the risks for hypertension, glucose intolerance and overweight 40 years after foetal exposure to famine during the Nigerian civil war (1967–1970) and found that adults exposed to foetal–infant famine are at greater risk of hypertension and impaired glucose tolerance/diabetes, contributing to cardiovascular disease. This observational study was based on the findings from a cohort of 1 339 ethnic Igbo, born before, during and after the Biafran famine. Participant selection was restricted

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to men and non-pregnant women who knew they were born in the south-east of Nigeria between 1965 and 1973. Data collected included socio-demographic status, current smoking, previously diagnosed hypertension or diabetes mellitus and treatment for these conditions. Measurements of blood pressure and plasma glucose were obtained. Results showed higher blood pressure, higher plasma glucose and higher weight in middle-aged people exposed to severe undernutrition in utero and in infancy. Comparing unexposed offspring with those of pregnant, starving women, foetal–infant undernutrition was associated with significant increases in the prevalence of hypertension (9.5 vs 24%) and impaired glucose tolerance or diabetes (8.0 vs 13%). Famine in early childhood was also associated with increased hypertension (16%). These results are in line with previous studies, suggesting that foetal under-nutrition contributes significantly to cardiovascular disease risk in adult life. Accelerated growth in later childhood and a high BMI in adult life have previously been found to have a strong adverse effect on hypertension and diabetes in people who were small birth-weight babies. The findings in this study of a higher-than-normal current weight, waist circumference and BMI in adults exposed to foetal–infant famine imply that accelerated growth in later childhood may be on the pathway between early under-nutrition and the metabolic syndrome in later life. Prevention of foetal and infant undernutrition could make a significant contribution to reducing the increased prevalence of hypertension and glucose intolerance in sub-Saharan Africa. This should be given high priority in national health agendas. Given that the highest risk of hypertension is in those undernourished in early life and then becoming overweight, it is important to consider that preventing excess growth in later childhood may be equally important for reducing adult ill health. Source: Hult M, Tornhammar P, Ueda P, Chima C, Bonamy AK, Ozumba B, Norman M. Hypertension, diabetes and overweight: looming legacies of the Biafran famine. PLoS One 2010; 5(10): e13582. PubMed PMID: 21042579; PubMed Central PMCID: PMC2962634.

The link between alcohol consumption patterns and non-communicable disease There is a strong link between alcohol consumption and non-communicable disease (NCD), particularly cancer, cardiovascular

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disease, liver disease, pancreatitis and diabetes. This narrative article summarises the relationships between different patterns of alcohol consumption on NCD outcomes, and estimates the overall impact of alcohol consumption on global mortality and burden of disease, with special emphasis on low- to middle-income countries. Alcohol is overwhelmingly detrimentally related to many cardiovascular outcomes including hypertension, haemorrhagic stroke and atrial fibrillation. For ischaemic heart disease and ischaemic stroke, the relationship is more complex. Chronic, heavy alcohol use has been uniformly associated with adverse cardiovascular outcomes, consistent with the physiological mechanisms of increased clotting and a reduced threshold for ventricular fibrillations which occur following heavy drinking. For light to moderate drinking there is a protective effect on ischaemic diseases, which disappears when this drinking style contains irregular heavy drinking occasions. The relationship between alcohol use and diabetes is again more complex. There is a U-shaped relationship between the average amount of alcohol consumed per day and the risk of type 2 diabetes. There appears to be a protective effect of moderate alcohol consumption on diabetes, particularly among women. Given the overwhelming evidence that alcohol is a major risk factor for NCDs, attention should be directed towards addressing the drivers of alcohol use, particularly those operating at a social and environmental level. Special attention should be directed at reducing the occurrence of episodes of heavy drinking. Source: Parry C, Patra J, Rehm J. Alcohol consumption and non-communicable diseases: epidemiology and policy implications. Addiction 2011 Aug 5. DOI: 10.1111/j.1360-0443.2011.03605.x. [Epub ahead of print] PubMed PMID: 21819471.

