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Featured in this issue Insulin therapy Vitiligo Genetic counselling in type 1 diabetes Diabetes and thyroid disorders Biosimilar insulins Thyroid supplements Hypertension control in diabetes Clinical perspectives on managing diabetes Managing heart failure patients Colorectal cancer reduction with low-dose aspirin

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No other basal insulin can offer you more References 1. Blonde L et al. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets – the TITRATE™ study. Diabet. Obes. and Metab. 2009;11:623–631. 2. Philis-Tsimikas A et al. Comparison of Once-Daily Insulin Detemir with NPH Insulin Added to a Regimen of Oral Antidiabetic Drugs in Poorly Controlled Type 2 Diabetes. Clin Ther 2006;28(10):1569–1581. 3. Rosenstock J et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008;51:408–416. 4. Hermansen K et al. A 26-Week, Randomized, Parallel, Treat-to-Target Trial Comparing Insulin Detemir With NPH Insulin as Add-On Therapy to Oral Glucose-Lowering Drugs in Insulin-Naïve People with Type 2 Diabetes. Diabetes Care 2006;29(6):1269–1274. 5. Klein O et al. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabet. Obes. and Metab. 2007;9:290–299. 6. World IMS Data, September 2009. Proprietary Name: Levemir®. Scheduling Status: S3 Composition: Insulin detemir 100 units /ml. Indication: Treatment of insulin requiring patients with diabetes mellitus. Registration Number: 38/21.1/0084. For full prescribing information refer to package insert approved by the medicines regulatory authority. 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/DUO3817/02/2010ver1

ISSN 1811-6515

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Diabetes & vascular disease VOLUME 8 NUMBER 1 • MARCH 2011 www.diabetesjournal.co.za

Corresponding Editor PROF WF MOLLENTZE Head of the Department of Internal Medicines, University of the Free State, Bloemfontein Consulting Editors PROF J-C MBANYA PROF AJ BRINK National Editorial Board DR A AMOD Centre for Diabetes, Endocrinology and Metabolic Diseases, Life Healthcare, Chatsmed Gardens Hospital, Durban SR K BECKERT Diabetes Nurse, Paarl PROF F BONNICI Emeritus Professor, Faculty of Health Sciences, University of Cape Town and President of Diabetes South Africa PROF R DELPORT Department of Family Medicine, University of Pretoria DR L DISTILLER Director of the Centre of Diabetes and Endocrinology, Houghton, Johannesburg DR F MAHOMED Department of Endocrinology, Grey’s Hospital, Pietermaritzburg PROF CD POTGIETER Specialist Nephrologist, University of Pretoria and Jakaranda Hospital, Pretoria PROF K SLIWA Associate Professor of Medicine and Cardiology, Baragwanath Hospital, University of the Witwatersrand, Johannesburg PROF YK SEEDAT Emeritus Professor of Medicine and Honorary Research Associate, University of Natal, Durban International Editorial Board PROF IW CAMPBELL Physician, Victoria Hospital, Kircaldy, Scotland, UK PROF PJ GRANT Professor of Medicine and head of Academic Unit of Molecular Vascular Medicine, Faculty of Medicine and Health, University of Leeds; honorary consultant physician, United Leeds Teaching Hospitals NHS Trust, UK PROF J-C MBANYA Professor of Endocrinology, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Cameroon and President, 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

CONTENTS Editorial 4

Insulin therapy in South Africa: barriers, dilemmas and paradoxes WF Mollentze

Reviews 5

Vitiligo BB Adamjee

Genetic counselling in type 1 diabetes mellitus BD Henderson

Diabetes and thyroid disorders G Brenta

The new world of biosimilars: what diabetologists need to know about biosimilar insulins I Krämer, T Sauer

Patient Information Leaflet

You and your thyroid supplement PM van Zyl

Diabetes Personality

A passion for people

Cardiovascular Focus

Extracts from the 11th annual South African Heart Association Congress, August 2010

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

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

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

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

Opinions in Hypertension Management

Improving hypertension control in patients with diabetes J Aalbers

Cutting Edge of Diabetes Technology

Report from the Advanced Technologies and Tratments for Diabetes meeting, London, 16–19 February 2011

Industry News

Boehringer Ingelheim and Eli Lilly and Company announce strategic alliance to bring new diabetes treatments to patients worldwide

Diabetes alliance between Novo Nordisk and Accu-Chek®

Drug Trends in Diabetes

Clinical perspectives on managing diabetes: an expert South African view J Aalbers

Managing heart failure patients: choosing the best angiotension receptor blockers J Aalbers

Substantial evidence for colorectal cancer reduction with daily low-dose aspirin J Aalbers

Journal Update

Autoimmunity in a South African and African context J Aalbers

Diabetes News

It's the shell that makes

Front cover photographs: • Left: Vitiligo affects up to 2% of the general population and diabetes may be associated with its appearance (page 5) • Centre: Autoimmune thyroid disease is more prevalent in patients with type 1 diabetes (page 14) • Right: Genetic counselling requires not only expertise but a sympathetic understanding of the impact of diabetes on the wider family (page 10)

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

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.

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

EDITORIAL

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Insulin therapy in South Africa: barriers, dilemmas and paradoxes WF MOLLENTZE

t is common knowledge that the quality of diabetes care is poor in the public healthcare sector in South Africa – evidence is not hard to find.1 Gill and co-workers demonstrated that it is possible to improve diabetes care at a rural primary healthcare clinic in KwaZulu-Natal by introducing a simple protocol and educationbased diabetes care intervention system.2 Although some slippage of control did occur, this improvement was sustained for up to four years.3 Similarly, a chronic diseases outreach programme in Soweto successfully supported primary-health nurses in detecting patients with advanced disease, and ensuring early referral to a specialist centre.4 Resistance to switching patients to insulin is at least partly to blame for the poor quality of diabetes care. Barriers to insulin therapy have been well described and include doctor, patient and system barriers.5 Doctors’ barriers include lack of knowledge, lack of experience with and use of guidelines related to insulin therapy, language barriers between doctor and patient, and fear of hypoglycaemia. Patients’ barriers are mistaken beliefs about insulin, non-compliance, lack of understanding of diabetes, use of traditional herbs, fear of injections, and poor socioeconomic conditions. System barriers are inadequate time, lack of continuity of care and financial constraints.5 System barriers described elsewhere include an overworked, poorly supported, poorly educated and frustrated primary healthcare team.4 Furthermore, Daniels et al. demonstrated that the passive dissemination of guidelines to health professionals in primary care was not effective due to attitudinal barriers to implementation.6 The so-called ‘insulin dilemma’ in resource-poor countries including sub-Saharan Africa (SSA) was recently reviewed.7 The dilemma refers to the disproportionate amount of the national healthcare budget in developing countries that is spent on insulin. Although this dilemma is very real for several SSA countries, including Tanzania and Mozambique,7 it has not been reported to be an issue in South Africa. Apart from analogue insulin preparations a wide spectrum of genetically engineered human insulin preparations are widely available at all levels in the public healthcare sector in South Africa. The paradox that does exist is the poor quality of care available to patients suffering from diabetes in the public healthcare sector in this country in spite of the availability of drugs including insulin. Even insulin pens, self-monitoring glucose meters and test strips are available when properly motivated. Admittedly, periodic supply-chain challenges are not uncommon to certain parts of the country, as was experienced in the Free State in the not-so distant past.

Correspondence to: WF Mollentze Department of Internal Medicine, University of the Free State, Bloemfontein. Tel: +27 (0) 51 405-3154 e-mail: wfm@mweb.co.za S Afr J Diabetes Vasc Dis 2011; 8: 4.

At the core of the diabetes paradox in South Africa lies the fact that our nurse-driven primary healthcare system simply cannot cope with the quadruple burden of disease in this country.8 This problem is further compounded by the fact that treatment guidelines and policies are developed centrally but that the implementation thereof is left to the nine different provincial departments of health. The ‘concerted action’ called for by the authors in the Lancet article to turn the tide8 is still not forthcoming, while the brain drain of doctors9 and nurses is continuing.10 A paradox of a different nature is the analogue insulin paradox.7 In spite of a lack of compelling evidence of better glucose control with analogues than with human insulin, apart from some reduction in hypoglycaemia (especially nocturnal hypoglycaemia), insulin analogues and their mixes captured a disproportionately large share of the global insulin market.11 The main reason behind this phenomenon is not evidence-based medicine but more likely marketing forces and personal beliefs among patients and doctors that new technologies provide better solutions, leading to human insulin replacing animal insulin, and later analogue insulin replacing human insulin.7 The cost of insulin contributes in no small way to the healthcare budget of most countries. The global annual expenditure on insulin increased from US$2 billion 1995 to $7.3 billion in 2005, and was projected to reach $11.8 billion in 2010.11 The expectation that generic human insulin or so-called ‘biosimilar insulins’ may drive the cost of insulin down is tempered by the complexities of producing safe and reliable alternatives to the reference products, as is so elegantly reviewed by Krämer and Sauer on page 19 of this edition.

References Steyn K, Levitt NS, Patel M, et al. Hypertension and diabetes: poor care for patients at community health centres. S Afr J Med 2008; 98(8): 618–622. 2. Gill GV, Price C, Shandu D, et al. An effective system of nurse-led diabetes care in rural Africa. Diabet Med 2008; 25(5): 606–611. 3. Price C, Shandu D, Dedicoat M, et al. Long-term glycaemic outcome of structured nurse-led diabetes care in rural Africa. Q J Med 2011 Jan 28. [E-pub ahead of print]. 4. Katz I, Schneider H, Shezi Z, et al. Managing type 2 diabetes in Soweto – The South African Chronic Disease Outreach Program experience. Prim Care Diabetes 2009; 3(3): 157–164. [E-pub 2009 Jul 28]. 5. Haque M, Emerson SH, Dennison CR, et al. Barriers to initiating insulin therapy in patients with type 2 diabetes mellitus in public-sector primary health care centres in Cape Town. S Afr Med J 2005; 95(10): 798–802. 6. Daniels A, Biesma R, Otten J, et al. Ambivalence of primary health care professionals towards the South African guidelines for hypertension and diabetes. S Afr Med J 2000; 90(12): 1206–1211. 7. Gill GV, Yudkin JS, Keen H, Beran D. The insulin dilemma in resource-limited countries. A way forward? Diabetologia 2011; 54: 19–24. 8. Mayosi BM, Flisher AJ, Lalloo UG, et al. The burden of non-communicable diseases in South Africa. Lancet 200912; 374(9693): 934–947. 9. Mullan F. The metrics of the physician brain drain. N Engl J Med 2005; 353(17): 1810–1818. 10. Dovlo D. Migration of nurses from sub-Saharan Africa: A review of issues and challenges. Hlth Serv Res 2007; 42(3 Pt 2): 1373–1388. 11. Holleman F, Gale EAM. Nice insulins, pity about the evidence. Diabetologia 2007; 50: 1783–1790. 1.

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Vitiligo BB ADAMJEE

itiligo is an acquired, idiopathic condition characterised by well-circumscribed flat, non-palpable areas (macules) of total loss of melanin pigment (depigmentation).1 This depigmented skin is functionally different from normally pigmented skin. It does not react normally to contact sensitisation or to contact allergens and while normal white skin is prone to skin cancers, skin with vitiligo is generally resistant to carcinogenesis of keratinocytic origin. It is not susceptible to melanomas, due to the absence of melanocytes. By contrast, skin in albinism is susceptible to squamous cell carcinomas and rarely melanomas.2 Vitiligo affects approximately 0.5 to 2% of the general population and may appear from after birth to senescence.1 Peak age of onset is between 10 and 30 years. Both genders are probably equally affected, but the female predominance in some studies is likely attributable to concern about a cosmetic problem.3

Pathogenesis Vitiligo is a multifactorial disease involving genetic and non-genetic factors. Between 30 and 40% of patients have a positive family history. Inheritance may be polygenic or autosomal dominant with variable penetrance. Segmental vitiligo is not familial. Many theories have been proposed regarding aetiology.1,4,5

Autoimmune hypothesis This theory proposes that altered humoral or cellular immunity results in the destruction of the melanocytes. Dysfunction of the humoral immunity is supported by the association of vitiligo with autoimmune endocrinopathies. These disorders are accompanied by circulating anti-organ antibodies. Organ-specific antibodies to thyroid and gastric parietal cells, and adrenal tissue are found more frequently in people with vitiligo than in the general population. Disorders associated with vitiligo4 (*auto-antibodies demonstrable): • thyroid disease* (hyperthyroidism and hypothyroidism) • pernicious anaemia* • Addison’s disease* • diabetes mellitus* • hypoparathyroidism* • myasthenia gravis* • alopecia areata • morphoea and lichen sclerosus • halo naevus* • malignant melanoma.*

BB Adamjee A complement-fixing antibody to melanocytes has been found in the sera of patients with alopecia areata, mucocutaneous candidiasis and multiple endocrine insufficiencies, in addition to vitiligo. These antibodies are directed against melanocyte antigens such as tyrosinase and tyrosinase-related proteins 1 and 2 (TYRP1 and TYRP2). Recently, two transcription factors SOX9 and SOX10, and the melanin-concentrating hormone receptor-1 have been identified as auto-antigens in patients with autoimmune polyendocrine syndrome type I and with idiopathic vitiligo. Evidence favouring the involvement of cellular immunity is also strong. The T cells that infiltrate perilesional epidermis are predominantly CD8+ T cells, which express cutaneous lymphocyteassociated antigen (CLA) and the interleukin-2 (IL-2) receptor. These CLA+ T cells are found primarily near disappearing melanocytes and many express perforin and granzyme B. Focal expression of intercellular adhesion molecule-1 (ICAM-1) and HLA-DR occurs within the epidermis at sites of interaction between immune infiltrates and disappearing melanocytes. Skin-homing T cells therefore play an important role in melanocyte death. Reduced serum-transforming growth factor-β levels have been observed and this may contribute to enhanced cellular immunity. Diminished maturation of regulatory T cells may lead to impaired inhibition of inflammation.6 Skin-homing melanocyte-specific cytotoxic T lymphocytes (CTLs) are often detected in the blood of patients with autoimmune vitiligo, implicating their involvement in the melanocyte destruction.

Intrinsic defect of melanocytes Correspondence to: Dr BB Adamjee Department of Dermatology, University of the Free State and Universitas Academic Health Complex, Bloemfontein. Tel: +27 0(51) 405-2546 e-mail: adamjeebb@yahoo.com S Afr J Diabetes Vasc Dis 2011; 8: 5–9.

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An abnormal structure of the rough endoplasmic reticulum of vitiligo melanocytes may play a role in the development of vitiligo.

Defective free radical defence(s) A metabolic defect in biopterin metabolism results in hydrogen peroxide (H2O2) overproduction. Accumulation of H2O2 in the

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epidermis leads to oxidative degradation of catalase. Other sources of epidermal H2O2 include increased catecholamine biosynthesis and inhibition of thioredoxin/thioredoxin reductase by calcium. These processes may lead to melanocyte destruction.

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Figure 1. Quadrichrome vitiligo.

Other theories Other hypotheses on the aetiology of vitiligo are: reduced melanocyte survival and dysregulation of melanocytes, destruction of melanocytes by autocytotoxic metabolites, membrane lipid alterations in melanocytes, deficiency of melanocyte growth factors, destruction of melanocytes by neurochemical substances and viral infection (e.g. cytomegalovirus).

Clinical features Vitiligo is commonly a totally amelanotic macule, surrounded by normal skin. The colour is uniformly milky or chalk-white. Individual macules and patches vary in size from millimetres to centimetres. There is an absence of inflammation or erythema (redness). The margins of vitiligo macules are usually discrete and their borders usually convex. Lesions may enlarge centrifugally over time and the rate of enlargement varies from slow to rapid. Fusion of neighbouring macules may result in complex patterns.1,3,4,7

Variants of vitiligo • Trichrome vitiligo: this refers to a tan zone of varying width between the normal and totally depigmented skin. Trichrome lesions naturally evolve to typical vitiligo macules. • Quadrichrome vitiligo: this refers to dark brown perifollicular pigmentation seen in repigmenting vitiligo (Fig. 1). • Vitiligo ponctué: this is characterised by small, confetti-like macules. • Inflammatory vitiligo: there is erythema of the margin of the vitiligo macule but there is no resemblance to an inflammatory dermatosis (Fig. 2).

Types of vitiligo Vitiligo vulgaris/Generalised vitiligo This is the commonest presentation. The distribution is usually strikingly symmetrical. Although vitiligo may affect any part of the body, characteristic patterns of involvement occur. Extensor areas, such as the interphalangeal joints, elbows and knees are often involved. The volar wrists, umbilicus, lumbosacral area and anterior tibia may also be involved. These are areas subjected to repeated trauma and friction. Areas that are normally hyperpigmented, such as the face, axillae, groin, areolae and genitalia are also frequently affected. Vitiligo is sometimes peri-orificial, where it may occur around the eyes, nose, ears, mouth and anus. Peri-ungual involvement may be found alone, or with the involvement of certain mucosae (lips, distal penis, nipples), called lip-tip vitiligo. Acrofacial vitiligo is the involvement of distal digits and peri-orificial face (Fig. 3). Universal vitiligo describes widespread involvement with few remaining normally pigmented areas. This is the type associated with multiple endocrinopathy syndromes. Isomorphic Koebner phenomenon is the development of vitiligo following trauma, such as a cut, burn or abrasion to ‘normal’ skin. The isomorphic Koebner phenomenon is more common in progressive vitiligo and the threshold for this phenomenon appears to be lower, such as friction from clothes.

Figure 2. Inflammatory vitiligo.

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Focal vitiligo One or more macules occur in an area, but are not clearly segmental.

Segmental vitiligo Sometimes vitiligo is unilateral and may have a dermatomal pattern (Fig. 4). This should be considered a special type with a stable course and is unlikely to be associated with other diseases. Segmental vitiligo usually has an earlier onset, is more stable and is not familial. These patients are unlikely to develop other lesions and the isomorphic Koebner phenomenon does not occur. Five

Figure 3. Acrofacial vitiligo.

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per cent of adults and more than 20% of children have segmental vitiligo. The trigeminal area is involved in over 50%, the neck in 23%, and trunk in 17% of patients. Up to 13% may have multiple sites of involvement and nearly half have poliosis (white hair).

Occurrence of vitiligo Vitiligo is less apparent in lightly pigmented people, but becomes more obvious during Woodâ&#x20AC;&#x2122;s lamp examination or after tanning of uninvolved skin (Fig. 5). Involvement of the palms and soles is less apparent in fair-skinned individuals. In darkly pigmented persons the contrast between vitiliginous skin and normally pigmented skin is striking, even in habitually unexposed sites. Spontaneous repigmentation occurs in 10 to 20% of patients, usually in sun-exposed areas. Repigmentation occurs in younger patients and is mainly perifollicular. The incidence of leukotrichia (depigmented hair) varies from 10% to over 60% because of dissociated behaviour between epidermal and follicular melanocytes. The occurrence of leukotrichia does not correlate with the activity of the disease. Vitiligo of the scalp may present as a localised patch of white or grey hair (usually), total depigmentation of all scalp hair or a scattering of white hair. Spontaneous repigmentation of depigmented hair in vitiligo does not occur. The commonest form of vitiligo seen in children is vitiligo vulgaris but the frequency of segmental vitiligo is significant. The incidence of endocrinopathies is lower than in adults, but autoantibody formation in children with vitiligo is more significant.

Figure 5. Vitiligo is less apparent in lightly pigmented people but becomes apparent after tanning of uninvolved skin.

Figure 4. Segmental vitiligo.

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Course of vitiligo The onset of vitiligo is insidious and asymptomatic. Many patients become aware of depigmented areas in the spring or summer when tanning accentuates the contrast between involved and uninvolved skin. The course of vitiligo is unpredictable. It is usually of slow progression, but may stabilise for a long period of time or progress rapidly. Total body involvement that occurs within weeks or days has been recorded. A degree of sun-induced or spontaneous repigmentation may occur but complete, stable repigmentation is rare.

Vitiligo and ocular disease1,3,4 The uveal tract (iris, ciliary body and choroid) and retinal pigment epithelium contain pigment cells. Generally vitiligo patients do not have eye problems, but may present with uveitis. The most severe form of uveitis occurs in Vogt-Koyanagi-Harada syndrome, which is characterised by uveitis, aseptic meningitis, otic involvement and vitiligo, especially of the head and neck region. Depigmented areas involving the ocular fundus have been seen in vitiligo, suggesting focal loss of melanocytes.1,3,4 Although abnormal sensory hearing loss suggests impairment of the cochlear melanocytes, there was no clear evidence of otic abnormalities until recently. In a recent study, 37.7% of patients were found to have hearing problems.8

Associated disorders1,3,4,8 Generally, people with vitiligo are healthy, but autoimmune endocrinopathies do occur in some. The strongest association is with thyroid dysfunction, either hyper- or hypothyroidism (Graves’ disease, Hashimoto’s thyroiditis, toxic goitre). Despite many clinical studies, it is difficult to conclude the strength of the association or the frequency of circulating antimicrosomal, antithyroglobulin or anti-TSH receptor antibodies. Vitiligo may begin before, with or after the thyroid disease, but neither the courses nor the treatments of the thyroid disease or vitiligo seem to have any effect on each other.

Figure 6. Depigmentation sometimes occurs in patients with malignant melanoma.

SA JOURNAL OF DIABETES & VASCULAR DISEASE

The validity of the association with diabetes mellitus has not been established. The incidence of Addison’s disease in vitiligo is reported to be 2% but is likely to be less. Two of Thomas Addison’s original patients also had vitiligo. Pernicious anaemia is rare, but is increased in frequency in vitiligo patients. In these patients, the vitiligo is reportedly more widespread, and pernicious anaemia has been reported in those with late-onset vitiligo. An increased incidence of antiparietal cell antibodies has been documented in vitiligo patients with gastric achlorhydria. Depigmentation sometimes occurs in patients with malignant melanoma, therefore sudden onset of progressive vitiligo in late adulthood warrants a search for a suspicious lesion (Fig. 6).9 Halo naevi (Fig. 7) occur frequently and antedate the vitiligo. There may be one or more halo naevi and confluence of these halo naevi leaves a vitiligo-like macule with scalloped borders. Alopecia areata (Fig. 8) has been reported in up to 16% of vitiligo patients and there have been reports of patients with alopecia universalis and extensive to universal vitiligo, having associated thyroid disease, multiple autoantibodies and hypoparathyroidism.

Autoimmune polyendocrine syndromes (APS) Four main types of APS have been described, types 1 to 4, with type 4 consisting of combinations not included in types 1 to 3.1,3,4,10 The most important dermatological form is APS type 1, which is usually due to the R257X mutation of the AIRE (autoimmune regulator) gene on chromosome 21. It is associated with approximately 13% of cases of Addison’s syndrome. This condition is also called mucocutaneous candidiasis-endocrinopathy syndrome, multiple endocrinopathy syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome or Whitaker’s syndrome. Dermatological features include: mucocutaneous candidiasis, nail dystrophy, alopecia areata, vitiligo and cutaneous features of Addison’s disease. A feature in this condition is the presence of complement-fixing melanocyte autoantibodies in almost all patients with vitiligo and APS type 1. Autoantibodies have been described in patients with Figure 7. Halo naevus.

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APS type 1 without vitiligo and have, in some cases, preceded the presentation. Some 63% of patients with APS type 1 and vitiligo have antibodies against transcription factors SOX9 and SOX10. Patients with APS types 2 and 3 more commonly have diabetes but less commonly have vitiligo or alopecia. They do not have chronic mucocutaneous candidiasis.

Treatment1,3,4,11 The aim of treating vitiligo is to achieve repigmentation, but treatment is unsatisfactory and in many cases, patients are advised to practise cosmetic camouflage.Psychological support in the form of explanation of the nature of the disease process and the available therapies (and their limitations) is mandatory. Support groups and psychological counselling may be required.

