SAJDVD Volume 7, Issue 2 by Clinics Cardive Publishing

THE SOUTH AFRICAN JOURNAL OF

Diabetes Vascular Disease OBESITY

LIPIDAEMIA DYS

IN RESISTANCE INSUL

HYPERTENSION

ETES & DIAB

HYPER INSULINAEMIA THROMBOSIS

ERGLYCAEMIA

June 2010

HYP

Printed by Durbanville Commercial Printers Tel: 021 946 4074

AR DISEASE

Volume 7 Number 2

ATH EROSCLEROSIS

CUL

Featured in this issue The heart in diabetes GLP-1 agonists in diabetic patients Atrial fibrillation in Africa Atrial fibrillation managed in primary, secondary or tertiary care The LEAD studies Silent myocardial ischaemia and diabetes mellitus

Providing Synergy , Prolonging Time 1

It's the shell that makes R

safer.

Safety-Coated R

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.

OBESITY IPIDAEMIA DYSL

ISSN 1811-6515

IN RESISTANC E INSUL

HYPERTENSION

DIABETES &

ATH EROSCLEROSIS

CULA

Diabetes & vascular disease

R DISEA

THE SOUTH AFRICAN JOURNAL OF

HYPER INSULINAEMIA THROMBOSI S HYP

ERGLYCA

E MI A

VOLUME 7 NUMBER 2 • JUNE 2010 www.diabetesjournal.co.za

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

CONTENTS

Editorials

The heart in diabetes JA Ker

B Rosenkranz

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-Elect, International Diabetes Federation (2006−2009) PROF N POULTER Professor of Preventive Cardiovascular Medicine, Imperial College, School of Medicine, London, UK DR H PURCELL Senior Research Fellow in Cardiology, Royal Brompton National Heart and Lung Hospital, London, UK

Atrial fibrillation in Africa G Visagie

PROF R DELPORT Department of Family Medicine, University of Pretoria DR L DISTILLER Director of the Centre of Diabetes and Endocrinology, Houghton, Johannesburg

GLP-1 agonists: a novel treatment for South African diabetic patients

Reviews

Atrial fibrillation: which patients should be managed in primary, secondary and tertiary care? D Jones, T Wong, D Gorog, V Markides

Meeting of the Minds JL Aalbers, P Wagenaar

Focus on liraglutide: the LEAD studies JL Aalbers, WF Mollentze

Achieving Best Practice

Clinical aspects of silent myocardial ischaemia: with particular reference to diabetes mellitus M Dweck, IW Campbell, D Miller, CM Francis

Diabetes Personality

Diabetic diets need to be realistic, balancing nutritional and economic concerns Marlene Gilfillan

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.

Diabetes News

Patient Support

No child should die from diabetes

Drug Trends in Diabetes

Diabetes myth-busters: A Novo Nordisk-sponsored education symposium JL Aalbers, P Wagenaar

Supplements

Report on the first international symposium, Integrated Approach to Disease Management: Endocrinology and Metabolic Disorders, Middle East, Russia and Africa Cape Town, 6–7 March 2010

International Global Diabetes Update: Recent advances in insulin treatment in type 2 diabetes mellitus hosted by sanofi-aventis in Johannesburg, Pretoria, Durban and Cape Town

Front cover photographs from left to right: • The problem of irregular heart rhythm and beating to a different drum needs to be addressed. This review on atrial fibrillation shows how to get the drummer back on form (page 56) • This issue concentrates on how to keep the vasculature of the diabetic patient in good shape, with good blood pressure management, and blood lipid and glucose control. • Young children with diabetes are entitled to the best support money can provide. Read about Lilly’s sponsorship of Life for a Child (page 53) Color profile: Generic CMYK printer profile Composite Default screen

It's the shell that makes safer.

Safety-Coated R

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.

55X78MM 23 September 2008 10:04:25 AM

Start Right… For newly diagnosed Type 2 Diabetes patients and those intolerant to immediate-release metformin due to gastrointestinal side effects remains the drug of choice “for fiMetformin rst-line therapy” …“should be initiated concurrent with lifestyle intervention at diagnosis ” Consider extended-release tablets when “GI side effects prevent continuation of metformin therapy ” 1

CO NEW NS EN SU

Society for Endocrinology, Metabolism and Diabetes of South Africa

Low incidence of GI side effects4 Powerful glycaemic control5 Significantly improved adherence to treatment6 No weight gain7 References: 1. IDF Clinical Guidelines Task Force. Global Guidelines for Type 2 diabetes. Brussels: International Diabetes Federation, 2005. 2. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycaemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologica 2006;49(8): 1711-1721. 3. SEMDSA Guidelines for Diagnosis and Management of Type 2 Diabetes Mellitus for Primary Health Care. JEMDSA 2009;14(1):55-58. 4. Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinal tolerability of Glucophage®XR extended-release tablets compared to immediate-release Glucophage® tablets - results of a retrospective cohort study. Curr Med Res Opin 2004; 20:565-572. 5. Fujioka K, et al. Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage®XR) in type 2 diabetic patients with inadequate glycemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. Current Therapeutics Vol 25, No 2:2003. 6. Donnelly LA, Morris AD, Pearson ER. Adherence in patients transferred from immediate-release metformin to a sustained release formulation: a population-based study. Diabetes, Obesity and Metabolism 2009;11:338-342. 7. Fujioka K, Joyal S, Bruce S. Type 2 Diabetes patients switched from immediate-release metformin bid to an extended release qd formulation in a randomized, controlled trial maintained comparable glycaemic control. Clin Ther 2003;25:515-529. S3 GLUCOPHAGE®XR 500 mg Modified Release Tablet. Each Modified Release GLUCOPHAGE®XR tablet contains 500 mg metformin hydrochloride. Reg. No. A39/21.2/0027. MERCK (PTY) LTD, Reg. no.: 1970/004059/07. 1 Friesland Drive, Longmeadow Business Estate South, Modderfontein 1645. Tel: 011 372 5000 Fax: 011 372 5252. 123838

Merck Pharma Customer Call Centre 08611 MERCK or 08611 63725.

Merck Serono CardioMetabolic Care

EDITORIAL

SA JOURNAL OF DIABETES & VASCULAR DISEASE

The heart in diabetes JA KER

i abetes mellitus is associated with a two- to four-fold increased risk of coronary artery disease, and in diabetic people, about two-thirds of deaths are cardiovascular (ischaemic heart disease, congestive heart failure and stroke).1 Some have suggested diabetes mellitus to be a coronary heart disease risk equivalent (having the same event rates as people without diabetes but with prior cardiovascular disease).2 However, this concept remains controversial, especially in younger patients. In the Interheart study, a standardised, case-control study in 52 countries of the risk factors for acute myocardial infarction, diabetes had an odds ratio of 2.37 with a population-attributable risk of 9.9%.3 The Reach Registry, a prospective international observational registry of 68 236 patients with three or more cardiovascular risk factors or established atherothrombotic disease, had 30 043 participants with diabetes.4 The one-year cardiovascular event rate was 40% higher in the diabetic patients than in the nondiabetic patients. The telomere length (on the far end of chromosomes) of leucocytes are shortened in persons with type 2 diabetes mellitus compared to healthy subjects, and even shorter in type 2 diabetes mellitus patients with coronary heart disease.5 Leucocyte telomere length might be a useful marker of tissue ageing and progression of both cardiovascular disease and diabetes. Although chest pain (angina, acute coronary syndrome) is considered to be a cardinal symptom of myocardial ischaemia, both silent (asymptomatic) myocardial infarction and silent ischaemic episodes (as seen on Holter testing) are more common in diabetic patients, with a higher risk of cardiac events, including death. The prevalence of silent ischaemia in non-diabetic patients may range from 0.89 to 4% whereas in diabetic patients it is estimated to be 10 to 20%.6 A meta-analysis of 12 studies demonstrated a consistent association between cardiac autonomic neuropathy (CAN) and painless (silent) myocardial ischaemia, with a pooled rate of prevalence risk of 1.96 (95% CI: 1.53–2.51, p < 0.001) out of a total of 1 468 patients.7 Given the high prevalence of silent ischaemia in diabetics, an attractive but controversial concept is that of screening of asymptomatic diabetics. Some risk factors may assist in the decision of who to screen: conventional cardiovascular risk factors, breathlessness on exertion, abnormal resting ECG, presence of peripheral vascular disease, cardiac autonomic neuropathy and erectile dysfunction.6 Diabetes is associated with cardiovascular risk factors including hypertension, dyslipidaemia, hypercholesterolaemia and abnormalities in fibrinolysis. In particular, hypertension is a major co-morbid condition for diabetes and an important risk factor for

Prof J Ker the development of cardiovascular and renal disease in diabetic patients. The co-existence of hypertension and diabetes provides an additive increase in the risk of vascular events: the concept of ‘terrible twins’. The Swedish Gotteborg study found that men over 25 years of age with both conditions had a 66% greater risk of stroke or myocardial infarction compared to men with hypertension alone.8 Recent clinical trials with anti-hypertensive therapy stressed the need to use drugs that did not increase the risk of developing diabetes during treatment. The Framingham Heart study showed heart failure to be twice as prevalent in diabetic men and five times as common in diabetic women aged 45 to 74 years than in age-matched control subjects.9 The cardiotoxic triad: myocardial ischaemia, hypertension and diabetic cardiac autonomic neuropathy, has led to the recognition of a specific cardiomyopathy of diabetes.10 Pathophysiological remodelling of the heart, ischaemia of the ventricle, hypertensive heart disease, left ventricular hypertrophy, diastolic dysfunction and diabetic cardiomyopathy alone or collectively are responsible for the high risk of heart failure in diabetic patients.11 Recently, diastolic heart failure (i.e. heart failure with normal ejection fraction) has been recognised as a major adverse manifestation of hypertension and diabetes. However, convincing therapeutic strategies other than strict risk factor control are still lacking.11 In conclusion, diabetes mellitus could be regarded also as a cardiovascular condition.

References 1.

Correspondence to: JA Ker Department of Internal Medicine, University of Pretoria, Pretoria Tel: 27 (0)12 354-1121 Fax: 27 (0)12 329-1351 e-mail: jker@medic.up.ac.za S Afr J Diabetes Vasc Dis 2010; 7: 48–49

Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology and management. J Am Med Assoc 2002; 287: 2570–2581. Haffner SM, Letito S, Rönnemaa T, Pyörölö K, Loakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subject with and without prior myocardial infarction. N Engl J Med 1998; 339: 229–234. Yusuf S, Hawken S, Junpuu S, Dans T, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (Interheart Study): case-control study. Lancet 2004; 364: 937–952. Krempf M, Parhofer KG, Steg G, Bhatt DL, et al. Cardiovascular event rates in

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

EDITORIAL

diabetic and non-diabetic individuals with and without established athethrombosis (from the Reduction of Athethrombosis for Continued Health [REACH] registry). Am J Cardiol 2010; 105: 667–671. Olivieri F, Lorenzi M, Antonicelli R, et al. Leucocyte telomere shortening in elderly type diabetes mellitus patients with previous myocardial infarction. Atherosclerosis 2009; 206: 588–593. Dweck M, Campbell IW, Miller D, Francis CM. Clinical aspects of silent myocardial ischaemia: with particular reference to Diabetes Mellitus. Br J Diabetes Vasc Dis 2009; 9: 110–116. Vinik AI, Moser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy.

Diabetes Care 2003; 26: 1553–1579. Almgren T, Wilmelmsen L, Samuelsson O, et al. Diabetes in treated hypertension is common and carries a high cardiovascular risk: results from a 28-year follow-up. J Hypertens 2007; 25: 131–137. 9. Kannel WB, McGee DL. Diabetes and cardiovascular disease: The Framingham study. J Am Med Assoc 1979; 241: 2035–2038. 10. Bell DSH. Heart failure: the forgotten and often fatal complication of diabetes. Diabetes Care 2003; 26: 2433–2441. 11. Pieske B, Wachter R. Impact of diabetes and hypertension on the heart. Current Opin Cardiol 2008; 23: 340–349.

André Francois Steyn André Francois Steyn is gebore op 22 Februarie 1931 op Caledon in die destydse Kaapprovinsie. Hy matrikuleer aan die Hoërskool Grey Kollege te Bloemfontein in 1948 en bly sy lewe lank ’n lojale ondersteuner van sy alma mater. Hy behaal die graad MB, ChB in 1954 aan die Universiteit van Pretoria en verrig sy internskap die daaropvolgende jaar aan die Nasionale Hospitaal, Bloemfontein. In dieselfde jaar tree hy in die huwelik met Jean Sonnenberg en word daar een seun en drie dogters uit die huwelik gebore. Na sy internskap vestig hy hom as algemene praktisyn te Bultfontein in die Vrystaat, waar hy vier jaar deurbring. Op 1 Januarie 1960 begin hy sy kliniese assistentskap in die interne geneeskunde, weereens aan die Universiteit van Pretoria. Gedurende sy opleiding bring hy een jaar in die Departement Neurologie deur, waar hy waardevolle ondervinding opdoen. Die welbekende Prof HW Snyman het ’n belangrike rol in die jong dr André Steyn se vormingsjare as internis gespeel. Vanaf 1964 tot 1973 praktiseer hy as private internis in Bloemfontein. Gedurende hierdie tydperk toon hy reeds sy belangstelling in die endokrinologie en verwerf hy gou bekendheid as ’n diabetes-outoriteit in die Vrystaat en aangrensende gebiede. Aan die begin van 1974 sluit hy hom aan as eerste spesialis/senior lektor by ’n klein groepie voltydse konsultante van die onlangs-gestigte Fakulteit van Geneeskunde aan die Universiteit van die Vrystaat. Dit was ook die jaar waarin die eerste inname van voorgraadse studente met hul kliniese opleiding begin het. Kenmerkend van die erns waarmee hy die nuwe uitdaging aanpak, staak hy sy praktyk drie maande voor die tyd sodat hy sy ‘kennis kon opknap’. Sy kennis en kliniese vaardighede word gou raakgesien en op 1 Oktober 1977 word hy bevorder tot hoofspesialis en professor, tweede in bevel van die Departement Interne Geneeskunde. Om hom beter toe te rus as eerste hoof van die Afdeling Endokrinologie bring hy ’n besoek aan die endokrien-eenheid te Groote Schuur Hospitaal in Kaapstad asook aan die bekende diabetes kliniek te King’s College Hospitaal,

VOLUME 7 NUMBER 2 • JUNE 2010

Londen, onder beheer van die vermaarde Prof David Pyke. Met hierdie agtergrond ontwikkel die Afdeling Endokrinologie gou tot ’n suksesvolle akademiese eenheid en talle publikasies uit sy pen, en dié van sy medewerkers, sien die lig. Prof Steyn, soos hy alom bekend was, kon die interessantste staaltjies uit sy opleidingsen praktykjare vertel. Hy was baie gewild (en gevrees) onder sy studente en het as mentor vir talle opgetree. Sy breë kennis van die endokrinologie en algemene interne geneeskunde, asook sy skerpsinnigheid en sin vir humor, was legendaries. Hy het intens in elk van sy studente belanggestel en sy eerste vraag op saalrondte aan elke nuweling was: ‘Vanwaar kom jy?’ waarna jy jou familiestamboom moes uitlê. Prof Steyn het gedurende sy middeljare iskemiese hartsiekte opgedoen. Dié wat hom beter geken het, het geweet dat wanneer hy tydens ’n saalrondte gaan sit het of sommer in die gang gaan staan het terwyl die groepie êrens heen op pad was, hy waarskynlik simptomaties was. Die kere wat hy gehospitaliseer moes word, het hy daarop aangedring om soos elke ander pasiënt behandel te word. Dit het beteken dat die een of ander beangste kliniese assistent hom moes opneem en dat hy vanuit sy hospitaalbed vrae aan die studente gestel het! Na sy aftrede vestig hy en sy vrou, Jean, hulle te Brenton-on-Sea. Hier het hulle deur die jare talle oudstudente en kollegas gulhartig ontvang en getrakteer. Die laaste aantal jare van sy lewe was gekenmerk deur swak gesondheid en was hy vir die laaste ses jaar bedlêend. Gedurende hierdie tyd het hy nooit teenoor buitestanders gekla nie en het hy sy sin vir humor tot op die laaste behou. Die liefde en deernis waarmee hy gedurende hierdie veeleisende tyd deur sy vrou en familie versorg en ondersteun is, het respek afgedwing. Ons groet ’n baanbreker en ’n groot gees! Ons innige medelye aan Jean en die familie.

WF MOLLENTZE

Prof André Steyn (22/2/1931–4/2/2010), first head, Endocrinology Division, University of the Free State Medical School.

Prof André Steyn, the first head of the Endocrinology Division, University of the Free State Medical School, passed away recently. He will be particularly remembered for his contribution to early endocrinological development in South Africa. His training of endocrinology specialists at the University of the Free State was characterised by his interest in every student in his care. He was interested in their development right from undergraduate years and was a mentor to many. The Journal and its editorial staff express their condolences to his wife Jean and family.

Now, with BYETTA, HbA1c reduction and weight loss are both achievable goals

ADA/EASD GLP-1 agonists (BYETTA) are now included in the ADA/EASD algorithm for the metabolic management of type 2 diabetes1 ConSEnSuS STATEmEnT

“I take pills for my diabetes, but it’s still progressing and I continue to gain weight.” “Isn’t there something that can help me gain control of both?”

BYETTA is indicated for treatment of type 2 diabetes mellitus in combination with metformin, and/or sulphonylureas in patients who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies

HbA1c

●

Sustained HbA1c reductions2

●

Progressive weight loss2

●

Fixed-dose BD subcutaneous injection - 5 or 10 mcg

Weight �❍ Dose twice daily, within 1 hour before the 2 main meals

(at least 6 hours apart)

�❍ Minimally invasive needle �❍ 1 pen lasts for a full month

Killian Webb 1283

�❍ After 1st month, switch to 10 mcg pen

Month 1

mcg

10 mcg

For the duration of therapy

S3 Byetta 5 µg, 10 µg. Reg. No. 41/34/0068, 41/34/0069. 0.25 mg exenatide per ml. For full prescribing information refer to the latest approved package insert. References: 1. Nathan ��, Buse �B, �avidson �B, et al. �edical management of hyperglycaemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy. �iabetes care. 2008;31(12):1-11. 2. Klonoff �C, Buse �B, Nielsen LL, Guan X, Bowlus CL, Holcombe �H, Wintle �E, �aggs �G. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr �ed Res Opin. 2008;24(1):275-286. Eli Lilly (S.A.) (Pty) Ltd. Reg. No. 1957/000371/07 Private Bag X119, Bryanston, 2021 Telephone: (011) 510 9300 A1783 �ay 09

SA JOURNAL OF DIABETES & VASCULAR DISEASE

EDITORIAL

GLP-1 agonists: a novel treatment for South African diabetic patients BERND ROSENKRANZ

y pe 2 diabetes has become an epidemic worldwide, including in South Africa, where it is the sixth most common cause of death.1 Treatment strategies to combat hyperglycaemia reduce complications in these patients.2 Conventional antidiabetics all have their own limitations, especially weight gain and the risk of hypoglycaemia. There is therefore a clear need for novel treatment options, given alone or as combination therapy. New medications should exhibit an ideal glucose-lowering efficacy profile, be extremely safe in a broad range of patients and ultimately reduce co-morbidities and complications of diabetes.3 The most recent addition to the spectrum of antidiabetic drugs in South Africa is the exendin-based glucagon-like peptide-1 (GLP1) receptor agonist, exenatide. What will the role of this novel drug be in the management of patients with type 2 diabetes? The gastrointestinal hormone (incretin) GLP-1 has been one of the main targets for development of new antidiabetic treatments in the past decade, as recently discussed in this journal.1,4 GLP-1 is secreted by the L-cells of the small intestine after food ingestion, and potentiates pancreatic insulin secretion.5 Since the insulinotropic effect of GLP-1 is better preserved in type 2 diabetic patients than that of the incretin, gastric inhibitory polypeptide (glucosedependent insulinotropic peptide, GIP), drug-discovery efforts have focused on GLP-1 as therapeutic target.6 GLP-1-based therapeutics stimulate insulin secretion glucosedependently and therefore result in a more physiological pattern of insulin secretion with less hypoglycaemia than with conventional treatments. GLP-1 agonists show additional potentially beneficial effects such as improvement of endothelial function.7,8 In patients with type 1 diabetes,9 and in islet-transplant recipients with allograft dysfunction,10 beta-cell mass is increased or preserved. The potential clinical benefits of these additional effects, however, remain to be demonstrated in large, controlled, clinical trials. Native GLP-1 is rapidly degraded by dipeptidyl-peptidase IV (DPPIV).5,11 Therefore, GLP-1-based therapeutics include two different classes of drugs: (a) the more stable GLP-1 agonists: exenatide (synthetic exendin-4 analogue, 53% homology with GLP-1), liraglutide (human GLP-1 analogue, 97% homology) (see page 70), albiglutide (GLP-1 conjugated to albumin), taspoglutide (93% homology), and a recombinant exendin-4 conjugated to albumin; and (b) the DPP-IV inhibitors: sitagliptin, vildagliptin and saxagliptin. While GLP-1 agonists are peptides and must be administered subcutaneously, DPP-IV inhibitors can be given orally. Liraglutide and sitagliptin are available in Europe and in the USA, whereas Correspondence to: Bernd Rosenkranz Division of Pharmacology, Department of Medicine, University of Stellenbosch, Tygerberg, Cape Town Tel: +27 (0)21 938-9331 Cell: 082 955 0017 e-mail: rosenkranz@sun.ac.za S Afr J Diabetes Vasc Dis 2010; 7: 51–53

VOLUME 7 NUMBER 2 • JUNE 2010

Bernd Rosenkranz vildagliptin is currently approved only in Europe. Other products are in various stages of development. Exenatide was introduced as type 2 diabetes therapy in the USA in 2005, and subsequently in Europe following a positive opinion by the European Medicines Agency (EMA) in 2006. It was registered in South Africa in December 2008 and launched in this country in April 2010 after clarification of the reimbursement of the drug. The indication is for treatment of type 2 diabetes mellitus, in combination with metformin and/or sulfonylureas in patients who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies.12 Exenatide lowers postprandial glucose, increases insulin secretion, reduces postprandial glucagon secretion, slows gastric emptying and reduces caloric intake in type 2 diabetic patients.13 It may halt or reverse the progressive loss of beta-cell function in this patient population by improving insulin deficiency, beta-cell secretory defects and reduced beta-cell mass.4,14 In large, controlled, clinical trials, efficacy was demonstrated by a decrease in HbA1c of approximately 0.5–1.0% over 30 weeks.3,5,12,15 This was associated with no weight gain or loss (about 1.5–3 kg over 30 weeks) and a lower risk of hypoglycaemia than with conventional antidiabetics. In the 30-week clinical studies, up to 46% of exenatidetreated patients achieved the target goals for HbA1c ≤ 7.0%, as recommended by the American Diabetes Association (ADA) guidelines, compared with up to 13% of placebo-treated patients.5 Although the drug has potentially beneficial effects on systolic blood pressure, cardiovascular function and lipid profiles,3,4,8,14 confirmatory clinical studies using hard cardiovascular endpoints are not available. Like other antidiabetic treatments, exenatide must be given on a long-term basis to sustain its beneficial effects. This has been shown in a group of 69 metformin-treated patients with type 2 diabetes,16 of whom 36 received exenatide and 33 insulin glargine.