Delayed complementary food introduction in infants associated with lower adult adiposity Studies from high-income settings are suggestive of lower blood pressure and a lower risk of type 2 diabetes in children and adults who were breastfed for a longer duration in infancy. This study tested the hypothesis that longer duration of breastfeeding and later introduction of complementary foods in infancy are associated with reduced adult cardiovascular risk. There was no evidence that initial breastfeeding or longer duration of breastfeeding

was protective against adult hypertension, diabetes or overweight/adiposity in the lowor middle-income populations comprising this study. Data from 10 912 subjects from five lowand middle-income country (including South Africa) birth cohort studies were examined for associations between infant feeding and adult blood pressure, plasma glucose concentration and adiposity. Adjustments were made for maternal socio-economic status, education, age, smoking, race, urban/rural residence and infant birth weight. No differences in outcomes were found in adults who had been breastfed opposed to those that had never been breastfed. Duration of breastfeeding was not associated with prevalence of adult diabetes or adiposity. Weak and inconsistent U-shaped associations were found between duration of breastfeeding and systolic blood pressure and hypertension. Later introduction of complementary foods was associated with a small reduction in adult adiposity, displaying lower adult BMI, waist circumference and percentage body fat; as well as thinner skin folds. There are many proven benefits of breastfeeding, but the evidence that it reduces the risk of adult chronic disease is not compelling. Delaying complementary food introduction until six months of age, as recommended by the World Health Organisation, may reduce the risk of adult overweight/adiposity, but the effect is likely to be small. Source: Fall CH, Borja JB, Osmond C, Richter L, Bhargava SK, Martorell R, et al; COHORTS group. Infant-feeding patterns and cardiovascular risk factors in young adulthood: data from five cohorts in low- and middle-income countries. Int J Epidemiol 2011; 40(1): 47–62. Epub 2010 Sep 17. PubMed PMID: 20852257; PubMed Central PMCID: PMC3043278.

Inhibition of DPP4 in pre-diabetic rats is cardioprotective; results in improved metabolic control Cardiovascular risk is closely associated with insulin resistance and type 2 diabetes. Therapy based on the actions of GLP-1 is currently seen as a novel approach to treating cardiovascular disease. The question of whether pre-treatment of obese, insulin-resistant, pre-diabetic rats with a DPP4 (dipeptidyl peptidase IV) inhibitor could protect the heart from ischaemia/reperfusion injury, and the possible mechanisms involved in such protection are examined in this study. The secretion of the incretin hormone GLP-1 is impaired in type 2 diabetes patients. The enzyme DPP4, situated on the endothe-

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lial lining of vasculature, regulates GLP-1 levels. Treatment with GLP-1 is effective in lowering blood glucose levels, is cardioprotective in type 2 diabetes patients, and possibly reduces cardiovascular risk when used in these patients. DPP4 inhibitors increase circulating levels of GLP-1 in animal models and may also have beneficial effects on pancreatic beta-cell regeneration. Obese, pre-diabetic rats were treated for four weeks with 10 mg/kg/day of a DPP4 inhibitor PFK275-055. Ex vivo perfusion was used to subject the hearts to ischaemia/reperfusion to determine infarct size, functional recovery and post-ischaemic activation of proteins associated with cardiac protection. Adult ventricular cardiomyocytes were isolated to determine insulin sensitivity. Other assessments included body weight, intra-peritoneal fat weight, and insulin and GLP-1 levels. Histological examination of the pancreas was also performed. Results indicated that treatment of obese, pre-diabetic rats with a DPP4 inhibitor for a period of four weeks normalised GLP-1 levels, improved beta-cell to alpha-cell ratios of the pancreas, lowered plasma insulin levels over time and protected the heart against ischaemia/reperfusion injury. This was evident from the smaller infarct development after a period of regional ischaemia followed by reperfusion. Source: Huisamen B, Genis A, Marais E, Lochner A. Pretreatment with a DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic rats. Cardiovasc Drugs Ther 2011; 25(1): 13–20. PubMed PMID: 21088878.

JOURNAL UPDATE

Non-communicable diseases in sub-Saharan Africa Current disease projections for sub-Saharan Africa (SSA) indicate increases in NCDs caused by demographic and epidemiological transitions, although estimates are based on sparse data. Drivers of these epidemics are urbanisation and changes in lifestyle, associated with economic development, including changes in diet, physical activity, smoking, adiposity and alcohol use. This literature review and data summary examines the prevalence and incidence of cardiovascular diseases, type 2 diabetes mellitus and cancer, and their risk factors in SSA. These were found to vary considerably between countries, urban/rural location and other sub-populations. Hypertension, smoking and obesity were the most frequently reported risk factors, although alcohol use, hypercholesterolaemia and sedentary behaviour were infrequently measured. Global burden of disease studies suggest that the age-standardised death rates from NCDs are higher in at least four SSA countries (DRC, Nigeria, Ethiopia and South Africa) than in high-income countries. Cardiac diseases and their risk factors are increasing in SSA, with ischaemic heart disease the leading cause of death among men (second among women)³ ≥ 60 years of age. The most important risk factors for nonfatal myocardial infarction were diabetes, hypertension, abdominal obesity, smoking and abnormal blood lipids. Higher income, education, urban living and psychosocial