Repigmentation therapies Narrowband UVB is safe and effective. Psoralen plus phototherapy (PUVA) is indicated for those in whom there is no other satisfactory option. Topical PUVA is indicated for isolated macules, involving 1 to 2%, occasionally 5% of the body surface, but the topical application of psoralens is hazardous and may cause blistering of the skin due to phototoxicity. Oral PUVA is effective but requires at least six month’s treatment and patients need to have reasonable expectations. Although there is a 50 to 70% chance of repigmentation of the face, neck, trunk, upper

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arms and legs, mucosal and acral vitiligo does not respond well. Topical corticosteroids are effective, but patients should be educated and monitored for side effects, such as atrophy and striae. Topical immunosuppressants such as 0.1% tacrolimus have resulted in repigmentation without the side effects associated with topical steroids. Surgical therapies, such as autologous transplantation may be effective in vitiligo: that is stable for at least six months, that has had an unsatisfactory response to medical therapy, in the absence of Koebner phenomenon, that has no tendency to scar or keloid formation, if the age of the patient is above 12 years. Micropigmentation is the process whereby a non-allergenic iron oxide pigment is tattooed into the skin to camouflage depigmentation. Although the colour may not be an exact match, the immediate results have an aesthetic advantage. The 308-nm excimer laser is close to narrowband UVB and is used for localised lesions. Focused microphototherapy irradiates only the depigmented skin, but is expensive and requires trained personnel.

Depigmentation This may be considered in widespread disease where few normally pigmented areas remain. It is vital that the patient realises that his/ her appearance will change dramatically and that he/she needs to use lifelong photoprotection.

Conclusion Figure 8. Alopecia areata has been reported in up to 16% of vitiligo patients.

Vitiligo may therefore present alone or as part of a complex of diseases (be it rarely). Therefore, when a patient presents with vitiligo, associated conditions should be excluded. The management of vitiligo itself does not differ when it occurs de novo or as part of a spectrum of diseases, but the other conditions require management. The psychological impact of this disease on quality of life must not be underestimated.11

References Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. 2nd edn. Spain: Mosby-Elsevier, 2008. 2. Nordlund JJ. Not just skin deep: The complicated pathogenesis of vitiligo. http:// www.dermquest.com/Expert_Opinions/Clinical_Updates/Not_just_skin_deep_ The_complicated_pathogenesis_of_vitiligo.html 3. Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, Fitzpatrick TB. Fitzpatrick’s Dermatology in General Medicine. 5th edn. New York: McGraw-Hill, 1999. 4. Burns T, Breathnach S, Cox N, Griffiths C. Rook’s Textbook of Dermatology. 8th edn. Singapore: Wiley-Blackwell, 2010. 5. Kovacs SO. Vitiligo. J Am Acad Dermatol 1998; 38; 647–668 6. Basak PY, Adiloglu AK, Ceyhan AM, Tas TK Akkaya VB. The role of helper and regulatory T cells in the pathogenesis of vitiligo. J Am Acad Dermatol 2009; 60; 256–260. 7. Hann SK, Lee HJ. Segmental vitiligo: clinical findings in 208 patients. J Am Acad Dermatol 1996; 35; 671–674. 8. Akay BN, Bozkir M, Anadolu Y, Gullu S. Epidemiology of vitiligo, associated autoimmune diseases and audiological abnormalities: Ankara study of 80 patients in Turkey. J Eur Acad Dermatol Venereol 2010; 24; 1144–1150. 9. Lerner AB, Kirkwood JM. Vitiligo and melanoma: can genetically abnormal melanocytes result in both vitiligo and melanoma within a single family? J Am Acad Dermatol 1984; 11; 696–701. 10. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Acta Bio Medica 2003; 74: 9–33. 11. May W, Linthorst Homan MW, Spuls PI, de Korte J, Bos JD, Sprangers MA, et al. The burden of vitiligo: Patient characteristics associated with quality of life. J Am Acad Dermatol 2009; 61; 411–420. 1.

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Genetic counselling in type 1 diabetes mellitus BERTRAM D HENDERSON Introduction

n 1976, James Neel, the renowned human geneticist, titled a book chapter ‘Diabetes mellitus: a geneticist’s nightmare’.1 Eleven years later, in 1987, Harry Keen wrote ‘The genetics of diabetes: from nightmare to headache’,2 closing with the title of Rotter’s 1981 article ‘no longer a nightmare but still a headache’.3 Since then a wealth of information has been accumulated about diabetes mellitus. Diabetes is now considered a group of metabolic disorders characterised by chronic hyperglycaemia resulting from defects in insulin secretion, action or both.4 In type 1 diabetes mellitus (T1D) there is destruction of the pancreatic islet β-cells. T1D is divided into type 1A where there is T-cell mediated destruction of the pancreatic islet β-cells, and type 1B where the destruction of these cells is not immune mediated.4 The full classification of diabetes is set out in Table 1.4,5 Diabetes mellitus, including T1D, is being diagnosed more frequently than previously,4,5 thus putting a greater demand on health resources. The identification of at-risk individuals in order to embark on preventative strategies has therefore become a valuable approach to the reduction of the diabetic burden of disease.

The genetics of type 1 diabetes mellitus The advent of new, powerful, analytical genetic techniques including candidate gene approaches, positional cloning, genomewide association studies and single nucleotide polymorphism (SNP) profiling has resulted in a vast amount of genetic information becoming available in a short period of time.6,7 T1D has been linked to more than 50 chromosome loci with at least 40 candidate causal genes identified. The most consistent and strongest linkage is with human lymphocyte antigen (HLA) on chromosome 6p21.3 and specifically the DRB1, DQA1 and DQB1 (DR3/DR4) loci, which accounts for 40% of familial aggregation.4,5,7,8 There is also strong linkage to genes involved in T-cell function (PTPN22, CTLA-4), the insulin gene (INS), interleukin-2 (IL2RA) and an interferon-induced helicase gene (IFIH1).5,7,8 Some of the other loci have inconsistent results and a number are linked with up to five other autoimmune disorders.7,8 Readers can access www. t1dbase.org for more detail on the genes within these loci.9 This plethora of information makes the understanding of the genetics less complicated than before but still poses a number of challenges, particularly for the healthcare practitioners with limited genetics training and knowledge.

Correspondence to: Bertram D Henderson Division Human Genetics, University of the Free State, Bloemfontein Tel: +27 (0) 51 405-3046 e-mail: Gnmgbdh@ufs.ac.za S Afr J Diabetes Vasc Dis 2011; 8: 10–13.

Differential diagnosis of insulin-dependent diabetes in children The majority of children presenting with insulin-dependent diabetes mellitus (IDDM) will have type 1A diabetes. A large United Kingdom study found that only 0.7% of children with IDDM had one of the rare non-immune mediated forms. Their causes include defects in insulin secretion, the so-called MODY (maturity-onset diabetes of the young) where seven genes are known to be involved and insulin receptor mutations result. Mutations in the glucokinase gene cause a non-progressive hyperglycaemia. Diabetes in infants under six months of age is usually due to mutations in the KCLN11 gene. Other disorders to consider, in which diabetes is part of the clinical features, are the autosomal recessive Alstrom, Bardet-Biedl, Wolfram (or DIDMOAD), Wolcott-Rallison or Rogers syndromes. Mitochondrial (same mutations that cause MELAS) mutations can also present with diabetes in childhood. Monogenic forms of diabetes are to be considered when diabetes is diagnosed before six months of age, there is an autosomal-dominant family history of diabetes, consanguinity, mild fasting hyperglycaemia in young people and extra-pancreatic features such as deafness, optic atrophy, liver disease or epiphyseal dysplasia.10-12

Genetic counselling The American Society for Human Genetics in 1975 adopted the description of genetic counselling13 as a communication process that deals with the human problems associated with the occurrence, or risk of recurrence, of a genetic disorder in a family. The process

Table 1. The classification of diabetes mellitus Type 1

β-cell destruction, usually leading to absolute insulin deficiency

Immune mediated

Idiopathic (non-immune)

Type 2

Non-insulin dependent diabetes mellitus. May range from predominantly insulin resistance with relative insulin deficiency to predominantly secretory defect with or without insulin resistance

Type 3

Other specific types

Genetic defects of β-cell function

Genetic defects in insulin function

Diseases of exocrine pancreas

Endocrinopathies

Drug or chemically induced

Infections

Uncommon forms of immune-mediated diabetes

Other genetic syndrome sometimes associated with diabetes

Type 4

Gestational diabetes

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involves an attempt by one or more appropriately trained persons to help the individual or family to: • comprehend the medical facts, including the diagnosis, probable course of the disorder, and the available management • appreciate the way heredity contributes to the disorder and the risk of recurrence in specified relatives • understand the alternatives for dealing with the risk of recurrence • choose a course of action which seems to them appropriate in view of their risk, their family goals and their ethical and religious standards, and to act in accordance with that decision • make the best possible adjustment to the disorder in the affected family member and/or to the risk of recurrence of that disorder. In 2006 the National Society of Genetic Counselors adopted a slightly different definition. This stated that genetic counselling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following: • interpretation of family and medical histories to assess the chance of disease occurrence or recurrence • education about inheritance, testing, management, prevention, resources and research • counselling to promote informed choices and adaptation to the risk or condition.14

family history, including relevant clinical features of those reported to be affected. The family history must be at least three generations and should be depicted as a family tree or genogram to facilitate interpretation of the data. Important information that can be obtained from the family history begins with the biological relationship between affected members, and the presence and degree of consanguinity if present. For those reported as affected, it is necessary to determine the regions where they were raised and live, the type of their diabetes, their age at onset and progression of the disease, as well as the presence of co-morbidities such as deafness, optic atrophy or skeletal dysplasia. From this information, the clinician should be able to identify monogenic forms of diabetes such as MODY, neonatal diabetes, Wolfram syndrome, mitochondrial (part of type 1B) and X-linked forms. Many cases of type 1B diabetes (insulin-dependent diabetes without evidence of antibodies) are reported to occur in persons of African or Asian descent.4 It is therefore important to consider other forms of diabetes, as shown in Table 1, in South Africa. Craig et al. tabulated the differences between T1D and monogenic forms.4 Genetic syndromes that are sometimes complicated by diabetes, such as cystic fibrosis (CF), Bardet-Biedl (BBS), Prader-Willi (PWS) and Turner syndromes may also be suspected or identified.10-12 Where such syndromes are suspected and/or identified, the individual and family need to receive specific care, including counselling, from a medical geneticist or genetic counsellor if available. Such counselling is outside the brief of this article. Despite a positive family history being obtained in about 10% of patients with T1D, a clear inheritance pattern for it has not been identified. T1D is considered to be multi-factorial in inheritance with

Establishing and interpreting the family history Vital to the process of counselling individuals (or for children and their parents) with or at risk of T1D is the documentation of a

Figure 1. Putative functions of non-HLA associated loci in T1D. The y-axis indicates the best estimate of the odds ratio for risk alleles of each of the indicated loci, based on current publications. The HLA region’s odds ratio is not indicated but is approximately 6.8. On the x-axis, possible candidate genes within the genomic regions with strong associations are indicated. The bars are coloured in accordance with known functions of these genes and to suggest a probable role in the susceptibility to T1D. At IL2RA and TNFAIP3 there is evidence of two different effects on risk and they therefore appear twice. From Concannon et al. 2009, reproduced with permission. 2.50 2.25

Insulin production and metabolism

Protection from beta-cell apoptosis

Immunity

Unknown function

2.00

Odds Ratio

1.75 1.50 1.25 1.00 0.75 0.50 0.25

TAGAP

TRNFAIP3

TNFAIP3

CIQTNF6

IL7RA

RGS1

UBASH31

CACH2

IL2

PRKCQ

IL2RA

CD226

CTSH

IFIH1

CCR5

PTPN2

IL18RAP

CTLA4

CLEC16A

PTPN2

ERBB3

SH2B3

IL2RA

PTPN22

INS

0.00

Locus

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a well-defined genetic susceptibility. This is supported by numerous factors, including that the concordance rate of T1D in monozygotic twins is only about 40% and the risk for a sibling to develop T1D is 4% at 20 years age and 9.6% by 60 years age. T1D is two to three times more common in offspring of a diabetic man compared to a diabetic mother.4 A child with both of the highest-risk haplotypes (DR3-DQ2 and DR4-DQ8) has a 5% chance of developing T1D by the age of 15 years but if that child has a sibling with the same haplotype and diabetes, the risk increases to about 55% compared to a population incidence of 0.5%.7,8 The high-risk haplotype is present in about 40% of children with T1D compared to about 2% in the general population.8 Table 2 lists the high-risk and protective HLA haplotypes.8 Fig. 1 represents the odds ratios and probable role of the non-HLA loci in T1D susceptibily.7 Andrew Hattersley states that a molecular diagnosis of diabetes is possible for most patients.6 This may be true in developed countries but not so in South Africa with our limited access to genetic testing. Immunological and genetic determination of the HLA haplotyping is available in South Africa, as well as genetic testing for some South African genetic diseases (CF, PWS, BBS) associated with diabetes. No laboratory offers routine analysis for the MODY, insulin-dependent or other genetic types of diabetes. We can therefore only use HLA haplotyping and the presence of auto-antibodies to refine the risk of developing T1D. It is generally accepted that an environmental trigger is required to initiate the autoimmune process that causes type 1A diabetes. Apart from congenital rubella, no other environmental agent has yet been convincingly shown to result in T1D.4,5,7,8,15 However, the involvement of IFIH1 in the innate immune recognition of picorna virus7 may add weight to theory of a viral trigger. The above figures form the basis of calculating the risk for developing T1D. Additional information can be obtained by testing for the presence of antibodies to pancreatic islet cells, insulin, glutamic acid decarboxylase (GAD) and protein tyrosinase phosphate (IA-2).16 The presence of antibodies does not always indicate the presence of β-cell destruction. Infants of type 1A diabetic mothers, who have GAD65 and IA-2 antibodies at birth but no insulin antibodies, have a reduced development of anti-islet Table 2. The HLA haplotypes associated with T1D

antibodies and do not develop diabetes.4,5 The HLA haplotype DQA1*0102DQB1*0602 is protective, with a markedly reduced association with diabetes.5,8 HLA haplotyping of black South Africans has to the author’s knowledge not been undertaken and therefore the risks associated with HLA haplotypes may need to be used with some caution, even though the HLA association has been confirmed in many different populations and ethnic groups across the globe. Using available genetic and aetiological information, prevention strategies have been undertaken in animal models. To date, safe prevention in humans has not been achieved but trials aimed at preventing diabetes are being undertaken. These trials target the prevention of the autoimmune process being initiated, or strategies to preserve pancreatic β-cells after diagnosis. The lack of precise and cost-effective identification of high-risk individuals means that large numbers of subjects need to undergo potentially harmful treatment to prevent a small amount of diabetes. Starting preventative strategies later will target persons with a more predictable risk but reduce the number of potential strategies and impact.16 Counselling on the course of the disease and lifestyle adaptation for T1D should be undertaken by diabetologists and dieticians experienced in the care of people with diabetes, rather than by medical geneticists or genetic counsellors. The same is probably true for regular screening of a person at increased risk of developing diabetes. Should lifestyle changes or other prevention strategies become available to offset the development of diabetes, this will probably also be part of the duties of a diabetologist or dietician experienced in the care of people with diabetes. Diabetic care, diagnosis, treatment and counselling is generally outside the expertise of medical geneticists and genetic counsellors, who will only encounter the condition when confronted with people with a syndrome in which diabetes is part of the phenotype.

Complications of diabetes Genetic markers that predict the development of specific complications of diabetes, such as nephropathy,17 retinopathy or vascular disease, are also available.18 The value of these markers is probably influenced by ethnicity but holds great promise for the practise of ‘personalised medicine’ in those persons with T1D, to modify the care that a specific patient receives to alleviate the problems of these complications.

High-risk haplotypes DR3

DRB1*0301

DQA1*0501

DQB1*0201

Conclusion

DR4

DRB1*0401

DQA1*0301

DQB1*0302

DR8

DRB1*0801

DQA1*0401

DQB1*0402

DR9

DRB1*0901

DQA1*0301

DQB1*0303

There have been major advances in the understanding of the aetiology, pathogenesis and genetics of T1D in recent years. Risk calculation and genetic counselling for people with or at risk of developing T1D is certainly no longer a nightmare but is still challenging and needs close attention to detail of the many different aspects of this complex disease. At least for the present, this should remain the responsibility of those with the relevant knowledge and experience to undertake the task, diabetologists and dieticians experienced in the care of people with diabetes.

DRB1*0402

DQA1*0301

DQB1*0302

DRB1*0405

DQA1*0301

DQB1*0302

DQA1*0101

DQB1*0501

Moderate-risk haplotypes DR1

DRB1*01

Strongly protective haplotypes DR2

DRB1*1501

DQA1*0102

DQB1*0602

Acknowledgements

DR6

DRB1*1401

DQA1*0101

DQB1*0503

DR7

DRB1*0701

DQA1*0201

DQB1*0303

The author thanks Profs A Christianson and W Mollentze for their encouragement and positive comments during the development of this manuscript.

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References 1.

2. 3.

4. 5. 6. 7. 8. 9.

Neel J. Diabetes mellitus: a geneticist’s nightmare. In: Creutzfeldt W, Kobberling J, Neel JV, eds. The Genetics of Diabetes Mellitus. Berlin: Springer-Verlag, 1976: 1–11. Keen H. The genetics of diabetes: from nightmare to headache. Br Med J 1987; 294: 917–919. Rotter JI. The modes of inheritance of insulin-dependent diabetes mellitus or the genetics of IDDM, no longer a nightmare but still a headache. Am J Hum Genet 1981; 33: 835–851. Craig ME, Hattersley A, Donaghue KC. Definition, epidemiology and classification of diabetes in children and adolescents. Pediat Diabetes 2009; 10(suppl 12): 3–12 Jahromi MM, Eisenbarth GS. Cellular and molecular pathogenesis of type 1A diabetes. Cell Mol life Sci 2007; 64: 865–872. Njølstad PR, Molven A, Groop L. Diabetes genetics: A seventh sense for the successful sequel of ‘come together’. J Pancreas 2009: 10(4); 466–471. Concannon P, Rich SS, Nepom GT, Genetics of type 1 diabetes. N Engl J Med 2009; 360: 1646–1654. Kantarova D, Buc M. Genetic susceptibility to type 1 diabetes mellitus in humans. Physiol Res 2007; 56: 255-266. Type 1 diabetes loci. Available at http://www.t1dbase.org/pages/regions (accessed on 14/01/2011).

10. Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue KC. The diagnosis of and management of monogenic diabetes in children and adolescents. Pediat Diabetes 2009; 10(suppl 12): 33–42. 11. Slingerland AS. Monogenic diabetes in children and adults: Challenges for researcher, clinician and patient. Rev Endocr Metab Disord 2006; 7: 171–185. 12. Barrett TG. Differential diagnosis of type 1 diabetes: which genetic syndromes need to be considered? Pediat Diabetes 2007; 8(suppl 6): 15–23. 13. Clinical genetics and genetic counseling. In: Jorde LB, et al., eds. Medical Genetics, 2nd edn. St Louis: Mosby, 1999: 292. 14. The National Society of Genetic Counselor’s Task Force: Resta R, et al. A new definition of genetic counselling: National Society of Genetic Counselor’s Task Force report. J Genet Couns 2006; 15(2): 77–83. 15. Peng H, Hagopian W. Environmental factors in the development of type 1 diabetes. Rev Endocr Metab Disord 2006; 7: 149–162. 16. Kishiyama CM, Chase HP, Barker JM. Prevention strategies for type 1 diabetes. Rev Endocr Metab Disord 2006; 7: 215–224. 17. Zhang D, Efendic S, Brismar K, Gu HF. Effects of MCF2L2, ADIPOQ and SOX2 genetic polymorphisms on the development of nephropathy in type 1 diabetes. BMC Med Genet 2010; 11: 116. 18. Möllsten A, Jorsal A, Lajer M, Vionnet N, Tarnow L. The V16A polymorphism in SOD2 is associated with increased risk of diabetic nephropathy and cardiovascular disease in type 1 diabetes. Diabetologia 2009; 52: 2590–2593.

Living with diabetes in the family

iabetes affects all members of the family, not just the individual suffering with the disease. Even when the patient is stable on medication, one tends to watch him like a hawk for any uncharacteristic behaviour that could indicate that something is amiss. Untreated sores could potentially become infected, lethargy could indicate hypoglycaemia, and lack of appetite any number of problems. And there is the constant niggle at the back of one’s mind about possible long-term organ damage. Having a diabetic in the home also tends to put a dampener on one’s social life. Several years ago, one of my boys became diabetic and needed insulin twice a day at mealtimes – insulin glargine at 7 am and 7 pm. This meant if I had a dinner date, I could only leave home after 7 pm. If I had an afternoon/evening function, I had to be back in time for the evening insulin injection. Going away for a weekend was difficult because most house-sitters won’t give insulin injections as part of their service. Once, when spending the weekend at a nearby hotel, I rushed home at 7 am to give him the injection and then went back for a leisurely breakfast! Type 2 diabetes seems to be relatively common in cats and dogs and can be triggered by many things. In our case, it may have been related to the stress of being trapped and put into an animal rescue organisation, together with the fact that Biggles had been homeless for some time preceding this. Also, he was about 10 years old at the time of diagnosis. The first indications were weight loss and increased drinking and urination, together with a dry, dull coat. Once Biggles was put onto insulin his condition rapidly improved and we settled into a routine of a commercial high-protein, reduced

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fat diet and the twice-daily insulin injections. I soon discovered that the easiest way to inject him was to wait until he was eating and his attention was diverted from what I was doing. He then didn’t mind me gently lifting the skin on the back of his neck and giving him the subcutaneous injection. He was an extremely good patient. Blood sugar is monitored in animals in the same way as in humans but because Biggles was so stressed at the vet, this could have affected his glucose reading. So a twice-yearly fructosamine test was the easiest and least disruptive way to monitor his blood sugar levels. The blood sample is done in the laboratory and the fructosamine value reflects the average glucose levels over the past fortnight. This routine went on for three or more years until I gradually became aware that Biggles was becoming less active and more lethargic than he had been. One Sunday he was really subdued and seemed to be in pain, so I rushed him to the vet. On hearing that he was diabetic, the vet immediately tested his glucose levels and found them drastically low, bordering on a diabetic coma. A syringe of glucose administered orally and an infusion of glucose pushed up his blood sugar levels, but by the next day, they had dropped way down again. The vet was baffled, so a battery of tests was ordered, but nothing else seemed to be amiss (except a bit of cervical arthritis). He was then taken off all insulin and diabetic food and we monitored his glucose levels daily. Fortunately they slowly rose over the next week and when we retested six months later, the level was still within the normal range. Biggles is now off insulin completely and

Biggles

eats normal cat food. He is doing very well and has regained his sparkle and zest for life. There is no obvious reason why his diabetes has disappeared, but apparently this is a phenomenon that has been known to occur in cats particularly. We of course are delighted that our boy is normal again. We no longer have to worry about every cut or scratch becoming infected, he doesn’t have to be kept calm, and the longterm damage to kidneys and other organs of the body is hopefully lessened. I am sure Biggles is also very pleased that we are no longer using his neck as a pincushion, but otherwise he seems oblivious to the worry and anxiety his disease has caused us. Shauna Germishuizen

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Diabetes and thyroid disorders GABrIElA BrENTA Abstract

t has long been recognised that thyroid hormones have marked effects on glucose homeostasis. Glucose intolerance is associated with hyperthyroidism and most recently it was shown that hypothyroidism is characterised by insulin resistance. Although autoimmune thyroid disease is more prevalent in type 1 diabetes as a result of their common origin, in patients with type 2 diabetes the prevalence of hypothyroidism and hyperthyroidism is similar to that of the general population. However, in type 2 diabetic patients, the presence of the highly frequent sub-clinical forms of hyperthyroidism and hypothyroidism should be ruled out since they may be associated with higher cardiovascular risk. While there are no doubts about the therapeutic impact of normalising hypothyroidism and hyperthyroidism, the information available about the benefit of treating subclinical thyroid disease in diabetes remains insufficient.