EDITORIAL

After cessation of both drugs at 52 weeks of treatment, betacell function and glycaemic control returned to pre-treatment values after a four-week off-drug period, confirming the need for continuous treatment. The drug is administered subcutaneously, twice daily because of its short half-life (about 2.4 h). In order to improve tolerability, treatment should be initiated with a dose of 5 μg, which should subsequently be increased to 10 μg as required. The dossier for a sustained-release (microsphere) formulation allowing a onceweekly dosing was submitted to the FDA in 2009. This application is currently under review; a reply to the FDA complete response letter was submitted by the manufacturer in April 2010. The new formulation is not currently approved by any regulatory agencies. Many diabetic patients suffer from upper and lower gastrointestinal symptoms.17 Treatment with antidiabetic drugs including exenatide contributes to these complaints. In clinical trials, 30 to 45% of treated patients experienced at least one episode of nausea, vomiting and/or diarrhoea during exenatide treatment.2 Mild to moderate hypoglycaemia has been reported when the drug was given in combination with a sulfonylurea and/ or possibly metformin (40% of treated patients). Other side effects of exenatide include decreased appetite, headache, dizziness, hyperhydrosis, feeling jittery or asthenia.12 Side effects tend to abate with time. In controlled clinical long-term registration trials, 8% of exenatide-treated patients withdrew from treatment due to adverse events (3% for placebo and 1% for insulin). Post-marketing cases of acute, mostly reversible pancreatitis have been reported (0.27 events per 1 000 patient-years).18 Although a cohort analysis using a large USA database did not confirm an association of acute pancreatitis with exenatide or sitagliptin treatment compared to metformin/glibenclamide,19 this does not exclude a possible drug-related causality.5,20 It is recommended that patients should be informed of the characteristic symptoms of pancreatitis, and to discontinue treatment in patients exhibiting such symptoms.12 From April 2005 to October 2008, the FDA has received 78 cases of acute renal failure or renal insufficiency.21,22 The drug should not be used in patients with severe renal impairment [creatinine clearance rate (CLcr) < 30 ml/min], and patients should be monitored carefully for the development of kidney dysfunction. Elimination of exenatide is reduced in patients with kidney disease, but these changes do not warrant a dosage adjustment in patients with mild to moderate renal impairment (CLcr > 30 ml/min).23 Low- or high-titre anti-exenatide antibody formation was observed in 44% of patients. The presence of antibodies was not usually associated with a loss of efficacy in drug-naïve patients,12 or with an increase in treatment-emergent adverse events (TEAEs) in patients re-exposed to the drug.24 The effect of exenatide on gastric emptying may reduce the extent and rate of absorption of other drugs given orally. Examples include paracetamol, lovastatin, digoxin, lisinopril and ethinyl estradiol (as a combination contraceptive).12 No dosage adjustment has been recommended for any of these drugs. Increased INR has been reported during concomitant use of warfarin and exenatide, in some cases associated with bleeding. INR should be monitored during initiation or dosage increase of exenatide in patients on warfarin or coumarol derivatives. In the past decade, new antidiabetic drugs (with novel mechanisms of action or pharmacokinetic/pharmacodynamic time profiles) have sparked a debate about their safety and risk–benefit

SA JOURNAL OF DIABETES & VASCULAR DISEASE

profiles after regulatory approval. This is not surprising, since these medications are administered to a large number of patients for a long time, whereas information about their safety is still limited by the time their marketing authorisation is granted. Knowledge about the safety profile of exenatide will therefore evolve further with increased post-marketing experience. Cost effectiveness of treatment with exenatide has been assessed using USA25,26 and UK databases.27 Exenatide therapy was associated with significantly higher overall and diabetes-related treatment costs, although annual total direct medical costs were usually less in exenatide-treated patients than in the comparator group in the USA.28 In the USA, the increasing use of new antidiabetics such as glitazones, new insulins, sitagliptin and exenatide largely account for the increase in the mean cost per prescription for type 2 diabetic patients (from $56 in 2001 to $76 in 2007).29 The interpretation of such cost-efficiency analyses must take into account the health system of the country involved and the applied methodology. The cost effectiveness of exenatide in the South African context is as yet unknown. Considering all of the above, what is the role of exenatide as new treatment option in the management of type 2 diabetic patients? The most recent (2009) joint consensus statement of the ADA and the European Association for the Study of Diabetes (EASD)2 recommends initiating insulin treatment at a much earlier stage than suggested by previous guidelines. Using this algorithm, exenatide should be considered as ‘second-tier’ option in selected clinical settings, especially when hypoglycaemia is particularly undesirable (e.g. in patients who have hazardous jobs) or if promotion of weight loss is a major consideration and the HbA1c level is close to target (< 8.0%). It remains to be seen if the algorithm for the management of type 2 diabetic patients will in the future include exenatide and other novel therapeutic options for earlier use, once evidence regarding sustained efficacy and safety accumulates.30 The UK National Institute of Health and Clinical Excellence (NICE)31 suggests exenatide as a third-line treatment option added to metformin and a sulfonylurea in patients with a body mass index (BMI) ≥ 35 kg/m2, who are concerned about their body weight, although there has been a debate about this restriction to patients with a high BMI.32 Exenatide may also be used in patients with a BMI < 35 kg/m2, in whom insulin would have substantial occupational implications or weight loss would benefit other serious co-morbidities related to obesity. Treatment should only be continued in patients who achieve a reduction of HbA1c of at least 1.0% and a weight loss of at least 3% of initial body weight over six months. In conclusion, exenatide will supplement the successful management of patients with type 2 diabetes in South Africa. Further post-marketing risk–benefit evidence as well as costeffectiveness considerations will assist in judging the contribution of this novel drug to the treatment algorithm in the private and public sectors in this country in the future.

References 1. 2.

Incretin therapy: A new treatment modality in the fight against the worldwide diabetes epidemic. S Afr J Diabetes Vasc Dis 2009; 6: 83–84. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Medical management of hyperglecemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2009; 32: 193–203. Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

4. 5. 6.

7. 8.

10.

11.

12.

13.

14.

15.

16.

based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care 2010; 33: 428–433. Nauck M. GLP-1 and GLP-1-based therapies: Addressing beta-cell dysfunction in type 2 diabetes. S Afr J Diabetes Vasc Dis 2009; 6: 100–106. Peters A. Incretin-based therapies: review of current clinical trial data. Am J Med 2010; 123: S28–S37. Nauck MA, Heimeaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeld W. Preserved incretin activity of glucagon-like peptide 1 (7-36 amide) but not of synthetic human gastric inhibitory polypeptide in patients with type 2 diabetes mellitus. J Clin Invest 1993; 91: 301–307. Mafong DD, Henry RR. The role of incretins in cardiovascular control. Curr Hypertens Rep 2009; 11: 18–22. Mudaliar, S, Henry RR. Effects of incretin hormones on β-cell mass and function, body weight, and hepatic and myocardial function. Am J Med 2010; 123: S19– S27. Kielgast U, Holst JJ, Madsbad S. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists. Curr Diabetes Rev 2009; 5: 266–275. Faradji RN, Froud T, Messinger S, Monroy K, Pileggi A, Mineo D, et al. Long-term metabolic and hormonal effects of exenatide on islet transplant recipients with allograft dysfunction. Cell Transplant 2009; 18: 1247–1259. Hoffmann T, Glund K, McIntosh CHS, Pederson RA, Hanefeld M, Rosenkranz B, Demuth H-U. DPPIV-inhibition as treatment of type II diabetes. In: Mizutani S, et al. (eds) Cell-surface Aminopeptidases: Basic and Clinical Aspects. Amsterdam: Elsevier Health Sciences, 2001; 381–387. European Medicines Agency. European Public Assessment Report (Byetta, exenatide): http://www.ema.europa.eu/humandocs/PDFs/EPAR/byetta/H-698PI-en.pdf, accessed 30 April 2010. DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, MacConell L. Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, crossover study. Curr Med Res Opin 2008; 24: 2943–2952. Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Eur J Int Med 2009; 20: S329–S339. Monami M, Marchionni N, Mannucci E. Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol 2009; 160: 909–917. Bunck MC, Diamant M, Corner A, Eliasson B, Malloy JL, Shaginian RM, et al. Oneyear treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: A randomized, controlled trial. Diabetes Care 2009; 32: 762–768.

VOLUME 7 NUMBER 2 • JUNE 2010

EDITORIAL

17. Koch CA, Uwaifo GI. Are gastrointestinal symptoms related to diabetes mellitus and glycaemic control? Eur J Gastroenterol Hepatol 2008; 20: 822–825. 18. Comments: Exenatide and rare adverse events. N Eng J Med 2008; 358:1969– 1972. 19. Dore DD, Seenger JD, Arnold Chan K. Use of a claims-based active drug surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin 2009; 25: 1019–1027. 20. Butler PC, Dry S, Elashoff R. GLP-1-based therapy for diabetes: What you do not know can hurt you. Diabetes Care 2010; 33: 453–455. 21. FDA MedWatch. Byetta – Renal failure. http://www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm188703.htm, accessed 30 April 2010. 22. Weise WJ, Sivanandy MS, Block CA, Comi RJ. Exenatide-associated ischemic renal failure. Diabetes Care 2009; 32: e22–e23. 23. Linnebjerg, H, Kothare PA, Park S, Mace K, Reddy S, Mitchell M, Lins R. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol 2007; 64: 317–327. 24. Faludi P, Brodows R, Burger J, Ivanyi T, Braun DK. The effect of exenatide re-exposure on safety and efficacy. Peptides 2009; 30: 1771–1774. 25. Misurski D, Lage MJ, Fabunmi R, Boye KS. A comparison of costs among patients with type 2 diabetes mellitus who initiated therapy with exenatide or insulin glargine. Appl Hlth Econ Hlth Policy 2009; 7: 245–254. 26. Lage MJ, Fabunmi R, Boye KS, Misurski DA. Comparison of costs among patients with type 2 diabetes treated with exenatide or sitagliptin therapy. Adv Ther 2009; 26: 217–229. 27. Woehl A, Evans M, Tetlow AP, McEwan P. Evaluation of the cost effectiveness of exenatide versus insulin glargine in patients with sub-optimally controlled type 2 diabetes in the United Kingdom. Cardiovasc Diabetol 2008; 7: 24. 28. Minshall ME, Oglesby AK, Wintle ME, Valentine WJ, Roze S, Palmer AJ. Estimating the long-term cost effectiveness of exenatide in the United States: An adjunctive treatment for type 2 diabetes mellitus. Value Hlth 2008; 11: 22–33. 29. Alexander GC, Sehgal NL, Moloney RM, Stafford RS. National trends in treatment of type 2 diabetes mellitus, 1994-2007. Arch Intern Med 2008; 168: 2088– 2094. 30. Rosenstock J, Fonseca V. Missing the point: Substituting exenatide for nonoptimized insulin. Diabetes Care 2007; 30: 2972–2973. 31. Adler AI, Shaw EJ, Stokes T, Ruiz F. Newer agents for blood glucose control in type 2 diabetes: Summary of NICE guidance. Br Med J 2009; 338: 1328–1329. 32. Idria I. National Institute of Clinical Excellence provides an update on the clinical management of patients with type 2 diabetes. Diabetes Obes Metab 2008; 10: 605–606.

EDITORIAL

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Atrial fibrillation in Africa GIDEON VISAGIE

t rial fibrillation is a common disorder with serious consequences. The estimated prevalence of this condition is between 0.4 and 1% in western populations.1 It amounts to an annual expenditure of approximately US$ 7 billion per year in the United States.2 No specific figures are available for South Africa, but in the Heart of Soweto study, it was reported that 7% of patients referred for a new cardiac problem had atrial fibrillation.3 The physician faced with a patient with atrial fibrillation has three points to consider in the management of this condition. The first is stroke prevention and the role of anti-coagulation; secondly, whether a rate- or rhythm-control strategy should be employed. Finally, referral to a cardiologist for advanced management should also be considered. In the last few years, exciting progress has been made concerning all aspects of atrial fibrillation management. One out of every six strokes occurs in a patient with non-valvular atrial fibrillation.4 The risk for stroke increases with an increased CHADS2 score, varying from 1.9% per year for a CHADS2 score of 0, to 18.2% per year for a CHADS2 of 6.1 It is therefore recommended that all patients with atrial fibrillation should be on anti-thrombotic therapy.1,4 The gold standard has been warfarin, which has a significant (> 50%) decrease in stroke rate compared to placebo.5 Alternatively, in patients with lower risk, aspirin or the combination of aspirin and clopidogrel also reduces stroke risk.6 A new era of anti-thrombotic agents has, however, dawned. The first of these agents to be evaluated in atrial fibrillation was the direct thrombin inhibitor, dabigatran. In the RELY study, which was published last year, this agent was shown to be as effective as warfarin in reducing stroke and embolism, with fewer haemorrhagic complications. The same trial demonstrated that with a slightly higher dose (150 mg), it was more effective than warfarin in preventing stroke and embolism, with a similar risk of haemorrhage.7 The additional advantage of not having to follow a patient’s INR makes this drug even more attractive. The next group of agents in the process of evaluation for atrial fibrillation is the oral factor Xa inhibitors. The two drugs in this class include rivaroxaban and apixaban. The ROCKET-AF study evaluating rivaroxaban was completed and results are pending. Apixaban was compared to warfarin in the ARISTOTLE study. A new inhibitor of vitamin K, epoxide reductase, code named ATI5923, is also in development.8 The second factor in the management of a patient with atrial fibrillation is whether a strategy of rate or rhythm control should be adopted. This question has been addressed by multiple large studies, including the AFFIRM, RACE, STAF, PIAF, HOT Café and, most recently, the AF-CHF study.4,9 These studies have shown that Correspondence to: Gideon Visagie Department of Internal Medicine, Faculty of Health Sciences, University of the Free State, Bloemfontein Tel: +27 (0)51 405-3154 e-mail: gideonvisagie@gmail.com S Afr J Diabetes Vasc Dis 2010; 7: 54–55.

Gideon Visagie

rate control is at least equal to rhythm control. Earlier this year, the RACE-II study was published, which investigated target heart rate if a rate-control strategy is to be followed. In the 2006 ACC/AHA/ESC guidelines, target heart rate was suggested to be between 60 and 80 beats per minute (bpm) at rest and between 90 and 115 bpm during exercise.4 The RACE-II study showed however that lenient control (resting heart rate of less than 115 bpm) was as effective as the above goals, and that this rate is more easily achieved.10 There has also been development on the front of anti-arrhythmic drugs for atrial fibrillation. Dronedarone is an amiodarone analogue with a shorter half-life and less systemic side effects. It has a lower efficacy than amiodarone and may not be used in patients with a left ventricular ejection fraction of less than 35%.11 In the ATHENA trial, it was shown that dronedarone substantially decreased allcause mortality and hospital admissions in patients with atrial fibrillation.12 Vernakalant is an atrial selective drug that is currently being compared to amiodarone in a phase 3 superiority trial (AVRO trial) for the treatment of atrial fibrillation.4 Catheter ablation techniques are becoming more important. These techniques include ablation of the AV node, with subsequent pacemaker implantation and pulmonary vein isolation. In recent trials, it was shown that patients who previously did poorly with anti-arrhythmic therapy, where catheter ablation was used as second-line therapy, sinus rhythm could be achieved in up to 74% of these subjects.13 There is also some evidence suggesting that radiofrequency catheter ablation improves the patient’s quality of life and may reduce the need for anticoagulation.14 A recently initiated study, the CABANA (Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial, is a multi-centre trial aiming to enrol 3 000 patients in order to ascertain whether catheter ablation is more effective than anti-arrhythmic therapy.15 Interventional cardiology is also providing alternatives to the use of anticoagulation. It is known that the left atrial appendage is the source of emboli in atrial fibrillation in more than 90% of cases.16

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

This is therefore a logical target for intervention in order to protect a patient from thrombo-embolic events. The auricle may be removed surgically or may be occluded by means of a percutaneous approach. Last year it was reported by the investigators of the PROTECT-AF study that the efficacy of left atrial appendage closure by means of the Watchman device was not inferior to the use of warfarin.16 There were, however, more adverse events in the group treated with the occlusion device. As the risk of serious haemorrhage is a reality for any patient treated with anticoagulation, this may be an alternative option. In this edition of the South African Journal of Diabetes & Vascular Disease, David Jones and colleagues review in depth the management strategies for atrial fibrillation. This review focuses on how this condition is managed in a first-world setting. The question is: How can this be applied to Africa? Some of the challenges facing doctors in South Africa include: the unavailability of tertiary resources; the geographic challenges, making it difficult to follow up on patients regularly; inconsistent medical supplies; and the poor level of education and lack of insight into their condition of many of our patients. There is also the duality with the private sector, where most of the first-world treatments are available. The reality is that in South Africa, most patients with atrial fibrillation will be managed with a rate-control strategy. This is not an inferior method of management and can be done by most primary physicians. The fact that it has been proven in the RACE-II trial that lower target heart rates are as effective as the previous goals set by the 2006 ACC/AHA/ESC guidelines makes this form of therapy even more attractive. Anticoagulation is a major problem in the South African context. The inability of patients to attend INR clinics regularly due to problems with transport and immobility makes therapy with warfarin a difficult option. Aspirin or the combination of aspirin and clopidogrel, which does not need regular monitoring, is an attractive option. Unfortunately we know that the efficacy of either of these regimes is much less compared to warfarin.17,18 Dabigatran will be launched in South Africa this year. This drug may be the answer to some of these problems. The results of the ROCKET-AF study are still pending. Rivaroxaban, which is already available in South Africa, might be another alternative to warfarin. When these drugs will be available in the state sector is currently a matter of uncertainty. Catheter ablation therapy is not generally available in South Africa. Some centres do offer it, but this therapy will be available to only a few selected patients. The procedure is not risk free and only experienced centres should offer it. Whether all patients should be referred to secondary or tertiary care is another difficult question. The ACC/AHA/ESC guidelines recommend that every patient diagnosed with atrial fibrillation should be evaluated with echocardiography.4 As rheumatic heart disease is still a major problem in South Africa, all patients should have an echocardiogram to exclude valvular pathology. Assessment of heart structure and function also helps in choosing an adequate management strategy. Due to limited resources, patients might

VOLUME 7 NUMBER 2 • JUNE 2010

EDITORIAL

have to wait to be evaluated in secondary care. The primary-care physician should therefore already start embolic risk-stratification and anticoagulation therapy. Patients who are still symptomatic despite a rate-control strategy, or with lone atrial fibrillation or structural heart disease should be referred to a cardiologist for further evaluation and management. Cardiologists will be the predominant physicians opting for a rhythm-control strategy in selected patients. The resources needed for this management strategy, such as transoesophageal echocardiography and knowledge of the use of antiarrhythmic drugs are in their domain of practice and freely available to cardiologists in a tertiary-care setting. The article by David Jones and colleagues provides a good background and guidelines on how to manage a patient with atrial fibrillation, and these principles should be applied to patients in South Africa as extensively as possible.

References 1. 2. 3.

6. 7. 8. 9.

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

17.

18.

Lopes RD, Piccini JP, Hylek EM, et al. Antithrombotic therapy in atrial fibrillation: guidelines translated for the clinician. J Thromb Thrombol 2008; 26:167–174. Rich MW. Epidemiology of atrial fibrillation. J Interv Card Electrophysiol 2009; 25: 3–8. Sliwa K, Wilkinson D, Hansen C, et al. Spectrum of heart disease and risk factors in a black urban population in South Africa (the Heart of Soweto Study). Lancet 2008; 371: 915–922. Fuster V, Rydén LE, Cannom DS. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation – executive summary. J Am Coll Cardiol 2006; 48(4): 854–906. Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131: 492–501. The ACTIVE investigators. Effect of clopidogrel added to asprin in patients with atrial fibrillation. N Engl J Med 2009: 360: 2066–2078. Conolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151. Usman MHU, Raza S, Raza S, Ezekowitz M. Advancement in antithrombotics for stroke prevention in atrial fibrillation. Electrophysiology 2008; 22: 129–137. Talajic M, Khairy P, Levesque S, et al. Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. J Am Coll Cardiol 2010; 55(17): 1796–802. Van Gelder IC, Groenveld HF, Crijns HJGM, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010; 362; 1363–1373. Dobrev D, Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation, Lancet 2010; 375:1212–1223. Hohnloser SH, Crijns HJGM, Van Eickels M, et al. Effact of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360: 668–678. Garlitski AC, Estes NAM. Emerging therapies for atrial fibrillation: is the paradigm shifting. J Interv Card Electrophysiol 2010; 28: 1–4. Terasawa T, Balk EM, Chung M, et al. Catheter ablation for atrial fibrillation. Ann Intern Med 2009; 151: 191–202. Wilber DJ. Pursuing sinus rhythm in patients with persistant atrial fibrillation. J Am Coll Cardiol 2009; 54(9): 796–798. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized non inferiority trial. Lancet 2009; 374: 534–542. Bousser MG, Bouthier J, Buller HR, et al. Comparison of idraparinux with Vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomized open-label non inferiority trial. Lancet 2008; 371: 315–321. Albers GW, Diener HC, Frison L, et al. Ximelgatran vs warfarin for stroke prevention in patients with non valvular atrial fribrillation: a randomized trial. J Am Med Assoc 2005; 293: 690–698.

REVIEW

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Atrial fibrillation: which patients should be managed in primary, secondary and tertiary care? David Jones, tom wong, diana gorog, vias markides

t rial fibrillation is the commonest sustained cardiac arrhythmia, and has a significant impact on morbidity and mortality. It is a leading cause of stroke, and suitable thromboprophylaxis should be considered in all patients. Treatment is tailored to the individual. This article will review the management strategies for patients with atrial fibrillation, and discuss the roles of primary, secondary, and tertiary care. In Circulation of the Blood (1628), William Harvey commented that: “It is … evident that the auricles pulsate, contract … and eject the blood into the ventricles. [The auricle] has to help infuse blood into the ventricle so that … [the ventricle] … may send it on with greater vigour.” This ‘primer pump’ function of the atria contributes about 10–20% towards ventricular filling and, although not vital for normal resting heart function, plays an increasing role in disease and in maximising cardiac output during exercise. This function is lost in atrial fibrillation (AF), when the atria undergo rapid and chaotic excitation, discharging at 300–600 beats per minute. In a normally functioning heart, the only electrical communication to the ventricles is through the atrioventricular (AV) node, whose electrical properties cause blockage of many of these impulses, so protecting the ventricles from life-threatening rapidity. However, during AF the ventricles are subjected to higher rates of excitation than normal, particularly during exercise, and beat-to-beat variability leads to an irregular pulse and suboptimal haemodynamics. Furthermore, the loss of atrial contraction encourages thrombus formation and can lead to the most feared complication of AF, embolic stroke. Correspondence to: David Jones Fellow in Cardiac Electrophysiology, Royal Brompton & Harefield NHS Foundation Trust and Imperial College London. e-mail: davidgarethjones@nhs.net Tom Wong, consultant cardiologist, Royal Brompton & Harefield NHS Foundation Trust and Imperial College London Diana Gorog, consultant cardiologist, East & North Hertfordshire NHS Trust and Imperial College London Vias Markides, consultant cardiologist, Royal Brompton & Harefield NHS Foundation Trust and Imperial College London

Definition Atrial fibrillation (AF) is defined electrocardiographically as the loss of distinct P waves on the surface ECG accompanied by an irregularly irregular ventricular (QRS) response (see Fig. 1). Low amplitude, extremely rapid and irregular (in rate and morphology) atrial activity may be discernible as ‘f ‘ waves. AF is usually, but not always, associated with inappropriately rapid heart rates. It can also be associated with significant bradycardia during sinus rhythm, and with tachycardia during paroxysms of atrial fibrillation (tachy-brady syndrome).

