SAJDVD Volume 9, Issue 1

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Volume 9 Number 1March 2012

SAJDVDThe South African Journal of DiAbeTeS & VASculAr DiSeASe

Reviews Ethics Focus Achieving Best Practice Diabetes Educator’s Focus News

The electronic version of the journal is available at

www.diabetesjournal.co.za

New antithrombotic drugs

Anticoagulation in diabetic patients

Gliptins in type 2 diabetes

Risk of cardiovascular disease in the Bellville pilot study

Serum levels of RAGE and TNF-α in type 2 diabetes

Serum tumour necrosis factor-α in type 2 diabetes

Improving warfarin control

Liraglutide: an incretin mimetic

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HYPERINSULINAEMIA

ISSN 1811-6515

THE SOUTH AFRICAN JOURNAL OF

Diabetes & vascular Disease

Corresponding EditorDr L LombarDNetcare, Kuilsrivier Hospital, Cape Town

Consulting EditorsProF J-C mbaNYaProF aJ brINKDr F maHomED

National Editorial BoardDr a amoDCentre for Diabetes, Endocrinology and metabolic Diseases, Life Healthcare, Chatsmed Gardens Hospital, Durban

Sr K bECKErTDiabetes Nurse, Paarl

ProF F boNNICIEmeritus Professor, Faculty of Health Sciences, University of Cape Town and President of Diabetes South africa

ProF r DELPorTDepartment of Family medicine,University of Pretoria

Dr L DISTILLErDirector of the Centre of Diabetes and Endocrinology, Houghton, Johannesburg

Dr F maHomEDDepartment of Endocrinology, Grey’s Hospital, Pietermaritzburg

ProF WF moLLENTZEHead of Department of Internal medicine, University of the Free State, bloemfontein

ProF CD PoTGIETErSpecialist Nephrologist, University of Pretoria and Jakaranda Hospital, Pretoria

ProF K SLIWaassociate Professor of medicine and Cardiology, baragwanath Hospital, University of the Witwatersrand, Johan-nesburg

ProF YK SEEDaTEmeritus Professor of medicine and Honorary research associate, University of Natal, Durban

International Editorial BoardProF IW CamPbELLPhysician, Victoria Hospital, Kircaldy, Scotland, UK

ProF PJ GraNTProfessor 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 mbaNYaProfessor of Endocrinology, Faculty of medicine and biomedical Sciences, University of Yaounde I, Cameroon and President, International Diabetes Federation

ProF N PoULTErProfessor of Preventive Cardiovascular medicine, Imperial College, School of medicine, London, UK

Dr H PUrCELLSenior research Fellow in Cardiology, royal brompton National Heart and Lung Hospital, London, UK

VOLUME 9 NUMBER 1 • MARCH 2012www.diabetesjournal.co.za

CONTENTS Editorial

3 New therapies change diabetes practiceL Lombard

Reviews

4 New antithrombotic drugs: a revolution in stroke managementA Bryer

7 Anticoagulation therapy in diabetic patientsPF Wessels

10 DPP-4 inhibitors (gliptins) in the management of type 2 diabetesL Lombard

14 High lifetime risk of cardiovascular disease in South Africans of mixed ancestry: findings of the Bellville, South Africa pilot study

G Hardy

Research Articles

16 Impact of vascular complications on serum levels of soluble RAGE and TNF-α in females with type 2 diabetes MA Zaki, KM Ahmed

22 Association of serum tumour necrosis factor-α and interleukin-6 with insulin secretion and insulin resistance in subjects with type 2 diabetes in a Bangladeshi populationM Hossain, O Faruque, G Kabir, I Khan, D Sikdar, L Ali

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R

Hp

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

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Assistant Editor: Special AssignmentsJULIa aaLbErSTEL: (021) 976-4378FAX: 086 610 3395e-mail: [email protected]

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The South African Journal of Diabetes and Vascular Disease is published four times a year for Clinics Cardive Publishing (Pty) Ltd and printed by Tandym Print. Online Services: Design Connection.

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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.