Gabriela Brenta

Keywords: diabetes, hyperthyroidism, hypothyroidism, insulin resistance, thyroid.

Introduction The term ‘thyroid diabetes’ was coined in the early literature to depict the influence of thyroid hormone excess in the deterioration of glucose control,1 and for nearly a century many publications focused on the relationship between diabetes and thyroid disease. The literature concerning the effects of thyroid hormones on glucose metabolism in normal and diabetic states has been evaluated in detail.2 This review will therefore address only specific issues of a broad field. It is intended to illustrate some aspects of the prevalence of thyroid disorders in the general population and in diabetic patients, the pathological mechanisms underlying both diseases and the use, or potential use, of pharmacological therapies to treat diabetic and thyroid patients. A brief overview of long-term mortality or morbidity studies in patients with thyroid dysfunction and diabetes will also be presented.

Prevalence of thyroid disorders in the general population and in diabetic patients Both hyperthyroidism and hypothyroidism are graded phenomena, ranging from very mild cases in which biochemical abnormalities are present without any symptoms or signs of thyroid hormone

Department of Endocrinology and Metabolism, Cesar Milstein Hospital, Buenos Aires, Argentina. Correspondence to: Dr Gabriela Brenta Virrrey del Pino 3370 3ºA, CABA 1426, Argentina. Tel: +5411 4555 7593 E-mail: gbrenta@gmail.com S Afr J Diabetes Vasc Dis 2011; 8: 14–18.

Abbreviations and acronyms AITD

autoimmune thyroid disease

ATP adenosine-5′-triphosphate BMI

body mass index

HbA1C

glycated haemoglobin A1C

HIF-1a

hypoxia-inducible factor 1a

MHC

major histocompatibility complex

NHANES

National Health and Nutrition Examination Survey

T3 triiodothyronine TSH

thyroid stimulating hormone/thyrotropin

excess or deficiency, to very severe cases that may end up as a life-threatening thyrotoxicosis crisis or myxoedema coma. Their prevalence varies according to the studied population. The Whickham survey, conducted in the north of England, revealed a prevalence of overt thyrotoxicosis or hypothyroidism of at least 2% in females and 0.2% in males.3 In the NHANES III study it was shown that 4.6% of the US population had hypothyroidism (0.3% clinical and 4.3% sub-clinical) and 1.3% had hyperthyroidism (0.5% clinical and 0.7% sub-clinical).4 The incidence of progression from sub-clinical to overt hypothyroidism is 5–15% per year; women with positive thyroid antibodies are especially at risk.3 Sub-clinical hypothyroidism, the most prevalent form of thyroid diseases, is more common in females and in the elderly, reaching a prevalence of up to 20% in women over 60 years old.5 This increased prevalence in the elderly was recently questioned by Surks et al.6 whose re-analysis of the NHANES data revealed that TSH serum values might be shifted toward higher levels with increasing age. Accordingly, TSH levels up to 7.5 μU/ml would be considered normal in a patient 80 years and older and about 70% of the

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raised values for this age group would fall within the 97.5 centile of their age-specific range. Sub-clinical hyperthyroidism is also more common in older age groups, but its female preponderance is less marked. The incidence of progression to overt thyrotoxicosis is approximately 5% per year; and patients with autonomous thyroid adenoma or nodular goitre are especially at risk.7 The main causes of hypothyroidism and hyperthyroidism are Hashimoto’s thyroiditis and Graves’ disease respectively, both of an autoimmune nature. Since type 1 diabetes also has autoimmunity as a pathophysiological detonator it is not unusual to find patients with concomitant diabetes and thyroid dysfunction. Some genetic factors might contribute to the co-occurrence of AITD and type 1 diabetes.8 Moreover the association between type 1 diabetes and AITD is considered one of the variants of the autoimmune polyglandular syndrome. The MHC locus on chromosome 6p21 is one of the susceptibility loci for both diseases. An odds ratio of approximately 2 has been reported for the association of the DR3 haplotype with Graves’ disease, which is even higher, between 3 and 4, in people who have type 1 diabetes. Several other factors that intervene in the immune response might also contribute to AITD and type 1 diabetes susceptibility. PTPN22, which encodes lymphoid tyrosine phosphatase, a negative regulator of T-cell antigen receptor (CD3) signalling and the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene have both been confirmed as major joint susceptibility genes for type 1 diabetes and AITD. Prevalence studies show that AITD is higher in type 1 diabetes. Perros et al.9 reported thyroid dysfunction in up to 31.4% of adult type 1 diabetic females. Moreover, in children with type 1 diabetes, the proportion of positive thyroid antibodies might increase up to 20% and about 3–8% of children and adolescents with type 1 diabetes have been reported to develop autoimmune hypothyroidism.10 Postpartum thyroiditis, a rather common event, with an incidence of 4–6% as evident from several populationbased studies, is threefold higher (up to 25%) in women with type 1 diabetes.11 Although thyroid disease, overt or sub-clinical, is reported to be relatively common in type 1 diabetes, a longitudinal Australian study in type 2 diabetic women without known thyroid disease showed that sub-clinical hypothyroidism is a common, but incidental finding.12 Nevertheless, increased risk for thyroid autoimmunity in adult type 2 diabetic patients with GAD65 autoantibodies has been reported, and these findings have been confirmed in paediatric populations.13,14 As regards the metabolic syndrome, as might be expected, the prevalence of sub-clinical hypothyroidism is higher in patients with the condition than in non-metabolic syndrome subjects.15 These findings can be explained by the concomitance of deranged serum lipid concentrations, obesity, hypertension and insulin resistance, all components present in metabolic syndrome as well as in hypothyroid patients. In view of the relatively high prevalence of both endocrinopathies, it is important to investigate all diabetic patients for thyroid disorders. However, screening has been recommended only in children and adolescents with type 1 diabetes.7,16 TSH should be tested several weeks after the diagnosis of type 1 diabetes, when metabolic control has been established. If the TSH level is normal, patients should have a repeat measurement every one to two years. Additional thyroid function testing should be obtained whenever thyroid dysfunction is suspected or thyromegaly is detected. With regard to diabetic adults, there is no consensus as to whether screening for thyroid disorders should be mandatory.

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Pathological mechanisms common to thyroid disorders and diabetes Thyroid hormones exert profound effects in the regulation of glucose homeostasis. These effects include modifications of circulating insulin levels and counter-regulatory hormones, intestinal absorption, hepatic production and peripheral tissues (fat and muscle) uptake of glucose (Fig. 1). It has long been known that thyroid hormones act differentially in liver, skeletal muscle and adipose tissue – the main targets of insulin action. While thyroid hormones oppose the action of insulin and stimulate hepatic gluconeogenesis and glycogenolysis,18,19 they up-regulate the expression of genes such as GLUT-4 and phosphoglycerate kinase, involved in glucose transport and glycolysis respectively, thus acting synergistically with insulin20,21 in facilitating glucose disposal and utilisation in peripheral tissues. The recent identification of another gene regulated by thyroid hormones in cultured human fibroblasts,22 the transcription factor HIF-1a, responsible for elevated expression of glycolytic enzymes and glucose transporters, is an example that the field of thyroid diabetes is still open to new discoveries. Thyroid disorders have a major impact on glucose control. When thyroid dysfunction ensues the glucose homeostatic balance is broken (Fig. 2). Insulin resistance, mainly associated with increased hepatic gluconeogenesis, is characteristic of an excess of thyroid hormones and explains why glucose control deteriorates when diabetic patients develop hyperthyroidism. Thyrotoxic patients show an increased glucose turnover with increased glucose absorption through the gastrointestinal tract, post-absorptive hyperglycaemia and elevated hepatic glucose output, along with elevated fasting or postprandial insulin and proinsulin levels, elevated free fatty acid concentrations and elevated peripheral glucose transport and utilisation. In peripheral tissues there is a massive arrival of glucose to the cells that overwhelms the Krebs cycle resulting in an increased metabolism of glucose through the nonoxidative pathway. Lactate produced in great quantities in the cells returns to the liver and participates in the Cori cycle where four ATP molecules are wasted for each glucose molecule that is created.23

Figure 1. Thyroid hormone (TH) effects on glucose homeostasis.

Euthyroidism

Increased intestinal glucose absorption

Increased hepatic gluconeogenesis glycogenolysis (insulin antagonism)

Glucose

Increased peripheral tissues glucose utilisation (insulin synergism)

Increased betacell function

Glut 4 TH

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Figure 2. Thyrotoxicosis and glucose homeostasis.

Hyperthyroidism

Thyrotoxicosis results in glucose intolerance and increased insulin requirements in diabetes

Highly increased intestinal glucose absorption

Figure 3. Hypothyroidism and glucose homeostasis.

Increased hepatic gluconeogenesis glycogenolysis with hepatic insulin resistance

Increased hepatic glucose output and postabsorptive glycaemia

Hyperthyroidism

Elevated fasting and/or postprandial insulin (at the expense of proinsulin/ inactive) levels. Apoptosis of insulinproducing cells

Decreased hepatic gluconeogenesis glycogenolysis

Reduced hepatic glucose output and postabsorptive glycaemia

Increased peripheral tissues glucose utilisation with peripheral insulin resistance

Although glucose uptake in peripheral tissues has been described as either normal or increased,24,25 reduced insulin stimulated peripheral glucose utilisation has also been demonstrated in hyperthyroidism.26 The notion that insulin stimulation of glucose uptake in thyrotoxic tissues may be impaired can be interpreted in the context of lower glucose extraction from serum in proportion to increased blood flow.27 As regards insulin secretion, thyrotoxicosis has been associated with normal, decreased or increased beta-cell function.2,28 However, it has been suggested that proinsulin in excess may account for the hyperinsulinemia observed with higher release of insulin both after absorption and at baseline, when compared with the euthyroid situation or with control subjects.2 Moreover, recent studies have shown that thyroid hormones increase beta-cell apoptosis and that this could be one major element responsible for deterioration of glucose tolerance in thyrotoxicosis.2,29 In hypothyroidism, glucose homeostasis is also affected although its clinical impact is less obvious (Fig. 3). Decreased glucose disposal (compared with euthyroid subjects) has been proved in hypothyroid patients by different methods including clamp studies,30,31 the arteriovenous difference technique in the anterior abdominal subcutaneous adipose tissue and forearm muscles after the consumption of a mixed meal,32 the insulin tolerance test33 and following intravenous34 or oral35 administration of glucose. Nonetheless, hypothyroidism results in unimpaired36 or decreased37,38 liver glucose output thereby compensating for insulin resistance present in peripheral tissues and accounting for the diminished insulin requirement for glycaemic control in hypothyroid diabetic patients. With regard to beta-cell function, normal or reduced basal plasma insulin levels have been described in hypothyroidism. These findings are quite consistent with the idea of attenuated endogenous glucose production in the hypothyroid state.2 On the other hand, increased glucose-stimulated insulin secretion has been recently described in humans and interpreted as a response to elevated whole-body insulin resistance increasing demand on beta-cells.31

Decreased intestinal glucose absorption

Reduced baseline plasma insulin levels with increased post glucose insulin secretion

Decreased peripheral tissues glucose disposal Glut 4

Although most of these observations apply to overt hypothyroidism, insulin resistance has been also reported in subclinical hypothyroidism,35 adding one more possible mechanism to the association of sub-clinical hypothyroidism and cardiovascular risk. Furthermore, it has been shown, both in euthyroid nondiabetic39 and diabetic adults,40 that small variations in TSH at different levels of insulin sensitivity might exert a marked effect on lipid levels. The interaction between insulin resistance and lower thyroid function might be a key determinant for a more atherogenic lipid profile in these populations (Fig. 4). Even though thyroid status, as assessed by plasma hormone levels, is a key indicator of glucose homeostasis, T3 intracellular pathways are also relevant. The hormonal message is modulated at a local level by a series of control steps, including the intracellular concentration of T3 via deiodinases, and the relative concentration of T3 receptor isoforms, co-activators, and co-repressors. These systems ultimately result in tissue-specific thyroid hormone action, which is relatively independent of the circulating thyroid hormone levels. Polymorphism Thr92Ala, which confers a lower activity to type 2 deiodinase, has been associated with insulin resistance in some populations41 and is a good example of hidden regulatory mechanisms.

Figure 4. Relationship between serum thyroid stimulating hormone (TSH) and cholesterol appears to be modified by insulin resistance (IR).

TSH Lower risk for dyslipidaemia

In euthyroid diabetic and non-diabetic subjects

Lipid parameters with adverse cardiac risks

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Intervention strategies for thyroid disorders Among the intervention strategies for hyperthyroidism, conventional treatment modalities include antithyroid drugs, radio-iodine or surgery. Hypothyroidism is conventionally treated with replacement doses of levothyroxine. As regards sub-clinical forms of both conditions, due to the paucity of conclusive data derived from clinical trials, evidence-based recommendations are cautious and sometimes not conclusive when TSH levels are slightly deranged.42 Individualisation of therapy is most probably the answer in these patients. The presence of several cardiovascular risk factors in diabetic patients with sub-clinical thyroid impairment should be taken into consideration for therapeutic purposes. Some special situations must be considered with regard to the pharmacological aspects of the drugs commonly used to treat diabetic and thyroid patients. It has been reported that certain sulphonylureas can inhibit the synthesis of thyroid hormone. They include older-generation drugs such as carbutamide, tolbutamide, methahexamide, and possibly chlorpropamide.43 Moreover, metformin has been shown to reduce thyrotropin levels in diabetic patients with primary hypothyroidism on thyroxine replacement therapy.44 Thiazolidinediones, on the other hand, have been reported to induce thyroid-associated orbitopathy.45 Another situation in which to apply caution is with the use of statins in diabetes. Myopathy can be much more common in statin-treated diabetic patients with undiagnosed hypothyroidism.46 Thyroid hormone analogues are still under development. They retain some of the beneficial aspects of thyroid action on liver, fat and muscle while sparing the detrimental effects of thyroid hormones on the heart.47 Some of these compounds have been shown to lower glucose levels in mice and are promising treatment modalities for diabetes.48

Diabetes plus thyroid disorders: long-term mortality or morbidity As previously mentioned, sub-clinical hypothyroidism and hyperthyroidism have both been linked to increased cardiovascular risk.49 Only a few studies have explored the effects of sub-clinical thyroid dysfunction in the diabetic population. One of these studies was performed in 588 Taiwanese type 2 diabetic patients with subclinical hypothyroidism compared with euthyroid patients. In the cross-sectional analysis, sub-clinical hypothyroidism was associated with a higher frequency of nephropathy (after adjustment for, among other factors, age, gender and HbA1C). After four years, sub-clinical hypothyroidism was associated with a higher rate of incident cardiovascular events in patients with type 2 diabetes, although this became non-significant after additional adjustment for urinary albumin:creatinine ratio.50 In line with these findings are the results of another cross-sectional study of 1 170 type 2 diabetic patients.51 Patients with sub-clinical hypothyroidism had a higher prevalence of retinopathy, especially the sight-threatening form, when compared with their type 2 diabetic euthyroid counterparts.51 Mortality has been explored in 382 women with type 2 diabetes belonging to the Fremantle Disease Study, which has a follow-up of nine years. Only a borderline significance for the effect of serum TSH status on all-cause and cardiac mortality was observed in the lowest serum TSH category.12 This study was included in a meta-analysis by Haentjens et al.52 which reported that compared with euthyroid control subjects, sub-clinical hyperthyroidism yielded a significant 1.49-fold increase in relative likelihood of death from all causes. In

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the general calculation, global mortality was not increased in subclinical hypothyroidism. However, after the analysis was stratified by studies with patients with co-morbidities (atomic bomb survivors, type 2 diabetes, cardiac, stroke, or hip-fracture patients) all-cause mortality was significantly higher than in the euthyroid population. On the other hand, a retrospective analysis of a diabetes database of 6,540 patients showed a lower mortality rate in patients with elevated TSH levels at baseline (mean age of patients was 73 years) versus an age-matched euthyroid group.53 These results support the previous notion that the higher mortality risk in a sub-clinical hypothyroid patient is mainly observed in patients below 65 years of age.54,55

Conclusions The impact of thyroid alterations on glucose metabolism has been known for a long time. Thyrotoxic patients usually lose their glucose control when thyroid decompensation is not promptly solved. Most recently, new pathways of thyroid hormone action at the tissue level have been unveiled and may be of relevance to the understanding of insulin resistance present both in the hypothyroid and hyperthyroid state. While thyroid disorders are more prevalent in people with type 1 diabetes, due to common autoimmune origin, a similar prevalence of thyroid disease has been reported in type 2 diabetes. On the other hand, a much higher frequency of sub-clinical hypothyroidism has been reported in metabolic syndrome patients. These findings are not surprising since several metabolic syndrome traits are associated with hypothyroidism. The co-existence of both diabetes and thyroid disorders has been associated with increased long-term morbidity and mortality. Although the benefits of treating overt thyroid disease are clear, the management of sub-clinical hypothyroidism or hyperthyroidism is not yet solved and conclusive intervention studies are required. It has been suggested that the decision to treat should be taken on an individual approach. In this case, insulin-resistant, dyslipidaemic or diabetic patients, who are at higher risk of cardiovascular disease, might be special cases for whom treatment of sub-clinical thyroid disease has to be seriously considered.

Key messages • In diabetes mellitus, the development of thyrotoxicosis is associated with deranged metabolic control, increased insulin requirements and ketoacidosis • Insulin resistance is evident in overt and sub-clinical hypothyroidism • Prevalence of AITD – is higher in type 1 diabetes – is similar in the general population and type 2 diabetes • In type 2 diabetes – AIDT increases cardiovascular risk – concomitant sub-clinical hypothyroidism increases risk of nephropathy and retinopathy

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25.

26. 27.

28.

Rohdenburg GL. Thyroid diabetes. Endocrinology 1920; 4: 63. Lenzen S, Bailey CJ. Thyroid hormones, gonadal and adrenocortical steroids and the function of the islets of Langerhans. Endocr Rev 1984; 5: 411–34. Boelaert K, Franklyn JA. Thyroid hormone in health and disease. J Endocrinol 2005; 187: 1–15. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002; 87: 489–99. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160: 526–34. Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab 2007; 92: 4575–82. Wiersinga WM. Subclinical hypothyroidism and hyperthyroidism. I. Prevalence and clinical relevance. Neth J Med 1995; 46: 197–204. Pearce SH, Merriman TR. Genetics of type 1 diabetes and autoimmune thyroid disease. Endocrinol Metab Clin N Am 2009; 38: 289–301. Perros P, McCrimmon RJ, Shaw G, et al. Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med 1995; 12: 622–7. Kordonouri O, Maguire AM, Knip M, et al. Other complications and associated conditions with diabetes in children and adolescents. Pediatric Diabetes 2009; 10: 204–10. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2007; 92: S1–47. Chubb SA, Davis WA, Inman Z. Prevalence and progression of subclinical hypothyroidism in women with type 2 diabetes: the Fremantle Diabetes Study. Clin Endocrinol (Oxf) 2005; 62: 480–6. Gambelunghe G, Forini F, Laureti S, et al. Increased risk for endocrine autoimmunity in Italian type 2 diabetic patients with GAD65 autoantibodies. Clin Endocrinol 2000; 52: 565–73. Libman IM, Sun K, Foley TP, Becker DJ. Thyroid autoimmunity in children with features of both type 1 and type 2 diabetes. Pediatr Diabetes 2008; 9: 266–71. Uzunlulu M, Yorulmaz E, Og˘uz A. Prevalance of subclinical hypothyroidism in patients with metabolic syndrome. Endocr J 2007; 54: 71–6. Standards of medical care in diabetes: 2008. Diabetes Care 2008; 31(suppl 1): S12. Kordonouri O, Maguire AM, Knip M, et al. International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2006–2007. Other complications and associated conditions. Pediatr Diabetes 2007; 8: 171–6. Raboudi N, Arem R, Jones RH, et al. Fasting and postabsorptive hepatic glucose and insulin metabolism in hyperthyroidism. Am J Physiol 1989; 256: E159–66. Weinstein SP, O’Boyle E, Fisher M, Haber RS. Regulation of GLUT2 glucose transporter expression in liver by thyroid hormone: evidence for hormonal regulation of the hepatic glucose transport system. Endocrinology 1994: 135: 649–54. Viguerie N, Millet L, Avizou S, et al. Regulation of human adipocyte gene expression by thyroid hormone. J Clin Endocrinol Metab 2002; 87: 630–4. Clément K, Viguerie N, Diehn M, et al. In vivo regulation of human skeletal muscle gene expression by thyroid hormone. Genome Res 2002; 12: 281–91. Moeller LC, Dumitrescu AM, Walker RL, et al. Thyroid hormone responsive genes in cultured human fibroblasts. J Clin Endocrinol Metab 2005; 90: 936–43. Potenza M, Via MA, Yanagisawa RT, et al. Excess thyroid hormone and carbohydrate metabolism. Endocr Pract 2009; 15: 254–62. Dimitriadis G, Baker B, Marsh H, et al. Effect of thyroid hormone excess on action, secretion, and metabolism of insulin in humans. Am J Physiol 1985; 248: E593–601. Muller MJ, Acheson KJ, Jequier E, Burger AG. Effect of thyroid hormones on oxidative and nonoxidative glucose metabolism in humans. Am J Physiol 1988; 255: E146–52. Shen DC, Davidson MB, Kuo SW, Sheu WH. Peripheral and hepatic insulin antagonism in hyperthyroidism. J Clin Endocrinol Metab 1988; 66: 565–9. Dimitriadis G, Mitrou P, Lambadiari V, et al. Insulin-stimulated rates of glucose uptake in muscle in hyperthyroidism: the importance of blood flow. J Clin Endocrinol Metab 2008; 93: 2413–15. Ortega E, Koska J, Pannacciulli N, et al. Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals. Eur J Endocrinol 2008; 158: 217–21.