Epidemiology AF is the most common sustained cardiac arrhythmia, affecting 1–2% of the general population.1,2 Recent studies indicate that the lifetime risk may exceed 20%.3 Prevalence increases with age, rising to 8% in people over 80 years,4 over two-thirds of individuals with AF are aged 65–85.5 It is estimated that there are 2.3 million people in the United States, and 4.5 million in the European Union with AF.2 The prevalence is increasing – in part due to population ageing, but also due to an increase in age-adjusted AF incidence – which clearly has significant implications for health service planning. AF is associated with increased mortality. In the Framingham Study, AF conferred a relative all-cause mortality risk of 1.8.6 Much of this is attributable to stroke, the risk of which is increased fivefold in those with AF – but which varies according to age and comorbidities.

Aetiology and pathogenesis AF is associated with several conditions, including hypertension, heart failure and valvular heart disease, thyrotoxicosis, and obesity.7 Many of these conditions can cause mechanical changes (including stretch and fibrosis) and electrical changes (remodelling) that, when coupled with a genetic predisposition8 and ectopic triggers during favourable autonomic activity, can precipitate AF. AF in itself enhances further remodelling, so encouraging its own perpetuation.9 The pathogenesis of AF involves a complex interplay between mechanisms of initiation (eg extremely rapid electrical activity

Figure 1. ECG in atrial fibrillation.

S Afr J Diabetes Vasc Dis 2010; 7: 56–63. doi: 10.3132/pccj.2010.001

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

REVIEW

Investigations Key messages • Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia • It is a leading cause of stroke, and suitable thromboprophylaxis should be considered in all patients • Treatment should be tailored to the individual

An ECG is useful in confirming the diagnosis while at the same time looking for evidence of left ventricular hypertrophy (hypertension, hypertrophic cardiomyopathy), previous myocardial infarction, and pre-excitation (a component of Wolff-Parkinson-White syndrome), even during sinus rhythm. Baseline blood tests should be performed including thyroid function, blood counts, and renal/liver function. This is both to rule out an underlying cause and to guide appropriate therapy.

• In asymptomatic individuals, rate control may suffice

Do I need to refer for an echocardiogram?

• In symptomatic patients, particularly those with paroxysmal AF, a rhythm-control strategy is generally recommended

While the European Society of Cardiology recommends an echocardiogram as part of baseline evaluation in all patients, NICE guidelines, which include analysis of cost effectiveness, recommend that transthoracic echo-cardiography (TTE) be performed in patients with AF: • for whom a baseline echocardiogram is important for longterm management, such as younger patients • for whom a rhythm-control strategy that includes cardioversion (electrical or pharmacological) is being considered • in whom there is a high risk or a suspicion of underlying structural/functional heart disease (such as heart failure or heart murmur) that influences their subsequent management (for example, choice of anti-arrhythmic drug) • in whom refinement of clinical risk stratification for antithrombotic therapy is needed.

• Catheter ablation is an effective therapy for symptomatic patients who fail or cannot tolerate antiarrhythmic drugs arising from pulmonary veins) and mechanisms of perpetuation (eg re-entry or circus movement of electrical waves in the atria). It is no surprise that AF is highly heterogeneous and that attempting to combat it is highly challenging.

Management Optimal management of AF requires: • Recognition of AF (symptomatic or asymptomatic) and treatment of underlying conditions • Assessment and optimisation of thromboembolic risk • Treatment of the heart rate and/or rhythm.

Recognition of AF Clinical history and physical examination AF may be suspected in a patient because of symptoms including palpitation, breathlessness, exercise intolerance, or dizziness, or simply because of the opportunistic finding of an irregular pulse. Indeed, the diagnosis may be easily missed unless the pulse is taken manually. The finding of an irregular pulse should prompt confirmation of the diagnosis by 12-lead ECG. Diagnosis may require ambulatory ECG recordings in cases of intermittent symptoms.

Identification of precipitating causes When AF occurs secondary to acute reversible causes such as hyperthyroidism, acute peri/myocarditis, alcohol, respiratory tract infections, acute myocardial infarction, and cardiac surgery, it usually responds to treatment of the underlying condition. It is important to evaluate for other medical conditions, particularly underlying structural heart disease. The majority of AF is associated with the presence of underlying co-morbidities – many of which can contribute to its pathophysiology, for example, hypertension, coronary artery disease, valvular (typically mitral but also aortic) disease, heart failure of any cause, diabetes mellitus, alcohol excess, and thyroid dysfunction. However, these are common conditions in the general population that simply increase the risk for developing AF. Some patients prone to AF, particularly if young and paroxysmal, have no apparent causative factor after thorough investigation. AF in these patients is termed ‘lone’,10 but its treatment remains the same.

VOLUME 7 NUMBER 2 • JUNE 2010

Characterisation of pattern of AF It is useful to identify the pattern of AF in a given patient, because this will affect the treatment strategy chosen. • First detected AF episode. Recurrent AF, which may be paroxysmal or persistent: • Paroxysmal – episodes which spontaneously terminate, < 7 days (usually < 48 hours) • Persistent – when sustained > 7 days • Permanent – long-standing AF, usually > 1 year, or when cardioversion has failed or not been attempted. In the modern era of catheter ablation, this may be termed ‘long-standing persistent’ as even permanent AF can be successfully treated and sinus rhythm restored in many patients.

Symptomatic status A significant proportion of patients, particularly the elderly, may not be aware of the arrhythmia, or disregard their mild symptoms as a feature of ageing. Evidence would suggest it is reasonable to manage these patients with anticoagulation and rate-control as needed. However, many patients present with symptoms due at least in part to AF. A scoring system (CCS-SAF), akin to that used in angina and heart failure, has been proposed to help categorise symptom severity in AF patients,11 which could be useful both in deciding on management strategies and assessment of its efficacy. It is the degree of symptoms that, in general, will govern the decision regarding referral for specialist care. For those with newlydiagnosed AF, the decision can often wait until the patient has been given a trial of appropriate pharmacological therapy (see below), unless acute hospital admission is warranted.

REVIEW

Treatment of underlying conditions It is important to establish there is no underlying thyroid disease, as AF responds poorly to treatment until euthyroid status has been re-established. Uncontrolled hypertension should be treated (if severe, before institution of antithrombotic therapy, given the risk of haemorrhagic stroke),15 and the choice of agents may be influenced by the need for some AF rate-controlling properties. Patients in heart failure and AF, with progressive symptoms, should be considered early for specialist referral.

Assessment and optimisation of thromboembolic risk AF is a major cause of thromboembolic stroke, conferring a five-fold increase in annual risk. Assessment and reduction of thromboembolic risk should be the priority in every patient with newly diagnosed AF. Stasis in the non-contracting atria encourages thrombus formation, most commonly in the left atrial appendage.12 Hypercoagulability and endothelial dysfunction also play a role.2 Warfarin, adjusted to a target INR of 2.5 (range 2–3), is known to provide the greatest risk-reduction for thromboembolic stroke. Aspirin (75–325 mg once daily) also reduces stroke risk, but has been shown to be less effective than warfarin in most trials, including the elderly13 and even when given in combination with clopidogrel.14

Who needs warfarin? All patients with mitral stenosis or rheumatic mitral valve disease and AF should be anticoagulated unless there is a very significant contraindication because there is an extremely high risk of thromboembolism.2 Even those in sinus rhythm have a significant risk of thromboembolism, particularly in the presence of significant atrial enlargement (> 50 mm) or (in mitral regurgitation) congestive cardiac failure. Anticoagulation is not recommended purely for aortic or tricuspid disease with AF, unless concomitant with congestive cardiac failure or other risk factors.16 For non-valvular AF (the majority), risk stratification scoring systems can help to decide on which patients to anticoagulate. NICE has published a stroke risk-stratification algorithm as part of its AF management guideline. Internationally, it is common practice to use the CHADS2 score: congestive cardiac failure, hypertension, age > 75, and diabetes mellitus all score 1 point, stroke/TIA 2 points (see Table 1). Warfarin is recommended for CHADS2 ≥ 2, warfarin or aspirin at 1, and aspirin (unless contraindications) for a score of 0.1,2,17,18 At low CHADS2 score (0–1), bleeding risk may outweigh the benefits of anticoagulation, and this remains an area of continued debate. Assessment of bleeding risk is complex,19 as is the quantitative comparison of the clinical impact of intracranial haemorrhage or other major bleeds versus that of ischaemic stroke or thromboembolism. There is evidence from the ACTIVE-W study that, even at a CHADS2 score of 1, warfarin confers a modest but significant advantage over antiplatelet therapy, with a low bleeding risk.20 The recently published ATRIA study of 13 559 patients found that the net clinical benefit of warfarin was negligible in CHADS2 score 0 and 1, increasing significantly, as expected, at higher scores. For example, the risk (event rate) of thromboembolism with CHADS2 score 4–6 was 6.34 off warfarin compared to 3.25 on warfarin per 100 patient years, while the risk of intracranial haemorrhage was 0.51 versus 1.08 per 100 patient years, respectively. Using an impact factor of 1.5 for intracranial haemorrhage, reflecting

SA JOURNAL OF DIABETES & VASCULAR DISEASE

its greater average morbid impact than ischaemic stroke, the net clinical benefit was 0.97 (CHADS2 = 2), 2.07 (3) and 2.2 (4–6) events per 100 patient years. After prior history of stroke (net benefit = 2.48), the group with next-greatest net benefit of warfarin was those aged over 85 (= 2.34).21 To add to the complexity, a recent study in patients with implanted pacemakers has shown that a combination of CHADS2 score with burden (frequency/duration) of AF episodes may enhance risk stratification and optimise choice of antithrombotic therapy. Although the CHADS2 score remains the basis for choice of antithrombotic therapy, a high AF burden may need to be an additional marker or risk that would push one towards full anticoagulation with warfarin even if the CHADS2 score is relatively low (0–1). Conversely, patients with brief AF paroxysms may be at lower risk than that purely predicted by the CHADS2 score alone.22 This issue requires further clarification from larger studies but, given that most patients do not have such constant heart rhythm monitoring, and that many episodes of AF are asymptomatic, suitable thromboprophylaxis should currently be offered to all patients regardless of whether their AF is paroxysmal or persistent, predominantly based upon the CHADS2 score (or equivalent).

Anticoagulation in the elderly The elderly have a higher stroke risk and potentially the most to gain from anticoagulation.23 Although bleeding risk also increases with age, the true risk of significant haemorrhage – particularly in patients deemed at risk from falls – may be overestimated by physicians, leading to underprescribing of warfarin, and the alternative use of aspirin.24,25 One recent study showed a high rate of major haemorrhage in the over-80s, particularly in the first three months of warfarin therapy.26 However, the risk of bleeding was greatest in those with the highest stroke risk (CHADS2 score ≥ 3). More recently, a study of 783 elderly patients (median age 75 years, with 180 patients over 80 years at study onset) showed a lower bleeding risk (major bleed rate 1.4 per 100 patient years), closer to earlier data, with the notable differences from the previous study being low concomitant use of antiplatelets, and a computer-assisted warfarin dosing regimen.27 Importantly, warfarin is far superior to aspirin in over75s for the prevention of stroke and with no significant difference in bleeding risk,13 and the net clinical benefit of warfarin in elderly patients is also supported by the ATRIA study.21 The decision to anticoagulate elderly patients remains a balanced one, but should take into account the ability to achieve a stable INR, control of hypertension, and (quality-adjusted) life expectancy more than a perceived bleeding risk from falls or age per se. Table 1. CHADS2 stroke risk score for patients with non-valvular atrial fibrillation18 Risk factor

Score

Congestive heart failure

Hypertension

Age ≥ 75 years

Diabetes mellitus

Stroke or TIA

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Antiplatelet therapy and anticoagulation Although antiplatelet therapy can have a role in combination with oral anticoagulation therapy, the ‘routine’ addition of aspirin to warfarin in patients with stable vascular disease is no longer recommended because it is associated with excess bleeding risk, particularly in the elderly, without clear benefit.28,29 Combination therapy may be helpful in some patients with prosthetic valves, and those with unstable cardiovascular disease where the risk:benefit ratio has to be judged individually. In patients with acute coronary syndromes, or in those undergoing coronary angioplasty/stenting, use of dual antiplatelet (aspirin plus clopidogrel) therapy is now routine. However, dual antiplatelet therapy itself is inferior to warfarin in stroke prevention,14 so cannot be regarded as a satisfactory replacement for AF patients in this context. Triple therapy (aspirin, clopidogrel, and warfarin), although associated with a moderate increase in bleeding complications, is sometimes used in these complex scenarios and is currently guided by consensus opinion, given limited trial data.29,30 Factors influencing type and duration of combination therapy include: coronary anatomy, presence of intracoronary stents, perceived bleeding risk, and CHADS2 score. After an initial period of triple therapy, stented patients may then be continued on warfarin plus a single antiplatelet (typically clopidogrel),2,30 with some cardiologists continuing this therapy beyond 12 months, although contemporary guidelines advise warfarin monotherapy in stable patients beyond this stage.31 The interventional cardiac centre should be contacted if the planned thromboprophylaxis strategy is not clear.

Thromboprophylaxis therapies for the future The benefit of warfarin is reduced, if not lost, when the INR is out of the therapeutic range for a significant proportion of the time. Indeed, it confers no advantage over antiplatelet therapy per se if the INR is out of range for more than 40% of the time.32 Even with specialist anticoagulation clinic input, achieving stable INRs can be challenging. This, together with the multiple food and drug interactions and the inconvenience of serial retesting, has driven the development of newer oral antithrombotic agents. Recently, dabigatran – a direct thrombin inhibitor – has been shown to be as efficacious as warfarin, but with a lower bleeding risk; furthermore, at a higher dose, it offered superior stroke prophylaxis with a similar rate of major haemorrhage to warfarin therapy.33 Its use does not require monitoring or dose adjustment, and appears ideal for those who cannot achieve stable INRs on warfarin. Ultimately, it appears likely that dabigatran and similar drugs34 will replace warfarin, which would herald a new era of anticoagulation and optimal management of thromboembolic risk. An obvious non-pharmacological target for reduction of thromboembolism is the left atrial appendage, given that it is responsible for more than 90% of thrombi in non-rheumatic AF.12 It may be excised or excluded in patients undergoing cardiac surgery,35,36 although prospective stroke outcome data are awaited. Percutaneous appendage closure devices have been developed recently, which may have much wider application than surgical techniques and could become an alternative to oral anticoagulation.38,39 However, general uptake will depend on proven long-term efficacy and cost-effectiveness compared with oral anticoagulation.

VOLUME 7 NUMBER 2 • JUNE 2010

REVIEW

Treatment of AF (rate and/or rhythm control) Acute symptomatic AF For many cases of AF, relatively stable clinical status at presentation allows initial management to take place in primary care. Sudden-onset AF, whether first-presenting or recurrent, associated with severe symptoms of dizziness, breathlessness, or palpitation should be considered for management in an acute secondary care setting. In particular, patients with a ventricular rate greater than 150 bpm, ongoing chest pain, or signs of critical hypoperfusion need emergency admission. Those with life-threatening haemodynamic instability should be treated by emergency electrical cardioversion. This particularly applies to the rare but life-threatening condition of pre-excited (broad complex) AF in the context of Wolff-Parkinson-White (WPW) syndrome – an irregular broad complex tachycardia, which may be the first presentation of some WPW patients. If the patient can be stabilised by medical therapy (including acute rate control), consideration is then given to duration of AF: • Greater than 48 hours or uncertain, the strategy should be anticoagulation and rate control in the first instance, with a view to cardioversion after > 3 weeks at therapeutic INR (target 2.5) • Less than 48 hours, attempts to restore sinus rhythm (typically intravenous flecainide if no structural heart disease, amiodarone otherwise) can be made.

Rate control Drugs achieve control of the ventricular rate during AF by acting on the atrioventricular (AV) node to reduce the number of impulses that get through. Ideally, rate-controlling agents should control the heart rate both at rest and during activity in a graded manner, as is the physiological norm in sinus rhythm. Although such an ideal does not exist, patients with otherwise good cardiac function may tolerate this state of ‘rhythm failure’ if excessive rate swings are prevented. Although the aim of rate control is primarily to improve haemodynamic stability and symptoms, it is known that persistently high rates put some patients at risk of subsequent cardiac failure – so-called tachycardia-related cardiomyopathy. This means that even asymptomatic patients should have their need for rate control assessed. Suggested targets for rate control are a resting heart rate of 60–80 beats/min, and 90–115 on moderate exercise.2 In the AFFIRM trial, goals were pre-defined as < 80 bpm at rest, and < 110 bpm during a six-minute walk test.39 In retrospective analysis of the RACE trial (target < 100 bpm at rest only) and AFFIRM data,40 the primary endpoint of mortality, cardiovascular hospitalisation, and myocardial infarction did not differ between those who achieved the rate target and those who did not. Therefore, although many cardiologists would use the target rate-control guidelines – particularly in symptomatic patients (before accepting that the ‘rate control strategy’ has failed), it remains uncertain how strict the goals should be. The ongoing RACE II study,40 prospectively comparing ‘strict’ with ‘lenient’ rate control outcomes, may provide further clarification.

How can rate control be assessed in primary care? The AFFIRM trial used the six-minute walk test to assess rate control, while other options include treadmill testing or 24-hour Holter

REVIEW

recordings, but these are not readily available in primary care. For many patients, assessing the rate at rest and then simply exercising the patient for one or two minutes can be a useful discriminator of rate control. Our strategy is to reassess heart rate (minimum of 30 seconds via precordial auscultation or carotid palpation, as the radial pulse may underestimate the true rate) after a brisk walk (corridor, stairs, or on the spot, depending on the individual) broadly applying the targets as set above. For patients who remain symptomatic after appropriate drug therapy, formal rate-control assessment is recommended with Holter monitoring (useful for correlating symptoms with rate) or exercise testing.

Drug therapy for rate control When possible, rate-controlling drugs are generally given once daily in the morning – medicating predominantly at night can lead to excess nocturnal bradycardia with suboptimal daytime control.

Beta-blockers Beta-blockers control the ventricular rate at rest and on exertion, improve symptoms, and are particularly useful as combination therapy with digoxin.41 They have an excellent safety profile, and are also indicated in the management of co-morbid conditions such as heart failure and ischaemic heart disease. Additionally, there is evidence for some ‘rhythm-controlling’ effect,42 perhaps through reducing ectopic triggers of AF. On this basis, beta-blockers can be considered a first-line agent in most patients with AF, regardless of persistence.1 Typical drugs include atenolol (25–100 mg once daily) and bisoprolol (2.5–10 mg once daily). In those with significant systolic dysfunction, bisoprolol or carvedilol (3.125–25 mg twice daily) should be up-titrated slowly after introduction, so the patient may take longer to achieve rate control – a decompensated patient with rapid AF and heart failure may need careful acute rate control in a monitored in-patient environment.

Calcium channel blockers Conduction through the AV-node depends largely on calcium currents, which may be suppressed by non-dihydropyridine calcium blockers. These are effective rate controllers, and may be superior to beta-blockers for rate control during exercise.43 They are particularly useful in patients with contraindications to, or intolerant of, beta-blockers. The main side-effects are relative hypotension, and occasionally ankle swelling. The available agents are diltiazem (typical AF dose 120–360 mg daily) and verapamil (120–360 mg daily), both in 1–3 doses depending on formulation. Diltiazem may also safely be combined with digoxin, a highly effective combination for rate control at rest and on exercise. Calcium channel blockers should generally be avoided in patients with significant systolic heart failure. Verapamil can have potent negative inotropic effects, and diltiazem has been associated with poor outcomes in ischaemic heart failure.44-48 The combination of diltiazem with beta-blockers can achieve rate control where the combination of either agent with digoxin is ineffective, although this strategy would usually be initiated in specialist care because there is a risk of marked bradycardia, particularly in those with a degree of conduction system disease (eg bundle branch block, or presence of 1st degree heart block in sinus rhythm).

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Digoxin Although historically the commonest drug used in atrial fibrillation, the routine use of digoxin for management of AF is no longer recommended for most patients. This is principally because although it controls heart rate modestly at rest, it does so poorly on exercise. However, digoxin is recommended as part of a combination ratecontrol strategy for those with significant LV dysfunction,2 given its positive inotropic functions and ability to improve heart failure symptoms, or in elderly, sedentary patients with good renal function and relatively good rate control at baseline. Caution should be exercised in those with renal dysfunction or who are on interacting drugs (eg amiodarone, verapamil): digoxin toxicity can ensue, and high digoxin levels have been associated with increased mortality in people with heart failure.49 Furthermore, digoxin is not advised for most patients who have paroxysmal AF, as a strategy to control rate during paroxysms should they occur because the previously listed drugs are more effective and may reduce frequency of paroxysms and some evidence suggests digoxin has a pro-arrhythmic effect and encourages persistence of AF.50 In summary, digoxin should not be used for rate-control monotherapy, except in sedentary patients.

Pacemakers Rate control is required at both ends of the spectrum. However, transient bradycardia is expected in AF, even when average rates are controlled, and does not necessarily cause symptoms unless profound and/or prolonged. In general, permanent pacing is not indicated unless the patient has symptomatic bradycardia. If this does occur, in the context of otherwise appropriate rate control, the patient should be referred to a cardiologist for consideration of permanent pacemaker insertion. For permanent AF, single-chamber pacemakers are used. For paroxysmal AF, the aim for patients with bradycardia during AF should be maintenance of sinus rhythm. Dual-chamber pacing may be indicated in the presence of (spontaneous or drug-induced) sinus node dysfunction associated with nonpermanent AF.

AV node ablation Patients who require rate control but who remain tachycardic despite optimal pharmacological treatment, have a further option: radiofrequency catheter ablation of the AV node, which achieves both rate control and regularisation of the ventricular rate.51 This necessitates implantation of, and dependency on, a permanent pacemaker in all cases so is typically reserved for older patients, or those in whom a pacemaker is already in situ. This ‘ablate and pace’ strategy is generally effective and well tolerated, with many studies showing an improvement in quality of life and left ventricular function.51-53 Some patients experience a worsening in symptoms after the procedure, especially if there is underlying ventricular dysfunction, although in some this may be ameliorated by biventricular pacing. Fibrillation of the atria, and risk of thromboembolism, both continue.

Rhythm control The aim of the rhythm-control strategy is to restore and maintain sinus rhythm. In general, this strategy is far more likely to involve access to specialist cardiology services. Patients often still require rate control until sinus rhythm is restored, and during any paroxysms that break through the control of anti-arrhythmic drugs.