26 Evidence in Practice

Patient Leaflet

29 Improving warfarin control: can we achieve 70% time in therapeutic range in South Africa?

Reports

31 SANofI specialist diabetes meeting, Cape Town

J Aalbers

37 IDF Watch: 2011 update from Dubai, United Arab Emirates

B Joffe, Dr A Kegne, J Aalbers

43 The diabetologist/cardiologist debate: a meeting of the minds

Drug Trends

47 Liraglutide, an incretin mimeticD Khutsoane

Page 26

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SA JOURNAL OF DIABETES & VASCULAR DISEASE EDITORIAL

VOLUME 9 NUMBER 1 • MARCH 2012 3

Correspondence to: Dr Landi LombardNetcare Kuilsrivier Hospital, Cape TownTel: +27 0(21) 900-6350e-mail: [email protected]

S Afr J Diabetes Vasc Res 2012; 9: 3

New therapies change diabetes practiceLANDI LOMBARD

T he rising prevalence of diabetes, as a result of urbanisation (and associated lifestyle changes) and demographic and epidemiological tran-

sitions, is a recurring consideration in primary healthcare. Diabetes is now among the most common non-communicable diseases in South Africa, with studies showing marked geographical and ethnic variations in prevalence. We know that diabetes, particularly type 2, is associated with cardiovascular disease (CVD). Mortality from CVD is two- to fourfold higher in the diabetic patient, regardless of variations in South African epidemiology.

Dysglycaemia and cardiovascular riskThe relationship between dysglycaemia and CVD is linear and sometimes starts below the diagnostic level of diabetes. In a study of mixed-ancestry South Africans in Bellville, Cape Town (page 13), researchers used a 30-year CVD risk-assessment model, with sobering results. Significant predictors of CVD were found to be sibling history of diabetes, and triglyceride, low-density lipoprotein cholesterol and glycated haemoglobin levels. More surprising however, was the finding of a high lifetime CVD risk in normoglycaemic and younger subjects. This has important public health implications, as CVD is often underestimated in the young. More local studies are urgently needed in our complex ethnic population and funding must be made available for this purpose.

Anticoagulation and antithrombotic therapyAmong CVD concerns is risk and management of cardioembolic stroke as well as venous and arterial thromboembolism. The use of warfarin as the cornerstone of antithrombotic therapy has both benefits and drawbacks. Warfarin has a narrow therapeutic range, leading to difficulties in achieving adequate time in therapeutic range (TTR). This is compounded by the numerous drug and dietary interactions of warfarin.

In this issue, Dr Wessels reviews anticoagulation therapy in diabetic patients prone to a high risk of developing arterial disease, including considerations of antiplatelet and anticoagulation combination therapy (page 6). Furthermore, a review of new antithrombotic drugs in stroke management (hailed a revolution in stroke management) by Dr Bryer, addresses the advent of the direct thrombin inhibitors and factor Xa inhibitors (page 4). These agents exhibit stable pharmacokinetics, obviating the

need for coagulation monitoring or dose titration. Another advantage is that, at this juncture, they do not have clinically significant interactions with food or drugs and have been shown to be either non-inferior or superior to warfarin in reducing the risk of stroke and systemic embolisation. However, long-term data and analysis of cost-effectiveness to assess their true risk benefit are required.

Familiarise yourself with agents such as dabigatran, apixaban and rivaroxaban, as it is likely that such agents will be an important replacement for warfarin as treatment of choice for the prevention of cardioembolic stroke. Unfortunately the price

of these agents will limit widespread usage. Also in this issue, the patient information leaflet has valuable tips on patient self-monitoring and the interaction of warfarin with other medications (page 29).

New therapeutic entities for the management of type 2 diabetesTwo topical articles on new therapeutic entities that have just been launched and will soon be available in South Africa present a comprehensive review of the DPP-4 inhibitors. The review gives the reader more information to be able to select the best DDP-4 inhibitor for the specific clinical setting (page 9). The second article, by Dr Khutsoane on liraglutide, a newly launched GLP-1 analogue, supports the many potential benefits of this class of drugs (page 47). It is unfortunate that these drugs are premium priced and therefore not available to most of the patients who desperately need them.