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29. Ximenes HM, Lortz S, Jörns A, Lenzen S. Triiodothyronine (T3)-mediated toxicity and induction of apoptosis in insulin-producing INS-1 cells. Life Sci 2007; 80: 2045–50. 30. Rochon C, Tauveron I, Dejax C, et al. Response of glucose disposal to hyperinsulinemia in human hypothyroidism and hyperthyroidism. Clin Sci 2003; 104: 7–15. 31. Handisurya A, Pacini G, Tura A, et al. Effects of thyroxine replacement therapy on glucose metabolism in subjects with subclinical and overt hypothyroidism. Clin Endocrinol (Oxf) 2008; 69: 963–9. 32. Dimitriadis G, Mitrou P, lambadiari V, et al. Insulin action in adipose tissue and muscle in hypothyroidism. J Clin Endocrinol Metab 2006; 91: 4930–7. 33. Brenta G, Celi FS, Pisarev M, et al. Acute thyroid hormone withdrawal in athyreotic patients results in a state of insulin resistance. Thyroid 2009; 19: 665–9. 34. Andreani D, Menzinger G, Fallucca F, et al. Insulin levels in thyrotoxicosis and primary myxoedema: response tointravenous glucose and glucagon. Diabetologia 1970; 6: 1–7. 35. Maratou E, Hadjidakis DJ, Kollias A, et al. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol 2009; 160: 785–90. 36. Müller MJ, Paschen U, Seitz HJ. Thyroid hormone regulation of glucose homeostasis in the miniature pig. Endocrinology 1983; 112: 2025–31. 37. Okajima F, Ui M. Metabolism of glucose in hyper and hypothyroid rats in vivo. Glucose turnover values and futile cycle activities obtained with 14C and 3H labelled glucose. Biochem J 1979; 182: 565–75. 38. McCulloch AJ, Nosadini r, Pernet A, et al. Glucose turnover and indices of recycling in thyrotoxicosis and primary thyroid failure. Clin Sci 1983; 64: 41–7. 39. Bakker SJ, ter Maaten JC, Popp-Snijders C. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab 2001; 86: 1206–11. 40. Chubb SA, Davis WA, Davis TM. Interactions among thyroid function, insulin sensitivity, and serum lipid concentrations: The Fremantle Diabetes Study. J Clin Endocrinol Metab 2005; 90: 5317–20. 41. Chidakel A, Mentuccia D, Celi FS. Peripheral metabolism of thyroid hormone and glucose homeostasis. Thyroid 2005; 15: 899–903. 42. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. J Am Med Assoc 2004; 291: 228–238. 43. Brown J, Solomon DH. Mechanism of antithyroid effects of a sulfonylurea in the rat. Endocrinology 1958; 63: 473. 44. Cappelli C, rotondi M, Pirola I, et al. TSH-lowering effect of metformin in type2 diabetic patients. Differences between euthyroid, untreated hypothyroid and euthyroid on l-T4 therapy patients. Diabetes Care 2009; 32: 1589–90. 45. Starkey K, Heufelder A, Baker G, et al. Peroxisome proliferator-activated receptorgamma in thyroid eye disease: contraindication for thiazolidinedione use? J Clin Endocrinol Metab 2003; 88: 55–9. 46. Venero CV, Thompson PD. Managing statin myopathy. Endocrinol Metab Clin North Am 2009; 38: 121–36. 47. Brenta G, Danzi S, Klein I. Potential therapeutic applications of thyroid hormone analogs. Nat Clin Pract Endocrinol Metab 2007; 3: 632–64. 48. Baxter J, Webb P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov 2009; 8: 308–20. 49. Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008; 29: 76–131. 50. Chen HS, Wu TE, Jap TS, et al. Subclinical hypothyroidism is a risk factor for nephropathy and cardiovascular diseases in type 2 diabetic patients. Diabet Med 2007; 24: 1336–44. 51. Yang JK, liu W, Shi J, li YB. An association between subclinical hypothyroidism and sight-threatening diabetic retinopathy in type 2 diabetic patients. Diabetes Care 2010; 33: 1018–20. 52. Haentjens P, Van Meerhaeghe A, Poppe K, et al. Subclinical thyroid dysfunction and mortality: an estimate of relative and absolute excess all-cause mortality based on time-to-event data from cohort studies. Eur J Endocrinol 2008; 159: 329–41. 53. Sathyapalan T, Manuchehri AM, rigby AS, Atkin Sl. Subclinical hypothyroidism is associated with reduced all-cause mortality in patients with type 2 diabetes. Diabetes Care 2010; 33: e37. 54. Ochs N, Auer r, Bauer DC, et al. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med 2008; 148: 832–45. 55. Razvi S, Shakoor A, Vanderpump M, et al. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a metaanalysis. J Clin Endocrinol Metab 2008; 93: 2998–3007.

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The new world of biosimilars: what diabetologists need to know about biosimilar insulins IrENE KräMEr, THOMAS SAUEr Abstract

iosimilar pharmaceuticals are emerging as patent protection on the original biopharmaceutical products expires. However, biopharmaceuticals are particularly complex molecules, and biosimilar insulins present special challenges. In part this reflects their structure and chemical modification after synthesis to attain a biologically active form. Their therapeutic window is narrow and the accuracy of their dosing is highly dependent on the formulation and quality of the administration device. For these reasons, the European Medicines Agency has issued stringent guidelines that must be fulfilled in order to receive approval as a biosimilar soluble insulin. Prescribers should therefore consider issues of manufacture, protein quality, formulation, reliability of supply, and other factors that might affect efficacy, safety and tolerability when making choices regarding the selection of biosimilar products.

Keywords: biosimilars, EMA, recombinant human insulin

manufacturing

processes,

Introduction Biopharmaceuticals are biological medicinal products derived from recombinant DNA and expressed by genetically engineered organisms to produce the target therapeutic proteins in large quantities. The first biopharmaceutical introduced into clinical use was recombinant human insulin (Humulin, Eli Lilly) in 1982. Since then, hundreds of biopharmaceuticals, including cytokines, enzymes, antihaemophilic factors and monoclonal antibodies have received marketing authorisation in various jurisdictions. As patents for the early biopharmaceuticals have already expired, requests for marketing authorisation of ‘similar’ biological medicinal products (so-called biosimilars) have been submitted in the EU, and various biosimilars such as epoetin alfa, somatotropin and GCSF are already available. The EMA was the first regulatory authority to implement a regulatory framework for the marketing authorisation of biosimilars. This requires the submission and approval of a dossier that, while comprehensive, is less detailed than that of the innovator product. Comparable procedures are in place in other jurisdictions including Malaysia, Taiwan and Australia. In the USA,

Thomas Sauer Industrial Affairs, Chemistry and Biotechnology, sanofi-aventis Germany, Frankfurt, Germany Correspondence to: Prof Irene Krämer Pharmacy Department, University Medical Center, Johannes GutenbergUniversity, Mainz, Germany. E-mail: kraemer@apotheke.klinik.uni-mainz.de S Afr J Diabetes Vasc Dis 2011; 8: 19–25.

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Abbreviations and acronyms CHMP

Committee for Medicinal Products for Human Use

CMC

chemistry, manufacturing, controls

EMA

European Medicines Agency

European Union

GCSF

granulocyte colony-stimulating factor

HCP

host-cell protein

IGF

insulin-like growth factor

NPH

neutral protamine Hagedorn

PD pharmacodynamic PK pharmacokinetic PZI

protamine zinc insulin

the Food and Drug Administration is also preparing a regulatory framework; products assessed by this new licensing procedure will be referred to as follow-on biologics (FOBs). In Europe, several human insulins are available, each with an independent marketing authorisation based on a full dossier. The different brands are authorised for use with specific administration devices (generally a single-use or reusable pen). In some countries where patent regulations are less rigorous human insulin and insulin analogues are available that are (by definition) neither innovator products nor biosimilars and are therefore called ‘other insulins’. In 2007, an application to the EMA for marketing authorisation of three biosimilar insulins was withdrawn after the CHMP issued a provisional opinion that the products could not be approved for human use.1 Biosimilars are not interchangeable with originator molecules or with each other as are traditional small-molecule generic drugs.2 In fact, the EMA has stressed that because biosimilars and their reference molecules are not identical, the interchange of a reference medicine for a biosimilar medicine should be based on the opinion of a healthcare professional.3 Hence, it is essential for prescribers to appreciate these issues in order to make informed choices about the biosimilars they will encounter. This article discusses key aspects to consider when evaluating a biosimilar, with a special focus on biosimilar insulin.

Complexities in the manufacture of insulin biopharmaceuticals Protein molecules have molecular weights which may be orders of magnitude higher than those of traditional small-molecule drugs. Their structures are also far more complex, requiring consistency of their primary structure (amino acid sequences), secondary and tertiary structures (three-dimensional folding patterns), and quaternary structure (stable association of two or more identical or different subunits). In the case of recombinant human insulin, the precursor protein is synthesised by genetically modified organisms and must be

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proteolytically cleaved to produce active insulin (Fig. 1). The insulin preparation must also be formulated to control the formation

Figure 1. The biosynthesis of insulin.

C-Peptide SH

SH COO–

A Chain

Signal sequence

H3 N

B Chain Preproinsulin

Signal peptidase cleavage

C-Peptide S

S A Chain S

Tryptic cleavage

B Chain Tryptic cleavage

Proinsulin

S A Chain S

B Chain Insulin

The insulin precursor preproinsulin contains a signal sequence that is proteolytically cleaved to yield proinsulin, whose C chain links the future A and B chains of mature insulin. Cleavage of the C chain converts proinsulin to insulin. Adapted from Joshi SR, et al. J Assoc Physicians India 2007; 55 (suppl): 19–25.14

of discrete hexamers (complexes of six insulin monomers), to confer the required absorption characteristics (Fig. 2). The more recent insulin analogues contain additional or substituted amino acid residues or other functional groups introduced by genetic engineering or by biochemical modification. These changes alter the speed of bioavailability and thereby modify the PK and PD profiles of the molecule. Given their structural complexities biopharmaceuticals are far more difficult to manufacture than small-molecule drugs. The use of living organisms introduces an inherent variability in the manufacturing process. To guarantee the quality and compliance of each production batch, absolute consistency of the manufacturing process is required. Even apparently slight changes in any of the manufacturing or formulation steps can have major clinical consequences.4–8 Manufacturers of biosimilar products must develop proprietary expression systems and processing steps independently. Thus biopharmaceuticals can never be identical copies of originator molecules, even when they have demonstrated comparable physicochemical and biological properties to a reference product using currently available tests. The most they can achieve is ‘biosimilarity’.5,9,10 For non-glycosylated products such as human insulin, PK and PD differences are most probably caused by differences in formulation, while for glycosylated products (e.g. epoetin), the glycosylation pattern is probably the major source of PK/PD variations. The essential steps in the manufacture of a biopharmaceutical and the loci of potential variability in their manufacturing processes are shown in Fig. 3.11 The first commercial insulins, extracted from beef and pork pancreata, became available shortly after the discovery of insulin in 1921, and the first long-acting insulins, PZI and NPH, had been developed by the 1940s. However, patients using animal insulin products that were not highly purified often had local injection site reactions or more rarely, systemic reactions such as IgE-mediated anaphylaxis.12 Highly purified products and recombinant insulins are associated with decreased levels of anti-insulin antibodies. Nonetheless, there is little evidence that antibody formation affects glucose control or causes other complications of insulin therapy.13 The more recent recombinant insulin analogues contain additional

Figure 2. Association of insulin monomers in the presence and absence of zinc and phenolic excipients.

Phenolic preservative

Zn2+

Insulin monomer

Insulin dimer

Insulin aggregates

Insulin hexamer (T6)

Insulin hexamer (R6)

Insulin readily associates into dimers, aggregates and (in the presence of divalent cations such as zinc), into hexameric forms. The presence of phenolic excipients causes these hexamers to undergo conformational changes that increase their stability. R6 = hexamer with insulin molecules whose B1–B8 residues are in an α-helical (R) conformation; T6 = hexamer with insulin molecules whose B1–B8 resi-dues are in an extended (T) conformation. Adapted from Beals, et al. Informa Healthcare: New York, 2008; 265–80.22

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Figure 3. Manufacture of a biopharmaceutical: opportunities for variation between manufacturers.11

Cloning and protein expression Transfer into host cell expression screening/selection

Cloning into DNA vector Source DNA

Target DNA Probably different vector

Possibly same gene sequence

Different cell expression system

Protein production, purification and validation Cell expansion

Cell production in bioreactors

Recovery through filtration or centrifugation

Purification through chromatography

Characterisation and stability

Purified bulk drug

Different cell line, growth media, method of expansion

Different cell line, growth media, bioreaction conditions

Different operating conditions

Different binding and elution conditions

Different methods, reagents, reference standards

Adapted from Mellstedt H, et al. Ann Oncol 2008; 19: 411–9.11

or substituted amino acid residues. The first short-acting analogues, insulin lispro and insulin aspart, were introduced in the late 1990s, and the first long-acting analogue insulin glargine in 2000. Each of these innovations was made with a view to improved onset and duration of action,14–16 to reduce hypoglycaemia and hyperglycaemia and to improve tolerability. The history of developments in insulin is summarised in Fig. 4 and a summary of available insulins is given in Fig. 5. In the manufacture of recombinant human insulin, the recombinant organism that actually expresses the precursor protein is generally Escherichia coli or a yeast such as Saccharomyces cerevisiae. The engineered gene encoding for the precursor protein must be inserted into a suitable stable expression vector. The choice and the characteristics of this construct will affect key aspects, such as the degradation characteristics of soluble proteins and the yield of the process. The recombinant cells are screened, and a well characterised master cell bank is established from a single clone. This master cell bank is used to create uniform working cell banks that are used to cultivate the cells and produce the desired product. During product synthesis the culture and fermentation conditions are tightly controlled in order to optimise yields and avoid formation of unwanted by-products.17 Generally, impurities come from either the growth medium (especially for products isolated from cell

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culture supernatant) or the host cells. These impurities can be hostrelated (e.g. endotoxins, HCPs, DNA, viruses), product-related (e.g. denatured protein, aggregates, protein fragments, deamidated species, conformational isomers), or process-related (e.g. growth medium components, metals, column material). When the product is recovered, modified and purified the formation of inclusion bodies (for example in high-yield E. coli processes), requires the disruption of the cells to release preproinsulin. This is then isolated, purified and folded, and then enzymatically cleaved to produce the mature insulin molecule.18–20 In the case of insulin, impurities such as desamido forms may arise as by-products of conversion from proinsulin to insulin by removal of the C-peptide and regeneration of the three-dimensional form of the molecule.21 After numerous purification steps, the insulin is crystallised or lyophilised and formulated. The insulin molecule is negatively charged at neutral pH, and readily associates into dimeric complexes or into zinc-containing hexamers (Fig. 2). Thus, zinc may be added to trigger aggregation into soluble discrete hexameric structures containing two zinc ions per hexamer.14 Phenolic excipients, added as antimicrobial agents, also bind to specific sites on hexameric insulin, changing its conformation to a more stable form (so-called T–R transition). Other agents added at the formulation stage may include physiological buffers (to maintain pH) and agents

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Figure 4. The development of therapeutic insulin: a timeline.14â&#x20AC;&#x201C;16 1921

1940

1960

Nobel Prize 1923

Nobel Prize 1958

PZI

1980

2000

Nobel Prize 1977 Long-acting analogue

NPH insulin Human insulin

Insulin discovered

Lente insulins

Rapid-acting analogue

Since the discovery of native insulin in 1921, successive discoveries have improved the production of therapeutic insulins as well as their pharmacokinetic and pharmacodynamic properties. Work on therapeutic insulins has garnered three Nobel Prizes. NPH = neutral protamine Hagedorn; PZI = protamine zinc insulin.

Figure 5. Insulin medicinal products currently available: a summary.

Insulin medicinal products

Rapid-acting insulin formulations Insulin analogues: insulin aspart, insulin glulisine, insulin lispro monomers, clear solution

Regular-acting insulin formulations Zn- and preservatives containing insulin hexamers clear solution

Intermediate-acting insulin formulations Insulin or insulin analogue isophane suspension (Cocrystallised insulin and protramine) turbid or cloudy suspension Long-acting insulin formulations Ultralente insulin-Zn-crystals: turbid suspension insulin analogues; insulin glragine, insulin determir clear solution

that maintain isotonicity (to minimise injection pain and tissue damage).22 Any variations in the entire process of insulin synthesis and formulation may result in a product which may be physicochemically very similar to an appropriate reference product, but which differs subtly in its clinical PK or PD characteristics.9,14 The steps in the manufacture of insulin are summarised in Fig. 6.

Insulin devices: an added complexity For biosimilar insulins, the additional dimension of the administration device should also be considered. Stringent regulatory requirements for insulin administration devices specify use of durable labels and distinguishing marks, visibility of the dose and accuracy with which it is dispensed after storage and handling under a variety of environmental conditions, including having been physically dropped. For example, cartridges, syringe/ needle systems, disposable and reusable pens and pumps must be tested with each insulin formulation and concentrations that will be used. Since the combinations of insulin and device may differ widely in their dosing characteristics, it cannot be assumed that an insulin biosimilar will be compatible with an existing administration device. For this reason the EMA requires that compatibility is demonstrated.23,24 Insulin pen injectors and cartridges (3.0 ml cartridge in the U-100 strength is the current market standard) provide more accurate and reproducible dosing than syringes and vials. They are also more convenient, easier to transport and may improve safety and adherence,25â&#x20AC;&#x201C;27 suggesting that the availability of pen injectors should be a requirement for insulin biosimilars.

Regulatory requirements for insulin biosimilars In recent years the EMA has produced an overarching guideline on biosimilars28,29 as well as guidance documents addressing quality issues,30 non-clinical and clinical issues,31 and guidelines for specific biosimilars, including soluble recombinant human insulin.21 As mentioned earlier9 the EMA requires that biopharmaceuticals undergo comprehensive comparability studies of both the drug substance and product to provide evidence that the biosimilar is indeed similar in quality, safety and efficacy to a single appropriately chosen reference product that has the same pharmaceutical form, strength and route of administration that is already approved in the EU. In general, required preclinical data include primary pharmacology and repeat-dose toxicology data. The EMA requires

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Figure 6. A highly complex process: steps in the manufacture of insulin.

Insulin glargine: Manufacturing is a complex, multi-step process By-product profile influenced by folding and cleavage E.coli cell

Isolation of cells

Inclusion body

Cell disruption via homogeniser

Typical operations for inclusion body processes

Fusion protein

Isolation and Purification Preproinsulin

Folding

Cleavage enzyme: specificity and selectivity

Enzymatic cleavage

Prepurification and concentration via absorption

Folding conditions influence by-product pattern

Arg-Insulin

Ion-exchange chromatography Chromatography defines purity

Reversed-phase chromatography Insulin Glargine

Fibrillation tendency

Crystallisation and lyophilisation

Blending/filling

Reproduced with kind permission from sanofi-aventis group.

toxicological studies that focus on potential immunogenicity, as well as in-vitro affinity bioassays, assays for insulin and IGF-1 receptor binding, and tests for intrinsic activity.28–31 One of the main concerns when switching or substituting insulin products is hypoglycaemia caused by differences in activity of different brands. Therefore, it is obligatory to ensure that the effects of any insulin product in clinical use are highly consistent and predictable. The EMA requires at least one PK single-dose crossover study that compares the biosimilar insulin with the reference product, using subcutaneous administration, preferably in patients with type 1 diabetes. Clinical activity must be determined in a comparative PD study, designed as a double-blind, crossover, hyperinsulinaemic, euglycaemic clamp study, to demonstrate the product’s hypoglycaemic response profile. Current EMA guidelines for soluble insulin biosimilars do not require a clinical efficacy trial, but do require a clinical safety study. The product’s immunogenicity must be investigated through clinical studies of at least 12 months, including a comparative phase lasting at least 6 months. Finally, the

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manufacturer must also design a pharmacovigilance programme that will rapidly detect any clinically significant immunogenicity that may emerge over extended time periods.21,28–30 The application for marketing authorisation of three biosimilar insulin formulations in March 2007 suggested deficiencies in long-term efficacy and inadequate immunogenicity testing.32–34 The details of these applications were recently reviewed by Kuhlmann and Marre in this journal.35

What clinicians should know before selecting a biosimilar insulin When contemplating biosimilar insulins, it is important to consider the manufacturer, protein quality and formulation, batch consistency and reliability of supply (Table 1).36,37 Reassurance can be gained from full disclosure of information to the healthcare community about the manufacturing process and about safety testing.

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Table 1. A checklist of issues to consider when selecting a biosimilar insulin product.36 Manufacturer • Reputation, reliability, experience with biopharmaceuticals • Location of manufacture of the medicinal product • Location of the manufacture of the active drug substance (are third parties involved?) • Dissemination of safety updates and changes in manufacturing process Protein quality and formulation • Bioassays: appropriateness, comparisons with reference product • Levels of foreign proteins, DNA, pyrogens, endotoxins, aggregates • Formulation: choice of excipients, stabilisers and preservatives • Administration device or technique; teaching materials for use of a different administration system • Shelf life, susceptibility to degradation • Consistency between batches; appropriate quality controls Reliability of supply • Stock position Clinical efficacy • Clinical trials carried out with different batches of the biosimilar product itself: adequacy of design, results, consistency and generalisability of results Clinical safety and tolerability • Comparison of safety and tolerability profile with reference product • Precautions or contraindications for use of the biosimilar • Serious adverse events • Immunogenicity (especially as compared to reference product); selection of antibody tests • Post-marketing risk management programmes: required laboratory tests, antibody testing, pharmacovigilance programmes to detect infrequent adverse events

With regard to quality, suppliers should be asked for a written statement that covers aspects such as the purity of the biosimilar protein, the upper limits for impurities such as aggregates or endotoxins, differences in isomer pattern, and clinical consequences of any potential differences. In the case of insulin impurities such as desamido forms may arise as by-products of conversion from proinsulin to insulin by removal of the C-peptide and regeneration of the three-dimensional form of the molecule.31 Moreover, with regard to formulation, any differences between the biosimilar and the originator molecule plus choice of excipients, stabilisers and preservatives should be provided, Additionally administration (either device or technique) should be explicit. If the biosimilar is administered by a different method from the originator product, e.g. with a new device, teaching materials should be available to train patients and caregivers to use the different system. It is also important to know the product’s shelf life and its susceptibility to degradation if it is stored improperly (for example, if accidentally stored at room temperature instead of being refrigerated). Quality control to ensure batch-to-batch consistency is paramount with insulin preparations. There should be a guaranteed stock position which will maintain supplies if a newly produced batch fails to meet all the required standards of quality. A sustainable supply chain with reliable transportation conditions should also be established.

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Particular attention should be given to any differences in clinical activity, biological activity per unit, relative biological potency and dosage of a biosimilar compared with the originator molecule. The known safety and tolerability profile of the biosimilar, as well as precautions or contraindications for its use, should be comparable with the originator molecule. Because clinical trials which enrol relatively small numbers of patients cannot identify rare sideeffects, it is obligatory to monitor safety during the post-approval phase. The use of more than one biosimilar product (for example, a biosimilar insulin and a biosimilar epoetin for the diabetic patient with renal failure) may present an additional layer of complexity regarding safety issues. Similarly, substituting one insulin for another may require dose adjustment. While the development of antibodies to insulin rarely has major clinical consequences, it may have an impact on efficacy (because higher insulin doses may be necessary) and tolerability (mainly in the form of local injection site reactions). Hence, a biosimilar product should receive thorough antibody tests extending into the post-marketing period.

Summary and conclusions Biosimilar products such as epoetin alfa biosimilars are already marketed in the EU, and biosimilar insulins are expected shortly. Patients with diabetes are often candidates to receive both types of products. Therefore, it is imperative for prescribers to be aware of issues presented by biosimilar products, and particularly the special challenges presented by biosimilar insulin. Biosimilars are not interchangeable with the corresponding originator biopharmaceuticals in the same way that non-peptide, smallmolecule generic molecules are interchangeable with the original products. Any apparently minor modification in the manufacturing or formulation of a product such as insulin, or in the administration device, has the potential to cause untoward clinical consequences, even if the product appears to be physicochemically equivalent to an accepted reference standard. The consequences are particularly relevant for insulin as the therapeutic window is narrow. For this reason, the EMA has developed robust regulatory requirements before marketing authorisation can be granted for a biosimilar insulin. Prescribers should consider critical issues regarding the manufacture, protein quality and formulation, supply, clinical efficacy, safety and tolerability of biosimilar insulins before substitutin

Key messages • Unlike non-peptide small-molecule generics, biosimilars are not identical to the originator • Biosimilar insulins are challenging because insulin has a complex structure and a narrow therapeutic window • The dosing accuracy of biosimilar insulins depends on the quality of the administration device • regarding biosimilars, consider the manufacturer, protein quality, formulation, reliability of supply, clinical efficacy, safety and tolerability

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Acknowledgment Editorial support for this article was provided by the medical writing agency PHOCUS and by the sanofi-aventis group. The opinions expressed in the current article are those of the authors. The authors received no honoraria or other form of financial support related to the development of this manuscript.

Declaration of conflict of interest IK has been a consultant, speaker and member of advisory boards of various (bio)pharmaceutical companies, which had no influence on the content of this article. TS is an employee of sanofi-aventis Deutschland GmbH.)