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

If AF requires cardioversion, this can be achieved pharmacologically or electrically. Each has its merits: acute AF (< 48 hours onset) can be treated in hospital with a slowly administered bolus of flecainide without the need for electrical cardioversion, avoiding the need for general anaesthesia or sedation, but this becomes less effective as the paroxysm continues past 24 hours. If restoration of sinus rhythm is required on haemodynamic grounds, acute electrical cardioversion can be offered under a brief general anaesthetic. It must be emphasised that if a clear onset of AF within 48 hours of presentation cannot be ascertained, restoration of sinus rhythm should be deferred pending therapeutic anticoagulation for at least three weeks, unless haemodynamic symptoms warrant a strategy of transoesophageal echocardiography to help exclude atrial thrombus followed by direct current cardioversion. The efficacy of pharmacological therapy when administered > 48 hours after onset of AF is modest and because therapeutic anticoagulation is required for at least three weeks before initiation of such therapy the preferred strategy is that such anticoagulation be followed by DC electrical cardioversion, usually as a day-case hospital admission. Maintenance of sinus rhythm, ie prevention of recurrent AF (either paroxysmal or persistent), usually requires anti-arrhythmic drug therapy. After a first AF episode, it is reasonable to await a second episode before commencing anti-arrhythmic therapy, because the time to recurrent AF is ‘unknown’.

Pharmacological therapy The overall approach should be ‘stepwise,’ moving from lower-risk interventions with some potential benefit to those that are more effective but carry a greater risk of adverse effects. The first-line agent, including after initial cardioversion, should generally be a standard (non-sotalol) beta-blocker. If, despite maximum tolerable dose-titration, this fails, the options are class I or III anti-arrhythmic drugs. In most cases, it is appropriate for these to be initiated by a cardiologist. Class I anti-arrhythmic drugs, which are sodium channel blockers related to local anaesthetic agents, can be highly effective at maintaining sinus rhythm. The main agents used in the UK are flecainide (100–300 mg daily in divided doses), and propafenone. They are negatively inotropic, have an association with poor outcomes in patients with previous myocardial infarction, and also increase the risk of electrical block in the His-Purkinje system, so patients should be screened for: • structural heart disease including previous myocardial infarction, symptomatic coronary artery disease, and cardiac failure • ECG abnormalities such as bundle branch block, 1st degree heart block, prolonged QT. However, in patients without structural heart disease, these drugs can be regarded as an early second line of therapy, and are often well tolerated. For infrequent symptomatic paroxysms, single-dose ‘pill-in-the-pocket’ therapy can be used. For daily use, even for those with normal baseline ECG, repeat ECG and possibly exercise testing should be considered after dose (particularly ≥ 200 mg daily) titration to establish there is not abnormal prolongation of QRS width or QT interval, both of which may be associated with pro-arrhythmia. This will usually be organised, or will need to be reviewed by, the initiating cardiologist. Class I drugs may also convert persistent AF to atrial flutter which may conduct rapidly

VOLUME 7 NUMBER 2 • JUNE 2010

REVIEW

(1:1) to the ventricle, so AV-node blocking drugs (beta/calciumblocker) are often co-administered with maintenance flecainide therapy to reduce this risk. Sotalol, a class III anti-arrhythmic related to beta-blockers, can also be effective in maintaining sinus rhythm. NICE guidelines recommend it is up-titrated from 80 mg twice daily to 240 mg twice daily. However, we would advise extreme caution when doing this, especially in a primary care setting. There is a risk of pro-arrhythmia due to QT prolongation and torsade de pointes ventricular tachycardia, more likely to occur in women and when the total daily dose of sotalol exceeds 160 mg.54 An ECG should be repeated 5–7 days after dose titration to check for excessive QT prolongation (caution if > 460 msec, and therapy should be discontinued immediately if QTc > 500 msec). Amiodarone has less pro-arrhythmic risk, but is associated with multiple extra-cardiac side effects, particularly thyroid dysfunction, pulmonary inflammation/fibrosis, and skin problems such as photosensitivity, corneal micro-deposits, and, less commonly, liver and neurological problems. It interacts with warfarin very significantly. Many effects are long term and dose dependent, so it is not a favoured strategy in younger patients or when considered for long-term use. The drug is, however, relatively safe in those with heart failure – being ‘reassuringly’ mortality neutral in the SCD-HeFT trial.55 Amiodarone is the rhythm-control agent of choice in the short– medium term for patients with structural heart disease, especially those with LV dysfunction, but remains generally unsuitable for long-term use. The elderly, in particular, are at risk of bradycardia during initial loading therapy, both in AF and if sinus rhythm is restored; thus caution should be exercised. However, it is probably one of the safest anti-arrhythmic agents to be initiated out of hospital. Loading regimens for amiodarone vary, with ≥ 1 g daily loading under initial specialist care, but low-dose standard regimens are advised in primary care (600 mg daily for one week in divided doses, then 400 mg for one week, followed by 200 mg daily). The patient must be counselled on the long-term side effects and will need to have regular follow up to ensure early recognition of any complications.

New oral anti-arrhythmics Several new oral anti-arrhythmics are on the horizon, which offer the potential for greater efficacy with fewer side effects. The first available new drug, dronedarone, is a non-iodinated derivative of amiodarone with less extra-cardiac toxicity but similar ‘broadspectrum’ anti-arrhythmic properties. Large clinical trial results look promising56 and, although its use may not extend to those with heart failure,57 it is likely to add to the armamentarium of AF therapies, particularly given its apparently improved safety profile, possibly at the expense of efficacy, compared with amiodarone.58 A move to atrial-specific anti-arrhythmics and more ‘up-stream’ therapies in at-risk populations may lead to arrest or reversal of the remodelling processes that encourage AF, and could offer new promise in the pharmacological management of AF.

Repeat electrical cardioversion Although routine repeat cardioversion for recurrent AF is no longer recommended (given the availability of anti-arrhythmic therapy and also data supporting rate control as an equivalent prognostic

REVIEW

strategy), it has a role for managing infrequent symptomatic episodes of persistent AF where a pill-in-the-pocket strategy is ineffective, particularly if there has been a recognised infrequent trigger such as respiratory tract infection or a surgical procedure. Also, if a first cardioversion was unsuccessful (either complete failure, or early recurrence of AF), a second attempt can be made on adjuvant anti-arrhythmic therapy, and/or via a specialist centre with high-energy external defibrillators or facilities for internal cardioversion. Beyond this, recurrence of AF should either prompt alteration to a rate-control strategy, or referral for consideration of catheter ablation.

Rate versus rhythm control The AFFIRM39 and RACE59 trials prospectively compared rate with rhythm control (RACE: cardioversion +/- drugs. AFFIRM: drugs +/- cardioversion) in relatively elderly, high-risk AF populations. In AFFIRM, rate control appeared non-inferior to rhythm control, and was associated with fewer hospitalisations, strokes, and episodes of torsade de pointes. However, a much greater proportion of patients had anticoagulation withdrawn in the rhythm-control arm once rhythm control was achieved, which may partly explain the increased risk of stroke. This is an important lesson learnt from AFFIRM – the decision to anticoagulate should, to a large extent, be based not on whether sinus rhythm has been restored with cardioversion or drugs, but on the pre-existing risk score (CHADS2). The AF-CHF trial has further examined the relative roles of rate and rhythm control in patients with heart failure.60 Rate control was non-inferior to (drug/cardioversion-based) rhythm control for cardiovascular and all-cause mortality, and stroke in a large proportion of patients. It remains possible that better rhythm-control treatments will shift the balance in favour of this strategy. AFFIRM and similar data, which suggested that drug-based rate and rhythm control strategies were equivalent, were also from an era when it was common practice to stop anticoagulation when rhythm control was achieved (regardless of risk of stroke). It is not known whether more modern comparisons of the latest generations of anti-arrhythmic drugs such as dronedarone which appears to reduce cardiovascular morbidity and mortality,56 in an era during which anticoagulation is based more on thromboembolic risk than rhythm, would produce similar results. Moreover, results of direct comparisons of drug-based rate control vs ablation-based rhythm control are not going to be available for a number of years, although there are some indications that that ablation may reduce cardiovascular morbidity61,62 and mortality.61 The consensus is that when AF is well tolerated in the over65s, it can reasonably be treated with a rate-control strategy. If, however, a patient remains symptomatic despite optimal rate control, the rhythm-control strategy is recommended. Appropriate thromboprophylaxis should be given regardless of the strategy.

Who should be referred to a tertiary care heart rhythm specialist (cardiac electrophysiologist)? NICE guidelines suggest the following patients should be referred: • those who have failed pharmacological therapy • those with lone AF • those with ECG evidence of an underlying electrophysiological disorder.

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Most younger patients, particularly those under the age of 60, should be assessed by an electrophysiologist. In particularly young patients (< 40 years) another arrhythmia capable of precipitating AF, such as WPW syndrome or supraventricular tachycardia, and that can be easily cured by catheter ablation can sometimes be identified. However, there also appears to be a distinct group of young (30–50 years) patients (men more frequently than women) with no obvious associated arrhythmias or structural abnormalities (lone AF) who are often quite symptomatic and who tend to require specialist advice/treatment. Many regions now have dedicated arrhythmia clinics, often with a nurse specialist in a central role working in collaboration with a cardiologist specialising in heart rhythm disorders. There are also an increasing number of physicians – within both primary and secondary care – with specialist expertise in medical management of AF. For most patients the diagnosis and initial management of AF can take place in primary care, but referral to an AF specialist physician or clinic can be useful when the appropriate management strategy is not clear or when initial therapies fail.

What are the specialist options? A cardiologist with a specialist interest in heart rhythm (cardiac electrophysiologist) can, amongst other things, offer the following therapeutic options: • further optimised anti-arrhythmic therapy and/or rate control • pacemaker insertion, eliminating bradycardias and allowing escalation in pharmacological therapy • catheter ablation of the AV node with pacemaker insertion • radiofrequency catheter ablation of atrial fibrillation. This last procedure has become established over the last 10 years, and is now an invaluable non-pharmacological rhythm-control option for symptomatic patients unresponsive to, or intolerant of, anti-arrhythmic drugs. The discovery in the late 1990s that AF could have a focal origin, often in the pulmonary veins, led to the use of minimally invasive radiofrequency catheter ablation techniques to destroy these areas,63 and later techniques to electrically disconnect the pulmonary veins from the atria – so-called ‘pulmonary vein isolation’. Subsequent advances in both understanding of AF pathophysiology, and available technology, including the 3-D reconstruction of the patient’s atria and pulmonary veins, have enabled creation of complete encircling and linear atrial lesions (Fig. 2), in addition to targeting other areas of pro-fibrillatory activity that contribute to the maintenance of AF. The procedures require significant expertise, although technologies for 3-D catheter localisation and reconstruction of the shape of the left atrium and pulmonary veins, as well as the recently introduced remote catheter navigation technologies are proving helpful. A typical procedure lasts 2–4 hours (less for some paroxysmal, more for some long-standing persistent/permanent AF), and is usually performed under sedation or general anaesthesia. Long-term freedom from AF can be expected in 70–90% of patients, depending on the duration and complexity of AF, with repeat procedures being necessary to achieve these results in a significant minority of patients. Important complications of the procedure include transient ischaemic attack or stroke (0.5–1.5%, largely dependent on age), tamponade needing drainage (1–3%), symptomatic pulmonary vein stenosis requiring stenting (< 0.5%), and right phrenic nerve palsy (0.3%, usually transient). These risks

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Figure 2: 3-D reconstruction of left atrium using NavX system (St Jude Medical, MN, USA). The left atrium is seen from above and behind, with left atrial appendage (green) top left. Circumferential ablation (red dots) has been performed around each pair of pulmonary veins (magenta, red; yellow, blue), resulting in their electrical disconnection from the left atrium, and a line of ablation created on the roof of the left atrium. This map can be navigated in real time allowing reduced use of X-ray fluoroscopy and accurate delivery of treatment.

REVIEW

NICE recommendations on initial strategy for treating AF Rate control

Rhythm control

• minimal or no symptoms

• symptomatic

• persistent AF

• paroxysmal or persistent < 1 year

• > 65 years old

• younger patients

• coronary artery disease

• first presentation with lone AF

• contraindications to anti-arrhythmic drugs

• AF secondary to a treated/ corrected precipitant

• unsuitable for cardioversion

• congestive heart failure*

• no congestive heart failure* *based on subgroup data from AFFIRM and RACE – not supported (for drugbased rhythm control) by AF-CHF data

Who should be referred for consideration of AF ablation?

need to be considered in the context of patient symptoms and their risk of stroke with non-intervention, as assessed by the CHADS2 score. In a non-randomised comparison of medical therapy with ablation in a general population of AF patients, ablation was associated with improved survival, reduced symptoms, reduced morbidity (including development of HF) and normalisation of quality of life.61 Several small randomised studies have compared catheter ablation with medical therapy for maintenance of sinus rhythm, and a meta-analysis of these has shown that ablation results in a marked increase in freedom from AF at one year, with an overall low level of complications comparable with other cardiac interventions. Ablation may also confer prognostic benefit in its ability to restore/maintain sinus rhythm without the adverse effects of antiarrhythmic drugs, which themselves have never been associated with prognostic advantage, although large prospective randomised trials with long-term follow up are awaited – such as the ongoing CABANA trial. Early non-randomised data suggest there is at least a significant symptomatic and haemodynamic benefit of ablation in patients with underlying heart failure.64,65

VOLUME 7 NUMBER 2 • JUNE 2010

AF is so common that catheter ablation cannot be offered to all patients. Thankfully, most patients can be managed medically, with appropriate reduction in thromboembolic risk and symptomatic control (with rate or rhythm control) as the cornerstones of treatment. However, ablation can be very useful for patients refractory to, or intolerant of, medical treatment. Younger, highly symptomatic patients with paroxysmal AF are obvious candidates for the procedure as they have the highest success and lowest complication rates, but the application of ablation techniques has been expanded to older patients and patients with long-standing AF. The current indication for AF ablation is symptomatic recurrent paroxysmal or persistent AF despite at least one class I or III antiarrhythmic drug (or if these drugs are contraindicated or not tolerated). If amiodarone is the only feasible option, then patients would be counselled regarding the option of catheter ablation as a ‘first-line’ rhythm control strategy, balancing the risks and benefits of each approach. Amiodarone would be regarded as a less favourable long-term strategy in the young.

Does catheter ablation render the patient safe to come off warfarin? There are, as yet, insufficient data to support a change in antithrombotic therapy after successful ablation. Warfarin is required for all AF ablation patients for 2–3 months post-procedure: those with a sufficiently low preoperative CHADS2 score, or equivalent, can resume aspirin therapy at the time, but patients with a score of ≥ 2 should continue with warfarin even after successful ablation. Patients should be considered for ablation based on symptoms and not based on a wish to stop warfarin. References available on www.diabetesjournal.co.za

MORE WITH

DIAMICRON MR ADVANCE

the largest, prospective study ever in 11 140 Type 2 diabetic patients2,3

• Diamicron MR* reduces serious diabetic complications 1 • Diamicron MR* significantly reduces renal events by 21% & macroalbuminuria by 30% 1 • Diamicron MR*: No weight gain & low hypoglycaemia1

For full prescribing information, refer to package insert approved by the medical regulatory authority.

DIAMICRON MR 30mg Tablets. Gliclazide 30mg. Reg. No. 35/21.2/0178. Each DIAMICRON Modified Release 30mg tablet contains 30mg Gliclazide. PHARMACOLOGICAL CLASSIFICATION A21.2 Oral Hypoglycaemics. PRODUCT REGISTRATION NUMBER 35/21.2/0178. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: Servier Laboratories South Africa (PTY) LTD (Reg No. 72/14307/07). Devcon Park, 7 Autumn Street, Rivonia, 2128. Tel: +27(0)11 233-6000. FAX: +27(0)11 233-6099. References: 1. ADVANCE Collaborative Group NEJM 2008;358;2560-72 . 2. Study rationale and design of ADVANCE. Diabetologia 2001; 44: 1118-1120. 3. ADVANCE patient recruitment and characteristics of the study population at baseline. Diabetes Med 2005;22: 882-888. * DIAMICRON MR based strategy.

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

SA JOURNAL OF DIABETES & VASCULAR DISEASE

REVIEW

Meeting of the Minds Common goals, different viewpoints: cardiologists and endocrinologists face off in a series of stimulating debates JL Aalbers, P Wagenaar

e rvier’s Meeting of the Minds, part two, which took place in Cape Town in March 2010, once again brought together cardiologists and endocrinologists to share their often opposing views on key issues relevant to both disciplines.

Should pre-hypertension in type 2 diabetes be treated? Dr Geoff Bihl, private practice nephrologist, Somerset West Arguing in favour of treatment, Dr Geoff Bihl, a nephrologist from the Winelands Kidney and Dialysis Centre in Somerset West, pointed out that high blood pressure imparts a significant risk for cardiovascular morbidity and mortality, even in the general population, and that this risk is two to four times higher in type 2 diabetics. ‘That’s the first argument for treatment’, he said. ‘Early treatment of hypertension – which might be considered normal/high-normal or pre-hypertension in nondiabetics – is therefore essential in diabetic patients. While the optimal blood pressure in diabetics is not clearly defined, anything above 130/80 mmHg should be viewed as requiring treatment.’ Not all diabetics are the same, so it is very important to individualise treatment. Factors to take into account include: • duration of diabetes • macrovascular disease • microvascular disease (including that of the kidney) • age of the patient • presence of autonomic neuropathy. ‘It has also been shown that overly quick and aggressive blood pressure reduction can be detrimental in these patients’, continued Dr Bihl. ‘Rather, we should be aiming for a gentle and slow reduction to below 130/80 mmHg over time.’ Pre-hypertension is commonly associated with the metabolic syndrome, which is an important factor in the pathogenesis of chronic kidney disease. Raised blood pressure is a common cause of altered kidney function, and treating pre-hypertension in diabetics also helps lower their risk on this front. ‘Treating pre-hypertension has been shown to reduce the risk of progression to end-stage renal disease by 46%’, said Dr Bihl. The ADVANCE study showed a reduced relative risk of 17% in combined primary outcomes – major macro- and microvascular events – with good blood pressure control. ‘We need to look at five- to 10-year outcomes, and these have shown that good blood pressure control has profound effects on cardiovascular and renal risk.’ Dr Bihl summarised his key arguments as follows. ‘Diabetics are at Correspondence to: JL Aalbers Special Assignments Editor, South African Journal of Diabetes and Vascular Disease Tel: +27 (0)21 976-4378 Fax: 086 610 3395 e-mail: jaalbers@icon.co.za P Wagenaar Gauteng correspondent S Afr J Diabetes Vasc Dis 2010; 7: 65–69.

VOLUME 7 NUMBER 2 • JUNE 2010

a high risk of cardiovascular and renal morbidity and mortality. The risk starts early and is worsened by pre-hypertension, which needs to be defined and diagnosed early. Most diabetics will progress to overt hypertension. Once lifestyle modifications have been implemented, the renin–angiotensin–aldosterone system (RAAS) requires early and aggressive management with drugs such as the ACE inhibitors and ARBs, which are well researched and inexpensive.’

The case against treatment of pre-hypertension Dr Aslam Amod, private practice endocrinologist, Durban Arguing the contrary view, Durban-based endocrinologist Dr Aslam Amod said that there is no debate about whether increasing blood pressure confers risk. ‘Ischaemic heart disease and stroke risk rise loglinearly with increasing systolic and diastolic blood pressure. The term pre-hypertension was first used in 1939 and resurrected in a 2002 Lancet study. The question is rather whether pharmacological treatment of pre-hypertension makes a difference.’ In American, but not European guidelines, the term ‘pre-hypertension’ (120–140 mmHg systolic BP) has superseded the use of ‘normal’ (120–130 mmHg) and ‘high normal’ (130–140 mmHg). Dr Amod’s first concern therefore is that the definition of pre-hypertension in diabetes is vague, especially when it comes to the diastolic measurement. ‘We treat above 130 mmHg systolic and 80 mmHg diastolic BP, which means we’re treating normal diastolic and high-normal systolic BP. Should we be setting the diastolic level at 75 mmHg or even 70 mmHg, and systolic at 120–129 mmHg?’ Regardless, he argued that pharmacological therapy should not be used. Few studies have been done in this regard in diabetics, however, so data have to be extrapolated from studies of pre-hypertension in non-diabetics. The TROPHY study, which concluded that treating pre-hypertension prevented the progression to hypertension, showed that pre-hypertensives receiving candesartan experienced a reduced risk of incident heart disease and that the treatment was safe and effective. Dr Amod, however, questioned these findings, pointing out that the patients’ blood pressures were recorded while on treatment, that their hypertension was treated rather than prevented and that the study was therefore compromised. A study of ramipril in pre-hypertension, published in the Journal of Hypertension, was similarly compromised by the fact that it entailed treatment of the endpoint being measured. He also challenged the findings of the ADVANCE study that blood pressure reduction in diabetics, even those without hypertension, was beneficial. He argued that the baseline blood pressure of all involved – 130/80 mmHg – could be construed as hypertensive in this population, and the lack of any evaluation of patients in the 120–129 mmHg systolic band meant that one could only conclude that those with a history of hypertension benefited. By contrast, two lifestyle-modification trials evaluating low-sodium diets showed a 30% risk reduction in cardiovascular endpoints, suggesting that lifestyle modification had a better outcome than drug treatment.

REVIEW

Dr Amod concluded that treating ‘diabetic pre-hypertensives’ pharmacologically would mean treating 140 million new patients worldwide – or 50% of the world’s diabetic population. ‘The consequences in respect of cost, adverse events and extra doctor visits are therefore staggering – and also impact on the cost of treating true hypertension, given the requirement to treat to lower targets. All it will really achieve is lower traces of albumin in urine samples!’ In the discussion that followed, Dr Amod reiterated his concern that as yet no study had evaluated whether it made a real difference to treat to a target of 120 mmHg systolic BP rather than 130 mmHg. ‘I’m happy to treat to 130 mmHg’, he said, ‘but below that, pharmacotherapy should not be involved.’ Dr Bihl picked up the point about lower albumin in urine, countering that this was an important consideration, reflecting a generalised ‘endothelialitis’ and was associated with greater cardiovascular and renal dysfunction. ‘Pre-hypertension seldom exists in isolation, so treating a pre-hypertensive diabetic who has microalbuminuria will reduce his/her cardiovascular risk.’ He agreed with Dr Amod that diagnosing pre-hypertension was a challenge and that if it were suspected, 24-hour blood pressure monitoring was essential to confirm the diagnosis, as office measurements are often unreliable. Both doctors agreed that individualisation of treatment thereafter was critical. ‘All type 2 diabetics will ultimately become cardiac patients – and it’s easier and more effective to lower blood pressure than blood sugar, concluded Dr Bihl. ‘It’s also cheaper!’