stress each appear to be associated with increased risk of myocardial infarction. Hypertension is the most important predictor of stroke in SSA, with the prevalence of hypertension consistently higher in urban areas. The prevalence of diabetes mellitus ranged from 0 to 16%, however some rural screening programmes found that up to 85% of cases were undiagnosed. Complications of poorly treated diabetes are common, with a high prevalence of retinopathy, nephropathy, neuropathy, diabetic foot and advanced peripheral organ damage. Diabetic morbidity and mortality in SSA are attributed to late diagnosis, severe vascular complications and generally poor blood glucose control. Irregular meals among poor populations contribute to frequent hypo- and hyperglycaemic episodes. Urgent action is required to mitigate the burgeoning epidemic of NCDs in Africa. Ongoing inadequate resources for treatment highlight the role of primary prevention in protecting public health, as late diagnosis leads to poorer health outcomes. Increased diagnoses of NCDs would lead to a corresponding need for higher-capacity health services, which are currently over-stretched, to diagnose and treat these conditions. Source: Dalal S, Beunza JJ, Volmink J, Adebamowo C, Bajunirwe F, Njelekela M, et al. Non-communicable diseases in sub-Saharan Africa: what we know now. Int J Epidemiol 2011 Apr 28. [Epub ahead of print] PubMed PMID: 21527446.

Glenda Hardy

Diabetes diary for 2011–2012 congresses DATE

PLACE

CONFERENCE

1–4 December 2011

University of Sharjah, UAE

12th Symposium of the International Diabetes Epidemiology Group

4–8 December 2011

Dubai, UAE

IDF World Diabetes Congress

8–11 February 2012

Barcelona, Spain

5th International Conference on Advanced Technologies and Treatments for Diabetes http://www2.kenes.com

5–9 May 2012

Florence, Italy

European Congress of Endocrinology

8–12 June 2012

Philadelphia, USA

72nd American Diabetes Association Scientific Sessions

10–13 October 2012

Istanbul, Turkey

ISPAD 2012 – 38th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes

4–6 December 2012

Dubai, UAE

1st American Diabetes Association Middle East Congress Diabetes Prevention and Treatment

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Patient information leaflet

Keep and Copy Series ASPIRIN IN PRIMARY PREVENTION OF VASCULAR EVENTS

S Afr J Diabetes Vasc Dis 2011: 8: 140

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WHY HAS MY DOCTOR PRESCRIBED ASPIRIN? Your doctor has assessed your risk for heart disease and stroke and is prescribing aspirin daily to reduce the risk of these life-threatening events. Heart attacks and ischaemic stroke (strokes) occur when blockages in the blood vessels that supply the heart or brain cut off blood supply long enough to damage parts of these organs. Aspirin decreases the chances of a heart attack or stroke in patients who have had heart attacks or strokes, and newer evidence suggests that aspirin is also beneficial in certain people who have not had a heart attack or stroke. This is particularly true for diabetic patients. However, some diabetic patients who are recently diagnosed or are at a low risk for cardiovascular disease (risk measured at less than 10% over the coming 10 years) may not require or benefit from aspirin therapy. Aspirin may cause uncommon but serious complications, such as bleeding in the digestive tract or brain. Enteric-coated aspirin can reduce the occurrence of this bleeding. The dose of aspirin for prevention should not be more than 150 mg/day and a dose of approximately 75 mg/day is as effective as higher dosages, which are associated with more bleeding complications. Evidence shows that aspirin decreases the incidence of heart attacks in men aged 45 to 79 years, and strokes in women aged 55 to 79 years, who are at increased risk for these events but have not yet had either of these problems. Aspirin also prevents more heart attacks and strokes in people with several risk factors for cardiovascular disease. However, taking aspirin does increase a person’s chances of bleeding in the stomach, intestine or brain (called haemorrhagic stroke). Your doctor will have carefully looked at this benefit–risk relationship.