Sanofi specialist diabetes meeting reportOf general interest is a report on the Sanofi specialist diabetes meeting in Cape Town (page 31), covering a range of topics. Included are summaries of presentations on the incretins and metformin. Other discussions included peripheral neuropathy (painful diabetic neuropathy), bariatric surgery, environmental interaction with our genomes (epigenetics) and the fascinating question of whether exercise improves or impedes glycaemic control in type 1 diabetes. We hope to have a more comprehensive article by the same author on this challenging entity in diabetes care in this journal in the future.

In addition, there is also a short report on another arrow in metformin’s quiver; it lowers the risk of pancreatic cancer in women. This interesting report adds to recent data suggesting that this drug also lowers the risk of many other cancers, which are known to be of increased prevalence in diabetics.

In two basic science research articles done in the clinical setting on diabetic patients, cytokines such as TNF-alpha and IL-6 and sRAGE were studied. They may hold promise for future prediction of vascular complications in diabetics.

Landi Lombard

REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE

4 VOLUME 9 NUMBER 1 • MARCH 2012

Correspondence to: Prof Alan BryerDivision of Neurology and Stroke Unit, Groote Schuur Hospital and University of Cape Towne-mail: [email protected]

S Afr J Diabetes Vasc Dis 2012; 9: 4–5

New antithrombotic drugs: a revolution in stroke managementALAN BRYER

Embolism of cardiac origin accounts for 20% of ischaemic strokes. Atrial fibrillation is by far the most common cause of cardioembolic

stroke, and anticoagulation is the treatment generally indicated for secondary, and in many cases, primary prevention.1 The decision to prescribe warfarin is usually based on an accurate assessment of the likely absolute annual risk of stroke without warfarin, and whether or not such benefits of warfarin treatment are likely to outweigh the risk of bleeding associated with its use.

For more than 20 years, the use of warfarin has been the cornerstone of antithrombotic therapy for patients with TIA or ischaemic stroke due to cardioembolism, particularly those associated with atrial fibrillation. Warfarin remains the commonest anticoagulant used worldwide (although other similar vitamin K antagonists are prescribed in many countries).

Adjusted-dose warfarin anticoagulation with an international normalised ratio (INR) range between 2.0 and 3.0 is significantly more effective than antiplatelet therapy for preventing recurrent stroke in patients with atrial fibrillation and results in a risk reduction of between 60 and 68% compared to placebo.2,3 By contrast, the most commonly used alternative to warfarin is aspirin, which provides substantially less-consistent benefit and reduces the risk of recurrent stroke and other major vascular events in patients with atrial fibrillation by only 17 to 21%.4,5

Similarly, combination antiplatelet therapy with aspirin and clopidogrel is not as effective as warfarin and is associated with a significant increase in major bleeding.6 Furthermore, although current data indicate that combination treatment with aspirin and clopidogrel does result in a greater reduction in major vascular events when compared with aspirin alone, this is offset by an increase in major haemorrhages. The absolute benefit of oral anticoagulation with warfarin versus antiplatelet therapy increases as patients with atrial fibrillation get older because stroke risk increases with age while the relative efficacy of oral anticoagulation therapy to prevent ischaemic stroke does not change.7

Despite the efficacy and affordability of warfarin, many patients with cardioembolic stroke or TIA are not treated with this agent because it is perceived to be inconvenient or hazardous. Although the benefits of oral anticoagulation with warfarin are supported by a high degree of evidence for stroke prevention due to cardioembolic stroke, there are many disadvantages associated with its use. The long-term efficacy and safety of warfarin depends

on maintaining a narrow range of anticoagulation intensity (INR 2.0–3.0) and this may be compromised by the patient’s dietary intake, exposure to other drugs, and co-existing illnesses. Consequently, many drug-compliant patients are not well controlled and require regular monitoring of the INR.

The need for sustained patient monitoring is not only inconvenient for the patient but also requires adequate healthcare infrastructure, which is often lacking in developing countries. For instance, patients who have residual disability after a cardioembolic stroke may experience significant difficulties in attending clinics where their INR can be monitored

and their warfarin dose adjusted accordingly. This problem is often compounded in rural areas where the distances patients have to travel to clinics may be considerable and infrastructure at such clinics for INR monitoring may be lacking.