Promoting early insulin usage in type 2 diabetes Dr Graham Ellis, endocrinologist, Somerset West ‘The longer we burden our patients with raised HbA1c levels, the greater the risk of micro- and macrovascular damage, devastating the productive lives of our patients’, Dr Ellis motivated. Many studies, including the results from the pivotal UKPDS of long-term type 2 diabetes management,1 have related increased micro- and macro-vascular events to increases in HbA1c. ‘In vitro studies have shown the extensive damage caused by glucotoxicity, mediated by increased free oxygen radicals and oxidative stress, including damage at a genetic level of the β-cells’, Dr Ellis pointed out. Oral agents do not offer enough HbA1c reduction; metformin monotherapy reduces HbA1c by about 1.5%, sulphonylureas reduce levels by between 1 and 2% and thiazolidinediones (mainly pioglitazone) on average reduce levels by 0.5 and 1.4%.2 ‘We really need to tackle our own treatment inertia, and studies using NPH insulin nocturnal plus metformin,3 and the INSIGHT study4 using insulin glargine at bedtime (normal dosage was 38 units per day) plus oral agents, compared to oral agents only showed that more patients reached an HbA1c of 6.5% earlier and importantly there was no difference in hypoglycaemic rates. ‘Weight gain is of course the excuse most often cited for not introducing insulin. In fact, weight gain with insulin is modest and if compared to optimal sulphonylurea dosages, insulin doesn’t do too badly’, Dr Ellis said. Today, clinicians are being told to use expensive GLP-1 agonists to save and preserve β-cell function. In fact, studies using intensive insulin early on diagnosis of type 2 diabetes has shown preservation of β-cell function.5,6 So why not use insulin to save β-cells? Furthermore, the evaluation of the ACCORD study with its increased mortality attributed this to poor glucose control, not to going for toolow targets and causing hypoglycaemic-related deaths. In fact, patients who achieved levels of HbA1c < 7% within three to six months had a lower risk of mortality, regardless of whether they were in the stand-

SA JOURNAL OF DIABETES & VASCULAR DISEASE

ard/intensive arm. ‘These targets of below 7% are very difficult, if not impossible to achieve with oral agents only, so early insulin is safe, effective and perhaps also cost-effective,’ Dr Ellis concluded.

Benefits of early insulin usage is not proven in type 2 diabetes Dr Ray Moore, Umhlanga Centre for Diabetes and Endocrinology, Durban ‘There is no current evidence supporting the early use of insulin, as many of the studies purporting to show some benefit have not taken into account the general improvement in β-cell function following reduction of glucotoxicity.’ Motivating this point of view, Dr Moore pointed out that in the UKPDS,1 improvement in microvascular events was related to improved glycaemic control and not to the particular medication utilised. ‘Only metformin, in a relatively small subgroup, was able to define itself as being of somewhat greater benefit, with a reduction in myocardial infarction rate over the other agents which did not achieve this’, he pointed out. In an instructive study undertaken in the 1980s,7 which compared diet alone, insulin and sulphonylurea therapy, it showed that with diet alone, there was an increase in insulin levels and a drop in blood glucose levels. ‘Why would one use insulin with its accompanying expensive monitoring costs, increased hypoglycaemic events (six-fold more than with sulphonylureas) and weight gain (7 kg on average in the UKPDS study), if diet, lifestyle and two/three oral agents can achieve the same results without increased cost and morbidity?’, Dr Moore asked. Perhaps the only exception to this position is when a patient presents at diagnosis of diabetes with an HbA1c of 10% or more. ‘Start shortterm therapy with insulin, to reduce glucose levels, and then revert to lifestyle and oral agents’, said Dr Moore. With regard to insulin usage and cancer risk, it was noted that insulin is a growth factor and in diabetic patients, there is an overall higher incidence of cancer. ‘It is simplistic to blame only one insulin. What is needed is a thorough prospective study comparing cancer risks across treatment modalities’, Dr Moore added. ‘The focal treatment of type 2 diabetes should be lifestyle change with back-up integrated care. If this is done consistently, diabetes can be extremely well managed at the primary-care level’, added Dr Larry Distiller, chairman of this session and organiser of the meeting.

Diabetic dyslipidaemia – current management with combination therapy Prof FJ Raal, Lipid Clinic, Witwatersrand University ‘Type 2 diabetes should be considered a coronary artery disease equivalent, and dyslipidaemia should be looked for and aggressively treated in every diabetic patient. There is an ongoing debate as to which lipidmodifying drug is the most appropriate for the treatment of diabetic dyslipidaemia. Statins should be considered first-line therapy following the disappointing results of the FIELD study and the positive results of the HPS and CARDS study. The role of combination therapy (statins plus fibrate and/or niacin) will be increasingly elucidated with the results of outcome studies.’ This view was strongly presented by Prof Raal. Results of the first of these outcome studies using combination therapy, the ACCORD Lipid trial,8 was announced at the recent 2010 American Cardiology Congress meeting. This study showed that the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, non-fatal myocardial infarction or non-fatal stroke, compared with simvastatin alone. ‘There was a possible benefit in patients with both a high base-

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

line triglyceride level and a low baseline level of high-density lipoprotein cholesterol’, but this category of dyslipidaemic patient represented only 17% (941 out of the 5 518) of the total patients in the study’, Prof Raal concluded.

The significance of microalbuminuria Dr Trevor Gernholtz, private practice nephrologist, Fourways, Gauteng Dr Trevor Gernholtz at the outset sought to define the best methods of determining microalbuminuria. Noting that the measurement of urinary albumin excretion (UAE) in a 24-hour collection is the gold-standard method of determining the presence and extent of microalbuminuria, it clearly no longer meets the demands of immediate clinical availability. In the search to define what techniques could best replace the 24-hour urine collection, Dr Gernholtz noted recent methodological research in Groningen, Netherlands,9 which has shown that the determination of the albumin:creatinine ratio (ACR) or the urinary albumin concentration (UAC) in the first morning void (FMV) relates best with the 24-hour UAE and was more consistent than the spot urine-sampling technique. ‘ACR in a FMV is the screening method of choice to determine the presence of early diabetic renal disease, yet its predictive value for determining the rate of progression of kidney disease is not consistent’, Dr Gerntholtz noted. Referring to the STENO trial,10 Dr Gerntholtz pointed out that type 2 diabetic patients treated with RAAS blockers achieved better blood pressure control and improvements in urinary albumin excretion rates, but over the eight years, there was no difference in the decline in glomerular filtration rates (GFR) in the intensive versus the non-intensive arm. ‘Over the eight years, there was an overall 3 to 4 ml/min decline in the GFR despite effective BP control, lifestyle modification and improved glucose and lipid control’, Dr Gerntholtz noted. ‘The intensive therapy did reduce all-cause and cardiovascular mortality and only one patient in the intensive arm progressed to end-stage renal disease versus the six patients in the conservatively treated group’, he added. A further series of studies indicative of a disconnection between microalbuminuria and declining kidney function was undertaken by G Jerums in Australia in 2008.11 ‘His studies showed that in late diabetic nephropathy only (both type 1 and type 2 diabetes) did reduction of albuminuria translate to a slower deterioration in glomerular filtration rate.’ ‘Microalbuminuria is more indicative of vascular changes in the kidney and also in the rest of the body than it is indicative of renal lesions. There is a wide range of structural renal lesions over similar ranges of normo/microalbuminuria.’ Notwithstanding the poor correlation with kidney function and microalbuminuria, albuminuria is a continuum from normal (< 30 mg/ day) to microalbuminuria (30–300 mg/day) to frank albuminuria (> 300 mg/day). Also, before a patient develops frank albuminuria, it is preceded by microalbuminuria, so that its detection remains important. For this reason, it is recommended that urine (FMV) be sent off on a six- to 12-monthly basis to assess the albumin:creatinine ratio.

The importance of risk assessment in coronary artery disease management Dr Colin Schamroth, private practice cardiologist, Milpark, Gauteng ‘Risk factor scores are important; yet the Framingham Heart study showed that a third of coronary artery disease (CAD) events occur at

VOLUME 7 NUMBER 2 • JUNE 2010

REVIEW

normal cholesterol levels and a fifth occur among individuals without recognised traditional risk factors (blood pressure, smoking status, hyperlipidaemia and the presence or absence of diabetes). The Framingham-derived scoring system, although used successfully for many years, has limitations, particularly in women, black patients, younger patients and with the ever-increasing presence of the metabolic syndrome.’ This view was expressed by Dr Colin Schamroth in his presentation on risk-factor models and the need for updating the 1980s-based Framingham score.12 ‘The addition of hsCRP (high sensitivity C-reactive protein) has received a great deal of attention and it certainly adds value as a clinical criterion for the metabolic syndrome and is capable of refining risk in those patients at intermediate risk (10–20%),13 as determined by the Framingham score. I use the Reynolds risk score, available on the internet (www.reynoldsriskscore.org), to assess risk and show the patient how modification of risk factors by lifestyle or therapeutics reduces his/ her risk of future cardiovascular events.’ The advantage of hsCRP is that the test is quick, standardised and not expensive. Looking at specific population groups, the Northern Manhattan Cohort study14 added factors such as weight circumference, alcohol consumption and physical activity as determining cardiovascular risk in this multi-ethnic population. However, the addition of these factors added very little predictive value over and above the Framingham risk score. A comprehensive study15 undertaken of whether erectile dysfunction could contribute to the prediction of cardiovascular risk was negative, although the presence of erectile dysfunction was significantly associated with cardiovascular incidence. Electron-beam computed tomographic determination of coronary artery calcium showed that in a cohort of apparently healthy, middleaged men, calcium determination contributed very little to the risk of already-determined Framingham risk of above 20%. Below 10%, coronary artery calcium was however negatively predictive and added value to the Framingham score. ‘Importantly, in the intermediate-risk group of 10 to 20%, a low calcium score did indicate a lesser risk.’ However, this is an expensive technique, and adds little to the predictive value of Framingham with hsCRP (the Reynolds risk score). Finally, the use of genetic testing using defined SNPS16 (9p21 genomic markers), undertaken as part of the Women’s Genome Health project, showed a net reclassification of the risk index from 0.1 to 4.8%. Genetic definition is still unhelpful at this stage of our knowledge’, Dr Schamroth concluded.

The management of silent myocardial ischaemia: intervention or non-intervention? Dr Adrian Horak, cardiologist, Vincent Pallotti Hospital, Cape Town Dr Adrian Horak made the case very strongly for intervention. ‘No contest!’, he said. For the purposes of his talk, Dr Horak said he was viewing silent myocardial ischaemia as being equivalent to normal ischaemia. ‘It is the same’, he said, ‘with the only difference being that there are no symptoms and the patient is therefore unaware of the problem’. Silent ischaemia is more prevalent in diabetics. He pointed out that doing nothing is an option, as is medical treatment, but that he would be focusing primarily on percutaneous coronary intervention (PCI) (angioplasty/stenting) and coronary artery bypass grafting (CABG). ‘In some respects it’s a silly topic to be debating as all patients are individuals and what may be right for one may not be right for another. Careful assessment is important to weight up the risk of intervention

REVIEW

versus no intervention. An angiogram is essential, and tools like the Syntax score and Euroscore can then be used to review the angiogram to assess whether risk is high or low – and whether disease is mild or severe. It’s imperative to intervene where disease is severe.’ Medical therapy is good up to a point, but there is still a fairly high degree of morbidity and mortality and numbers needed to treat are high, irrespective of the type of drug used (ARBs, ACEs, aspirin, statins). ‘Revascularisation, however, relieves ischaemia, improves quality of life, reduces the medication burden as well as the associated adverse events, and improves prognosis.’ He cited a number of studies in support of his view. Both the ACIP and SWISS II studies showed that revascularisation was better than medical therapy for the relief of ischaemia. The perfusion sub-study of the COURAGE trial showed that it reduced ischaemia by 33% (vs 19% for medical therapy) and severe ischaemia by 78% (vs 52%). Large observational trials have also shown prognostic benefits associated with revascularisation in severe ischaemia. Dr Horak added the caveat that real-life individual patients do not reflect the ‘perfect patients’ seen in trials. He referred to 30 trials comprising 44 to 2 368 patients, underscoring that all were highly selective, allowed crossover and were underpowered to detect mortality and infarction differences. ‘The COURAGE study started the whole debate in that there was no difference in mortality and infarct rate between the medical and the PCI groups. Yet half the participants had minimal or no angina and the extent of the ischaemia was not severe. Also, the quality of the revascularisation was open to question, the study was underpowered, and an over-sensitive definition of infarction was used.’ Meta-analyses have all tended to show the superiority of PCI over medical treatment, however, with approximately 20% reductions in mortality and myocardial infarction. Dr Horak is adamant that there are trials that are sufficiently powered to prove that revascularisation saves lives. ‘Also, we’re improving our techniques all the time. Fractional flow reserve (FFR) guided PCI improves outcomes, while intravascular ultrasound (IVUS) can detect angiographically silent ischaemia. As we keep on individualising and finding vulnerable patients, we’ll see even better results. FFR is a functional measurement that acts as a guide to important lesions, ensuring fewer stents per patient. With FFR guidance, we’ll see better-than-ever results with both angioplasty and stenting in these important lesions.’ Dr Tony Dalby, a cardiologist from Milpark Hospital, Johannesburg, feels, however, that intervention is not to be taken lightly, especially when it comes to diabetics. Angiograms are often difficult to interpret and he contends that FFR has in some ways exacerbated this, as often, what looks right is not, and vice versa. If the decision is made to proceed, much thought must be given to whether the choice is for PCI or CABG. In the COURAGE trial, adopting PCI as an initial strategy provided no incremental benefit over intensive medical therapy, including those patients with diabetes or coronary artery disease. The BARI-2D trial showed no difference between CABG and optimal medical therapy, while also showing CABG to be superior to PCI. Many issues need to be taken into account when dealing with diabetics, including age, obesity, left ventricular and renal dysfunction, as well as the presence of rapidly progressing disease. ‘Repeat revascularisation is often required in diabetics and in this regard both PCI and CABG have a bad outlook. It is therefore important to first consider optimal medical therapy comprising lifestyle management, glycaemic control and aggressive secondary-prevention measures. This has to be

SA JOURNAL OF DIABETES & VASCULAR DISEASE

the basis of anything we do.’ (He acknowledged, however, that CABG was found to be superior to optimal medical therapy in the ACIP trial.) Patients are not always properly informed and have unrealistic expectations of PCI. ‘Seventy per cent of patients believe it will prolong life and 70% that it will prevent myocardial infarction’, said Dr Dalby. ‘In reality, PCI alleviates angina for two to three years – after which further revascularisation is likely to be needed.’ If intervention is chosen, Dr Dalby feels that CABG is the better choice. ‘The SYNTAX study, in which 30% of patients were diabetic, set out to prove the non-inferiority of PCI to CABG. Based on the oneand two-year results, PCI failed the test. The CARDia study produced similar results showing that, on balance, PCI is not non-inferior. A study by Hlatky published last year in the Lancet showed worse outcomes associated with PCI in diabetics, and recommended that diabetics over 65 years should be offered CABG in preference.’ He agreed with Dr Horak that it was important to assess patients individually. ‘Coronary anatomy needs to be correlated with symptoms and function, and careful thought needs to be given to when optimal medical therapy is the best choice and intervention should be held in reserve. Certainly we should start with optimal medical therapy and observe, before rushing into interventional surgery. Where we do decide to intervene, CABG should be preferred over PCI when multivessel disease is present.’ 1.

2. 3. 4.

6. 7.

8. 9. 10.

11.

12. 13. 14.

15. 16.

The UKPDS group: Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352(9131): 854–865. De Fronzo RA. Valuing quality of life and improvement in glycaemic control in people with type 2 diabetes Diabetes Care 1998; 21(Suppl 3): C44–C52. Yki Jarvinen H. Fat in the liver and insulin resistance. Ann Med 2005; 37(5): 347–356. Gerstein HC, et al. A randomised trial of adding insulin glargine vs avoidance of insulin in people with type 2 diabetes on either no oral glucose lowering agents or submaximal doses of metformin and/or sulphunyl ureas. INSIGHT study. Diabetes Med 2006; 23(7): 736–742. Iikova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E. Induction of long-term glycaemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 1997; 20(9): 1353–1356. Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care 2004; 27(5): 1028–1032. Kosaka K, et al. Increase in insulin response after treatment of overt maturity onset diabetes is independent of the mode of treatment. Diabetologia 1980; 18: 23–28. The ACCORD study group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Eng J Med 2010, March 18 (e-Pub). Witte EC, et al. First morning voids are more reliable than spot-urine samples to assess microalbuminuria. J Am Soc Nephrol 2009; 20(2): 436–443. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Eng J Med 2003; 348(5): 383–393. Jerums G, et al. Lowering of proteinuria in response to antihypertensive therapy predicts improved renal function in late but not in early diabetic nephropathy – a pooled analysis. Am J Nephrol 2008; 28(4): 614–627. Wilson PW, et al. Coronary risk prediction in adults (the Framingham Heart study). Am J Cardiol 1987; 59: 91G–94G. Ridker PM, et al. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk. Circulation 2004; 109: 2818–2825. Sacco RL, et al. Improving global vascular risk prediction with behavioural and anthro pometric factors. The Northern Manhattan Cohort study. J Am Coll Cardiol 2009; 54(2): 2303–2311. Araujo AB, et al. Does erectile dysfunction contribute to cardiovascular risk beyond the Framingham risk score. J Am Coll Cardiol 2010; 55(4): 350–356. Palomaki GE, et al. Association between qp21 genomic markers and heart disease: a meta-analysis. J Am Med Assoc 2010; 303(7): 648–656.

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

REVIEW

Diabetic prevalence and genetic determinants of diabetes among black South Africans: Servier supports South African diabetes studies As part of its ongoing commitment to medical research, Servier has funded the second prevalence and trend survey of diabetes among urban Africans in South Africa. The last time a study of this kind was undertaken was in the 1990s. A second Servier-sponsored study to determine the genetic basis of diabetes among the Zulu community has also been initiated to provide essential information on the genetic vulnerabilities and trends in diabetes in this South African community. Steve Speller, CEO of Servier South Africa stressed the importance of this initiative. ‘From Servier’s perspective, the support of research into diabetes, be it epidemiological or scientific, remains an important priority for the company. The increase in incidence of diabetes in developing countries such as South Africa has reached almost epidemic proportions and research is therefore not only important to better understand how to treat diabetes, but also to appreciate the magnitude of the problem so that resources can be allocated appropriately.’

Prevalence study in urban Africans The University of Cape Town’s Department of Medicine and the MRC Research Unit for Chronic Diseases of Lifestyle initiated this prevalence study as a collaborative undertaking. The study is being lead by Prof Naomi Levitt (UCT) with Dr Krisla Steyn and co-workers from both institutions. This study has already completed data collection among the representative sample of 25- to 74-year-old urban Africans, randomly selected from the townships of Langa, Guguletu, Crossroads, Nyanga and Khayelitsha. More than a thousand participants were examined for the presence of diabetes and other cardiovascular risk factors. Commenting on the relevance of this study, Prof Levitt pointed out that there are no available data that track the trends in diabetes prevalence in urban South Africans. ‘With increasing obesity and rapid urbanisation, with its accompanying lifestyle changes and increases in psychosocial stress, diabetes is highly likely to be on the increase in our African communities. This Servier-sponsored study will be indicative of prevalence changes among urban black South Africans in other major urban settings across the country and will provide vital data for policy makers in Government’, Prof Levitt stressed.

VOLUME 7 NUMBER 2 • JUNE 2010

Genetic determinants of type 2 diabetes in black South Africans A large study on the genetic basis of type 2 diabetes among black South Africans has been initiated at the University of KwaZulu-Natal, with financial support from Servier Laboratories, South Africa. This is an important study as there is currently very little data available on the genetic polymorphisms that predispose to or protect black Africans from developing type 2 diabetes. Equally, there is not a great deal known about genetic polymorphisms in type 1 diabetes in black South Africans, although Dr Fraser Pirie and co-workers have identified a polymorphism in the TLR 3 gene which may be associated with type 1 diabetes in South Africans of Zulu descent in KwaZulu-Natal.1 Smaller studies on black South Africans with type 2 diabetes have been undertaken by Dr Pirie and colleagues to identify whether genetic variants identified in European subjects could be detected in Indian and African subjects. ‘These studies are small and statistically underpowered, but have indicated that these variants present in Caucasians are not well represented in our African population’, Dr Pirie pointed out. The current study will be a full genome study of 1 500 type 2 diabetes patients and 1 500 controls from the African population of Zulu descent in KwaZulu-Natal. Collaboration with Oxford University will allow this large-scale genetic study to be done using automated genetic profiling. ‘With 3 000 samples being evaluated, we should be able to determine which polymorphisms occur commonly in our population, and relate these variants/loci to the occurrence of type 2 diabetes, hypertension and obesity’, Dr Pirie said. ‘We are hoping to complete the study in the next two to three years and provide unique data of significant value to our South African and African communities’, Dr Pirie concluded. This study will provide vital data, which are currently lacking, as to the genetic basis of diabetes pertinent to African populations. There are similar studies being undertaken in Uganda with support from Universities in the UK and this will provide additional insights on African communities. 1.

Pirie FJ, Pegoraro R, Motala AA, Rauff S, Rom L, Govender T, Esterhuizen TM. Toll-like receptor 3 gene polymorphisms in South African blacks with type 1 diabetes. Tissue Antigens 2005; 66(2): 125–130.

REVIEW

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Focus on liraglutide: the LEAD studies JL AALBERS, WF MOLLENTZE

i raglutide is a very close analogue of the human glucagonlike peptide-1 (GLP-1), with a 97% sequence identity to the physiological GLP-1 gut hormone1 and a plasma half-life of 13 hours.2 The close identity of liraglutide to the human GLP-1 hormone has advantages in achieving reduced antibody production,1 which may well translate into a longer effective period of use for this agent in the glycaemic control of type 2 diabetic patients. Both the European Medicines Evaluation Agency (EMEA) and the Federal Drug Agency (FDA) have approved liraglutide for the treatment of type 2 diabetic patients. In this issue of the Journal, an editorial deals with these new entities as a class and provides data related mainly to exenatide, as it is currently available on the South African market3 (see page x). The clinical usefulness of these agents is likely to lead to the registration of liraglutide in South Africa, and review of this novel agent is pertinent for local physicians. In addition, South African specialist groups will seek to place these GLP-1 analogues into their protocols, and data on the value and clinical experience with liraglutide is pertinent to these developments. As is advocated in evidence-led clinical practice, the overall longterm use of all GLP analogues awaits outcome data and ongoing post-marketing surveillance will bring further clarity to their sustained use.