HOW DO I KNOW WHAT MY RISK LEVELS ARE? For men, patients and doctors should consider age, blood pressure and cholesterol level, and whether he is a smoker or diabetic when deciding whether to use aspirin to prevent heart attacks. (A tool to calculate your risk as a man for a heart attack is available at http://healthlink.mcw.edu/article/923521437.html.) For women, patients and doctors should consider age, blood pressure, whether she is diabetic or a smoker, has abnormal heart rhythms, an enlarged heart or has a history of other cardiovascular disease. (A tool for estimating your stroke risk is available at www.westernstroke.org/PersonalStrokeRisk1.xls.) Men aged 45 to 79 years should take aspirin if the chances of preventing heart attack outweigh the chances of bleeding in the digestive tract. Women aged 55 to 79 years should take aspirin if the chances of reducing ischaemic stroke outweigh the chances of bleeding in the digestive tract. Men younger than 45 years and women younger than 55 years who have not previously had a heart attack or stroke should not take aspirin for prevention. It is still unclear whether the benefits of aspirin outweigh the risks for patients 80 years or older. WHAT ARE THE CAUTIONS TO ASPIRIN USAGE? Always follow the advice of your doctor/nurse. Take your medication regularly as prescribed. If you are taking other medication, tell your healthcare provider. Read the package insert of the medicine carefully. Source US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease. Ann Int Med 2009; 150: 396–404.

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DRUG TRENDS

Drug Trends

South Africa’s poor warfarin control raises questions of benefit above other anticoagulant therapies in atrial fibrillation

S

outh African patients entered into the ACTIVE-W trial were outside the ideal INR targets of 2–3 for 60% of the time while on warfarin therapy. This poor control of warfarin reduces benefit and raises the question as to whether other newer anticoagulant therapies should be used for stroke prevention in atrial fibrillation. New management strategies are also needed to improve warfarin control. Poor control of warfarin was a very significant feature of the South African-entered patients and, in fact, South Africa as a country was at the bottom of the log of achieved time in therapeutic range (TTR) (See Table 1, amended from reference 1). Furthermore, no South African patients were in the upper quartiles of TTR control. South Africa entered patients with atrial fibrillation into the ACTIVE-W (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events) trial, in which patients were randomised to receive dual antiplatelet therapy (clopidogrel 75 mg/day plus aspirin 75–100 mg/day or oral anticoagulation). In South Africa, the vitamin K antagonist used was warfarin. Ninety-eight South African patients were randomised to warfarin therapy and included in the post hoc study on the influence of INR control on ACTIVE-W results. The overall outcome (stroke, myocardial infarction, systemic embolism or vascular death) was found to be increased with clopidogrel plus aspirin, compared to oral antico-

agulation. The mean TTR for all patients in ACTIVE-W was 63.4% (median 65%). While there are differences between centres within a particular country, South African centre-specific data was not disclosed. However, the authors noted that in the three countries with the lowest mean TTRs (South Africa, Brazil and Russia), 86% of patients had TTRs below the mean. In South Africa’s case, 86% of patients therefore had mean TTRs even lower than 46.3. Overwhelmingly, these data point to very poor warfarin control-to-target INRs in South Africa.

Effect of TTRs on treatment effect of warfarin The effect of TTRs on treatment benefit of warfarin was evaluated in terms of TTR achieved at a particular centre. This was also adjusted for the patients’ characteristics and then evaluated in terms of the patients’ CHADS2 score (≥ 2 vs < 2), and finally, in a population-averaged model reflecting a country-level response. Under all four criteria, patients in the lowest quartile of TTR in terms of their centres did not benefit and were at greater risk on their warfarin therapy then they would have been on anti-platelet therapy: clopidogrel plus aspirin. Across all these factors, the observed effect of the TTR quartile on warfarin or alternative oral treatment was robust and determined the level of benefit for individual patients.

Using these data in a population-averaged model, this study was able to estimate the minimum TTR needed to have at least some benefit from oral anticoagulation. This level was determined to be above 58%, a countrywide objective that South Africa did not reach. The role of self-monitoring could be helpful in the South African situation, as can the newer anticoagulants such as dabigatran, which is registered in the United States for stroke prevention in atrial fibrillation. In the RE-LY trial and further evaluation of dabigatran’s efficacy and safety, the advantages of dabigatran remained, irrespective of the centres’ quality of INR control. In fact, for all vascular events, non-haemorrhagic events were greater at sites with poor INR control than at those with good INR control.2 J Aalbers, Special Assignments Editor 1.

2.

Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, et al. on behalf of the ACTIVE-W investigators. Benefit of oral anticoagulation over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centres and countries as measured by time in therapeutic range. Circulation 2008; 118: 2029–2037. DOI: 10.1161/ CIRCULATIONAHA.107.750000 Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Grazia Franzosi M, Pais P, et al. on behalf of the RE-LY investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet, published online Aug 29 2010. DOI: 10.1016/S0140-6736(10)61194-4.

Table 1. TTR and time of risk of stroke, myocardial infarction, systemic embolism, vascular death, or major haemorrhage for some of the 15 countries participating in Active-W Patients per TTR quartile (low to high) (n)

Clopidogrel + aspirin

Clopidogrel + ASA vs OAC

OAC

Country

1

2

3

4

Mean TTR

Events

%/y

Events

%/y

RR

95% CI

p

South Africa

55

43

0

0

46.3

5

8.42

8

14.94

0.57

0.19–1.75

0.33

Brazil

188

25

25

8

47.1

13

9.38

14

9.43

1.01

0.47–2.15

0.98

Russia

188

28

0

41

53.4

13

7.92

7

4.16

1.88

0.75–4.70

0.18

United States

135

460

363

116

62.9

59

8.02

48

6.6

1.25

0.85–1.83

0.26

Netherlands

65

98

163

49

64.0

15

6.65

7

3.17

2.12

0.86–5.20

0.10

Australia

5

12

54

145

74.5

18

12.92

5

3.76

3.60

1.34–9.71

0.01

United Kingdom

2

34

59

199

74.8

12

7.03

7

3.97

1.79

0.71–4.55

0.22

ASA: acetylsalicyclic acid; OAC: oral anticoagulation; RR: relative risk, rows are ordered by mean TTR.

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Getting to the root of diabetes: the promise of liraglutide

A

meeting hosted by Novo Nordisk at Zimbali Lodge near Durban in late May 2011 spotlighted the promise of incretinbased therapies for type 2 diabetes, particularly the glucagon-like peptide-1 (GLP-1) analogue, liraglutide.

The science behind the molecule Dr Anne Mette Rosenfalck, endocrinologist and vice-president, Novo Nordisk, Denmark The development of liraglutide, which was patented in 1997, marked the culmination of a long journey – several decades of research, in fact. Over the past decade and a half, the number of articles evaluating the role of GLP-1 in diabetes has increased dramatically, reflecting an explosion of interest in the subject. Much research and development effort at Novo Nordisk led to liraglutide being approved in Europe in 2009 and in the USA in 2010. It is currently approved in 58 countries worldwide and has been launched in 32, most recently in China in March 2011. GLP-1 is a gut hormone, a member of the incretin family, which is secreted in response to meal ingestion. It, in turn, stimulates the secretion of endogenous insulin – the so-called ‘incretin effect’, which is severely impaired in individuals with type 2 diabetes. This suggests that introducing GLP-1 from outside can address this impairment. The infusion of a GLP-1 analogue is associated with increased secretion of insulin. As the blood glucose levels normalise, the incretin effect wears off, which means that incretin therapy does not carry the risk of hypoglycaemia that comes with insulin therapy. ‘Because GLP-1 is glucosedependent, the secretion thereof declines to normal levels as the glucose levels go down, minimising the risk of hypoglycaemia. Treatment with GLP-1 therefore does not impair the hypoglycaemic counter-regulatory response.’ ‘Much of the research has focused on the pancreas’, said Dr Rosenfalck. ‘GLP-1 has an impact on all functional pancreatic cells and is responsible for an increase in both earlyand late-stage insulin secretion and synthesis. But it also has important effects on the

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brain, liver, heart and gastrointestinal tract.’ The first proof of the benefit of GLP-1 infusion came in a 1997 study by Rachman et al.1 that was published in Diabetologia. A 17-hour infusion of a GLP-1 analogue improved diabetic blood glucose to levels similar to those of healthy controls. In 2001, Toft-Nielsen et al.2 showed safe and effective blood glucose lowering with a fourhour GLP-1 infusion. There was no decrease to hypoglycaemic levels and there were no non-responders. Subsequent studies have shown that in addition to its blood glucoselowering effects, GLP-1 stimulates beta-cell regeneration and reduces beta-cell apoptosis in animal models. Zander et al.,3 in a study published 2002, showed that GLP-1 improved beta-cell function in humans, controlling blood glucose levels and body weight in type 2 diabetes. Dr Rosenfalck underscored that this was an important finding, as improving blood glucose control with currently available therapies usually leads to increase in weight. The indications are therefore clear that pharmacological doses of GLP-1 can restore insulin responses to normal physiological levels in those with type 2 diabetes. Additional beneficial effects include improved learning and memory function, neuroprotection, improved cardiac function and the promotion of greater feelings of satiety and hence reduced food intake. ‘GLP-1 was initially shown to reduce both the number and size of meals in animal models’, she said, ‘findings that were repeated in human subjects. GLP-1 leads to reduced energy intake, proving that liraglutide provides dose-dependent weight reduction.’ Where cardiac benefits are concerned, GLP-1 reduces systolic blood pressure. ‘In a mouse model of myocardial infarction (MI), it was also associated with better survival and improved cardiac output. A human study confirmed that it improved left ventricular function. ‘That it improves biomarkers of cardiovascular risk adds to its importance in type 2 diabetes’, said Dr Rosenfalck. To use GLP-1 pharmacologically required some structural changes to the molecule, because native GLP-1 has a very short halflife and is quickly degraded in the body by