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European Medicines Agency. Press release: Marvel Life Sciences Ltd withdraws its marketing authorisation applications for Insulin Human rapid Marvel, Insulin Human Long Marvel and Insulin Human 30/70 Mix Marvel. 16 January 2008. EMEA/2435/2008. London: EMA, 2008. Schellekens H. Follow-on biologics: challenges of the ‘next generation’. Nephrol Dial Transplant 2005; 20 (suppl 4): iv31–6. European Medicines Agency. Questions and Answers on biosimilar medicines (similar biological medicinal products). 22 October 2008. Doc. Ref. EMEA/74562/2006 rev.1. London: EMA, 2008. http://www.emea.europa.eu/ pdfs/human/pcwp/7456206en.pdf. Schellekens H, Ryff JC. ‘Biogenerics’: the off-patent biotech products. Trends Pharmacol Sci 2002; 23: 119–21. Locatelli F, roger S. Comparative testing and pharmacovigilance of biosimilars. Nephrol Dial Transplant 2006; 21 (suppl 5): v13–16. Locatelli F, Del Vecchio L, Pozzoni P. Pure red-cell aplasia ‘epidemic’: mystery completely revealed? Perit Dial Int 2007; 27 (suppl 2): S303–07. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002; 346: 469–75. Schellekens H. Immunologic mechanisms of EPO-associated pure red cell aplasia. Best Pract Res Clin Haematol 2005; 18: 473–80. Kuhlmann M, Covic A. The protein science of biosimilars. Nephrol Dial Transplant 2006; 21 (suppl 5): v4–8. roger SD. Biosimilars: how similar or dissimilar are they? Nephrology 2006; 11: 341–6. Mellstedt H, Niederwieser D. Ludwig H. The challenge of biosimilars. Ann Oncol 2008; 19: 411–9. Grammer L. Insulin allergy. Clin Rev Allergy 1986; 4: 189–200. Fineberg SE, Kaabata TT, Finco-Kent D, et al. Immunological responses to exogenous insulin. Endocrine Rev 2007; 28: 625–52. Joshi SR, Parikh RM, Das AK. Insulin: history, biochemistry, physiology and pharmacology. J Assoc Physicians India 2007; 55 (suppl): 19–25. Sattley M. The history of diabetes. Diabetes Health 2008. http://www. diabeteshealth.com/read/2008/12/17/715/the-history-of-diabetes/(accessed 10 May 2009). Teuscher A. The history of insulin. In: Insulin: A Voice for Choice. Basel: Karger, 2007; 10–13. http://content.karger.com/ProdukteDB/Katalogteile/ isbn3_8055/_83/_53/Insulin_02.pdf (accessed 10 May 2009). Neubauer RP, Lin HY, Mathiszik B. Metabolic load of recombinant protein production: inhibition of cellular capacities for glucose uptake and respiration after induction of a heterologous gene in Escherichia coli. Biotechnol Bioeng 2003; 83: 53–64. Panda AK. Bioprocessing of therapeutic proteins from the inclusion bodies of Escherichia coli. Adv Biochem Eng Biotechnol 2003; 85: 43–93.

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19. Winter J, Lilie H, rudolph r. renaturation of human proinsulin: a study on refolding and conversion to insulin. Anal Biochem 2002; 310: 148–55. 20. Singh AM, Panda AK. Solubilization and refolding of bacterial inclusion body proteins. J Bioscience Bioeng 2005; 99: 303–10. 21. Committee for Medicinal Products for Human Use. Annex guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing recombinant human insulin. London: EMA, 2006. http://www.emea. europa.eu/pdfs/human/ biosimilar/3277505en.pdf (accessed 13 April 2009). 22. Beals JM, DeFilippis Mr, Kovach PM. Insulin. In: Crommelin DJA, Sindelar RD, Meibohm B (eds.). Pharmaceutical Biotechnology: Fundamentals and Applications, 3rd edn. Informa Healthcare: New York, 2008; 265–80. 23. European Medicines Agency. Guideline on the suitability of the graduation of delivery devices for liquid dosage forms. Doc ref EMEA/CHMP/ QWP/178621/2004. London: EMA, 2004. http://www.emea.europa. eu/pdfs/ human/qwp/17862104en.pdf (accessed 10 May 2009). 24. International Organization for Standardization. Pen-injectors for medical use. Part 1: Pen-injectors. requirements and test methods (ISO 11608–1:2000). Geneva: ISO, 2000. 25. Brunton S. Initiating insulin therapy in type 2 diabetes: benefits of insulin analogs and insulin pens. Diabetes Technol Ther 2008; 10: 247–56. 26. Korytkowski M, Niskanen L, Asakura T. FlexPen: addressing issues of confidence and convenience in insulin delivery. Clin Ther 2005; 27(suppl B): S89–100. 27. Korytkowski M, Bell D, Jacobsen C, Suwannasari r. FlexPen Study Team. A multicenter, randomized, open-label, comparative, two-period crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial/syringe for insulin injection in patients with type 1 or 2 diabetes mellitus. Clin Ther 2003; 25: 2836–48. 28. Wiecek A, Mikhail A. European regulatory guidelines for biosimilars. Nephrol Dial Transplant 2006; 21(suppl 5): v17–20. 29. Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products. London: EMA, 2005. http://www. emea.europa.eu/pdfs/ human/biosimilar/043704en.pdf (accessed 13 April 2009). 30. Committee for Medicinal Products for Human Use. Guidelines on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues. London: EMA, 2006 http:// www.emea.europa.eu/pdfs/ human/biosimilar/4934805en.pdf (accessed 13 April 2009) 31. Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London: EMA, 2006 http://www.emea. europa.eu/pdfs/human/biosimilar/4283205en.pdf (accessed 13 April 2009) 32. European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use. Withdrawal Assessment report for Insulin Human rapid Marvel. 21 February 2008. Document reference EMEA/CHMP/317778/2007. London: EMA, 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAr/insulinhumanrapidma rvel/31777807en.pdf (accessed 1 May 2009) 33. European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use. Withdrawal Assessment report for Insulin Human Long Marvel. 21 February 2008. Document reference EMEA/CHMP/70349/2008. London: EMA: 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAr/insulinhumanrapidma rvel/7034908en.pdf (accessed 1 May 2009) 34. European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use. Withdrawal Assessment report for Insulin Human 30/70 Mixed Marvel. 21 February 2008. Document reference EMEA/CHMP/70179/2008. London: EMA: 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAr/insulin humanrapidmarvel/701790en.pdf (accessed 1 May 2009) 35. Kuhlmann M, Marre M. Lessons learned from biosimilar epoetins and insulins. Br J Diabetes Vasc Dis 2010; 10; 90–7. 36. Krämer I, Tredree R, Vulto AG. Points to consider in the evaluation of biopharmaceuticals. EJHP Practice 2008; 14: 73–6. 37. Crommelin D, Bermejo T, Bissig M et al. Pharmaceutical evaluation of biosimilars: important differences from generic low-molecular-weight pharmaceuticals. Eur J Hosp Pharm Sci 2005; 11: 11–7.

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Patient information leaflet

Keep and Copy Series YOU AND YOUR THYROID SUPPLEMENT Dr PM van Zyl Clinical pharmacologist S Afr J Diabetes Dis 2011; 8: 26.

Levothyroxine (T4) is the preferred drug for the treatment of hypothyroidism. Liothyronine (T3) is used in extreme cases requiring rapid response. TAKING LEVOTHYROXINE To avoid overdosing, therapy is started at a relatively low dose and then increased very gradually (every two to four weeks) until thyroid function tests confirm that the desired level of activity has been reached. If you have a cardiac problem, therapy will be started at half the normal dose. Elderly patients require smaller doses in general. Take the drug on an empty stomach with water, preferably half an hour to one hour before breakfast and at least four hours apart from antacids, iron and calcium supplements. Tablets may be crushed and mixed with 5 to 10 ml of water. Capsules must be swallowed whole. Store the medication at room temperature (25°C) and protect from light and moisture. TAKING OTHER MEDICATION WHILE ON THYROID REPLACEMENT THERAPY Many drugs can have significant interactions with thyroid hormones. It is especially important to be vigilant about possible interactions with chronic drugs and drugs that easily become toxic. Interactions are prevented by close monitoring, dose adjustments or avoiding a particular drug. The list below highlights some important ones: • Antidiabetic drugs: monitor diabetes control. May require increased dose of antidiabetic drug. • Digitalis: monitor digitalis levels. May require increased dosage of digitalis. • Oestrogen: monitor thyroid function. May require increased thyroid hormone dose. • Kelp: unpredictable effect on thryoid function. AVOID • Warfarin: monitor anticoagulant. May require reduced warfarin dose (may cause bleeding).

AVOID drugs that increase the pulse rate and consult your doctor about the safety of over-the-counter (OTC) drugs. GENERIC SUBSTITUTION If well controlled on a specific brand: DO NOT SWITCH BRANDS, as there may be significant differences in the amount of drug reaching the bloodstream. POSSIBLE SIDE EFFECTS Side effects are mostly dose related: at high doses you may experience palpitations, weight loss, increased appetite, diarrhoea, flushing, sweating and headache. Report these symptoms to the doctor. Thyroid replacement can potentially aggravate cardiovascular disease, manifesting as angina and myocardial infarction. Other serious side effects are: liver failure, osteopenia, pseudotumor cerebri and seizures. WHAT ABOUT PREGNANCY AND BREASTFEEDING? Levothyroxine is safe during all trimesters of pregnancy, as it does not cross the placenta. Pregnancy may cause requirements to fluctuate. Small amounts are excreted in breast milk, yet it is considered compatible with breastfeeding. WARNINGS This drug should not be taken if you have an acute myocardial infarction, are allergic to any component of the product, if you suffer from non-toxic diffuse goitre or nodular thyroid disease (with suppressed TSH) or have thyrotoxicosis or uncorrected adrenal insufficiency. It should never be used for the treatment of obesity. If the thyroid function is normal, it will be ineffective at normal doses and high doses can cause life-threatening side effects. MONITORING THERAPY Expect the peak effect after three to four weeks. Therapy is monitored clinically and with a blood test. Thyroid function tests are done four to six weeks after dose adjustments to confirm whether dosing is optimal.

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Diabetes Personality A PASSION FOR PEOPLE S Afr J Diabetes Dis 2011; 8: 27–28.

ort Elizabeth-based diabetes nurse educator, Sr Hannie Williams, believes that you cannot be a good nurse if you do not have a passion for people. She therefore makes her patients – and their individuality – central to her work. A registered nurse, Hannie got into the diabetes arena in 2004. She and her husband had moved to Port Elizabeth in 2001 and she’d temporarily left the profession to help him out in his business. But she really missed nursing and wanted to get back into the field. So, in 2004 she started sending out her CV to local medical practices, and even went so far as to circulate flyers. It was on the strength of one of the latter that Dr Gracjan Podgorski, a specialist physician with a particular interest in diabetes, contacted her. And the rest, as they say, is history. In the intervening years, Dr Podgorski has mentored and encouraged her, something for which she is deeply grateful. ‘He is a master in his field and has opened so many doors for me, not least giving me access to sponsorships that allowed me to attend several local, national and international meetings. In addition, he constantly shares his own knowledge with me. I owe him a great deal and consider it a real

Educating a gestational diabetic patient.

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privilege to work with him.’ Hannie feels that as an educator, her primary purpose is to communicate the practicalities of diabetes to her patients so that they are empowered with useful knowledge. ‘Once they understand the physiology, they need to know the “what, where and how” of their treatment, be it oral antidiabetic agents, insulin or both. Given the central role that the funding industry plays, I also help them with the practicalities of dealing with medical aids, so that they can get their medication from the ‘chronic’ funding and hopefully eliminate co-payments. It’s an ongoing challenge too, given the restrictive formularies, to help patients comply with those formularies when changing treatments. This results in lots of time spent writing motivations to medical aids.’ Of course, much emotional support is also required. ‘First and foremost, patients are individuals, and the major worries and concerns differ from patient to patient. Inevitably there’s a burning question in the patient’s mind – “Will I go blind?” or “Will I lose my toes?” – and it’s crucial to address this first, because if you don’t, the odds are they won’t take in anything else you tell them. It’s also important not to overload them with too much information. It’s been shown that people remember at most 40% of what they hear on any one occasion. It’s therefore necessary to repeat the information at follow-up visits.’ Hannie’s passion for people means that she wants to assist her patients in ways that produce quick results. ‘I often refer to it as giving them a “kiss-it-better bandage”’, she laughs. ‘When consulting a patient for the first time, I don’t have a magic wand to make all “wrongs” right. I can, however, give of myself by listening to him/her, addressing his/her concerns and helping him/her make sense of what’s happening. At the end of such a session, it leaves me feeling humble, but with a great sense of satisfaction, if I see that

Diabetes Personality the patient has relaxed and thanks me for my help.’ Hannie finds teenage diabetics a particular challenge – and she encounters quite a lot of them in her work. ‘Teenagers can be difficult at the best of times, and teenage diabetics are often not compliant with treatment and tend to lapse. As a result, there is a lot of stress on parents and healthcare providers. It’s very rewarding, then, to see them coming around and no longer straying from treatment. I recently saw one of my problem children transformed into the perfect patient. It was wonderful. She now comes in for regular check ups, follows our guidance and, in consequence, her overall control is improving. I think it also helps that she recently acquired a boyfriend who is so understanding and supportive of her condition.’ In addition to educating patients, Hannie is always happy to share her knowledge with other healthcare providers and has given talks both locally in Port Elizabeth and nationally. ‘Because I believe in practical solutions, I stay away from the airy-fairy stuff and focus on what works and how to do things’, she says. Asked what makes a good educator, Hannie feels that sensitivity to the

patients is key, along with a fine balance between humility and dynamism. ‘They need to feel your confidence and positive energy, but not to a degree that they feel overpowered; and they need to be assured of your absolute willingness to help at all times’, she concludes. Peter Wagenaar

Hannie with her mentor, Dr G Podgorski.

In Memoriam Dr Mojapela Mhlakaza

r Mojapela Mhlakaza (52 years old) lost his life at the hands of unknown assailants who shot and killed him when he arrived home on 29 November 2010. A colleague described Dr Mhalakza as a softly spoken introvert and a gentleman. After qualifying as a medical practitioner in the USSR, Dr Mhlakaza eventually settled in Bloemfontein where he set up practice as a general practitioner with an interest in diabetes. His passion for helping patients with diabetes soon became known and he attracted patients from far and wide. Dr Mhlakaza was a regular attendee at diabetes updates, symposia and SEMDSA congresses where his keen interest in and depth of knowledge on diabetes were apparent. Dr Mhlakaza was popular and well liked by his colleagues at the Netcare-Universitas Private Hospital where he admitted some of his patients. His passion to improve diabetes care at primary healthcare level was demonstrated by his regular involvement in outreach programmes such as the World Diabetes Day initiative held at Pelonomi Hospital on 13 November 2010 where this last photograph of him was taken. This friendly and humble man will be missed by his colleagues, patients and friends. Our condolences go to his family. WF Mollentze (Acknowledgement: Volksblad)

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CARDIOVASCULAR FOCUS

Cardiovascular Focus Extracts from the 11th annual South African Heart Association Congress, August 2010 Antiplatelet agents

he platelet is one of the central role players in acute coronary syndromes and the antagonism of their function is therefore one of the big research topics in cardiology. Currently, platelets can be antagonised via the thromboxane antagonists, the ADP receptor blockers or the GP IIb/IIIa receptor blockers. All these drugs have their own intricacies, and Prof B Meier referred to some of these issues. Questions raised in this lecture included: how long to continue with dual anti-platelet therapy; should aspirin be used in combination with clopidogrel for secondary prevention; and the possibility of drug interactions, especially with proton pump inhibitors (PPIs) and ADP receptor blockers. The duration of dual anti-platelet therapy is still a matter of opinion. In the CHARISMA trial, it was shown that there is a benefit to using dual anti-platelet therapy, including aspirin and clopidogrel, for secondary prevention. Patients on anti-platelet therapy are at increased risk for gastrointestinal bleeding. They are however also at risk for major adverse cardiac events should their anti-platelet therapy be ineffective. The TIMI 38 trial compared the effectiveness of clopidogrel and a PPI vs prasugrel and a PPI. It found that there was a better outcome with the prasugrel combination than the clopidogrel combination in patients with ST-elevation myocardial infarction. The mortality was, however, raised in patients with non-ST elevation myocardial infarction. Further studies are awaited. Prof Meier also briefly discussed some of the problems with the newer anti-platelet agents. It seems that there is the possibility of an increased risk of malignancy with prasugrel compared to placebo in patients treated with this drug. He also referred to the side effects of dyspnoea and bradycardia in patients treated with the new drug ticagrelor. In Prof Meier’s opinion, patients with mild coronary artery disease should be treated with aspirin only, and patients with more severe disease should be treated with combination therapy including aspirin and one of the newer agents.

Acute coronary syndrome and atrial fibrillation The recent RELY trial has brought attention back to atrial fibrillation and anticoagulation.

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Prof Ezekowitz, an ex-South African and principal investigator of the RELY trial, was therefore invited to the SA Heart Association congress. It is known that the mortality of acute coronary syndrome (ACS) is doubled if a patient concomitantly has atrial fibrillation (AF). There are, however, no studies studying anticoagulation in this population group. This is reflected by the fact that the European Society for Cardiology and the American College of Cardiology/ American Heart Association guidelines also have different recommendations. It was stressed that anticoagulants out perform anti-platelet drugs when it comes to stroke prevention. There is also a lower mortality in patients with ACS and AF if treated with anticoagulation and anti-platelet combinations, compared to anti-platelet therapy alone or no therapy (data is from a prospective cohort in Sweden). In all these groups, the bleeding risk was similar and the stroke rate was less in the anticoagulation groups. Prof Ezekowitz concluded that there are no good data to know how to treat these patients. Triple therapy, including two antiplatelet drugs (according to ACS guidelines) and an anticoagulant is superior. Drug-eluting stents should be avoided in order to decrease time on triple anticoagulation. Newer agents should be explored in this patient group.

Primary pulmonary hypertension Prof L Rubin used this session as an overview of primary pulmonary hypertension. This rare disease, with a prevalence of 2/1 000 000, occurs much more frequently in women (three to four females are affected for each male). Vascular remodelling is at the core of this disease’s pathophysiology. The interaction of endothelin with smooth muscle cells leads to alternate handling of intracellular calcium, with subsequent increased vasocontraction, up-regulated vaso-proliferation and altered cell death. There are three pathways at the core of this disease’s pathophysiology. Pharmaceutical agents may target all of these pathways, which include the prostaglandin pathway, the endothelin pathway and the nitric oxide pathway. Prognosis in primary pulmonary hypertension is related to the progressive decline in right heart function. It should be noted that pulmonary artery pressure does not correlate with patient outcome. Echocardiography is

therefore an excellent tool to use in the prognostication of patients with primary pulmonary arterial hypertension. Of the echo indices, TAPSE (tricuspid annular plane systolic excursion) seems to be the best index to use. Other possible markers of prognosis include N-terminal pro-BNP and the six-minute-walk test. Prof Rubin concluded his talk by saying that disease severity is a function of right heart function and that assessing this can help in guiding the management of these patients.

Coronary heart disease and the millennium woman Prof N Wenger from the Emory School of Medicine in Atlanta started her lecture on national Women’s Day by commenting on how the epidemiology of diseases affecting females have changed. The average age of women in the 1900s was 48 years, in the year 2000 it is 80. The main causes of mortality in the 1900s were TB and childbirth; this has now shifted to heart disease. Coronary artery disease is the leading cause of death worldwide for males and females. Young adults currently have an increasing risk of coronary artery disease due to the epidemic of obesity, diabetes and hypertension. Females with stable angina have a slightly different profile to that of males. They are older, have more hypertension, diabetes and cardiac failure, and are less likely to have myocardial infarction and coronary artery bypass graft surgery. Women are also less likely than their male counterparts to have an exercise test and have statins and anti-platelet agents prescribed by a cardiologist. The WISE (women ischemia syndrome evaluation) study, however, shows that women have twice the risk of major adverse cardiac events as males. To complicate matters further, 50% of females with ischaemic-type chest pain have no flow-limiting coronary artery disease. Intravascular ultrasound performed on females show that they have a higher atherosclerotic burden with decreased coronary flow reserve. Sub-endocardial ischaemia can be demonstrated by magnetic resonance imaging. It seems that women have more endothelial dysfunction, with hormones, inflammatory mediators and traditional risk factors all playing an important role.

CARDIOVASCULAR FOCUS

Females with acute coronary syndrome are more likely to present with unstable angina and are less likely to have ST-elevation myocardial infarction. These women are again older and have diabetes and hypertension more often than their male counterparts. They also experience more in-hospital complications than males. Females often present atypically with no chest pain but rather with angina equivalents. Females are often diagnosed late and are treated less aggressively than males. In summary, cardiovascular disease is a common disease in females, with a high mortality rate. Females often present atypically and are treated differently from males.

Cardiotoxicity of anti-cancer agents, particularly in breast cancer Prevention, monitoring and treatment ‘Not all heart failure is the same’ was the phrase used by Prof M Ewer from the University of Texas. There are two types of cancer drug-related cardiac failure. Type 1 is the typical anthracycline-induced cardiac failure that is related to cumulative dose and has clear changes on myocardial biopsy. Type 2 is caused by cellular dysfunction. The drug trastuzumab is commonly responsible for this condition and it is not associated with cumulative dose. He also pointed out that one can have acute cardiotoxicity with anthracyclines. This condition presents with chest pain, ECG changes and raised troponins, and is a myopericarditis. It is however not deemed to be of major clinical importance. Why is the heart damaged by chemotherapy? Reasons include that the heart is sensitive to the effect of these drugs, it has no biochemical reserve, and is a terminally differentiated organ. Prevention is the solution to this problem. Firstly, one should recognise a high-risk patient. Features of such a patient include cumulative dose of anthracycline, previous cardiac disease, hypertension, and the patient’s age, to name but a few risk factors. When treating such a patient, the maximum cumulative dose of anthracyclines should be kept below 400 mg/m2, and drugs such as epirubin and mitoxantrone should preferentially be used. Angiotensin converting enzyme inhibitors and beta-blockers should be used concomitantly to protect the heart. The patients should be followed up regularly and it should be noted that LVEF is not a sensitive

SA JOURNAL OF DIABETES & VASCULAR DISEASE

screen for myocardial damage in this situation.

Direct thrombin inhibitors in atrial fibrillation This topic was discussed by Prof MD Ezekowitz, the principal investigator of the RELY trial. There are currently three therapeutic groups that can possibly prevent thrombo-embolism in atrial fibrillation. These groups include the anticoagulants, the anti-platelet agents and the group of non-antithrombotic drugs. The anticoagulants can be divided into the coumarins, the factor Xa inhibitors, and the direct thrombin inhibitors. Multiple trials including AFASAK, BAATAF, CAFA, SPAF and SPINAF have proven stroke risk reduction with warfarin, which is currently the therapeutic standard. Xymalagatran (a direct thrombin inhibitor) was shown to be non-inferior to warfarin in stroke prevention. This drug, however, caused a rise in the transaminases and was subsequently rejected by the FDA. Dabigatran was consequently developed and was shown in the RELY trial to be non-inferior to warfarin and had no liver side effects. This drug is a direct thrombin inhibitor in a prodrug form. It is converted to its active metabolite by tissue esterases and is therapeutic within two hours of administration. The drug has a twice-daily dosage and is mostly (80%) eliminated by the kidney. It has interaction with proton pump inhibitors and with drugs metabolised by p-glycoprotein. Side effects of this drug include dyspepsia. In the RELY trial, the bleeding complications were less than with warfarin in the lower (110-mg) arm and the same as warfarin in the 150-mg arm. This is therefore a drug that might change our management of atrial fibrillation in the future.