As patients on warfarin need to be within the target INR range in order to achieve benefit, there is also an increased risk for serious bleeding complications when the target INR is exceeded. In a post-hoc analysis of the RE-LY trial, a wide variation in the time in therapeutic range (TTR) across participating countries persisted despite efforts to improve the generally poor quality of INR control seen in many trials. This ranged from a high 77% in Sweden to as low as between 41 and 58% in 16 other countries, mostly Asia, Eastern Europe, South America and South Africa.8

An audit of anticoagulation was undertaken in a cohort of patients attending a prothrombin clinic at a tertiary South African hospital in order to determine the TTR on dose-adjusted warfarin. Patients were included in the audit if the indication for warfarin was atrial fibrillation or a mechanical valve replacement and they had been on warfarin for at least one month. Of the 190 patients included in the analyses, the mean TTR was 55.5%, with a complication rate of 8.4% (5.8% bleeding, 2.6% thrombotic). The TTRs for the majority of the patients in this study were lower than acceptable, at the lower end of published norms and associated with a high complication rate. Neither clinic attendance nor time on warfarin correlated with the TTR. The results of this audit indicate that the level of anticoagulation was inadequate in the majority of patients treated with warfarin at this large clinic.9 It is likely that these results reflect the situation in many clinics in the developing world.

Numerous drug and dietary interactions compound the problem of warfarin’s narrow therapeutic range and the difficulties in achieving adequate TTR. Warfarin can interact with a multitude of commonly prescribed drugs (such as statins, various antibiotics, non-steroidal anti-inflammatory agents and some of the most popular over-the-counter analgesics such as paracetamol and aspirin). Given the problems associated with its use, clinicians are frequently compelled to prescribe less efficacious antiplatlet agents for prevention of cardioembolic stroke.

Alan Bryer

SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW


The advent of the direct thrombin inhibitors and factor Xa inhibitors represents a quantum leap forward in the long-term prevention of recurrent stroke of cardiac origin. The two overwhelming advantages of the new agents are that they exhibit stable pharmacokinetics, obviating the need for coagulation monitoring or dose titration, and that they lack clinically significant food or drug interactions. Additional advantages are that they offer fixed once- or twice-daily oral dosing and a rapid onset of action. It seems likely that, in time, these agents will replace warfarin as treatment of choice for the prevention of cardioembolic stroke.

September 2009 heralded the publication of the first of three important studies in which the front runners of these new agents, dabigatran, and subsequently apixaban and rivaroxaban, were each compared to warfarin in patients with atrial fibrillation, in order to determine whether or not these new agents provided more consistent and predictable anticoagulation than warfarin for a primary endpoint of stroke or systemic embolism. Results from these trials indicate that all three novel anticoagulants are either non-inferior or superior to warfarin in reducing the risk of stroke and systemic embolisation.10-12 Furthermore, all three drugs have either an equivalent or reduced risk of major bleeding and intracranial haemorrhage compared with warfarin. However, there is continued debate and discussion in the literature concerning the variability in the trial designs of these studies, particularly pertaining to issues such as the differences in the case mix affecting stroke risk (e.g. differences in the CHADS2 scores, prevalence of prior stroke, patient age, whether or not patients were warfarin naïve, and the interpretation of the TTR data).

Although the current trials show favourable safety profiles for these newer agents, long-term data are still required, as most patients with atrial fibrillation require lifelong oral anticoagulation. Nevertheless, these agents appear to provide a number of significant benefits over warfarin, and potential patients should be informed of these in order to make informed choices. On the other hand, there are a number of concerns which will need to be addressed.

Widespread use of these newer agents is expected in the future once they are approved by the relevant regulatory authorities. Inevitably, the potential risk for overdose will increase in this population, particularly among the elderly, and there is currently no easy way of detecting this with routine coagulation tests. There is also currently no solid evidence to guide the management of bleeding complications that can occur with these newer agents. The thrombin time and ecarin clotting time do illustrate a linear response to serum dabigatran concentration, but are not readily available. Consequently, many patients already taking and tolerating warfarin, with good INR control, may reasonably prefer not to switch to dabigatran or one of the factor Xa inhibitors until there is more clarity on these issues.