dipeptidyl-peptidase-4 (DPP-4). ‘Much work was done to get around this, resulting in two kinds of incretin therapies, namely DPP-4 inhibitors and GLP-1 receptor agonists. Liraglutide belongs to the latter class and is a once-daily human GLP-1 analogue, which is 97% similar to native GLP-1, having undergone only two small molecular changes. The latter ensured that it is absorbed more slowly and remains longer in the blood. Its half-life has been increased to 13 hours and its susceptibility to DPP-4 degradation has been reduced. Exenatide, the other GLP-1 receptor agonist on the market, requires twice-daily administration and is only 53% similar to native GLP-1. ‘Liraglutide’s greater similarity to native GLP-1 means it produces fewer antibodies than exenatide’, observed Dr Rosenfalck. Summing up, Dr Rosenfalck concluded that liraglutide is a very interesting molecule. ‘It offers efficacious glucose lowering, reduces body weight and has the potential to halt disease progression.’

Getting to the root of the LEAD study results Wolfgang Schmidt, professor of Medicine, Gastroenterology and Diabetology, Ruhr University Bochum, Germany Liraglutide’s promise was confirmed in a series of trials collectively known as the LEAD studies. Prof Schmidt reviewed some of the key findings and what they have taught in respect of how type 2 diabetes should be treated in 2011. ‘We know that beta-cell dysfunction is critical to the development of type 2 diabetes, but we’ve learned that alpha-cell dysfunction plays a role too, with hypertrophy of those cells producing hyperglucagonaemia. Previously, we were only able to “interfere” with the beta-cell dysfunction, but the inhibitory effect of incretin therapy on alpha-cells opens up new treatment possibilities.’ Key to the evaluation of new treatment paradigms is the need to avoid hypoglycaemic episodes and treatment-related weight gain. Stringent and safe glycaemic control

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after early diagnosis should be aimed for, along with attempts to reconstitute beta-cell function and stop or delay the loss thereof. GLP-1 therefore has very positive implications. It normalises glucose levels in poorly controlled type 2 diabetics without increasing hypoglycaemic episodes, given its inbuilt protective mechanism. As normal levels are reached, the inhibition of glucagon declines. Beta-cell apoptosis is inhibited, maintaining human islets. GLP-1’s inhibition of gastric emptying could be the factor associated with the reduction of nausea over time. It has beneficial effects on the cardiovascular system and, perhaps most importantly, it has a direct effect on satiety, appetite and food intake, which serves as a basis for potential weight loss. This is the result of its direct effect on the hypothalamus. ‘The effect on the hypothalamus is one of the important factors that distinguishes the GLP-1-receptor agonists from the DPP-4 inhibitors’, said Prof Schmidt. The LEAD studies compared liraglutide to standard treatments for type 2 diabetes, both as monotherapy and in a variety of combinations. They involved over 4 000 patients. ‘When all the results were combined, it was clear that liraglutide reduced HbA1c levels and that it was clearly superior or non-inferior to comparator treatments. It showed strong additive effects and, in a direct head-to-head comparison, it proved superior to exenatide’, he continued. Key findings • In LEAD-2, more than 75% of patients lost weight, a mean of 7.7 kg. Both visceral and subcutaneous fat was lost, and the weight loss remained stable over two years. • LEAD-3 confirmed that liraglutide was not associated with any hypoglycaemia. Hypoglycaemia only occurred when it was used in combination with a sulphonylurea. • LEAD-6 evaluated liraglutide against exenatide. While both treatments lowered HbA1c levels and body weight, the most important outcome was that liraglutide produced much less nausea. • The most important cardiovascular finding was that liraglutide was associated with a substantial reduction in systolic