Chronic pulmonary thromboembolic disease Three to 5% of patients with venous thromboembolism develop chronic thrombo-embolic pulmonary hypertension. These patients often have no history of venous thrombo-embolism and may present similarly to idiopathic pulmonary hypertension. Risk factors for this disease include: age, prior pulmonary embolism, anticardiolipin antibodies and other pro-thrombotic states. The prognosis of this disease is a function of the pulmonary arterial pressure, with mortality rising once the pulmonary pressure is higher

than 30 mmHg. Surgery might reverse the pulmonary hypertension associated with chronic embolisation. Pulmonary endarterctomy can be considered in patients with pulmonary arterial pressures of more than 40 mmHg, a pulmonary vascular resistance of more than 300, symptomatic individuals with proximal emboli, and absence of co-morbid disease. This procedure is done under cardiac bypass and has a mortality rate of approximately 5%. Complications of this procedure include: reperfusion pulmonary oedema, haemorrhagic pulmonary infarction, residual pulmonary hypertension and subsequent development of small-vessel pulmonary hypertension. This surgery is, however, only indicated for proximal disease. In distal disease, the goal is to improve haemodynamics with prostacyclins, sildenafil or bosentan. Prof Rubin’s message with this talk was that one should consider this condition in the differential of pulmonary hypertension and that surgical treatment can have benefit in these patients.

Cardiovascular care of older adults: challenging dynamics Prof N Wenger, in her talk, eluded to the ‘Tsunami of aging’, with 20% of the population being older than 65 years. Cardiovascular disease also becomes more prevalent with older age and has a worse outcome in the elderly. To complicate matters further, there is a disproportionate age-related therapeutic risk. Prof Wenger suggested that the following points should be kept in mind when treating the elderly. Firstly, what is the outcome desired for the individual? Is it quality of life, functionality, or simply avoiding an adverse outcome? Secondly, one should evaluate cognition and pharmacological interactions in the specific patient when deciding on treatment goals. Thirdly, adverse drug reactions should be kept in mind as this makes up 30% of hospital admissions. Fourthly, one should evaluate one’s threshold for interventions. Finally, the specific cardiovascular syndrome should be considered. There are no simple answers when dealing with elderly patients. Evaluating these principles can help the physician to develop a more rational treatment plan for his/her patient.

Gideon Visagie, Department of Internal Medicine, University of the Free State, Bloemfontein

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OPINIONS IN HYPERTENSION MANAGEMENT

Opinions in Hypertension Management Improving hypertension control in patients with diabetes: the case for telmisartan-based therapy

trategies to improve hypertension control are clearly warranted in light of the frequently expressed view that only 50% of treated hypertensive patients are able to meet their target blood pressure levels. While data from the USA has shown improved control over recent years, a study in 2008 of South African general medical practice (private sector) showed that 61% of patients reached their target blood pressure levels. If the even-stricter target blood pressure levels of 130/80 mmHg were applied to those patients with diabetes who needed to reach and maintain these lower levels, only 40% of patients were successfully treated.1 In primary-care, public-sector facilities in South Africa, special efforts to improve hypertension management have shown that 68% of patients treated for their hypertension can achieve their targeted blood pressure levels.2 Without these intensive programmes, however, hypertension control in the South African public sector is likely to be much less effective and lower than in the well-serviced private sector. Reducing the cardiovascular and renal consequences of hypertension is dependent on sustained, long-term blood pressure control, implying that patient compliance is also a key factor for success. The physician’s choice of effective therapy will take this aspect fully into account and he/she will adopt approaches that will sustain patient compliance. Modern therapeutic agents that block the renin–angiotensin–aldosterone system (RAAS) and protect target organs without causing compliance-reducing symptoms should be the first choice in at-risk diabetic patients with hypertension.

Achieving sustained blood pressure control Once-a-day dosage Patients typically prefer to take their medication in the morning as part of their everyday routine. Compliance is improved by once-daily medication and physicians are keen to ensure that the prescribed antihypertensive medication meets the criteria of full 24-hour control and provides cover for the early morning rise in blood pressure. This rise in blood pressure is due to both orthostatic changes and the circadian rhythm of the RAAS system. It is also

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linked to an increased risk of cardiovascular events during the early morning hours.3 Accurate assessment of blood pressure control is determined by self-measurement of blood pressure or by automated ambulatory 24-hour measuring devices. The MICARDIS Community Access Trial of Telmisartan in the primary-care setting (MICCAT-2)4 study showed that telmisartan alone or in combination with HCTZ produced significant reductions in blood pressure, which extended into both day and night time. Telmisartan reduced systolic and diastolic blood pressure (SBP/DBP) by 17.2/10.1 mmHg in the first four hours post-awakening in patients whose early morning blood pressure rose more than 30 mmHg prior to therapy.

ARB efficacy versus ACE inhibitors ARBs are a good choice for hypertensive patients with the metabolic syndrome (associated obesity) and there are compelling indications for their use in post-myocardial infarction, left ventricular hypertrophy, chronic kidney disease, type 2 diabetes with microalbuminuria or albuminuria, for ACE-intolerant patients and for the secondary prevention of stroke.5 The evidence for therapeutic equivalence of telmisartan versus ACE inhibitors resides in direct major comparison trials with ramipril and perindopril. In the PRISMA-1 study (Prospective Randomised Investigation of the Safety and efficacy of MICARDIS versus ramipril) also conducted in South Africa, 1 613 hypertensive patients were treated either with temisartan 40–80 mg or ramipril (uptitrated from 2.5–10 mg) in the morning, and resulting blood pressure was evaluated using ambulatory blood pressure monitoring. Telmisartan provided more effective blood pressure lowering in this study and was particularly more efficient in the last six hours of the 24-hour dosing interval. Similar results were obtained by PRISM-2, which was conducted in the USA and Canada. A pooled analysis of both trials also showed a greater blood pressure lowering with telmisartan (–14.1/–9.6 vs –11.1/–7.2 mmHg).6 In a double-blind study of telmisartan 80 mg versus perindopril 4 mg, similar results in blood pressure lowering were obtained but telmisartan resulted in lower diastolic blood pressures over the last eight hours of therapy. Other studies versus lisinopril

produced similar results. Telmisartan is the only ARB that has demonstrated therapeutic equivalence to the ACE inhibitor ramipril in hypertensive patients at increased vascular risk. The patient population in this study (ONTARGET) is of particular interest as it is representative of the majority of hypertensive patients seen in everyday clinical practice. The findings from this study showed that telmisartan 80 mg per day was as efficacious as the proven dosage of ramipril (10 mg/day) in reducing risk of cardiovascular death, myocardial infarction, stroke and hospitalisation for heart failure in a broad cross section of highrisk cardiovascular patients. It achieved these results with far fewer side effects, resulting in significantly fewer patients discontinuing therapy.

Choosing telmisartan over other ARBs: the evidence Pharmacological evidence of telmisartan’s efficacy in terms of blocking the angiotensin II type 1 receptor is accumulating. A recent Japanese study of constructed models of ARB molecules has found that the delta lock structure of telmisartan offers a superior fit to the receptor, compared to the other ARBs.7 This fit may explain the highest lipophilicity, the greatest volume distribution and the strongest binding affinity of telmisartan to the type 1 receptor when compared to other ARBs. This receptor affinity is likely to contribute to the clinical evidence for telmisartan’s greater blood pressure lowering compared to other ARBs, particularly losartan and valsartan.8-10

Choosing the combination of telmisartan + HCTZ Blood pressure control in some patients is ineffective with just monotherapy, and combinations of antihypertensive agents offer an opportunity to intensify treatment without adding to the pill load. In African patients where there may be evidence of less involvement of the RAAS system, the initial choice in the public sector is often a diuretic. A recent study in KwaZulu-Natal looked at prescribing habits in 54 public-sector hospitals in this region and compared this to supply data and to the SA Hypertension Guidelines.11

CUTTING EDGE OF DIABETES TECHNOLOGY

It found that the most commonly used agents were diuretics (42%) and ACE inhibitors (27%) and that these prescriptions correlated well with supply data for these frequently used medications. Calcium channel blockers and beta-blocker usage was 6% each. Clearly, as ARBs become more available in the public sector, the opportunities offered by the combination of telmisartan and HCTZ should receive wider use. Publicity given to the lack of dialysis facilities for kidney failure in the public sector in South Africa should also add to the imperative to improve hypertension control. The blood pressure of patients who are at particular risk of cardiovascular disease, such as those who are obese or have type 2 diabetes, are often difficult to control. The SMOOTH study (Study of Micardis on Obese/Overweight Type 2 diabetes patients with HypErtension) showed the superior effect of telmisartan 80 mg plus HCTZ 12.5 mg, compared to valsartan 160 mg plus HCTZ 12.5 mg over 24 hours and especially in the early morning period.12 J Aalbers, Special Assignments Editor

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Rayner B, Schoeman HS. Across sectional study of blood pressure control in hypertensive patients in general practice (the I-Target study). Cardiovasc J 2009; 20: 224–227. Coleman R, et al. Non-communicable disease management in resource-poor settings: a primary care model from rural South Africa. Bull Wld Hlth Org 1998; 76(6): 633–640. Galzerano D, Capogrosso C, Di Michele S, Galzerano A, et al. New standards in hypertension and cardiovascular risk management: focus on telmisartan. Vasc Hlth Risk Mgmt 2010; 6: 113– 133. P10-02804. White WB, Giles T, Bakris GL, et al. Measuring the efficacy of antihypertensive therapy by ambulatory blood pressure monitoring in theprimary care setting. Am Heart J 2006; 151: 176–184. How do recent developments affect the angiotensin receptor blockers as a class? Cardiovasc J Afr 2009; 20(2): 145. Gosse P, Neutel JM, Schumacher H, et al. The effect of telmisartan and ramipril on early morning blood pressure surge: a pooled analysis of two randomized clinical trials. Blood Press Monit 2007; 12: 141–147. Ohno K, Amano Y, Kakuta H, Niimi T, Takakura S, Orita M, Miyata K, et al. Unique “delta lock” structure of telmisartan is involved in its strongest binding affinity to angiotensin II type 1 receptor. Biochem Biophys Res Commun 2011; Jan 7: 404– 407. Epub 2010 Dec 3.

10.

11.

12.

13.

Mallion JM, Siché JP, Lacourcière Y; The Telmisartan Blood Pressure Monitoring Group. ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mild-to-moderate hypertension. J Hum Hypertens 1999; 13: 657–664. Ding PY, Chu KM, Chiang HT, et al. A double-blind ambulatory blood pressure monitoring study of the efficacy and tolerability of once-daily telmisartan 40 mg in comparison with losartan 50 mg in the treatment of mild-to-moderate hypertension in Taiwanese patients. Int J Clin Pract Suppl 2004; 58: 16–22. Lacourcière Y, Krzesinski JM, White WB, et al. Sustained antihypertensive activity of telmisartan compared with valsartan. Blood Press Monit 2004; 9: 203–210. Pillay T, Smith AJ, Hill SR. A comparison of two methods for measuring anti-hypertenstive drug use: concordance of use with SA standard treatment guidelines. Bull Wld Hlth Org 2009; 87: 466–471. Sharma A, Davidson J, Koval S, et al. Telmisartan/ hydrochlorothiazide versus valsartan/ hydrochlorothiazide in obese hypertensive patients with type 2 diabetes: the SMOOTH study. Cardiovasc Diabetol 2007; 6: 28. Neldam S, Edwards C. Telmisartan plus HCTZ vs amlodipine plus HCTZ in older patients with systolic hypertension: results from a large ambulatory blood pressure monitoring study. Am J Geriatr Cardiol 2006; 16: 151–160.

Cutting Edge of Diabetes Technology Report from the Advanced Technologies and Treatments for Diabetes meeting, London, 16–19 February 2011

fter completion of yet another successful ATTD conference, the mind is suitably topped up with the latest advances in diabetes care. This is the fourth annual conference, which has grown from a mere 250 delegates in 2008 to over 1 200 delegates in 2011, testimony to the thirst for knowledge in the diabetes field and the calibre of the content of this meeting. The ATTD meeting provides a forum for exchange of ideas with chief opinion leaders and researchers in diabetes and what follows is a summary of some of the major themes and sessions. Let us begin by setting the stage. We have known since the publication of the landmark DCCT and UKPDS studies that intensive glycaemic control can reduce or delay both the macro- and definitely the microvascular complications of diabetes. In the pre-insulin era, long-term complications were unheard of as nobody lived long enough to get them, but glycaemic control through ‘starvation’ diets

could prolong life. In 1922 the discovery and rapid deployment of insulin across the globe turned a ruthless quick-acting killer into a stalker, and provided the hunted with the ability to evade the stalker for periods of time. Limiting our ability to prevent long-term complications, caused from prolonged periods of hyperglycaemia, is the ever-present spectre of hypoglycaemia that limits our ability to maintain blood sugars within a ‘safe’ range. After the publication of the DCCT in 1993, the recommendation for tighter and more intensive management brought about an impressive decline in HbA1c, but was accompanied by an equally impressive rise in rates of severe hypoglycaemia. The trend in improved glycaemia has continued to today, while the rates of severe hypoglycaemia have been reigned in, through the introduction of rapid-acting analog insulin in 1996, long-acting basal analog insulin and insulin pumps. A further advance has been the introduction of continuous glucose monitoring

(CGM) and in some cases coupling this to csii (continuous subcutaneous insulin infusion aka pump) therapy. CGM has the potential to allow the user to spend more time within a safe target zone, with fewer highs, fewer lows and less time spent in both of these extremes. Not everyone benefits from this more expensive therapy though. Only those who wear the CGM almost continuously achieve benefit. CGM is currently being integrated into closed-loop systems where interstitial blood sugars are sampled, sent through to a receiver where a computer algorithm integrates the rate and direction of change in blood glucose and alters the rate of insulin delivery to keep the blood sugars within a predefined range. A number of teams have such closed-loop systems undergoing human tests, with impressive early results. Problems still encountered with all of these systems include: • the absence of extremely rapid-acting insu-

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lin, which would mitigate against the inevitable insulin stacking that occurs • a need for a robust interstitial blood glucose sensor • a need for a dual hormone pump where glucagon is released and insulin delivery suspended to prevent or treat hypoglycaemia • algorithms that are fail safe and capable of handling ALL real-world situations. Patch pumps filled an entire session, with the enticement of a much smaller, hopefully cheaper insulin pump that can be worn on any area of the body. The technology and behindthe-scenes regulatory, legal and engineering genius of these developments are mind blowing. It is easy to envisage the benefits that safe, simple delivery devices could offer to thousands of people with diabetes. We await the introduction of these new technologies as eagerly as we await the inclusion of artificialintelligence algorithms that would make the attainment of euglycaemia safer and easier. However, hypoglycaemia remains a clear and present danger to the attainment of perfect glycaemic control. Fear of hypoglycaemia leads patients to run higher sugars and adopt avoidance behaviours that sabotage long-term control. Prof Phil Cryer (Mr Hypoglycaemia) presented a paper at the session on hypoglycaemia. It is now well recognised that hypoglycaemia may account for between 4 and 10% of the mortality in diabetes, with many of the deaths being attributed to cardiac arrhythmias rather that hypoglycaemic seizures and coma. While an attempt was made to reach a consensus of the exact value that defines hypoglycaemia, this has greater relevance for regulatory authorities and clinical trials than it does for real-world patient care. A value of 3.9 mmo/l may be too high for clinical trials, but provides a buffer zone for people with diabetes. It must however be pointed out that there is not much scientific support for this value. Hypoglycaemia and its symptoms and consequences vary from time to time in any given patient and probably are best defined by a

CUTTING EDGE OF DIABETES TECHNOLOGY

range of blood sugars rather than an absolute value. This range needs to be tailored to the clinical situation, the age of the patient, the duration of disease and concomitant medical problems. Lessons learned from both inpatient (NICE-SUGAR) and outpatient (ACCORD, VADT) clinical trials targeting very strict glucose control have resulted in unexpected increases in morbidity and mortality. A particular concern is the entity of hypoglycaemia-associated autonomic failure and hypoglycaemia unawareness. In elegant PET scan studies of humans with and without hypoglycaemia unawareness, there appears to be a loss in perception of any noxious stimulus related to hypoglycaemia in those with hypounawareness. The net effect is that these individuals do not feel their hypos but in particular will take no evasive action to avoid such episodes, even if they are made aware of them, because they do not feel bad with them. This helps to explain the difficulties faced in trying to ‘re-train’ these individuals to run higher sugars and feel their lows, and the high rate of refractory hypo-unawareness. A particularly interesting session on multimodal treatment of type 2 diabetes covered the use of leptin combined with amylin in reducing glycaemic variability, possibly through the regulation of gastric emptying and incretin hormone induction. A brief but interesting mention of the role of glucagon in maintenance of dysglycaemia again raised the notion that glucagon targeting may be a therapeutic option. However, the most interesting session was on the possibility, or better yet the probability of curing type 2 diabetes with surgery. The benefits of gastric bypass procedures were presented to look like a treatment panacea for the myriad of disorders associated with obesity and insulin resistance, or rather should we say that stem from hyperinsulinaemia. The concept of a ‘gastric diabetogenic factor’ (GDF) was raised and supported. It certainly sounds plausible that the contact of food with enterocytes in the gastric mucosa could lead to the

release of this GDF, which results in a state of hyperinsulinaemia and with it all of the welldescribed consequences of hyperinsulinaemia. Watch this space... Finally, tucked away in a single lecture, seemingly out of place, was a talk on biosimilar insulins. It was my impression that from an organising committee standpoint, they could no longer ignore the elephant in the room and were forced to make some mention of them. This, while remembering that conferences of this type could not be held without the significant financial support of those companies driving the new developments and new drugs. It was estimated that by the year 2018, biosimilar insulin would have eroded the normal insulin market by some six billion dollars. Biosimilar insulins at a cost of $6.75 per 1 000 IU versus $32.00 per 1 000 IU for normal insulin would make them hard to ignore. The impression I got from the moderators was distinctly negative towards biosimilar insulins. I can only think back to the discovery of insulin in 1922 when Banting was offered millions of dollars by a Wall Street consortium to sell the rights to insulin. Sir Frederick Banting at best was struggling financially but he held firm, dismissing the offer, saying that ‘the indigent diabetic is our greatest problem. Every effort must be made to reduce the cost of insulin and remove the necessity of expensive diets so that they can look after themselves’. I would venture to say that more lives are lost today because insulin could not be accessed than are lost to the devastating complications of the disease. While it is scientifically laudable to push the frontiers to develop new designer drugs and gadgets to normalise blood sugars, we should never forget the many lives that are lost because patients never got a chance to sample the ‘unspeakably wonderful’ benefits of insulin. David Segal Paediatric endocrinologist, CDE, Parktown, Johannesburg

Diary for 2011 diabetes congresses DATE

PLACE

CONFERENCE

WEBSITE

9–11 April

UFS, Bloemfontein

SEMDSA, LASSA, DESSA congress

www.semdsa.org.za

24–28 June

San Diego, California, USA

71st American Diabetes Association (ADA)

www.diabetes.org

22–24 July

Johannesburg, SA

13th CDE Postgraduate Forum in Diabetes Management (CDE)

www.cdecentre.co.za

1–2 September

Berlin, Germany

4th EPCCS annual scientific meeting for primary care in cardiovascular disease

www.epccs.eu

12–16 September

Lisbon, Portugal

47th EASD meeting

www.easd.org

4–8 December

Dubai International Convention & Exhibition Centre Dubai, UAE

IDF World Diabetes congress

www.worlddiabetescongress.org

VOLUME 8 NUMBER 1 • MARCH 2011

INDUSTRY NEWS

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Industry News

Boehringer Ingelheim and Eli Lilly and Company announce strategic alliance to bring new diabetes treatments to patients worldwide • Major diabetes care agreement centres on four pipeline compounds representing several of the largest and most promising product classes. • Companies will jointly develop and commercialise a pipeline of oral diabetes agents and basal insulin analogues. The alliance also includes the option to co-develop and co-commercialise an anti-TGF-beta monoclonal antibody. • Boehringer Ingelheim’s innovative latestage diabetes pipeline drives its expansion into a new therapeutic area, supplemented by two basal insulin analogues, currently under development from Lilly. • Agreement furthers Lilly’s commitment to offer one of the broadest portfolios in diabetes care and provide, together with Boehringer Ingelheim, more options for people with diabetes, their healthcare providers and payers. • Boehringer Ingelheim hosted a media event and Lilly hosted an investor conference call to discuss the content and benefits of the alliance. Boehringer Ingelheim (Germany and Indianapolis, USA) and Eli Lilly and Company (NYSE: LLY) recently announced a global agreement to jointly develop and commercialise a portfolio of diabetes compounds currently in mid- and latestage development. Included are Boehringer Ingelheim’s two oral diabetes agents, linagliptin and BI10773, and Lilly’s two basal insulin analogues, LY2605541 and LY2963016, as well as the option to co-develop and co-commercialise Lilly’s anti-TGF-beta monoclonal antibody. Linagliptin is a dipeptidyl peptidase-4

(DPP-4) inhibitor discovered by Boehringer Ingelheim and being developed as an oral once-daily tablet for the treatment of type 2 diabetes. It is currently under regulatory review in the USA, Europe and Japan. Boehringer Ingelheim’s BI10773, a sodium-dependent glucose co-transporter-2 (SGLT-2) inhibitor, began enrolment in phase III clinical trials last year. It belongs to a new, emerging class of diabetes compounds that block tubular re-absorption of glucose in the kidney. Currently there are no SGLT-2 inhibitors approved for use. Lilly’s two basal insulin analogue candidates are expected to enter phase III clinical testing in 2011. These are LY2605541, a structurally novel basal insulin analogue, and LY2963016, a new insulin glargine product. The agreement also includes an option for Boehringer Ingelheim to co-develop and co-commercialise another Lilly diabetes molecule, an anti-TGFbeta monoclonal antibody, which is currently in phase II of clinical testing in patients with diabetes and chronic kidney disease. The alliance will leverage the collective scientific expertise and business capabilities of two leading research-driven pharmaceutical companies to address patient needs arising from the growing global diabetes epidemic. ‘We are very excited about this new and extensive alliance with Boehringer Ingelheim, with whom we have partnered successfully in the past’, said John C Lechleiter, PhD, Lilly chairman and chief executive officer. ‘Working together, we will comprise one of the most robust diabetes pipelines in the pharmaceutical industry. For Lilly, this alliance expands our range of offerings for people with diabetes,

strengthens our diabetes care capabilities and offers the prospect of near-term revenue opportunities as we address the upcoming loss of patent exclusivity for several of our products.’ ‘Boehringer Ingelheim and Lilly have agreed to form a strategic alliance in diabetes at a time point when we at Boehringer Ingelheim are entering another new therapeutic area with innovative compounds from our own research and development. This cooperation will give Boehringer Ingelheim and Lilly the combined benefits of Lilly’s expertise in the diabetes market and two basal insulin analogues, as well as Boehringer Ingelheim’s rich and innovative late-stage pipeline’, said Prof Andreas Barner, chairman of the Board of Managing Directors of Boehringer Ingelheim. For further information please contact: Ms Sue Thomas (Medical Information Manager) on +27 11 348 2514 or Dr Kevin Ho (Medical Director) on +27 11 348 2517. 1.

The International Diabetes Federation Diabetes Atlas. Available at: http://www.diabetesatlas.org/ content/some-285-million-people-worldwide-willlive-diabetes-2010. Accessed September 10, 2010. Diabetes Statistics. American Diabetes Association. Available at: http://www.diabetes.org/diabetesbasics/diabetes-statistics/. Accessed September 10, 2010. Direct and Indirect Costs of Diabetes in the United States. American Diabetes Association. Available at: http://www.diabetes.org/how-to-help/action/ resources/cost-of-diabetes.html. Accessed September 10, 2010. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. J Am Med Assoc 2004; 291: 335–342.