Liraglutide in the LEAD studies The LEAD (Liraglutide Effect and Action in Diabetes) studies1,4-7 constitute a well-constructed series of phase III trials which were undertaken to determine the efficacy and safety of liraglutide across the continuum from early type 2 diabetes management as monotherapy to combined use with available oral anti-diabetic agents. The most recent LEAD study investigated the value of liraglutide compared to insulin glargine therapy in type 2 diabetes.7

Rationale for liraglutide use in type 2 diabetes with special reference to the pharmacokinetics The development of GLP-1 analogues is based on providing a longer-acting molecule to extend the physiological actions of the native GLP-1, which has a very short half-life of approximately one hour in humans after subcutaneous administration, because of its Correspondence to: JL Aalbers Special Assignments Editor, South African Journal of Diabetes & Vascular Disease Tel: +27 (0)21 976-4378 Fax: 086 610 3395 e-mail: jaalbers@icon.co.za Correspondence to: WF Mollentze Department of Internal Medicine, University of the Free State, Bloemfontein Tel: +27 (0)51 405-3154 Fax: +27 (0)51 444-3138 e-mail: wfm@mweb.co.za S Afr J Diabetes Vasc Dis 2010; 7: 70–73.

rapid degradation by the dipeptidyl peptidase IV (DPP-IV) enzyme. Liraglutide is a human GLP-1 analogue with 97% homology to native GLP-1.4 By the addition of a fatty acid side chain (that promotes binding to albumin) and a single amino acid substitution, the resulting molecules self-associate and thus prolong its absorption after subcutaneous injection.4 The albumin-bound portion of the molecule is also resistant to DPP-IV degradation.4 The resistance to GLP-1 inactivation allows liraglutide to reach maximum concentrations within 10 to 14 hours, with a half-life of 13 hours.2 This longer plasma half-life makes liraglutide very suitable as a once-a-day treatment for people with type 2 diabetes. In the developmental phase II clinical trials in healthy male volunteers, headache and dizziness occurred in 47 and 53% of subjects, respectively, while gastrointestinal side effects including abdominal pain, loss of appetite and nausea were reported in 27 to 33% of subjects, most likely due to delayed gastric emptying.2

Liraglutide added to a sulphonylurea compared to adding rosiglitazone or placebo (LEAD-1 SU)1 In this 26-week, double-blind, double-dummy, active control trial of 1 041 subjects randomised into five arms, all subjects received glimeperide 2–4 mg/day in conjunction with: • one of three liraglutide doses (0.6, 1.2 or 1.8 mg/day injected subcutaneously) and rosiglitazone placebo (therefore two active substances: liraglutide and glimeride) • liraglutide placebo and rosiglitazone placebo (therefore glimeperide as the only active substance) • liraglutide placebo and rosiglitazone 4 mg/day (therefore two active compounds: glimeperide and rosiglitazone). All three doses of liraglutide added to glimeperide significantly reduced HbA1c concentrations after 26 weeks. Both liraglutide doses of 1.2 and 1.8 mg/day decreased HbA1c by 1.1% from baseline. Liraglutide 0.6 mg/day as well as rosiglitazone resulted in a decrease in HbA1c of approximately 0.4%. More subjects (42%) treated with liraglutide 1.8 mg/day reached an HbA1c target of < 7.0%, while 21% reached a target HbA1c of < 6.5% after 26 weeks. The average BMI of subjects in each of the five arms was approximately 30 kg/m2. Liraglutide 1.8 mg/day resulted in a decrease in body weight of 0.2 kg after 26 weeks. Liraglutide 1.2 and 0.6 mg/day resulted in a weight increase of 0.3 and 0.7 kg, respectively, whereas rosiglitazone resulted in a weight increase of 2.1 kg. Nausea was more common in patients treated with liraglutide, especially during the first four weeks, where after it dissipated. One patient without a history of previous pancreatic disease developed chronic pancreatitis while taking liraglutide 0.6 mg/day. Five more patients with a previous diagnosis of pancreatitis were enrolled in the trial. All six patients completed the trial without reporting any symptoms related to pancreatitis. One major episode of hypoglycaemia was reported in one patient taking liraglutide 1.8 mg/day in conjunction with glimeperide. The dose of glimeperide was reduced in this patient. Minor episodes of hypoglycaemia occurred in 10% of patients and it was more common in patients

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

receiving the higher liraglutide doses. Antibodies to liraglutide developed in 9 to 13% of subjects but had no effect on HbA1c. It was reassuring that plasma concentrations of calcitonin were no different in the three groups treated with liraglutide compared to rosiglitazone and placebo. In conclusion, liraglutide once daily was an effective and welltolerated GLP-1 analogue used in combination with a sulphonylurea for the management of type 2 diabetes.

The efficacy and safety of liraglutide in combination with metformin (LEAD-2 study)4 In this study, overweight (BMI ≤ 40 kg/m2), recently diagnosed type 2 diabetics who had been treated with either metformin or a combination of oral agents including metformin, for a period of three months, were randomly assigned to liraglutide treatment as a once-daily injection at dosages of 0.6, 1.2 or 1.8 mg/day, or to glimepiride (4 mg once daily), or to a placebo, thereby creating a metformin-only treated group. In the oral combination group, liraglutide replaced one of the oral agents but not metformin. The study set out to determine whether glycaemic control, measured as HbA1c concentrations, was better with liraglutide added to metformin than with metformin monotherapy, and as good as that achieved with combination therapy of metformin and glimepiride. Baseline HbA1c levels were between 7 and 11%. The study design was a double-blind multi-centre study conducted in 21 countries; 1 091 patients were evaluated for a period of 26 weeks. At study end, the mean HbA1c values for the overall population decreased by 0.7 ± 0.1% for the 0.6-mg/day liraglutide group and by 1.0 ± 0.1% for both the 1.2- and 1.8-mg/day liraglutide groups and for the glimepiride group, and increased by 0.1 ± 0.1% for the placebo group (all values means ± SEM). The estimated treatment differences of all three liraglutide groups compared with the placebo group and the resulting 95% confidence intervals demonstrated that liraglutide-treated subjects had superior glycaemic control compared with those in the placebo group [0.6 mg liraglutide versus placebo –0.8% (95% CI: –1.0 to –0.6); 1.2 mg liraglutide versus placebo –1.1% (–1.3 to –0.9); and 1.8 mg liraglutide versus placebo –1.1% (–1.3 to –0.9)]. Analysis of the estimated treatment difference in HbA1C levels between liraglutide and glimepiride demonstrated that 1.2- and 1.8-mg/day liraglutide treatments were non-inferior to treatment with glimepiride [1.2 mg/day liraglutide versus glimepiride 0.0% (–0.2 to 0.2) and 1.8 mg/day liraglutide versus glimepiride –0.0% (–0.2 to 0.2)]. In the patients receiving doses of liraglutide more than 1.2 mg/ day, significant reductions in systolic blood pressure occurred, perhaps beyond the weight-reduction effect. Side effects were most commonly nausea, vomiting and diarrhoea, which led to liraglutide withdrawal in 5% of all liraglutide-treated subjects. The extent of the gastrointestinal disorders was dose-dependent and occurred mainly during the first month of treatment. Minor hypoglycaemia occurred at low incidence (~3% of subjects in the placebo and liraglutide groups and 17% in the glimepiride group), resulting in a relatively low rate of reported minor hypoglycaemia (0.03–0.14 events/year for the placebo and liraglutide groups and 1.23 events/year for the glimepiride group), which was significantly less for all three liraglutide groups than for the glimepiride group (p < 0.001). No major hypoglycaemic events

VOLUME 7 NUMBER 2 • JUNE 2010

REVIEW

were reported. Patients treated with glimepiride and metformin had greater weight gain and significantly more hypoglycaemia than the liraglutide-treated group. This study showed that liraglutide could be used with metformin and was superior to metformin monotherapy and non-inferior to glimepiride and metformin.

Comparison of liraglutide to glimepiride monotherapy in early type 2 diabetes (LEAD-3 Mono)5 In this trial comparing liraglutide (1.2 or 1.8 mg/day) to glimepiride (8 mg/day), a traditional first-line sulphonylurea therapy for type 2 diabetes, patients were included who were thought to be in the early stages of disease because they were drug-naïve, were treated with lifestyle modification, or had failed to achieve control with a single oral drug at less than 50% of maximum approved dose. Previous treatment had to be for a period shorter than two months and patients were switched to glimepiride or liraglutide on study entry. The study was double-blind and conducted over 52 weeks in a multi-centre trial in the United States and Mexico; 745 patients participated in the trial in the three active treatment arms, with similar demographic and baseline characteristics – equal numbers of men and women, average BMI of 33 kg/m2 and likely duration of diabetes of five years. The primary outcome was change in value of HbA1c from baseline to 52 weeks. Secondary outcomes included changes in body weight, fasting plasma glucose levels, self-measured eightpoint plasma glucose profiles (measured before each meal, 90 min after the start of each meal, at bedtime, and at 03:00), blood pressure, β-cell function [pro-insulin to insulin ratio and two models of β-cell function; homoeostasis model assessment (HOMA)-B and HOMA-IR (insulin resistance)], fasting glucagon, and patients’ reported assessment of quality of life. Treatment with liraglutide provided better glycaemic control over the 52-week period than with glimepiride. Liraglutide reduced both fasting and post-prandial glucose in its once-daily dosage regimen. Importantly, at the dosage of 1.8 mg/day of liraglutide, no tailing off of HbA1c reduction was seen over the 52-week period, supporting the concept of a longer duration effect on HbA1c levels with liraglutide. At the end of the study, 28% of participants treated with the lower dose of liraglutide and 38% treated with the higher dose achieved HbA1c levels below 6.5%, compared with 16% on glimepiride (6.5% is the target level of the American Association of Clinical Endocrinologists). In those patients who were oral drug treatment-naïve, the treatment success rates were even higher, with 43 and 51% in the two dosage formats reaching target levels of less than 7%. HOMA-IR and fasting glucagon showed significant decreases with liraglutide but mean increases with glimepiride treatment. Insulin resistance decreased in both liraglutide groups but increased on glimepiride therapy. Participants in the liraglutide groups lost weight whereas those on glimepiride gained weight. There was no relationship between duration of nausea with liraglutide and achieved weight loss. Importantly, patients randomly assigned to liraglutide 1.8 mg/day reported improved quality of life with regard to both physical and emotional factors. No major hypoglycaemic events requiring third-party assistance occurred in any of the treatment groups. Minor hypoglycaemic

REVIEW

events were fewer with liraglutide (12 and 8% in the lower and higher dosages, respectively) than with glimepiride (24%). In terms of adverse events, a weak association between development of pancreatitis and liraglutide treatment could not be excluded as only two participants experienced pancreatitis – one after 197 days of treatment and one after 133 days. Both patients recovered and one continued in the study. This study is important, as traditional first-line therapy is not appropriate for all patients. Metformin is frequently not well tolerated and clinicians may avoid using metformin in patients with renal impairment. A study of liraglutide reported no need for dose adjustments in patients with severe renal impairment.8 The LEAD-3 study is being continued for a further four years in order to assess the durability of liraglutide therapy and the prevalence of antibodies, and to identify sub-populations that may best respond to this therapy.

Eefficacy and safety of liraglutide in combination with metformin and rosiglitazone (LEAD-4 Met+TZD)6 In this 26-week, double-blind, parallel-group, placebo-controlled trial, 533 subjects with type 2 diabetes of a mean duration of nine years and a mean HbA1c concentration of 7 to 11% were randomised into three groups. All three groups received metformin 1 g twice daily and rosiglitazone 4 mg twice daily. In addition, one group received once-daily liraglutide 1.2 mg subcutaneously (sc), another group once-daily liraglutide 1.8 mg sc, and the last group placebo sc once daily. At the end of the study, HbA1c levels decreased significantly by 1.5% for both the 1.2- and 1.8-mg/day liraglutide groups compared to a decrease of 0.5% in the placebo group. At study end, 58 and 54% of the subjects in the 1.2- and 1.8-mg/day liraglutide groups, respectively, attained an HbA1c concentration < 7.0% compared with 28% of subjects in the placebo group, whereas 37 and 36% of subjects, respectively, reached an HbA1c level of < 6.5% compared to 14% of subjects in the placebo group. Fasting as well as post-prandial glucose levels were also significantly reduced in both liraglutide groups compared with placebo. Improved glycaemic control occurred against a background of a significant improvement in β-cell function. Weight loss of 1.0 and 2.0 kg occurred in the 1.2- and 1.8-mg/ day liraglutide groups, respectively, during the study period, whereas the placebo group gained 0.6 kg in weight. Systolic blood pressure decreased by 6.7 and 5.6 mmHg in the liraglutide 1.2- and 1.8-mg/day groups, respectively, compared to a decrease of 1.1 mmHg in the placebo group. This phenomenon may be related to reduced renal sodium reabsorption. Nausea, vomiting and diarrhoea were collectively reported by 45% of subjects in the 1.2-mg/day liraglutide group, and by 56% of subjects in the 1.8-mg/day group, compared to 19% of the placebo group. The majority of nausea was transient, as it occurred in the first four weeks. There were no episodes of pancreatitis and no deaths occurred. Minor hypoglycaemia occurred at a low incidence and there was no significant treatment effect of 1.8 mg/ day liraglutide on calcitonin compared to placebo.

Liraglutide versus insulin glargin and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes (LEAD-5 met+SU)7 Of more interest to clinicians is whether liraglutide could

SA JOURNAL OF DIABETES & VASCULAR DISEASE

be effectively utilised in combination with metformin and a sulphonylurea (glimepiride) and how this GLP-1 agonist compares to basal insulin with regard to glycaemic control in type 2 diabetes. In this careful 26-week study, type 2 diabetic patients 18 to 80 years old were randomised into parallel groups receiving liraglutide 1.8 mg/day (blinded) injection, or a placebo (blinded) injection, or open-label insulin glargine; 581 patients were randomised in this multi-centre and multi-country study and 522 patients completed the study. At baseline, the HbA1c was between 7.5 and 10% on multi-oral therapy. Patients were excluded if they had impaired hepatic or renal function, clinically significant cardiovascular or extensive microvascular disease (proliferative retinopathy or maculopathy) or were hypertensive (≥ 180/100 mmHg). During a six-week run-in period, participants were placed on a standard combination therapy with metformin and glimepiride up-titrated to maximum doses of 2 g/day metformin and 4 mg/day glimepiride. If fasting plasma glucose (FPG) was between 7.5 and 12.8 mmol/l following the run-in period, patients were randomised to the three arms. Insulin glargine was self-titrated by patients according to a dosing algorithm for insulin glargine, based on fasting blood glucose levels.9 The primary-efficacy outcome measure was change in whole blood HbA1c concentrations after 26 weeks of treatment. The secondary outcome measures included changes in body weight, waist circumference, fasting plasma glucose, eight-point plasma glucose (PG) profiles, beta-cell function (pro-insulin to C-peptide ratio) and blood pressure. The reduction in HbA1c concentration was significantly greater with liraglutide (1.33%) (final mean HbA1c 7.0%) than with insulin glargine (1.09%) (final mean HbA1c 7.2%) and placebo (0.24%) (final mean HbA1c 8.1%). Also significantly more patients reached HbA1c levels below 6.5% (AACE target) and below 7.0% (ADA target) on liraglutide compared to insulin glargine. This difference in HbA1c was within the predefined non-inferiority margin of 0.4 percentage points. The mean weight loss of 1.8 kg from baseline achieved with liraglutide was significantly superior to the reduction in the placebo group. Weight increased by 1.6 kg with insulin glargine. Waist circumference decreased by 1.5 cm in the liraglutide group and increased by 0.89 cm in the insulin glargine group. Overall, weight loss with liraglutide was independent of nausea, although weight loss in eight patients with sustained nausea was on average 3.2 kg. Beta-cell function improved in the liraglutide group as measured by the pro-insulin to C-peptide ratio. Systolic blood pressure dropped by 4 mmHg on liraglutide and was unchanged with insulin glargine. This drop in systolic blood pressure occurred before substantial weight loss. The proportion of patients experiencing minor hypoglycaemia (FPG < 3.1 mmol/l) during the treatment period in the liraglutide group (27.4% patients) was not different from that in the insulin glargine group (28.9%) but higher compared with the placebo group (16.7%). The rate of hypoglycaemic episodes (major, minor and symptoms only) was, respectively, 0.06, 1.2 and 1.0 events/ patient/year in the liraglutide group; 0, 1.3 and 1.8 events/patient/ year in the glargine group; and 0, 1.0 and 0.5 events/patient/ year in the placebo group. Five patients (2.2%) in the liraglutide group reported major hypoglycaemic events, one required medical assistance, and none resulted in coma or seizures. None of the

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

REVIEW

hypoglycaemic episodes was nocturnal. No major hypoglycaemic events were reported in the glargine or placebo groups. The increase in major hypoglycaemic events with liraglutide was ascribed to the combination of a sulfonylurea with a GLP-1 analogue, which has been shown to increase the risk of hypoglycaemia. Nausea occurred in 14 patients in the liraglutide group, decreasing after one to three weeks, while four patients withdrew from the study within two weeks due to a gastrointestinal adverse event. No case of pancreatitis was reported. Although calcitonin levels increased significantly after 26 weeks in both the liraglutide and insulin glargine-treated groups of patients, the estimated mean calcitonin level at 26 weeks was still within the normal range. Antibodies to liraglutide were present in 10% of patients but did not appear to alter the glucose-lowering effect. Overall, the LEAD trials have demonstrated the antihyperglycaemic efficacy of liraglutide injections at a dosage of 1.2 or 1.8 mg daily in monotherapy and in combination with up to two oral anti-diabetic medications. Additionally, liraglutide added to metformin and sulphonylureas produced significant improvement in glycaemic control and body weight compared with insulin glargine. As with all anti-diabetic medications, hypoglycaemic events can and do occur. Longer-term outcome trials and post-marketing surveillance will guide clinicians as to how to maximise the advantages of the GLP-1 agonists in the regimen of care of type 2 diabetic patients.

References 1.

3. 4.

Marre M, Shaw J, Brändle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med 2009; 26: 268–278. Agersø H, Jensen LB, Elbrønd B, Rolan P, Zdravkovic M. The pharmacokinetics, pharmakodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 2002; 45: 195–202. Rosenkranz B. GLP-1 agonists: a novel treatment for South African diabetic patients. S Afr J Diabetes Vasc Dis 2010; 7: 51–53. Nauck M, Mitha IH, Frid A, et al. Efficacy and safety comparison of liraglutide. glimeperide, and placebo, all in combination with metformin, in type 2 diabetes. The LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care 2009; 32: 84–90. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimeperide monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III doubleblind, parallel-treatment trial. Lancet 2009; 373: 373–381. Zinman B, Raskin P, Gerich J, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009; 32: 1224–1230. Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulphonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia 2009; 52: 2046–2055. Jacobsen LV, Hindsberger C, Robson R, Zdravkovic M. Pharmakokinetics of the long-acting GLP-1 analogue liraglutide in subjects with renal impairment. Diabetologia 2007; 50:(Suppl 1) S352. Davies M, Storms F, Shutler S, Bianchi-Biscay M, Gomis R, for the AT-LANTUS study group. Improvement of glycaemic control in subjects with poorly controlled type 2 diabetes: Comparison of two treatment algorithms using insulin glargine. Diabetes Care 2005; 28: 1282–1288.

Eating for Sustained Energy 4: Gabi Steenkamp and Liesbet Delport

a bi Steenkamp and Liesbet Delport, both registered dieticians, have recently released Eating for Sustained Energy 4, published by Tafelberg. Gabi Steenkamp has been in private practice for over 30 years, specialising in the nutritional management of diabetes and colon dysfunction. Gabi is at present the voluntary consulting dietician for the Diabetes Association of South Africa (Diabetes SA). She has presented many lectures and workshops on various nutrition-related topics, and has also published articles in many journals and magazines. Her involvement in the food industry as a nutrition and food-labelling consultant gives her a unique insight into South African foods and food products. She has written eight books together with several other dietitians. Liesbet Delport is a founder member of the Glycaemic Index Foundation of South Africa (GIFSA) and a partner in a successful private practice in Nelspruit. She has co-authored seven nutrition-related books and has written articles on various aspects of nutrition for magazines and scientific journals. Eating for Sustained Energy 4 is the fourth in a series of low-GI and low-fat recipe books for the whole family. It is filled with modern and traditional everyday and party fare that is

VOLUME 7 NUMBER 2 • JUNE 2010

quick and easy to prepare as well as being full of good nutrition. It was written in response to a genuine need among Gabi and Liesbet’s patients for a practical, easy way to use slowrelease (low-GI) carbohydrates in everyday meals. The glycaemic index (Gl) is a physiological measure of how a carbohydrate food affects blood glucose levels. It is a solid nutritional tool that works best to regulate blood glucose levels, resulting in sustained energy all day long. The more Liesbet and Gabi applied it, the more they realised its beneficial impact in their patients’ lives. Not only does using the GI markedly improve blood glucose control in those with diabetes, it also curtails hunger in slimmers, combats fatigue, helps children with concentration problems, enhances sports performance, and combats high blood pressure and longstanding excessive weight. In short, everybody should know how to use the GI as a means of attaining optimum health, which can lead to an energetic lifestyle. To win a copy of Eating for Sustained Energy 4 in English or Afrikaans, e-mail Wendy on wendy.icon@wol.co.za with your name, language preference, speciality and postal address by 1 August 2010.

GI VE AW AY

ACHIEVING BEST PRACTICE

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Clinical aspects of silent myocardial ischaemia: with particular reference to diabetes mellitus Marc dweck, ian w campbell, douglas miller, c mark francis Abstract

i lent ischaemia is a common, under-recognised condition that is associated with an adverse prognosis. It is a marker of significant underlying coronary artery disease and therefore of future cardiovascular events. It is more prevalent in the diabetic population and diagnosis is usually made by a positive exercise tolerance test, positive myocardial perfusion scan or stress echo. The basis of treatment, in diabetic and non-diabetic subjects, is risk factor modification and coronary revascularisation of prognostically important coronary disease. Diabetic patients should receive risk factor modification even in the absence of ischaemia. Detection of silent ischaemia allows patients with prognostically important disease to be offered further treatment. The difficulty lies in deciding who to investigate further for this surreptitious disorder. The following clinical markers are of predictive use in this regard: electrocardiographic changes; erectile dysfunction; peripheral vascular disease and cardiac autonomic neuropathy. Their presence should prompt further investigation for silent ischaemia. Conventional risk factors and breathlessness on exertion may also be helpful. We have proposed an algorithm for the detection, investigation and management of silent myocardial ischaemia in diabetic patients. Keywords: diabetes, infarction, myocardial ischaemia, silent.

Introduction Angina pectoris has been considered the cardinal symptom of myocardial ischaemia for over 200 years. The concept of silent ischaemia came to the fore in the 1980s with the advent of 24-h ambulatory (Holter) monitoring.1,2 This allowed the ECG to be monitored for signs of ischaemia during everyday life. It was soon established that patients were frequently having episodes of myocardial ischaemia without experiencing angina. In fact, it is now recognised that the most common manifestation of CAD is silent ischaemia and not angina.1 At the most severe end of the spectrum, MI can also be silent in nature. Both silent myocardial ischaemia and infarction are more common in diabetic patients. The mechanisms of silent myocardial ischaemia are discussed herein3 and in previous reviews.4 The aim of this review is to discuss Mark Dweck, Department of Cardiology, Victoria Hospital, Kirkcaldy, UK. Ian W Campbell, Douglas Miller, University of St Andrews, St Andrews, UK. Correspondence to: Dr C Mark Francis Department of Cardiology, Victoria Hospital, Kirkcaldy, Fife KY2 5AH, UK. Tel: + 44 (0)1592 643355 Fax: + 44 (0)1592 648058 E-mail: mark.francis@faht.scot.nhs.uk S Afr J Diabetes Vasc Dis 2010; 7: 74–79.

the prevalence, prognosis, diagnosis and treatment of this important condition. There is evidence that silent ischaemia is associated with an adverse prognosis and that treatment in the form of risk factor modification and revascularisation results in clinical benefit. Silent myocardial ischaemia is therefore an important issue in the care of diabetic and non-diabetic patients, and because of its surreptitious nature, a high index of suspicion is required for its detection.