VOLUME 8 NUMBER 3 • SEPTEMBER 2011

DRUG TRENDS

blood pressure – which was shown in LEAD-4. It could therefore be considered a moderate antihypertensive that reduces the risk of two important clinical endpoints, namely stroke and MI. • Liraglutide may modify food preferences towards healthier diets. • A single dose of liraglutide restores betacell sensitivity. This immediate resensitisation is a very important phenomenon. • Relative to the DPP-4 inhibitor, sitagliptin, liraglutide was superior in respect of both reduction of HbA1c levels and weight loss. • When insulin detemir was added to a combination of liraglutide and metformin, it showed additional benefit, with no negative effects on weight loss and no significant additional hypoglycaemia. An additional 17% of patients reached target, over and above the 61% who had already reached target on liraglutide and metformin. • ‘When one looks at the triple endpoints of HbA1c control, weight loss and the avoidance of hypoglycaemia, the whole LEAD programme showed liraglutide to be the most active choice to achieve it. Exenatide came in second; all other treatments were less effective’, observed Prof Schmidt. So who will benefit most from incretinbased treatment? Prof Schmidt cited patients not achieving goal HbA1c levels on metformin monotherapy; patients who are metformin intolerant; patients on sulphonylureas who experience recurrent hypoglycaemia; and patients who really want/need to lose weight. ‘Therapy needs to be individualised according to patient needs’, he concluded. ‘GLP-1 analogues have great potential, because the important limitations of other treatments are avoided.’

Liraglutide in clinical practice, and preliminary results of the DURATION-6 study Wolfgang Schmidt, professor of Medicine, Gastroenterology and Diabetology, Ruhr University Bochum, Germany Spotlighting the use of liraglutide in clinical practice, Prof Schmidt once again underscored the problems and limitations of current treatment, notably therapy-induced

hypoglycaemia, which was significant in the ACCORD, VADT and ADVANCE studies. ‘In ACCORD, intensive treatment was associated with severe hypoglycaemia and grotesque weight gain’, he said. ‘The VADT study emphasised that severe hypoglycaemia is a predictor of cardiovascular death – not a risk factor as such, but certainly an important risk indicator.’ Hypoglycaemic episodes impair brain function. Even one severe episode increases the relative risk of dementia later in life. Treatment-related weight gain (highlighted in the UKPDS and ADOPT studies) was shown to be an important risk factor for various diseases. It is also associated with increased all-cause, cardiovascular, diabetes and cancer mortality. Another major limitation of current treatments is that they do not address progressive beta-cell loss. Prof Schmidt went on to cite three case studies, which showed the benefit of liraglutide in specific patients. The first was a 45-year-old man, who had had type 2 diabetes for 3.5 years. He had a fasting plasma glucose (FPG) level of 9.4 mmol/l and a BMI of 48.2 kg/m2. Lifestyle modification was not working in the long term and he had subsequently been put onto metformin, ramipril and simvastatin. After initiation of liraglutide, his FPG dropped to 7.2 mmol/l at week two and 6.2 mmol/l at week eight. After eight weeks he had lost 6 kg and had near-normal blood pressure. By three months, he had lost 10 kg; this had reached 18 kg by six months, at which time his HbA1c level was 6.9%. The second patient was a 63-year-old woman. She had been diabetic for eight years and had had a previous MI. She had elevated plasma lipid levels and blood pressure, and gradually deteriorating glycaemia. The introduction of pioglitazone decreased her HbA1c levels, but at the expense of dramatic weight gain. It was discontinued and liraglutide introduced. After three months, she had lost 6 kg and her HbA1c level was 7.2%. At six months she had lost 12 kg and her HbA1c level was 6%. The third case was one where exenatide was switched for liraglutide. The patient was a 58-year-old woman who had been diabetic for 14 years. Initial good control had gradually deteriorated over the past six

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

to eight years. She was both metformin and sitagliptin intolerant. A combination of gliclazide and pioglitazone resulted in weight gain, and the introduction of exenatide over and above these was associated with persistent nausea despite improved HbA1c levels and weight loss. Switched to liraglutide, her nausea settled within a day. After six months her HbA1c level was stable and her weight continued to decline, at which point the pioglitazone was discontinued. ‘She was therefore successfully switched from exenatide to liraglutide’, said Prof Schmidt. Turning to the DURATION-6 study, he explained that it entailed a head-to-head comparison of once-weekly exenatide 2.0 mg to once-daily liraglutide 1.8 mg. The subjects were a ‘normal’ population of stable type 2 diabetes patients on various standard treatments. By 26 weeks, liraglutide was clearly superior in terms of its effect on HbA1c levels, and there were no major hypoglycaemic episodes. While liraglutide was associated with more gastrointestinal side effects, he added the concluding rider that these take longer to manifest with exenatide and it was

too soon to draw a final conclusion in this regard.