Diabetes alliance between Novo Nordisk and Accu-Chek®

ovo Nordisk (Pty) Ltd and Roche Diabetes Care – Accu-Chek® are proud to announce that they have formed a partnership to improve the overall management of patients with diabetes through a comprehensive product and support package. These two leading companies aim to change diabetes care in South Africa and strengthen the way forward for those people living with diabetes. Mr David Broomfield, head of Marketing and Sales at Novo Nordisk says ‘our leadership position in diabetes is stronger than ever, not only in terms of absolute sales and market shares of insulin (private market IMS), but also

in increased support to people who care for or live with diabetes. With a strong diabetes pipeline, we are geared to continue to be the preferred partner in diabetes’. Dr Mary Atkinson, head of Diabetes Care at Roche says ‘we are dedicated to empower people living with diabetes to lead spontaneous, active and fulfilled lives’. Accu-Chek is the market leader both locally and globally in blood glucose monitoring systems, and according to a recent customer survey, Accu-Chek Active is the most frequently recommended blood glucose meter among healthcare professionals in South Africa.

Both companies are confident that the patient and healthcare professional will be the beneficiaries of optimised and efficient delivery of diabetes management solutions. For further information please contact: Zella Young, Novo Nordisk (Pty) Ltd on: 011 2020500 or e-mail: zyo@novonordisk.com. Website: www.novonordisk.co.za Corine Muller, Roche Diabetes Care, Roche Diagnostics on: 011 504-4600 or e-mail: corine.muller@roche.com. Website: www. accu-chek.co.za

VOLUME 8 NUMBER 1 • MARCH 2011

• In control of your prescription • In control of your patient’s blood pressure • Putting them in control of their lives

TELMISARTAN + HCTZ

TELMISARTAN 80 MG putting you back in control

S3 PRITOR® 40 mg. Each tablet contains telmisartan 40 mg. Reg. No. 33/7.1.3/0022. PRITOR® 80 mg. Each tablet contains telmisartan 80 mg. Reg. No. 33/7.1.3/0023. S3 CO-PRITOR® 40/12,5 mg. Each tablet contains telmisartan 40 mg and hydrochlorothiazide 12,5 mg. Reg. No. 35/7.1.3/0347. CO-PRITOR® 80/12,5 mg. Each tablet contains telmisartan 80 mg and hydrochlorothiazide 12,5 mg. Reg. No. 35/7.1.3/0348. Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd, 407 Pine Ave, Randburg. Tel: +27 (011) 348-2400. Fax: +27 (011) 787-3766. Cpy. Reg. No. 1966/008618/07. For full prescribing information refer to the package insert approved by the medicines regulatory authority. BI Ref 50/2010 (MAR 10)

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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

SA JOURNAL OF DIABETES & VASCULAR DISEASE

DRUG TRENDS

Drug Trends Clinical perspectives on managing diabetes: an expert South African view

t a recent meeting of specialist diabetologists held in Sun City, out-spoken South African clinicians challenged firstly, the simplistic approach of treating all type 2 diabetes patients as a single homogenous group, and secondly, compartmentalising type 1 and type 2 diabetes into two separate groups. Human nature seeks to simplify and reduce complexity in order to manage the issues at hand; yet in doing this, clinicians may undervalue breakthroughs in knowledge and practice.

Dr Aslam Amod

Using clinical insight to treat the diversity of the type 2 condition ‘Treating type 2 diabetes as a single disease contributes to the development of dogma and broad standard guidelines that may result in poorer individual clinical care. This grouping of multi-aetiology type 2 diabetes as a single condition may also contribute to weaker results in diabetes clinical trials.’ This view was presented by Dr Aslam Amod from Durban, who noted the muddled thinking presented to patients by many healthcare professionals. ‘They present the concept that you are overweight because you are insulin resistant. This is physiologically incorrect. Insulin’s function is predominantly anabolic and it promotes weight gain. In its functional absence, the result is weight loss. In severe cases of insulin resistance, such as children with an inherited condition of extreme insulin resist-

VOLUME 8 NUMBER 1 • MARCH 2011

ance (leprachaunism) and in polycystic ovarian syndrome, diabetic patients do not have subcutaneous fat and are not obese’, Dr Amod argued. ‘If the primary event is insulin resistance, the patient is not overweight. If however the primary event is being overweight, then insulin resistance follows as a secondary event to protect the body from the consequences of being overweight. These two distinct versions of a type 2 diabetic patient could perhaps be called the Jekyll and Hyde of type 2 diabetes. The same patient; or a very different patient, in my view’, Dr Amod said. ‘In the overweight situation where the insulin-resistant patient has normal β-cell function, glucose levels remain normal. If, however, there is a β-cell defect, insulin production falters, with resultant hyperglycaemia’, Dr Amod pointed out. ‘The role of insulin resistance as a protection mechanism in the overweight situation may be a reason why the insulin-sensitising glitazones show poorer-than-expected outcome results in clinical studies’, Dr Amod speculated. ‘In treating the non-obese type 2 diabetic patient with insulin resistance, even metformin has little or no science behind its use’, Dr Amod added. ‘However, we use this agent for practical reasons without solid outcomes data.’ ‘In insulin-resistant, overweight patients, treatment with metformin, acarbose and exenatide makes physiological sense. Treating non-obese, insulin-resistant patients with sulphonylureas followed by insulin, then adding metformin also makes physiological sense. If you follow the step-by-step guidelines of SEMDSA and other expert bodies, you certainly will get to effective care, but you may well have lost valuable time and perhaps the β-cells of your patient’, he added. A neglected diagnosis in type 2 diabetes is the descriptive ‘lemon on a matchstick’ phenomenon of lipidodystrophic diabetes. ‘This has not been identified as being genetically determined as yet, but it is probably due to a post-receptor defect in the peripheral tissue. Therapy should be targeted at maximising insulin sensitivity with pioglitazone, metformin and GLP-1 agonists. Adding insulin also becomes necessary.’

Adding to the diversity of diabetic aetiology are cases of pancreatic diabetes, latent autoimmune diabetes, pan-hypopituitarism and drug- or chemical-induced diabetes. In conclusion, Dr Amod argued for the development of an approach to the diagnosis of type 2 diabetes as one of diagnostic exclusion: ‘exclude the genetic aspects, disease of the pancreas and other aetiologies, then conclude that your patient is in fact a type 2 diabetic characterised by overweight, insulin resistance and β-cell dysfunction.’

Dr Brian Kramer

The metabolic syndrome: weighing up its value The metabolic syndrome exists but it has little medical value as it does not contribute to improved clinical management of patients. ‘Syndrome X has in fact become an X syndrome and recent reviews by WHO, EASD and ADA expert committees have indicated that further efforts to define the condition are inappropriate’, Dr Brian Kramer, CDE, Houghton, told delegates at the Sanofi-Aventis-sponsored academic meeting at Sun City. ‘Clustering symptoms together as a syndrome should contribute to the understanding of the syndrome or identifying causes of the condition. As an example, the cluster of cough, weight loss and night sweats, initially described in a single entity as consumption, later led to the discovery of Mycobacterium tuberculosis’,

DRUG TRENDS

SA JOURNAL OF DIABETES & VASCULAR DISEASE

to rg en ot

In a journey to look at 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: firstly, neuro-economics (the cost–benefit of obtaining food), and secondly, 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

ce le

The changing gut microbiome: is it killing us?

Dr David Segal

mechanisms, they have failed to give us a prac- islets, a human leukocyte antigen (HLA) link to diabetes and islet antibodies. We do not have tical option to control obesity’, he said. The field of neuro-economics applied a clue as to what triggers the immune system to food calculates the price-cost in energy to attack the b-cell’, Dr Segal said. An hypothesis that is gaining credence is expended, and the risk and effort to procure the food that we eat, and relates it to demand, the ‘accelerator’ hypothesis which proposes which is ever present as appetite, and supply, that weight and associated insulin resistance which in urban areas is plentiful at the nearest accelerate loss of b-cells in both type 1 and type 2 diabetes and the only thing that distinsupermarket. ‘In neuro-economic terms, our food is very guishes these two forms of diabetes is the rate cheap and is extra-ordinarily palatable, thereby of progression. There is considerable evidence stimulating excess demand. This demand that weight gain in early life can be used to will remain consistently high unless we can predict at two years of age the risk of islet increase the energy-risk cost or reduce the pal- immunity in children with first-degree relatives atability’.1 ‘In effect, this means that we cannot with type 1 diabetes.3 Also, over the past 20 control obesity in our modern urban setting’, years, there has been a steady increase in BMIs Dr Segal pointed out. in girls and boys at the time of diagnosis of In a study on the burden of diabetes among their type 1 diabetes.4 ‘If we look at HLA risk markers for diabetes, American youth, the SEARCH study2 has shown the rising prevalence of type 2 diabe- it is evident that there are genotypes that are tes in different racial groups in six states in the related to the development of type 1 diabetes, USA. Among younger children from birth to 1.5 latent autoimmune diabetes in adulthood nine years of age, type 1 diabetes accounted (LADA) and type 2 diabetes’, Dr Segal said. for approximately 80% of diabetes cases, Because of environmental pressures, a lower while among the older group (10–19 years) predisposing genetic component is needed type 2 diabetes ranged from 6% in the non- today to result in the development of diabeHispanic whites, to 76% (1.74% per 1 000 tes than was required in the 1930s. ‘The precases) among American Indians. disposing reactive genotype leads in fact to a Interestingly, the only group in the 15- to faster tempo of b-cell loss in the presence of 19-year-olds to show the same prevalence increasing insulin resistance’, Dr Segal pointed (3/1 000) for both type 1 and type 2 diabetes out (Fig. 1). was the African-American female population. In adolescents, it is the ongoing weight gain ‘Type 2 diabetes in adolescents is associated that predicts the development of type 2 diabewith increased obesity, with a five-year lead tes rather than glucose levels, insulin resistance time between obesity occurrence (BMI ≥ 30 Figure 1. Relationship between the accelerator genotype, insulin resistance kg/m2) and the develand the probability of diabetes. opment of diabetes’, Dr Segal noted. In evaluation of the rising trend of childhood type 1 1.0 diabetes, there is an 0.9 association with rising 0.8 childhood obesity. Up until the 1950s, 0.7 diabetes was seen 0.6 as a single disorder 0.5 with an aggressive 0.4 presentation in the 0.3 young. ‘In the 1960s, 0.2 scientific evidence 0.1 saw the emergence 0.0 of an auto-immune basis for type 1 diabetes with lymphoInsulin resistance cytic infiltration of the Probability of diabetes

Dr Kramer said. The search for a common aetiology for the metabolic syndrome was first grounded in insulin resistance but this unifying aetiology has remained unproven. Subsequently, visceral obesity, inflammation and hyper-insulinaemia were explored as a common aetiology, but these attempts also failed. So there was no real advantage in calling these conditions the metabolic syndrome’, Dr Kramer explained. At the practical level of general practitioner and patient communication, the cluster of dysglycaemia, hypertension and dyslipidaemia in the presence of visceral obesity may perhaps usefully be described as ‘the syndrome that was once known as the metabolic syndrome’, Dr Larry Distiller added.

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

or C-peptides. ‘This is because the BMI is a reliable reflection of insulin resistance over time’, Dr Segal argued. ‘If the accelerator theory is correct, the occurrence of type 1 and type 2 diabetes will converge over time and this has already occurred in African-American females.’ ‘But the added weight is in fact a bystander injury, it is our high fat and refined carbohydrate intake which is hammering the b-cell. This high fat, high carbohydrate intake is also causing oxidative stress and the release of inflammatory cytokines.’ Evidence is emerging linking the trillions of bacteria living in our gut to the development of obesity and diabetes. These gut organisms, collectively known as the gut microbiome, are so vastly altered that in fact this microbiota can promote a ‘leaky gut’, an increase in systemic inflammation and show an increased capacity for energy harvesting. ‘So not only are overweight people taking in an excess in calories, their gut is harvesting more nutrients than the lean individual’, Dr Segal pointed out. Signals from the gut can promote the diversion of calories into fat storage and suppress fat burning. The perfect storm is however created in the gut lining, which has been shown in type 1 diabetes to develop leaks. This results in increased permeability to dietary antigens, changing mucosal immunity and contributing to the pathogenesis of type 1 diabetes. In conclusion, Dr Segal noted that in future we may find ways of rebalancing our gut by altering the foods we eat. In the interim, rebalancing the gut microbiota by returning to a highfibre, low-fat, reduced refined carbohydrate diet may contribute to slowing the advance of both type 1 and type 2 diabetes worldwide.

Prof Brynne Ascott-Evans

VOLUME 8 NUMBER 1 • MARCH 2011

DRUG TRENDS

Carefully consider the routine use of aspirin in primary prevention of CVD in low-risk diabetic patients Any benefit of aspirin in primary prevention of cardiovascular disease (CVD) in low-risk diabetic patients is minimal and may well be out weighed by the side effects, especially the increase in gastrointestinal bleeds. This view was expressed by Prof Brynne Ascott-Evans, Division of Diabetes and Endocrinology, Stellenbosch University, and substantiated primarily from evidence published in a meta-analysis by the Anti-Thrombotic Trialists (ATT) collaboration5 and specific trials in diabetic patients from Scotland (POPADAD) and Japan (JPAD). In the ATT meta-analysis, only 5% of patients were diabetic, and the trials included were older studies with a mixed bag of patients and doses. ‘However, individualised data for each patient in the various studies were utilised in the meta-analysis.’ The ATT study found that there was a significant 12% drop in any serious vascular event on aspirin (primarily due to a significant drop in non-fatal myocardial infarction). However, aspirin usage did not affect mortality in this meta-analysis. In the subgroup of diabetic patients, the benefit of reduced vascular events was not significant, but haemorrhage and extra-cranial bleeds were increased. Referring to two modern studies,6,7 POPADAD (Prevention Of Progression of Arterial Disease And Diabetes) in asymptomatic type 1 and type 2 diabetes who were given 100 mg aspirin and followed for 6.7 years (mean), and JPAD in healthy type 2 diabetics with no vascular disease clinically or on ECG and were followed for 4.4 years, the benefits of aspirin therapy were not statistically significant. In POPADAD there was no statistically significant difference in death from coronary artery disease and stroke, while increased gastrointestinal bleeds affected four per 1 000 patients on aspirin. In the JPAD study, the hazard ratio for atherosclerotic events was reduced by 20% in aspirin users, but the number of events was small and the difference was not statistically significant. In the 2010 position paper of the ADA, AHA and the ACC Foundation,8 diabetic patients from the ATT meta-analysis were pooled with those from POPADAD, JPAD and an older large retinopathy study (where patients received 650 mg aspirin daily and which contributed 50% of the total study population of 7 500 patients in this new meta-analysis). Nonetheless, only a 15% relative risk reduction (RRR) in stroke was

seen, which was not statistically significant. There was a risk of haemorrhagic stroke of 1:10 000 per year and a gastrointestinal tract (GIT) bleed risk of 3:10 000 per year. However, it must be remembered that patients at higher risk of bleeding were not included in these cohorts of diabetic patients. The consensus view was that aspirin (81– 162 mg) should be recommended for diabetic patients with a 10-year cardiovascular disease risk above 10%, and for those below 5% no aspirin should be given. ‘In essence, the 10% risk can be simply assessed as diabetic men (above 50 years of age) and women (above 60 years of age) with at least one additional major risk factor’, Prof Brynne Ascott-Evans pointed out. He concluded that these recent studies reaffirm that cheap and seemingly fairly safe interventions, e.g. aspirin, do not necessarily benefit patient cohorts that are the target. Treatment should be individualised.

Dr Larry Distiller

The obese very insulin-resistant type 2 diabetic patient: what are the treatment options? Treating the obese, extremely insulin-resistant type 2 diabetic patient with a long duration of illness is very difficult and published research provides little guidance for treatment of this patient population. This view was expressed by Dr Larry Distiller, CDE Houghton, and supplemented by an appeal to the endocrinologists present to join a planned clinical study of these patients in order to evaluate prospectively the value of concentrated insulin (U-500) and other techniques to improve outcomes in these patients. ‘These patients are injecting large volumes

DRUG TRENDS

SA JOURNAL OF DIABETES & VASCULAR DISEASE

of insulin, with resulting problems at the injection sites and reduced patient compliance. Their HbA1c levels are often high (> 10%) and lifestyle change is poorly supported’, Dr Distiller pointed out. The use of U-500 produced by Eli Lilly and available on request for named patients under a Section 21 approval is a useful tool to help these patients. ‘Although U-500 is not commercially available anywhere in the world, there are a few retrospective studies that guide its use in these special patients’, Dr Distiller said.9 The studies used both insulin pumps and injections and showed improved HbA1c levels (reduction from 10–8.4%), small weight gain equivalent to the improved glucose control (average of 4 kg) and no severe hypoglycaemic events. ‘As one unit of U-500 equals five units by volume of regular insulin, using this concentrated insulin requires in-depth understanding by the healthcare professional and the patient. This insulin is much more stable, and in the obese patient reaches peak levels after about eight and a half hours and offers duration of action of 24 hours’, Dr Distiller noted. The application form for use can be obtained from Lilly and it takes about two weeks to process. As the insulin is affordable, there are not any funder-related problems’, Dr Distiller concluded.

Dr Stan Landau

Cancer: the forgotten ‘complication’ of diabetes ‘The most appropriate causative factor related to the observed increased cancer occurrence in type 2 diabetes is the presence of insulin resistance and hyperinsulinaemia’, Dr Stan Landau CDE, Houghton, stated and set out to show

data supporting this concept. ‘It is important to clarify the issues around cancer and type 2 diabetes as, based on epidemiological data, a patient with both these conditions is exposed to a 40% increase in the risk of death compared to an age- and cancer-matched patient without diabetes’, he noted.10 While cancer is a leading cause of death, specific cancers such as lung, breast and colon are dominant in prevalence, while others such as lung, stomach and liver cancer are the main causes of cancer deaths. The complete pathophysiological pathways of both diabetes and cancer are incompletely understood, adding to the complexity of evaluating the relationship between these two disease states. ‘In terms of epidemiological studies, we know that simple elevation of glucose levels is associated with increased cancer occurrence. Also, that as impaired glucose tolerance (IGT) moves into the diabetic ranges, cancer rates increase.’ Data from the European Prospective Investigation into Cancer and nutrition (EPIC) studies and the DECODE study11 are adding to the quite solid basis of evidence that links increased blood sugar to cancer provocation. Specifically in the DECODE study of European populations, there were significant increases in deaths from cancer of the stomach, colon–rectum and liver in men with pre-diabetes and diabetes, and increased deaths from cancers of the liver and pancreas in women. A further pathway to increased cancer risk may relate to the chronic inflammatory nature of diabetes, which produces excessive reactive oxygen species. ‘The most appropriate causative association in my view is that of insulin resistance and hyperinsulinaemia, which leads to a 35% increased risk of cancer; likely due to insulin growth factor-1 (IGF-1) release, which stimulates cell proliferation of the mitogenic pathway in a susceptible genetic environment. However, there are no prospective clinical data linking IGF-1 stimulation to mitogenic development, only laboratory-based studies. In my view, the insulin supply hypothesis as opposed to the glucose supply hypothesis is more likely and is the major contributor to increased cancer risk’, Dr Landau noted. ‘When we assess the cancer risk of diabetes treatment using insulins, we raise a multiplicity of variables: duration of insulin therapy, adherence, insulins in multiple treatment protocols over time, all of which complicate any determination of a specific insulin therapy and cancer

risk. Insulin is certainly a mitogenic hormone but to prove that insulin analogues are related to cancer provocation, one would need more than the present in vitro studies of IGF activity.’ Currently, the only prospective data on an insulin analogue (glargine) compared to NPH insulin with regard to cancer risk comes from a study of ocular complications in diabetic patients using these therapies.12 This study over a five-year period found no greater risk of cancer or cancer death in the glargine-treated compared to the NPH insulin-treated group. In conclusion, Dr Landau expressed the view that better understanding is required and that ‘no evidence of risk’ does not equal ‘no risk’ and prospective trials of specific insulins and specific cancer types in specific diabetic populations will be required to clarify the real cancer risks in type 2 diabetes.

Dr Ray Moore

Future diabetic therapies and unmet clinical needs in type 2 diabetes Unmet clinical needs including increasing HbA1c levels reflecting poorer glucose control over time, reduced β-cell function, which decreases by about 4% annually, and an inability to significantly reduce the macrovascular consequences of diabetes, are being targeted by newer medications. ‘But will they fulfil this promise?’ Dr Ray Moore, from Durban asked. His answer seems to indicate some improvement on the pharmaceutical front, but no real panacea. ‘There are new formulations of older drugs such as slow-release gliclazide (Diaglucide MR, Diamicron MR), sustained-release metformin (Glucophage XR), and combinations of oral anti-diabetic medications such as glucovance (metformin and glibenclamide). These drugs

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

may aid compliance, reduce polypharmacy and are often more cost effective but unfortunately they do not offer advantages over their initial value’, he noted. ‘The incretins offer the promise of saving β-cells but until we use these agents earlier in the treatment protocols, we will not realise this for our patients. Cost is the barrier to early use’, Dr Moore noted. The once-a-week exenatide or even once-amonth formulation, which are in clinical trials at present, offer an interesting option, particularly if nausea and gastrointestinal side effects are lessened in these formulations. ‘Liraglutide, a slightly modified version of the GLP-1 molecule, which is attached to albumin to extend its pharmacokinetic profile over 24 hours and with lower gastrointestinal side effects, will be widely used if costs can be addressed’, Dr Moore noted. ‘We do need outcome data for these medications, and the LifeLink database is beginning to show that exenatide can reduce cardiovascular events, mainly due to reductions in cardiovascular-related hospitalisation’, Dr Moore pointed out. ‘This is re-assuring.’ The DPP-4 inhibitors, such as sitagliptin (Januvia) and saxagliptin from Astrazeneca, have an advantage in reducing triglyceride levels, which may prove to be of added value. ‘But again we do not yet have outcome data

DRUG TRENDS

on these new agents. Clinical outcome trials are being done for some DPP-4s with our South African centres participating’, Dr Moore noted. In conclusion, Dr Moore noted that none of these oral therapies work well in patients who do not adapt their lifestyle. ‘With adolescent obesity and emerging type 2 diabetes occurring in the 20-year-old, we will have cardiovascular consequences much earlier, in the 30- to 40-year age group for example. This presents a significant challenge to healthcare systems worldwide. J Aalbers, Special Assignment Editor 1.

Rowland NE, Vaughan CH, Mathes CM, Mitra A. Feeding behaviour, obesity and neuroeconomics. Physiol Behav 2008; 93(1-2):97-109. E-pub 1 Jul 2008. Search for Diabetes in Youth study group. The burden of diabetes mellitus among US youth. Pediatrics 2000; 118(4): 1510–1518. Couper JJ, Beresford S, Hirte C, Baghurts PA, Pollard A, Tait BD, et al. Weight gain in early life predicts risk of Islet autoimmunity in children with a firstdegree relative with type 1 diabetes. Diabetes Care 2009; 32(1): 94–99. Wilkin TJ. Diabetes: 1 and 2, or one and the same? Progress with the accelatator hypothesis. Pediat Diabetes 2008; 9 (3 part 2): 23–32. Anti-Thrombotic Trialists collaboration (ATT). Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of

individual participant data from randomised trials. Lancet 2009; 373: 1849–1860. 6. Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, Lee R, et al. The Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial: factorial ramondised placebo controlled trial in aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. Popadad. Br Med J 2008; 337: a1840. doi:10.1136/ bmj.a.1840. 7. Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, et al. A low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomised controlled trial. J Am Med Assoc 2008; 300(18): 2134–2141. 8. Pignone M, Alberts MJ, Colwell JA, Cushman M, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Circulation 2010; 121(24): 2694–2701. E-pub May 27 2010. 9. Lane WS, Cochran EK, Jackson JA, Scism-Bacon JL, et al. High-dose insulin therapy: is it time for U-500 insulin? Endocrine Pract 2009; 15: 71–79. 10. Rnehan A, Smith U, Kurkman MS. Linking diabetes and cancer: a consensus on complexity. Lancet 2010; 375(9733): 2201–2202. 11. Zhou SH, Qiao Q, Zethelius B, et al. Diabetes, prediabetes and cancer mortality. Diabetologia 2010; 53(9): 1867–1876. 12. Rosenstock J, Fonseca V, McGill JB, et al. Similar risk of malignancy with insulin glargine and neutral protamine hagedorn (NPH) insulin in patients with type 2 diabetes: Findings from a 5-year randomised open label study. Diabetologia 2009; 52(9): 1971– 1973.