Prevalence Known coronary artery disease Studies in the 1980s showed for the first time that silent ischaemia was the most common manifestation of cardiac ischaemia.1 Among patients with known CAD, the prevalence of silent ischaemia is quite high. It has been reported that 15–30% of MI survivors have silent ischaemia,5,6 as do 30–40% of patients with unstable angina despite optimal medical therapy.1,7 In patients with stable angina, it is estimated that up to two-thirds of ischaemic episodes are silent.1,8,9

Asymptomatic non-diabetic patients In asymptomatic, non-diabetic men, aged 40–59 years, with no previous history of CAD, an Italian group estimated the prevalence of silent ischaemia (confirmed by coronary angiography) to be 0.89%.10 Other studies have suggested a prevalence of 1–4%.11,12 This incidence increases with coronary artery calcification, identified on CT scanning,13 and with the number of risk factors – approaching 10% in patients with two or more risk factors.14

Asymptomatic diabetic patients Diabetes mellitus appears to confer a dramatic increase in the risk of silent ischaemia, with most studies suggesting a prevalence of 10–20%.15,16 Although in one report of 1 900 asymptomatic patients with type 2 diabetes, the prevalence of silent ischaemia, as confirmed by stress echo and angiography, was around 60%.17 The increased prevalence of silent ischaemia in diabetes is likely to be due to an increased prevalence of coronary atherosclerosis in this group in combination with the presence of can.3

Prognosis Silent ischaemia is associated with an adverse clinical outcome across a range of patient groups. The MRFIT trial of 12 866 asymptomatic diabetic and non-diabetic men with two or more risk factors showed a significant relationship between silent ischaemia and mortality.18

Diabetic patients Silent ischaemia appears to be an especially important prognostic factor in patients with diabetes. In a study by Rutter, et al.,19 silent ischaemia was significantly related to future coronary events

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Abbreviations and acronyms asIsT Atenolol Silent Ischaemia STudy bnp

Brain Natriuretic Peptide

Cad

Coronary Artery Disease

Can

Cardiac Autonomic Neuropathy

Cards

Collaborative Atorvastatin Diabetes Study

Confidence Interval

Courage

Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation

Computed Tomography

Danami

Danish Trial in Acute Myocardial Infarction

Diad

Detection of silent myocardial Ischaemia in Asymptomatic Diabetics

Ecg

Electrocardiogram

Erectile Dysfunction

Ett

Exercise Tolerance Testing

Myocardial Infarction

Mrfit

Multiple Risk Factor Intervention Trial

Pvd

Peripheral Vascular Disease

Tibbs

Total Ischemic Burden Bisoprolol Study

in asymptomatic diabetic patients after 2.8 years (risk ratio of 21; 95% CI: 2â&#x20AC;&#x201C;204). The combination of silent ischaemia and microalbuminuria identified a particularly high-risk group.19

Stable angina In patients with stable angina, it is well established that silent ischaemia, whether present on exercise testing or Holter monitoring, is associated with a higher risk of coronary events and cardiac mortality.20-22 It is, however, worth noting that the prognosis in stable angina is relatively good once appropriate medical therapy has been instigated. It follows that once silent ischaemia has been detected and similar treatment commenced the prognosis should be equivalent.

Acute coronary syndromes The prognostic significance after MI is well known, and predischarge exercise testing is used commonly in clinical practice. Trials have suggested a two- to four-fold increase in cardiac events in patients with silent ischaemia compared with those without evidence of ischaemia.5,6,23 The worst prognosis, however, is reserved for patients with angina post-MI.24 Finally, in patients with unstable angina, one or more episodes of ST depression on 24-h continuous ST segment monitoring was associated with a 7.43 relative risk of cardiac death or MI at 30 days.25

ACHIEVING BEST PRACTICE

ischaemia is associated with sub-endocardial necrosis.26 In humans, myocardial biopsies from hypokinetic territories supplied by stenosed coronary arteries have shown areas of fibrosis and myocyte death, in the absence of features of infarction.27

Diagnosis The ischaemic cascade describes the sequence of events occurring after the onset of myocardial ischaemia (Fig. 1). The perception of pain occurs late in this sequence and is preceded first by changes in left ventricular function and then in ECG. These two markers are therefore a more sensitive means of detecting ischaemia than the presence of angina. As discussed earlier, silent ischaemia was first diagnosed using Holter monitoring. Episodes of ischaemia are characterised by flat or down-sloping ST depression, of at least 1 mm, which lasts for more than 1 min and has both a gradual onset and recovery.1,2 The most commonly used test, however, is the ETT, for which the haemodynamic response and ST segment deviation are used to detect underlying CAD. Indeed ambulatory monitoring does not appear to add significantly to the findings of ETT. Transient ischaemia on Holter monitoring appears to occur almost exclusively in patients with a positive ETT, especially those with a positive test at low workload.28 However, the specificity of exercise testing is

Figure 1. The ischaemic cascade. In the absence of angina silent ischaemia may be diagnosed by the detection of impaired left ventricular diastolic and systolic function on stress echo; and ECG changes on exercise testing or Holter monitoring

Myocardial Oxygen Supply:Demand Mismatch

Left Ventricular Diastolic Dysfunction

Left Ventricular Systolic Dysfunction

ECG Abnormalities

Mechanisms for the adverse prognosis The exact reason for the poor prognosis associated with silent ischaemia is not clear. Most likely, silent ischaemia simply confirms the presence of significant underlying CAD. Therefore this population is more at risk from future coronary events than those without significant coronary disease. In addition it is thought that repeated episodes of silent ischaemia could do harm. They are thought to lead to progressive fibrosis, which in turn can progress to left ventricular systolic dysfunction or life-threatening arrhythmias. In animal models repeated transient

VOLUME 7 NUMBER 2 â&#x20AC;˘ JUNE 2010

Angina

Key: ECG = electrocardiogram

ACHIEVING BEST PRACTICE

limited and obeys Bayesian theory, that is, it depends on the pretest probability of detecting CAD. Therefore false positive results are common in patients who do not describe angina and have no high-risk markers. In such patients confirmation should be sought with myocardial perfusion imaging or stress echocardiography.29 Stress echocardiography is especially appealing as impairment of left ventricular diastolic and then systolic function occurs early in the ischaemic cascade, before the development of ECG changes. These can be observed as regional wall motion abnormalities on echo. Stress echo is well recognised to provide greater diagnostic accuracy than ETT in the general clinical population.30 Furthermore dobutamine stress echocardiography allows for the functional assessment of patients unable to exercise. Stress echo has been used effectively in studies to detect silent myocardial ischaemia.17 Cardiac CT scanning allows the non-invasive visualisation of the coronary anatomy. Furthermore, calcification severity predicts the presence of significant anatomic CAD.31 While associated with a radiation dose it avoids the other potential complications associated with percutaneous coronary angiography. It has been demonstrated that the coronary artery calcium score can identify high-risk asymptomatic individuals as having myocardial ischaemia.32 In the UK cardiac CT scanning is less widely available than ETT or stress echo. With wider access and further studies, it may emerge as a valuable tool in the diagnosis of occult CAD.

Treatment Risk factor modification

SA JOURNAL OF DIABETES & VASCULAR DISEASE

revascularisation are limited, although several small trials have suggested a trend towards improved outcomes.39-41 However, extrapolation of the results of the courage trial,42 in patients with stable angina, would suggest that optimal medical therapy is as effective as revascularisation in patients with non-prognostic disease. The evidence for coronary revascularisation is more clear in the post-MI setting. The danami trial, which included patients with symptomatic and asymptomatic ischaemia, compared medical management with revascularisation in patients with inducible ischaemia post-MI.43 The primary end-point (mortality, re-infarction, unstable angina) occurred less frequently in the invasive group at one, two and four years of follow-up.

Anti-ischaemic therapy Beta-blockers have been shown to reduce the adverse outcome associated with silent ischaemia. This may be due to a reduction of the ischaemic load and therefore of the adverse effects of recurrent silent episodes. However, no other anti-anginal agents have shown a similar effect. The ability of beta blockers to prevent arrhythmia and cardiac remodelling may also be of importance. The asist trial evaluated the effect of atenolol 100 mg versus placebo in patients with silent ischaemia.44 It confirmed a reduction in the ischaemic burden on Holter monitoring, prolonged eventfree survival and increased time to first event. In the tibbs trial, patients who had > 50% suppression of silent ischaemia, with bisoprolol, had an improved event-free survival at 1 year.45

Silent ischaemia, like angina, is a marker of underlying CAD. Therefore perhaps the most important strategy is aggressive risk factor modification to stabilise and prevent the progression of atherosclerosis. The MRFIT trial found that men with elevated risk factors, who had an abnormal exercise test response, derived substantial benefit from risk factor reduction.18 The DIAD-2 study followed a cohort of type 2 diabetes patients for three years. They showed that the prevalence of silent myocardial ischaemia decreased over this time period. This was attributed to the intensification of medical treatment in the form of statins, aspirin and angiotensin-converting enzyme inhibitors over that time.33 In the non-diabetic population it is therefore of importance to detect silent ischaemia because risk factor modification will improve prognosis. However, diabetes has been recognised as a cardiovascular disease risk equivalent. Most diabetic patients therefore require intensive risk factor modification even in the absence of silent ischaemia.34,35

Given the high incidence of silent ischaemia in diabetic populations, screening asymptomatic diabetic patients for CAD is an appealing concept. However, no prospective trial has shown clinical benefit of such a strategy; the prevalence of prognostically important disease is unclear; and the financial implications of screening all these patients are considerable. At present most national and international guidelines do not recommend routine screening. Cases are currently picked up on an opportunistic, individual basis. Deciding when to investigate for silent myocardial ischaemia is not straightforward. There are, however, several strong predictive markers as to its presence. These can be used to identify patients at high risk of silent ischaemia who would benefit from further investigation. Guidelines from the American Diabetes Association suggest that ECG changes and atypical cardiac symptoms are of particular use.46 We will address these first.

Coronary revascularisation

Breathlessness on exertion

This begs the question whether the detection of silent ischaemia in diabetic patients impacts upon their treatment? Unfortunately even after risk factor modification, the cardiovascular mortality of diabetic patients remains high: it was 1.54 per 100 person-years at risk, in the treatment arm of the CARDS trial.36 This high mortality will, in part, be due to silent, prognostically important CAD (e.g. left main stem, proximal left anterior descending or three-vessel disease). If this disease can be detected and revascularised then the poor prognosis will improve.37,38 This represents a powerful argument in favour of investigating high-risk diabetic patients for silent ischaemia. In patients with non-prognostically important disease, data on

Breathlessness on exertion involves a wide differential diagnosis. However, it may signify angina equivalent and underlying myocardial ischaemia. In this case, breathlessness is due to impaired ventricular performance which occurs early in the ischaemic cascade (Fig. 1). Diabetic patients describing breathlessness have been shown to have a significantly higher likelihood of myocardial ischaemia and a worse outcome than those who were completely asymptomatic or suffered from angina.47 Unfortunately breathlessness is a common symptom in the diabetic population and often due to other causes such as respiratory disease and weight gain. Often it will be multifactorial. Great care is therefore required in trying to exclude other causes.

Deciding who to investigate

VOLUME 7 NUMBER 2 â&#x20AC;˘ JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

ACHIEVING BEST PRACTICE

Abnormal resting ECG

Cardiac autonomic neuropathy

An abnormal resting ECG is also a useful marker. Q waves and deep T-wave inversion can signify previous myocardial infarction. In addition, non-specific ST–T wave changes appear to be a strong predictor of silent ischaemia. Rajapolan, et al.48 showed that 43% of diabetic patients with Q waves, and 26% of those with ST–T wave abnormalities had high-risk myocardial perfusion scans. Among the high-risk single photon emission computed tomography scans the majority had prognostically important CAD.

The presence of a postural drop in blood pressure suggests an underlying CAN in diabetic patients. Other features may include unexplained tachycardia or reduced heart rate variability. CAN is associated with a poor prognosis in type 2 diabetes52 and an increased prevalence of silent myocardial ischaemia and infarction.53,54 A study by O’Sullivan, et al.53 showed that the prevalence of silent ischaemia in diabetic men with demonstrable autonomic neuropathy was 64.7% versus 4.1% in those without.

Peripheral vascular disease

Erectile dysfunction

Rajapolan, et al. identified PVD as an important marker: 28% of patients with PVD had a high-risk perfusion scan. Nesto, et al.49 suggested that the prevalence of silent ischaemia in asymptomatic diabetic patients with PVD was 47%. Thirty-seven per cent had evidence of a previous silent MI. Previous studies50,51 have found a high prevalence of CAD in diabetic patients with PVD.

Recent studies have suggested ED to be an important marker of CAD in diabetes. Ma, et al.55 showed that type 2 diabetic men, without documented CAD, but with ED, had double the incidence of future coronary heart disease events than those without ED (19.7/1 000 patient-years versus 9.5/1 000 patient-years). Gazzaruso, et al.56 confirmed a strong independent association between ED and silent

Figure 2. Proposed algorithm for the diagnosis and management of silent ischaemia in the diabetic population. Positive exercise tolerance test is defined as > 2 mm of flat or downsloping ST depression in two or more adjacent leads.

DECISION TO INVESTIGATE DIABETIC PATIENTS FOR SILENT ISCHAEMIA 1) Erectile dysfunction 2) Peripheral vascular disease 3) Postural drop in BP as marker of CAN 4) Abnormal ECG 5) High clinical suspicion

EXERCISE TOLERANCE TEST

POSITIVE TEST

INTERMEDIATE TEST

NEGATIVE TEST

Confirm with Stress Echo or Myocardial Perfusion Scanning

CORONARY ANGIOGRAPHY

PROGNOSTICALLY IMPORTANT CAD 1) Revascularisation 2) Risk factor modification 3) Beta blockers to reduce ischaemic load

NON-PROGNOSTICALLY IMPORTANT CAD 1) Risk factor modification 2) Beta blockers to reduce ischaemic load

NO SIGNIFICANT CAD 1) Risk factor modification

Key: BP = blood pressure; CAD = coronary artery disease; CAN = cardiac autonomic neuropathy; ECG = electrocardiogram; ETT = exercise tolerance test

VOLUME 7 NUMBER 2 • JUNE 2010

ACHIEVING BEST PRACTICE

SA JOURNAL OF DIABETES & VASCULAR DISEASE

CAD. The prevalence of ED in diabetic patients with silent CAD was 33.8% versus 4.7% in those without silent ischaemia. ED was shown to be a more efficient predictor of silent CAD than smoking, microalbuminuria and low-density lipoprotein concentrations.56

Conventional risk factors By convention, smoking, hypertension, hypercholesterolaemia, family history and microalbuminaemia have been considered the key risk factors in the development of atherosclerosis in diabetic patients. However, their value in predicting silent ischaemia has been widely questioned: including in recent guidelines from the American Diabetes Association.46 In diabetic patients, the DIAD study found they were not a good predictive marker for the presence of silent ischaemia.57 This finding was confirmed by Scognamiglio, et al.17 in a study of 1 899 asymptomatic patients with type 2 diabetes. However, the same group also showed that subjects with two or more risk factors were more likely to have prognostically significant disease.17 Diabetic patients with such disease require revascularisation, and if conventional risk factors can indeed bring these patients to our attention then they still have an important role.

Conclusion: an algorithm for diagnosis and management of silent ischaemia On the basis of the above discussion we have formulated an algorithm describing one possible approach to the diagnosis and management of silent ischaemia in the diabetic population. It is summarised in Fig. 2. Population screening is not feasible but diabetic patients at high risk of silent ischaemia should be identified and investigated further. We have proposed a system based around the presence of hard clinical markers that are associated with a high predictive value for silent ischaemia. The markers selected are as follows: ED, PVD, CAN and an ischaemic resting ECG. We feel that the presence of one of these factors increases the risk of silent ischaemia sufficiently to warrant further investigation. They can all be quickly identified in the outpatient clinic. Patients can be asked about erectile function and intermittent claudication. Examination may reveal the presence of a postural drop (as evidence of CAN) carotid bruits or absent pulses. An ECG can finally be performed to look for ischaemic changes at rest. Breathlessness on exertion and presence of conventional risk factors are important in risk stratification. However, both have their limitations and we have not included them in their own right. We feel that breathlessness is too common a symptom with too wide a differential diagnosis to merit investigation without other markers of risk. Conflicting results have been reported in the literature regarding the value of conventional risk factors in predicting silent ischaemia. One trial has suggested that the presence of two or more risk factors can predict prognostically important disease. However, all diabetic patients with the metabolic syndrome will have two risk factors and it is not practical to screen all these patients. We have therefore suggested that conventional risk factors and breathlessness on exertion should be considered as part of an overall impression for the risk of silent ischaemia. If this is felt to be high then patients should be investigated. Other factors should also be considered in this impression. For example, BNP release has been shown to be elevated in patients with CAD as well as heart failure. Rana, et

Key messages Silent myocardial ischaemia: • is common especially in the diabetic population • is a marker of significant caD • is associated with an adverse prognosis • is diagnosed by a positive eTT, myocardial perfusion scan or stress echo • high-risk markers in diabetes are abnormal resting ecg; peripheral vascular disease; erectile dysfunction and can • requires intensive risk factor modification • requires coronary revascularisation in prognostically important disease. al.58 showed that BNP was of value in predicting silent ischaemia in asymptomatic type 2 diabetic subjects. We have based diagnostic investigation around the ETT, which is the most widely available and used test in the UK. Given the predictive power of our clinical markers, confirmation with stress echo or myocardial perfusion imaging will not usually be necessary. They may be used as an alternative investigation: if patients are unable to exercise or if ECG changes will interfere with ETT interpretation. If the ETT is clearly positive for silent ischaemia (> 2 mm of flat or down-sloping ST depression in two or more adjacent leads) then patients require aggressive risk factor modification, a beta-blocker to reduce the ischaemic load, and an angiogram to establish the nature of their CAD. Prognostically important disease should be treated with revascularisation. If the ETT is clearly negative then patients require risk factor modification but no other treatment. If the ETT result is equivocal then confirmation should be sought with either stress echo or myocardial perfusion imaging, before deciding on whether the positive or negative test pathways should be followed.

Acknowledgements This review is based upon a dissertation submitted to Bute Medical School, University of St Andrews, by Douglas Miller.

References 1. 2.

4. 5.

6. 7.

Deedwania PC, Carbajal EV. Silent myocardial ischaemia: a clinical perspective. Arch Intern Med 1991; 151: 2373–82. Sajadieh A, Nielsen OW, Rasmussen V, et al. Prevalence and prognostic significance of daily-life silent myocardial ischaemia in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J 2005; 26: 1402–09 Dweck M, Miller D, Campbell I, Francis C. Mechanisms of silent myocardial ischaemia: with particular reference to diabetes mellitus. Br J Diabetes Vasc Dis 2009; 9: 99–102. Cohn PF, Fox KM, Kaly C. Silent myocardial ischaemia. Circulation 2002; 108: 1263–77. Gottlieb SO, Gottlieb SH, Achuff SC, et al. Silent ischaemia on Holter monitoring predicts mortality in high-risk post infarction patients. J Am Med Assoc 1988; 259: 1030–5. Tzivoni D, Gavish A, Zin D, et al. Prognostic significance of ischaemic episodes in patients with previous myocardial infarction. Am J Cardiol 1988; 62: 661–4. Gottlieb SO, Weisfeldt ML, Ouyant P, et al. Silent ischaemia as a marker for early unfavourable outcomes in patients with unstable angina. N Engl J Med 1986; 314: 1214–19. Langou RA, Huang EK, Kelley MK, et al. Predictive accuracy of coronary artery calcification and abnormal exercise test for coronary artery disease in

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

9. 10.

11.

12.

13.

14.

15. 16.

17.

18.

19.

20. 21.

22.

23.

24.

25.

26.

27. 28.

29. 30.

31.

32.