Getting to the root of safety Dr

Isidora

Kitsou-Mylona,

Novo

Nordisk

regional medical advisor for the Middle East and Africa Dr Kitsou-Mylona addressed two major safety concerns associated with GLP-1 analogues, namely the risks of pancreatitis and thyroid cancer. She underscored that those with type 2 diabetes already have an increased risk for pancreatitis, something of which physicians need to be aware. In the LEAD studies, a total of seven cases was observed, five acute and two chronic. ‘This is consistent with what would be expected in a background population of patients with type 2 diabetes and is too low a number to establish a cause-and-effect relationship’, she said. ‘We saw an increase in c-cell thyroid cancer in rodent models, so we monitored this. In the human trial subjects, we saw no increase in calcitonin levels, and there is no evidence that liraglutide is genotoxic, either in vitro or in vivo. C-cells are very sen-

sitive to GLP-1 and rats and mice have far greater numbers of these cells than humans. Because humans have fewer c-cells and therefore fewer GLP-1 receptors, they are not at risk of producing the calcitonin levels seen in the animal models. The FDA agreed with Novo Nordisk’s conclusion that the high rodent cancer risk does not translate into a similar risk for humans.’ She concluded by underscoring that there was therefore no evidence to support the suggestion that GLP-1 agonists increase the risk of development of c-cell cancer in humans. Peter Wagenaar, Gauteng correspondent 1.

2.

3.

Rachman J, Barrow BA, Levy JC, Turner RC. Nearnormalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 1997; 40(2): 205–211. Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 2001; 86(8): 3717–3723. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002; 359(9309): 824–830.

OBESITY

LIPIDAEMIA DYS

IN RESISTANCE INSUL

HYPERTENSION

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HYPER INSULINAEMIA THROMBOSIS

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This peer-reviewed journal is available as full text at all tertiary institutions in South Africa, presenting a great opportunity to submit your good-quality original articles for speedy publication. Recent user research has shown that some 10 000 annual topic searches were done on the SA Journal of Diabetes & Vascular Disease database, which contains seven years of published material.

Call for Articles

The SA Journal of Diabetes & Vascular Disease aims to provide a forum for specialists involved in the care of people with diabetes, to exchange information, promote better management and stimulate research in Africa. This quarterly journal publishes original research and scholarly reviews about prevention and management of diabetes, relating to both general and specific issues. The SA Journal of Diabetes & Vascular Disease invites you to submit your articles online only. Read the Instructions to Authors at www.diabetesjournal.co.za for more information on the journal’s policies and the submission process.


Are you looking at every part of diabetes? You might be missing GLP-1. It’s a natural hormone that helps regulate glucose metabolism. It also slows gastric emptying, promotes satiety, and plays a significant role in beta-cell function.1 Its multiple actions throughout the body are critical in diabetes. Unfortunately, your patients might be missing GLP-1, too. Many people with type 2 diabetes may have impaired GLP-1 secretion and impaired beta-cell response to GLP-1.2,3 This could contribute to the pathogenesis of the disease.1 Looking at the whole problem is the most important part of understanding it. That’s why Novo Nordisk is dedicated to ongoing research and development in the management of diabetes.

Diabetes | A whole new perspective

References: 1. Zander M, et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and ß-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824-830. 2. Toft-Nielsen M-B, et al. Determinants of the Impaired Secretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients. J Clin Endocrinol Metab. 2001;86(8):3717-3723. 3. Kjems LL, et al. The Influence of GLP-1 on Glucose-Stimulated Insulin Secretion. Effects on ß-Cell Sensitivity in Type 2 and Nondiabetic Subjects. Diabetes. 2003;52:380-386. Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. PO Box 783155, Sandton, 2146. Tel: (011) 202 0500 Fax: (011) 807 7989 www.novonordisk.co.za NN/DUO/4244/09/10/VER1


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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.

SAJDVD Volume 8, Issue 3  

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