This meeting was sponsored by

VOLUME 8 NUMBER 1 • MARCH 2011

DRUG TRENDS

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Managing heart failure patients: choosing the best angiotension receptor blockers Heart failure registry differentiates between the ARBs, candesartan and losartan

ortality in heart failure patients with impaired left ventricular ejection fraction (LVEF) was significantly reduced with candesartan in comparison to losartan in a large population of patients in everyday care.1 Fifteen per cent of the patients in this registry study of Swedish patients had diabetes; as could be expected from broad estimations that one in five diabetic patients will develop heart failure in the course of their disease. Heart failure and diabetes are inextricably linked. Because of this and the high incidence and financial burden of these conditions, preventing heart failure patients from developing diabetes; preventing those with diabetes from developing heart failure; and improving the prognosis of those with diabetes and heart failure are important therapeutic goals.2 Most algorithms for the pharmacological management of heart failure recommend the use of an angiotensin II receptor antagonist (ARB) in ACE-intolerant patients. Currently, only candesartan and valsartan have evidence to support their use in heart failure, with positive outcome data from the CHARM group of studies when candesartan was used together with an ACE inhibitor and a β-blocker. In contrast, valsartan, in the VAL-HEFT study, when used with an ACE inhibitor and a beta-blocker, led to an adverse trend of increasing mortality and morbidity.3 The positive results for candesartan in this latest evaluation in a ‘real-world’ situation were maintained after adjustment for numerous clinical variables, including dose (the comparative losartan dose was set at 150 mg/day in accordance with the HEAAL study4), selection bias and outcome. In the evaluation of doses in this study, 70% of the candesartan group received the target dose defined as 32 or 50 mg/day. The benefit in all-cause mortality with candesartan was seen in both the one- and fiveyear survival data of patients with a LVEF of less than 40% and in those with a LVEF of 40% or more. The one-year survival was 90% for patients receiving candesartan and 83% for patients receiving losartan. The five-year survival was 61% for candesartan-treated patients and 44% for losartan-treated patients. The hazard ratio (HR) for all-cause mortality of losartan compared with candesartan was 1.43 overall, and similar in those patients with impaired LVEF and those with LVEF greater than 40% (HR of candesartan compared to losartan was 0.70).

As the patients included in this study were being treated both in hospital and on an outpatient basis (54.5% of patients), overall mortality was low (1 329 deaths in the 5 139 patients included in the analysis). The limitations of the study relate mainly to its non-randomised character, yet this real-world situation seems to reflect and amplify the differences seen in the randomised clinical trials of these two ARBs. Candesartan is well known to South African clinicians following the results of the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity) randomised clinical trial (RCT) studies published in 2005.5,6 In CHARM, analysis of the effects of candesartan (Atacand) on myocardial infarction (MI) across the full data set showed that candesartan significantly reduced the risk of the primary composite outcome of cardiovascular death or non-fatal MI in patients with symptomatic heart failure.7 This study provided contributory evidence to refute suggestions that ARBs, unlike ACE inhibitors, may not reduce myocardial infarction.8 The findings from CHARM were consistent across all pre-determined subgroups and across the component CHARM trials (added to an ACE inhibitor, alternative to ACE inhibitors and in patients with preserved LVEF), including patients treated with other therapies proven to be effective in reducing the risk of MI or reinfarction. This analysis of CHARM provided further support for the benefit of candesartan in this patient group with New York Heart Association class II to IV symptoms. The overall CHARM cohort consisted of 7 599 patients; 4 004 (53%) had experienced a previous MI, and 1 808 (24%) currently had angina. At baseline, 3 125 (41%) were receiving an ACE inhibitor, 4 203

(55%) a beta-blocker, 3 153 (42%) a lipidlowering drug, 4 246 (56%) aspirin, and 6 286 (83%) a diuretic. During the median follow-up of 37.7 months, the primary outcome of cardiovascular death or non-fatal MI was significantly reduced in the candesartan group (Table 1). J Aalbers, Special Assignments Editor 1.

2. 3.

Eklind-Cervenka M, Benson L, Dahlstrom U, Edner M, et al. Association of candesartan vs losartan with all-cause mortality in patients with heart failure. J Am Med Assoc 2011; 305(2): 175–182. Kirby M. Heart failure and diabetes in primary care. S Afr J Diabetes Vasc Dis 2007; 4: 64–69. Cohn JN, Tognoni G, Valsartan Heart Failure trial investigators. A randomised trial of the ARB Valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667–1675. Konstam ME, Neaton JD, Dickstein K, et al; HEAAL investigators. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double blind trial. Lancet 2009; 374(9704): 1840–1848. Granger C, McMurray JJ, Yusuf S, et al; CHARM investigators and committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003; 362(9386): 772–776. McMurray JJ, Ostergren J, Swedberg K, et al; CHARM investigators committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362(9386): 767–771. Demers C, McMurray JJV, et al. Impact of candesartan on non-fatal myocardial infarction and cardiovascular death in patients with heart failure. J Am Med Assoc 2005; 294: 1794−1798. Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. Br Med J 2004; 329: 1248−1249.

Table 1. Effect of candesartan on development of MI, CV mortality and hospitalisation for unstable angina or coronary revascularisation procedures Candesartan (n = 3 803) n, %

Placebo (n = 3 796) n, %

p-value

CV death/non-fatal MI

775, 20.4

868, 22.9

0.004

Non-fatal MI

116, 3.1

148, 3.9

0.03

CV death

691, 18.2

769, 20.3

0.01

Fatal MI, sudden death or non-fatal MI

459, 12.1

522, 13.8

0.02

Sudden death/fatal MI

360, 9.5

394, 10.4

0.11

Hospitalisation, unstable angina

394, 10.4

397, 10.5

0.60

Coronary revascularisation procedures

236, 6.2

241, 6.4

0.50

Outcome

VOLUME 8 NUMBER 1 • MARCH 2011

Not an actual patient

AstraZeneca Pharmaceuticals (Pty) Limited. Reg. No. 1992/005854/07. 5 Leeuwkop Road, Sunninghill, 2157. Tel: (011) 797-6000. Fax: (011) 797-6001. www.astrazeneca.co.za. 速 is a registered trademark. S3 Atacand速 8 mg (Tablet). Each ATACAND 8 mg tablet contains 8mg candesartan cilexetil. 32/7.1.3/0099. S3 Atacand速 16 mg (Tablet). Each ATACAND 16 mg tablet contains 16 mg candesartan cilexetil. 32/7.1.3/0100. EPI date: 27/06/2007. S3 Atacand速 32 mg (Tablet). Each ATACAND 32 mg tablet contains 32 mg candesartan cilexetil. A39/7.1.3/0244. EPI date: 13/12/2007. INDICATIONS: ATACAND is indicated for mild to moderate hypertension. It may be used alone or in combination with other antihypertensive agents such as thiazide diuretics and dihydropyridine calcium antagonists, for enhanced efficacy. Heart Failure:Treatment with ATACAND reduces mortality, reduces hospitalisation due to heart failure, and improves symptoms in patients with left ventricular systolic dysfunction (LVEF 40%). For full details relating to any information mentioned above please refer to the package inserts. Candesartan Cilexetil is manufactured under the license from Takeda Chemicals Industries, Ltd. Date compiled: February 2011.

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Reduce morbidity and mortality in men and women at risk for CVD 2 l

Persistent thromboxane production has been associated with poor patient outcome. 3

Compared to the lower doses (75 mg) of plain Aspirin tablets, 100 mg of enteric-coated Aspirin is recommended to ensure adequate inhibition of thromboxane production. 3

Enteric-coated Aspirin offers effective protection against gastric mucosal injury by eliminating the injury caused by Aspirin. 4

Bayer® Aspirin CardioTM 100 mg is indicated to reduce the risk of myocardial infarction and stroke in patients who have had a previous myocardial infarction, stroke or transient ischaemic attack. 1

Bayer® Aspirin CardioTM 100 mg daily is recommended to reduce the risk of myocardial infarction in people with cardiovascular Today’s risk factors. 1

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References: 1. Bayer® Aspirin CardioTM 100 Package Insert. 2. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomized trials of antiplatelet therapy. Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ Jan 1994; Vol. 308:81-106. 3. Cox D, Maree AO, Dooley M, Conroy R, Byrne MF, Fitzgerald DJ. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke 2006;2153-2158. 4. Cole AT, Hudson N, Liew LC, et al. Protection of human gastric mucosa against aspirin-enteric coating or dose reduction? Aliment Pharmacol Ther. 1999 Feb;13(2):187-93. S0 Bayer® Aspirin CardioTM 100. Each tablet contains 100 mg of acetylsalicylic acid (ASA). Reg. No. 31/8/0413. For full prescribing information refer to the package insert approved by the Medicines Regulatory Authority.

Bayer (Pty) Ltd t/a Bayer Schering Pharma; Reg.No.1968/011192/07. 27 Wrench Road, Isando, 1609. Tel (011) 921-5911. L.ZA.GM.10.2010.0065 121848

SA JOURNAL OF DIABETES & VASCULAR DISEASE

DRUG TRENDS

Substantial evidence for colorectal cancer reduction with daily lowdose aspirin

igh-dose aspirin (≥ 500 mg daily) taken for a period of five years has been shown in long-term follow-up studies to reduce the risk of colorectal cancer in the next decades of the patient’s life. However, the greater risk of bleeding complications at this high dose reduces aspirin’s potential in primary prevention of cancers. New data from four trials of aspirin,1 using daily dosages from 75 to 300 mg were compared to the high-dose aspirin studies and showed: • 75 mg aspirin taken daily is as effective as high-dose aspirin in reducing the 20-year incidence of colorectal cancer (by 30%) if taken for approximately five years. • Not only did the lower dose of aspirin reduce the incidence of these cancers,

•

it also reduced mortality from colorectal cancer. The reduction in fatal colorectal cancer tended to be greater than the reduction in incidence. Very low daily doses of aspirin tended to not be effective in the prevention of colorectal cancer. The reductions in both incidence and death due to colorectal cancer were greater for proximal cancer tumours than distal colon or rectal tumours. The reduction in 20-year risk of death due to colorectal cancer was larger than expected. Larger doses, above 300 to 1 200 mg daily, did not confer any additional benefits in terms of reduced incidence or deaths from

colorectal cancer. The long-term absolute risk reduction of 1–5% after long-term, low-dose aspirin treatment has implications for clinical practice. It adds to the primary preventative benefits of aspirin and may tip the balance in favour of aspirin compared to newer anti-platelet agents.2 J Aalbers, Special Assignments Editor 1.

Rothwell PM, Wilson M, Elwin CE, Norrving B, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. Published online Oct 22, 2010. DOI:10.1016/S0140-6736(10)61543-7. Benamouzig R, Uzzan B. Aspirin to prevent colorectal cancer: time to act? Lancet. Published online Oct 22, 2010. DOI:10.1016/501406736(10)61509-7.

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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.

SA JOURNAL OF DIABETES & VASCULAR DISEASE

JOURNAL UPDATE

Journal Update Autoimmunity in a South African and African context

his review of the latest international journals focuses on the theme of autoimmunity with the particular inclusion of recent articles by South African researchers in the broader field of diabetes care.

Autoimmunity, Addison’s disease and accompanying autoimmune conditions in a large South African cohort In patients with Addison’s disease in South Africa, accompanying autoimmune diseases such as primary hypothyroidism (47%) premature ovarian failure (8%) and type 1 diabetes (7%) were the most prevalent. This study1 of 144 South African Addison’s disease patients (94 of European descent, 34 mixed ancestry, five Asians and 11 Africans) recruited mainly from major centres (often treated at teaching hospitals) showed that autoimmunity accounts for at least half of the patients with Addison’s disease. The genetic assessment excluded patients with autoimmune Addison’s disease and associated autoimmune conditions, to eliminate the bias these conditions can create with HLA associations. The presence of type 1 diabetes was reportedly strongly associated with DQB1 *0201 and DQB1 *0302 alleles. When Addison’s patients with type 1 diabetes were removed from the evaluation, an association with *0201 and *0302 remained. HLA DQB1 *0201 alleles predominated in the autoimmune group, but none of the black Africans or Asians in this cohort had adrenal antibodies. The authors noted the limiting factor in this group was related to small sample size and requires confirmation in larger studies. Source: Ross I, Boullet A, Soule S, Levitt N, Pirie F, et al. Clin Endocrinol 2010; 73: 291–298. DOI: 10.1111/j.13652265.2010.03807.x

Management of diabetes – South African paediatric study of type 1 diabetic patients In a comparative efficacy and safety study of insulin glulisine and insulin lispro, given as part of a basal-bolus insulin regimen over 26-weeks to paediatric type 1 diabetic patients, this Cape Town-managed study showed both treatments were equally effec-

tive and similarly well tolerated. The study included 572 children and adolescents (4–17 years old) using insulin glargine or neutral protamine Hagedorn insulin as basal insulin, who were enrolled to receive glulisine (n = 277) or lispro (n = 295) 0–15 min pre-meal. The results showed similar baseline-toendpoint HbA1c changes. Overall, for all age groups together, the percentage of patients achieving American Diabetes Association age-specific HbA1c targets at endpoint was however significantly higher (p = 0.039) with glulisine (38.4%) than lispro (32.0%). Symptomatic hypoglycaemic rates were similar. Source: Philotheou A, Arslanian S, Blatniczky L, Peterkova V, Souhami E, Danne T. Diabetes Technol Ther 2011 Feb 3. Published ahead of print.

Malnutrition-related diabetes seen in northern Ethiopia A detailed clinical, biochemical and immunological study of a group of ‘type 1 diabetic patients’ was undertaken at Mekelle Hospital in northern Ethiopia, which serves a poor rural area; 36% of the total group (105 patients) had immunological or C-peptide characteristics inconsistent with typical type 1 or 2 diabetes. The clinical characteristics, local prevalence of under-nutrition and GADA and C-peptide heterogeneity are suggestive of a malnutrition-related form of diabetes. Of the 105 patients, 74 (68%) were men, mean age (± SD) was 41 ± 16 years and diabetes duration [median (interquartile range)] was 5 (3–10) years. A family history of diabetes was present in 10 (9%) patients; median (interquartile range) BMI was 20.6 (18.5–23.9) kg/m2. Treatment was with diet (n = 1), oral agents (n = 35) and insulin (n = 69). Only 5% of patients were hypertensive (BP > 140/80 mmHg). Glycaemic control was poor with HbA1c high at 11.3 ± 2.8%. The failure of C-peptide to correlate negatively and GADA positively is explored further in Table 1, and led to the subdivision of the group into: (1) ‘definite’ type 1 diabetes (GADA-positive, C-peptide-negative and on insulin); (2) ‘definite’ type 2 diabetes (GADA-negative, C-peptide-positive and on any treatment); and (3) ‘uncertain’ (all other patients).

These revised groupings gave a much more expected proportion of type 1 diabetes patients at 17%, with type 2 diabetes comprising 47% and the ‘uncertain’ group 36%. Patients in the latter group were closer to type 1 than type 2 diabetes in terms of age (current and at diagnosis), BMI and HbA1c levels, with 89% on insulin, 29% GADA-positive and 71% C-peptidenegative. Table 1. Interrelations between GADA and C-peptide status in 105 Ethiopian diabetic patients. Variable

Negative Positive p-value

C-peptide Number of patients

GADA-positive, n (%)

10 (40)

60 11 (18) 0.04

On insulin, n (%)

42 (93)

27 (45) 0.0001

GADA Number of patients

C-peptide-negative, n (%) 18 (62)

27 (35) 0.016

On insulin, n (%)

45 (59) 0.037

24 (83)

Source: Gill GV. Tekle A, Reja A, Wile D, English PJ, et al. Diabetologia 2011; 54: 51–57. DOI: 10.1007/s00125010-1921.

Traditional root bark from tree (Euclea undulata) in Limpopo province shows hypoglycaemic activity In this study from the Department of Plant Science, University of Pretoria, an acetone plant extract from Euclea undulata var. myrtina (Ebenaceae) used by traditional healers was tested for hypoglycaemic activity on myocytes and ability to inhibit L-glucosidase. The positive results obtained from the in vitro assays on the main fractions with myocytes (C2C12), pre-adipocytes (3T3-L1) and chang liver cells led to the isolation of four compounds for further testing. These compounds were L-amyrin-30β-(5-hydroxy) ferulic acid, lupeol, betulin and epicatechin. These compounds were then assessed for their ability to inhibit the carbohydratehydrolising enzyme L-glucosidase. The ferulic acid was shown to inhibit L-glucosidase, while epicatechin had some effects in vitro on the cell lines to lower blood glucose levels. Source: Deutschlander MS, Lall N, van de Venter M, Hussein AA. J Ethnopharmacol 2011; 133: 1091–1095.

VOLUME 8 NUMBER 1 • MARCH 2011

JOURNAL UPDATE

SA JOURNAL OF DIABETES & VASCULAR DISEASE

South African participation in study of exenatide twice daily with TZD or metformin highlighted in published study South African centres participated in the phase 3, randomised, double-bind, placebocontrolled, 26-week trial of exenatide in which twice-daily exenatide was added to TZD alone, or used in combination with metformin, compared to added placebo. Other centres were in Mexico, Romania, Canada and the United States. Doses of exenatide were 5 mcg for the first four weeks and 10 mcg thereafter. Recruited into the study were 165 patients with sub-optimal control, and after a two-week, single-blind lead-in period, they were randomly assigned (2:1) to added exenatide or placebo. The primary endpoint was HbA1c change at endpoint. Only eight subjects were treated with concomitant TZD alone. Exenatide reduced HbA1c levels significantly more than placebo [–0.84% (SE: 0.20) vs –0.10% (SE: 0.23), treatment difference –0.74% (SE: 0.16), p < 0.001)]. Mean reductions in body weight were similar in both treatments at endpoint [exenatide, –1.4 kg (SE: 0.6) vs placebo, –0.8 kg (0.7, p = 0.176)]. Nearly 71% of subjects had a reduction in both HbA1c levels and body weight with exenatide, compared with 54% on placebo. The most common adverse events (exenatide vs placebo) were nausea (12 vs 2%,

p = 0.037), vomiting (8 vs 0%, p = 0.031) and headache (4 vs 4%). Confirmed (blood glucose < 3.0 mmol/l) minor hypoglycaemia was experienced by 4 and 2% of subjects treated with exenatide and placebo, respectively. Incidence of hypoglycaemia was not significantly different between the groups. Source: Liutkus J, Rosas Guzman R, Norwood P, Pop L, Northrup J, et al. Diab Obesity Metabol 2010; 12: 1058– 1065.

Vitamin D and type 1 diabetes For many years vitamin D was defined simply by whether or not the patient had symptoms of the bone disease rickets (osteomalacia in adults). However, an entirely new perspective on vitamin D has arisen from the observation that serum levels of the main circulating form of vitamin D (250 HD3) as high as 75 nM correlate inversely with parathyroid hormone. This has prompted the introduction of a new term, vitamin D insufficiency, defined by serum levels of 250 HD3 that are sub-optimal (< 75 nM) but not necessarily rachitic (< 20 nM). Unlike serum concentrations of 1.25 (OH)2D3, which are primarily defined by the endocrine regulators of the vitamin D activating enzyme, I alpha-hydroxylase, circulating levels of 25 OHD3 are a direct reflection of vitamin D status, which for any given individual depends on access to vitamin D, either through exposure to sunlight or through dietary intake.

The net effect of this is that vitamin D status can vary significantly in populations depending on geographic, social or economic factors. As a result of these new parameters for vitamin D status, a consensus statement from the 13th Workshop on Vitamin D concluded that vitamin D insufficiency was a worldwide epidemic. Moreover, recent studies have shown that in the last 10 years alone, serum vitamin D levels have on average fallen by 20%. Published reports suggest that there is a link between vitamin D deficiency and type 1 diabetes. Low circulating levels have been seen in adolescents at the time of diagnosis of type 1 diabetes, while there are increased data documenting the beneficial effects of vitamin D supplementation protecting against type 1 diabetes. Disease severity of patients with diabetes is increased under conditions of dietary vitamin D restriction. Genetic variations of the CYP27b1 gene for the vitamin D receptor also affect susceptibility to type 1 diabetes, while other gene haplotypes of the vitamin D receptor seem to confer protection against diabetes. Future studies are needed to focus on the beneficial effects of supplementary vitamin D with respect to infectious and autoimmune diseases. Source: Hewison M. Endocrinol Metabol Clin N Am 2010; 39: 365–379. DOI: 10.1016/j.ecl.2010.02.010.

J Aalbers, Special Assignments Editor

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Diabetes News Changing Diabetes Day village – ‘Let’s take control of diabetes – now’

elonomi Hospital was the host of the World Diabetes Day event, organised by Novo Nordisk, on Saturday 13 November 2010. In excess of 400 diabetics from mostly rural areas in the Free State attended, to see healthcare workers and practitioners who could improve their quality of life. These diabetics travelled from districts as far away as Xhariep, Fezile Dabi, Lejweleputswa and Motheo. The day’s objective was to carry out holistic check ups and screen for possible complications, either treating the patients at the village or referring them back to their

respective clinics. The three partners in this venture included the Department of Health, the Medical Faculty of the University of the Free State and Novo Nordisk. Local dedicated nurse educators and private-sector doctors volunteered to assist with random blood glucose, blood pressure and body mass index assessments. Novo Nordisk transformed their Changing Diabetes bus into a screening area for ophthalmology. Ophthalmologists from the national hospital and other volunteers screened with two fundus cameras in excess of 180 patients

Volunteer ophthalmologists help patients in the Changing Diabetes bus.

on the bus. At the podiatry tent, eight nursing sisters were trained to assess in excess of 800 feet for ulcers and other ailments. The patients were advised on foot care and the importance of good foot care with diabetes. Other services also offered were counselling on good nutrition and exercise. ‘It was indeed a humbling experience and one of which we are very proud. To give back to communities in need is of prime importance and we feel that we achieved this and more at the village’, said Donovan Swanepoel from Novo Nordisk.

There was a hive of activity at the podiatry tent.

Diabetes youth camps

he Centre for Diabetes and Endocrinology (CDE) organises camps for youth with diabetes throughout the year. In October, one was held in Jonkershoek, Western Cape. These camps educate young people with diabetes about their disease, and allow them to participate in new, fun activities in a safe environment, with trained medical staff and Children who attended the camp in October 2010.

educators constantly on hand. They need not worry about feeling ‘funny’ and they realise that there are other children who also struggle with ‘hypos’ and ‘hypers’, and have to calculate the amount of carbohydrates in a sandwich. For young people with diabetes, going on these camps is a very valuable experience. Youth from different backgrounds and family Learning the importance of good nutrition with diabetes.

environments are brought together to share their experiences of diabetes, and they can all feel ‘normal’ at camp. They come away with a renewed sense of motivation and self-esteem that enables them to stay positive in their daily lives. Afterwards, they are able to form social networks and support groups to help deal with the day-to-day realities of living with the disease. Learning the importance of exercise with diabetes.

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