33.

asymptomatic men. Circulation 1980; 62: 1196–203. Yeung AC, Barry J, Orav J, et al. Effect of asymptomatic ischaemia on long-term prognosis in chronic stable coronary disease. Circulation 1991; 83: 1598–604. Fazzini PF, Prati PL, Rovelli F, et al. Epidemiology of silent myocardial ischaemia in asymptomatic middle-aged men (the eccis project). Am J Cardiol 1993; 72: 1383–8. Froehicher VF, Thompson AJ, Longo MR Jr, et al. Value of exercise testing for screening asymptomatic men for latent coronary artery disease. Prog Cardiovasc Dis 1976; 18: 265–76. Thaulow E, Erikssen J, Sandik L, et al. Initial clinical presentation of cardiac disease in asymptomatic men with silent myocardial ischaemia and angiographically documented coronary artery disease: the Oslo ischemic study. Am J Cardiol 1993; 72: 629–33. He ZX, Hedrick TD, Pratt CM, et al. Severity of coronary artery calcification by electron beam computed tomograpgy predicts silent myocardial ischaemia. Circulation 2000; 10: 244–51. Laukkanen JA, Kurl S, Lakka TA, et al. Exercise-induced silent myocardial ischaemia and coronary morbidity and mortality in middle aged men. J Am Coll Cardiol 2001; 38: 72–9. Langer A, Freeman MR, Josse RG, et al. Detection of silent myocardial ischaemia in diabetes mellitus. Am J Cardiol 1991; 67: 1073–8. Naka M, Hiramatsu K, Aizawa T, et al. Silent myocardial ischaemia in patients with non-insulin-dependent diabetes mellitus as judged by treadmill exercise testing and coronary angiography. Am Heart J 1992; 123: 46–53. Scognamiglio R, Negut C, Ramondo A, et al. Detection of coronary artery disease in asymptomatic patients with type 2 diabetes mellitus. J Am Coll Cardiol 2006; 47: 65. Multiple risk factor intervention trial research group. Exercise electrocardiogram and coronary heart disease mortality in the multiple risk factor intervention trial. Am J Cardiol 1985; 55: 16–24. Rutter MK, Wahid ST, McComb JM, Marshall SM. Significance of silent ischemia and microalbuminaemia in predicting coronary events in asymptomatic patients with type 2 diabetes mellitus. J Am Coll Cardiol 2002; 40: 56–61. Deedwania P, Carbajal EV. Silent ischemia during daily life is an independent predictor of mortality in stable angina. Circulation 1990; 81: 748–56. Deedwania P, Carbajal EV. Prevalence and patterns of silent myocardial ischemia during daily life instable angina patients receiving conventional antianginal drug therapy. Am J Cardiol 1990; 65: 1090–6. Forslund L, Hjemdahl P, Held C, et al. Prognostic implications of ambulatory myocardial ischemia and arrhythmias and relation to ischemia on exercise in chronic stable angina pectoris (the Angina Prognosis Study in Stockholm [apsis]). Am J Cardiol 1999; 84: 1151–7. Deedwania PC. Asymptomatic ischemia during pre-discharge Holter monitoring predicts poor prognosis in the post infarction period. Am J Cardiol 1993; 71: 773–7. Nairns CR, Zareba W, Moss AJ, et al. Clinical implications of silent versus symptomatic exercise-induced myocardial ischaemia in patients with stable coronary disease. J Am Coll Cardiol 1997; 29: 756–63. Nørgaard BL, Andersen K, Dellborg M, et al. The trim study group. Admission risk assessment by cardiac troponin T in unstable coronary artery disease: additional prognostic information from continuous ST segment monitoring. J Am Coll Cardiol 1999; 33: 1519–27. Geft I, Fischbein M, Ninomiya K. Intermittent brief episodes of ischaemia have a cumulative effect and may cause myocardial necrosis. Circulation 1982; 66: 1150–3. Schaper J. Effects of multiple ischaemic events on human myocardium: an ultrastructural study. Eur Heart J 1988; 9(suppl a): 141–9. Mulcahy D, Keegan J, Sparrow J, et al. Iscahemia in the ambulatory setting: the total ischaemic burden: relation to exercise testing and investigative and therapeutic implications. J Am Coll Cardiol 1989; 14: 1166–72. Deedwania PC. Should asymptomatic subjects with silent ischaemia undergo further evaluation and follow up? Int J Cardiol 1994; 44: 101–3. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. Acc/aha/ase 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2003; 42: 954–70. Rumberger JA, Sheedy PF, Breen JF, et al. Electron beam computed tomographic coronary calcium score cut points and severity of associated angiographic lumen stenosis. J Am Coll Cardiol 1997; 29: 1542–8. He Z, Hedrick T, Pratt C. Severity of coronary artery calcification by electron beam computed tomography predicts silent myocardial ischaemia. Circulation 2000; 101: 244–51. Wackers F, Chyun D, Young L, et al. Resolution of asymptomatic myocardial iscemia in patients with type 2 diabetes in the detection of ischemia in

VOLUME 7 NUMBER 2 • JUNE 2010

ACHIEVING BEST PRACTICE

asymptomatic diabetics (DIAD-2). Diabetes Care 2007; 30: 2892–8. 34. National Institute for Health and Clinical Excellence. Lipid modification. Cardiovascular risk assessment and modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE clinical guideline. London: NICE, 2008. 35. National Institue for Health and Clinical Excellence. Type 2 diabetes. The management of type 2 diabets. NICE clinical guideline. London: NICE, 2008. 36. Colhoun HM, Betteridge DJ, Durrington PN, et al. Cards investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (cards): multicentre randomised placebo-controlled trial. Lancet 2004; 364: 685–96. 37. Sorajja P, Chareonthaitawee P, Rajagopalan N, et al. Improved survival in asymptomatic diabetic patients with high risk spect imaging treated with coronary artery bypass grafting. Circulation 2005; 112: 1311–6. 38. The Bari investigators. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing cabg and ptca in patients with multi-vessel disease: the bypass angioplasty revascularisation investigation. Circulation 1997; 96: 1761–9. 39. Rogers W, Bourassa M, Andrews T, et al. Asymptomatic Cardiac Ischemia Pilot study; outcome at 1 year for patients with ischemia randomised to medical therapy or revascularisation. J Am Coll Cardiol 1995; 26: 594–605. 40. Bourassa MG, Pepine CJ, Forman SA, et al. Aysmptomatc Cardiac Ischemia Pilot (acip) study: effects of coronary angioplasty and coronary artery bypass surgery on recurrent angina and ischemia. J Am Coll Cardiol 1995; 26: 606–14. 41. Davies RF, Goldberg D, Forman S, et al. The acip investigators. Asymptomatic Cardiac Ischemia Pilot (acip) study two-year follow up. Outcomes of patients randomised to initial strategies of medical therapy versus revascularisation. Circulation 1997; 95: 2037–43. 42. Boden WE, O’Rourke RA, Teo KK. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356: 1503–16. 43. Madsen JK, Grande P, Saunamaki K, et al. On behalf of the danami study group. Danish multicentre randomised study of invasive versus conservative treatment in patients with inducible ischaemia after thrombolysis in acute myocardial infarction (danami). Circulation 1997; 96: 748–55. 44. Pepine CJ, Cohn PF, Deedwania PC, et al. Effects of treatment on outcome in mildly symptomatic patients with ischaemia during daily life. The atenolol silent ischaemia study. Circulation 1994; 90: 762–8. 45. Von Arnim T. The tibbs investigators. Prognostic significance of transient ischemic episodes: Response to treatment shows improved prognosis. Results of the Total Ischemic Burden Bisoprolol Study (tibbs) follow-up. J Am Coll Cardiol 1996; 28: 20–4. 46. American Diabetes Association. Standards of medical care in diabetes 2008. Diabetes Care 2008; 31(suppl 1): s12–54. 47. Zellweger MJ, Hachamovitch R, Kang X, et al. Prognostic relevance of symptoms versus objective evidence of coronary artery disease in diabetic patients. Eur Heart J 2004; 25: 543–50. 48. Rajagopalan N, Miller TD, Hodge DO, et al. Identifying high-risk asymptomatic diabetic patients who are candidates for screening stress single photon emission computed tomography imaging. J Am Coll Cardiol 2005; 45: 43–9. 49. Nesto PW, Watson FS, Kowalchuk GJ, et al. Silent myocardial ischemia and infarction in diabetics with peripheral vascular disease: assessment by dipyridamole thallium-201 scintigraphy. Am Heart J 1990; 120: 1073–7. 50. Belch JJF, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med 2003; 163: 884– 92. 51. Hertzer NR, Beven EG, Young JR, et al. Coronary artery disease in peripheral vascular patients: a classification of 1000 coronary angiograms and results of surgical management. Ann Surg 1984; 199: 223–33. 52. Vinik AI, Maser RE, Mitchell BD. Diabetic autonomic neuropathy. Diabetes Care 2003; 26: 1553–79. 53. O’Sullivan JJ, Conroy RM, MacDonald K, et al. Silent ischaemia in diabetic men with autonomic neuropathy. Br Heart J 1991; 66: 313–5. 54. Niakan E, Harati Y, Rolak LA, et al. Silent myocardial infarction and diabetic cardiovascular autonomic neuropathy. Arch Intern Med 1986; 146: 2229–30. 55. Ma RC, So WY, Yang X, et al. Erectile dysfunction predicts coronary heart disease in type 2 diabetics. J Am Coll Cardiol 2008; 51: 2045–50. 56. Gazzaruso C, Giordanetti S, De Amici E, et al. Relationship between erectile dysfunction and silent myocardial ischaemia in apparently uncomplicated type 2 diabetic patients. Circulation 2004; 110: 22–6. 57. Wackers FJ, Young LH, Inzucchi SE, et al. Detection of silent myocardial ischaemia in asymptomatic diabetic subjects. Diabetes Care 2004; 27: 1954–61. 58. Rana BS, Davies JI, Band MM, et al. B-type natriuretic peptide can detect silent myocardial ischaemia in asymptomatic type 2 diabetes. Heart 2006; 92: 916– 20.

Diabetes Personality DIABETIC DIETS NEED TO BE REALISTIC, BALANCING NUTRITIONAL AND ECONOMIC CONCERNS S Afr J Diabetes Vasc Dis 2010; 7: 37–38

Photos by GG Photography Correspondence to: Marlene Gilfillan Department of Human Nutrition, Kalafong Hospital, Pretoria Tel: (0)12 318-6412 e-mail: gilfillanw@telkomsa.net

ultidisciplinary approach is key to the manm agement of diabetes – and physicians, counsellors, biokineticists, dieticians and educators all have important roles to play. This is the view of clinical dietician, Marlene Gilfillan, who is based at Kalafong Hospital in Pretoria. She has high praise for the ‘closely networked’ team in which she works, and feels that the successful interdisciplinary co-operation at Kalafong more than compensates for the resource shortages that are par for the course in the public sector. A lack of diabetes educators at Kalafong, however, sees Marlene taking on that role herself in addition to her primary focus on patients’ dietary management. Like so many other healthcare workers, she finds that

Providing appropriate nutritional information to clients for varying socio-economic backgrounds is vital in diabetes care.

her principal difficulties lie in getting patients to accept and understand the implications of the diagnosis and then comply with the prescribed treatment strategies. ‘Diabetes is an extremely complex and labour-intensive illness’, she says. ‘When patients are first referred to me I spend an hour to 90 minutes with them, to assess them and individualise a treatment strategy. The challenges are many, especially when you’re working with children, which is a particular speciality of mine. It’s very difficult to make them understand the disease, which is why it’s critical to involve parents and caregivers in the process. I also treat a lot of poor patients, who have many more pressing concerns in their lives than diabetes. The fact that they’re often not in pain, or experiencing any symptoms, means that they tend not to take the condition seriously, despite my best efforts to make them aware of its gravity, even to the point of showing them graphic illustrations of the complications of uncontrolled diabetes.’ Managing the diets of diabetics is very important, as even when patients are compliant in respect of their medication, it is often not sufficient to achieve good glycaemic control. ‘It’s so much easier to pop a pill than make fundamental changes to an unhealthy lifestyle’, Marlene says. ‘Most type 2 diabetics are overweight, and in addition to the difficulty in trying to change their diet and exercise habits, one also encounters cultural challenges. For many patients, being overweight is seen as something positive, indicative that one is financially well off and/or HIV-free.’ She admits frankly that it can be disheartening when one doesn’t see results. ‘And yet, often when we test patients’ knowledge, we find that they might indeed understand what we’ve told them, but it still doesn’t translate into compliance. I feel, too, that we

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

really need a psychologist to help patients deal with the emotional processes they need to go through. But what we’re doing works well when patients follow through. Those who are compliant gain control fairly quickly and remain controlled. Seeing a patient achieve this is what makes it all worthwhile for me and keeps me doing everything I can to help. I never want to ever find myself in a situation where I feel I didn’t do enough.’ When it comes to the specifics of dietary management, Marlene explains that she starts by evaluating a patient’s nutritional status and taking a dietary history. ‘From these you can ascertain whether the modifications required are dramatic or minor’, she says. ‘When weight loss is required, as is usually the case, it’s important to implement a stepwise approach that results in a gradual loss. We also need to accommodate the modifications to the structure of the patient’s life. For example, a construction worker has set breaks from work during the day and his eating plan needs to take that into account when timing his meals.’ Diets are tailored to individual patients and need to be energy-appropriate for their daily activities, while also

Marlene talking to a patient at her work station in the clinic.

balancing nutritional concerns against economic ones. ‘It’s no use prescribing foods that an underprivileged patient is unable to afford’, says Marlene. ‘In general, I advise diets that are high in carbohydrates, as these promote satiety. The intake of fat is restricted, but not completely, as fats are important to ensuring food’s palatability. They’re also needed to provide essential fatty acids. The rest of the diet is made up of protein, and of course there are lots of fruit and vegetables, which are beneficial in the control of blood sugar and they provide antioxidants. We do also take glycaemic index into account, and teach patients to combine foods in such a way as to ensure meals with lower glycaemic loads.’ Marlene underscores that there is not one ‘perfect diet’ for everyone. ‘What’s important is to give patients something workable and attainable. Something too extreme is likely to be rejected out of hand, with patients making no changes at all. Something more realistic might only get them 50% of the way there, but 50% is better than nothing’, she concludes. Specially chosen foods are important in diabetic diets.

VOLUME 7 NUMBER 2 • JUNE 2010

DIABETES NEWS

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Diabetes News Local diabetes research project selected for international funding Stellenbosch University’s research project in the Western Cape has been awarded a substantial international grant to benefit local diabetes patients.1 This grant forms part of a long-term funding relationship to identify, test and publish practical solutions to improve outcomes for people with diabetes throughout the world.2 BRIDGES (Bringing Research in Diabetes to Global Environments and Systems) is a programme initiated by the International Diabetes Federation (IDF) and supported by an educational grant from a leading pharmaceutical company, Lilly.3 This seven-year project, launched at the end of 2006, sees $10 million being contributed internationally into research to find practical diabetes-care strategies and solutions for people living with diabetes.4 The BRIDGES project seeks proposals from research bodies globally, which support costeffective and sustainable interventions that can be adopted in real-world settings, ultimately for the prevention and control of diabetes.3 The first South African research project to be awarded funds from BRIDGES was announced by the IDF earlier this month, and is one of only nine projects selected globally during this round of proposals. Stellenbosch University, in association with the Sub-Saharan African Centre for Chronic Diseases and the Western Cape Department of Health, has been awarded $65 000 towards a two-year community-based research project to be conducted in Cape Town.1 The Western Cape has a large number of diabetic patients andCMYK this printer number is expected Color profile: Generic profile screen to Composite increase Default substantially over the next few

It's the shell that makes

efit most, those people living with diabetes. Ground-breaking ideas are urgently needed to help people with diabetes achieve better outcomes and live a healthier and more fulfilling life. While Lilly continually remains committed to medical research into this disease, we realise that success in the management and education of diabetes will not come through our research alone. We congratulate Stellenbosch University and look forward to their shared findings in this vital exploration of how to improve diabetes education and management,’ said Jacques Blaauw, managing director of Lilly6 South Africa. This research proposal, along with all other submissions, was peer reviewed and prioritised by a multi-disciplinary review committee, managed by the IDF.7 1. Bringing Research in Diabetes to Global Environments and Systems. International Diabetes Foundation. 2007 (http://www.idfbridges.org/supported-projects). Website accessed on 23 February 2010. 2. IDF and Eli Lilly and company partner to uncover practical solutions for better diabetes outcomes. Press release 5 December 2006. (http://www.idf.org/ node/1351?unode=1D292091-67DA-48BB-81B073112469D36E).Websiteaccessedon23February2010. 3. Welcome to BRIDGES (http://www.idfbridges.org/). Website accessed on 23 February 2010. 4. BRIDGES IDF grant research programme fact sheet (www.idf.org/webdata/docs/BRIDGES%20Fact%20 Sheet.doc). Website accessed on 23 February 2010. 5. Katzenellenbogen L, Blaauw R, Steyn N. Assessment of the perceived impact of diabetes on quality of life in a group of South African diabetic patients. December 2008 (http://etd.sun.ac.za/jspui/bitstream/ 10019/1947/3/Katzenellenbogen%2c%20L.pdf). Website accessed on 23 February 2010. 6. About Lilly (http://www.lillydiabetes.com/content/ about-lilly.jsp). Website accessed on 23 February 2010. 7. BRIDGES IDF grant research programme timeline of key dates (www.idf.org/.../BRIDGES%20Timeline%20 of%20Grant%20Program.doc). Website accessed on 23 February 2010.

Diabetes Care Products Trimega provides essential fatty acids R

safer.

Safety-Coated R

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

years. Most of these patients are cared for by nurses within the public sector, with education about their disease often being supplied in a makeshift and unpredictable manner.1 Diabetes and its related complications have grown exponentially over the last few years. The increasing number of patients diagnosed with diabetes each year results in increased costs being placed on health services to care for patients. Diabetes is an expensive and complex disease and ideally requires ongoing education and management on the part of both the healthcare practitioner and the patient. Furthermore, diabetes greatly affects a patient’s quality of life as it poses many lifestyle demands and debilitating complications, which can sometimes be difficult for patients to live with.5 Titled ‘Effectiveness of a group diabetic education programme using motivational interviewing in underserved communities in South Africa’, this project will take the form of a randomised control trial, evaluating ways to improve the lives of thousands of diabetes patients whose quality of care and health education to date has generally been very poor.1 This research project, headed by principal investigator Robert Mash, will evaluate the merits of structured group-educational programmes supported by appropriate educational materials and delivered by health promoters who have been specifically trained in better communication, installing in patients a degree of motivation, leading to increased self management of their disease.1 Through BRIDGES, researchers in various cultural settings globally can share insights and advice from their individual projects, leading to findings that can be used in different settings. ‘We at Lilly are proud to partner with the IDF and enable the translation of findings learnt in clinical settings to those who can ben-

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.

Trimega capsules contain the omega-3 essential fatty acids, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), formulated in a single gelatine-free capsule. Most western diets are thought to be deficient in these fatty acids. In view of the latest overwhelming evidence on the benefit of these fatty acids in the secondary prevention of cardiovascular disease, Trimega capsules have recently become available in South Africa. Current AHA dietary guidelines recommend combined EPA and DHA in a dose of approximately 1 000 mg/day in patients with coronary heart disease, and Trimega in a twice-daily dosage satisfies this criterion.

Trimega capsules contain 500 mg of EPA and DHA per capsule (SABS tested) and the raw material has been certified free of heavy metals. Further information from: Pharmafrica (Pty) Ltd: 0800 601 098 toll free

55X78MM

82 23 September 2008 10:04:25 AM

VOLUME 7 NUMBER 2 • JUNE 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Patient Support Keep and Copy Series NO CHILD SHOULD DIE FROM DIABETES

S Afr J Diabetes Vasc Dis 2010; 7: 00

‘Life for a Child’ manager visits Lilly South Africa to share growing success of support programme Dr Graham Ogle, programme manager for the International Diabetes Federation’s Life for a Child programme, visited Lilly’s Johannesburg head office in April to report on the progress being made helping children with diabetes globally, and to thank Lilly for their support. The Life for a Child programme was established in 2001 by the International Diabetes Federation (IDF), with support from Diabetes Australia and HOPE worldwide.1 This sustainable support programme helps children with diabetes in developing countries and is currently supporting diabetes services in over 25 countries, 11 of which are in Africa.2 Life for a Child offers assistance to the most needy children at supported diabetes centres, including the provision of sufficient insulin and syringes, blood glucose monitoring, appropriate clinical care and diabetes education in countries where governments do not supply these services free of charge.3 Although it has been nearly 90 years since life-saving diabetes medication became available, insulin is still not reaching many of the world’s most vulnerable patients – children with type 1 diabetes. ‘No child should die from diabetes, yet many still do. All children with diabetes deserve the best healthcare possible, and the chance to live a full and healthy life. In many developing countries, the average life expectancy of children with diabetes is unknown due to a lack of awareness, education and evidence. In some countries, there are few, if any, long-term survivors of type 1 diabetes’, explains Dr Ogle. Lilly, a global leader in diabetes care for over 80 years, has been involved in the Life for a Child programme for some time, initially through the adoption of employee fundraising efforts to contribute to the programme. Through this, Lilly employees have helped provide insulin, supplies and diabetes education and care to hundreds of children in developing nations.4 It was due to this support that Life for a Child was able to start assisting in Africa. More recently, in 2008, Lilly committed to donating more than 800 000 vials of insulin to the programme. This donation is the biggest medicine donation ever made by Lilly and will eventually provide life-saving medication to as many as 24 000 who currently have no access to dia-

VOLUME 7 NUMBER 2 • JUNE 2010

betes treatment.5 ‘The number of children being assisted through Life for a Child has rapidly increased over the last 12 months, due largely to this donation of insulin by Lilly’, said Dr Ogle. Around 3 500 children are now supported, and this will grow to around 9 000 by the end of 2010. ‘We are now urgently searching for companies to provide large-scale inexpensive or free test strips to further assist patients globally.’ Johannesburg is also an important hub for Life for a Child as most of the insulin and other provisions donated to many African and Asian countries are distributed from there. While in South Africa, Dr Ogle also met with UTi Pharma, which is responsible for the logistics and transport of supplies. A diagnosis of type 1 diabetes for any child in any country can be devastating, but more so for children in developing countries. The full cost of complete management for a child with type 1 diabetes (who require insulin to stay alive) in most third-world countries is more than they can afford. In fact, the cost of insulin, syringes and testing strips alone exceeds the annual income of many poor families in these countries. The cost of full care for a patient with type 1 diabetes can be as much as US $500 to $700 a year. Furthermore, the IDF estimates that 64% of the world’s children under the age of 15 with type 1 diabetes live in low-income countries.2 ‘We are proud to be associated with Life for a Child and we are inspired by the progress being made by this programme in caring for the most needy, helping them to stay alive and improving their quality of life’, said Jacques Blaauw, managing director for Lilly South Africa. Contact Life for a Child on www.lifeforachild.idf.org References 1. Life for a Child. The program (http://www.lifeforachild.idf.org/en/pages/program). Website accessed 15 April 2010. 2. Ogle G. Life for a Child. Presentation – 15 April 2010. 3. Life for a Child. Press release 18 September 2007 (http://www.idf.org/life-child). Website accessed 15 April 2010. 4. Lilly’s commitment to Life for a Child. Sponsors (http://www.lifeforachild.idf.org/pages/ eli-lilly). Website accessed 21 April 2010. 5. Lilly makes insulin donation to International Diabetes Federation’s Life For a Child program. 13 November 2008 (http://www.medicalnewstoday.com/articles/129183. php). Website accessed 21 April 2010.

Colour makes all the difference.

KwikPenTM with colour-coded dose knobs makes product identification a lot easier Available in three pre-filled variants:

KwikPenTM fits into your patients’ lives and helps give them the insulin they need S3 Humalog® (Solution for Injection). 29/21.1/0785. S3 Humalog® Mix25 (Suspension for Injection). 33/21.1/0073. S3 Humalog® Mix50 (Suspension for Injection). 33/21.1/0074. Eli Lilly (S.A.) (Pty) Ltd. Reg No. 1957/000371/07. 1 Petunia Street, Bryanston, 2021. Telephone: (011) 510 9300 A2175, February 2010.

124005

Answers That Matter.

SA JOURNAL OF DIABETES & VASCULAR DISEASE

DRUG TRENDS

Diabetes myth-busters A Novo Nordisk-sponsored education symposium Insulin resistance, pre-diabetes and metformin: much ado about nothing? Dr Aslam Amod, Durban Plasma glucose levels are used to predict the risk of microvascular complications, of developing diabetes in the future and of cardiovascular morbidity and mortality. ‘If we’re using plasma glucose for three different purposes, we cannot expect one value to give us the same prediction rate’, said Durban-based endocrinologist, Dr Aslam Amod, speaking at the annual pre-SEMDSA Novo Nordisk Diabetes Update symposium this year, titled ‘Diabetes myth-busters’. For example, the curves for retinopathy are different from those for mortality. There is no discrete cut-off point. The same is true for predicting diabetes risk. The higher up one goes in the so-called normal range, the greater the risk. ‘For all three tests, the risk is continuous, extending below the lower limits of the range and becoming disproportionately greater at the higher ends’, observed Dr Amod. Any value chosen is therefore by definition arbitrary, balancing sensitivity against cost effectiveness. Currently the cut-off for fasting plasma glucose is 6–6.9 mmol/l or 5.6–6.9 mmol/l (depending on which definition is followed), for two-hour plasma glucose it is 7.8–11 mmol/l, and for HbA1c 5.7–6.4 mmol/l. ‘Pre-diabetes’ is an umbrella term applied to impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Dr Amod pointed out that IFG and IGT are not equivalent conditions, however, and that IGT carries the higher relative risk for progression to diabetes, cardiovascular risk and cardiovascular mortality. In patients with pre-diabetes (whether IGT or IFG), 50% progress to diabetes, 25% revert to normal and 25% remain in the pre-diabetic state. ‘The rationale for prevention is therefore clear, and we need to change the natural history of the disease to prevent micro- and macrovascular complications.’ Regarding pharmacological interventions in pre-diabetes, Dr Amod referred to various trials that supported the use of drugs in pre-diabetic patients, and showed the glitazones to be more powerful than metformin. However, he