A major limiting factor for the future widespread use of the newer anticoagulants in the developing world will be their high cost compared to warfarin. In evaluating the health economics of introducing these newer therapies into the public health domain of African countries, the cost of these drugs will need to be compared not only with the cost of warfarin but also with the cost and availability of INR-monitoring facilities. Furthermore, the cost of non-compliance and inadequate TTR on warfarin treatment, as well as associated complications of warfarin therapy will need

to be carefully considered. The analysis of cost-effectiveness of the new drugs will need to include these ramifications for stroke prevention so that their true risk–benefit can be properly assessed.

Fortunately there are a number of competing drugs in this new class, with other similar products in development (betrixaban, edoxaban). This is likely to drive down the prices of these new agents, allowing for more widespread use. These drugs also have the potential to expand the number of patients eligible for oral anticoagulant therapy, including those patients with atrial fibrillation who are unable or unwilling to use warfarin.

Dabigatran has already received regulatory approval in the United States for use in patients with atrial fibrillation and it has rapidly entered clinical practice. It is likely that apixaban and rivaroxaban will also get regulatory approval and the debate in the literature concerning their comparative efficacy and safety will continue.

Many physicians are reluctant to prescribe warfarin for elderly patients in atrial fibrillation for various reasons (e.g. concerns for risk of falls, history of previous bleeding) despite clear evidence of increased benefit in these patients compared with younger patients. These physicians would likely have fewer reservations about prescribing one of the newer agents. The consistent anticoagulant effect achieved with the new oral anticoagulants may also translate into greater efficacy and safety due to avoidance of the frequent sub- and supra-therapeutic drug levels, which are common with warfarin and the other vitamin K antagonists.

ReferencesFont MA, Krupinski J, Arboix A. Anti thrombotic medication for cardioembolic 1. stroke prevention. Stroke Res Treatment 2011: 607852. Epub 2011 June 22.Hart RG, Benadente O, McBride R, Pearce LA. Antithrombotic therapy to 2. prevent stroke in patients with atrial fibrillation: a meta-analysis. A Int Med 1999; 131(7): 492–501.Saxena R, Koudstaal PJ. Anticoagulants for preventing stroke in patients with 3. non-rheumatic atrial fibrillation and a history or stroke or transient ischaemic attack. Cochrane Database Syst Rev 2003; 3: CD000185.European atrial fibrillation study group. Secondary prevention in non-rheumatic 4. atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342:1255–1262.The atrial fibrillation investigators. The efficacy of aspirin in patients with atrial 5. fibrillation. Analysis of pooled data from 3 randomized trials. Arch Internal Med 1997; 157(11): 1237–1240.ACTIVE writing group. Clopidogrel plus aspirin versus oral anticoagulation for 6. atrial fibrillation in the atrial fibrillation Clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903–1912.Hankey GJ, Eikelboom JW. Antithrombotic drugs for patients with ischaemic 7. stroke and transient ischaemic attack to prevent recurrent major vascular events. Lancet neurol 2010; 9: 273–284.Wallentin L, Yusuf S, Ezekowitz MD, 8. et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376: 975–983.Stanley A, Ntsekhe M, Commerford PJ. An audit of an anti-coagulation clinic at 9. a tertiary hospital. Poster presentation, Department of Medicine Research Day Groote Schuur Hospital, University of Cape Town, South Africa. Oct 2008.Connolly SJ, Ezekowitz MD, Yusuf S,10. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151.Granger CB, Alexander JH, McMurray JJV, 11. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981–992. Patel MR, Mahaffey KW, Garg J,12. et al. Rivaroxaban versus warfarin in non-valvular atrial fibrillation. N Engl J Med 2011; 365: 883–891.

THINGS ARE ABOUT TO CHANGE IN

ANTICOAGULATION THERAPY

Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd, 407 Pine Ave, Randburg.

Tel: +27 (011) 348 2400 • Fax: +27 (011) 787 3766 • Company Reg. No. 1966/008618/07.

BI Ref No. 254/2010 (Nov 10)

EVERY DAY IN SOUTH AFRICA

44** PATIENTS WILL HAVE AN AF* RELATED STROKE1, 2, 3

22** OF THEM WILL DIE WITHIN A YEAR (50 %)4

90 % OF STROKE PATIENTS WITH KNOWN AF WERE NOT THERAPEUTICALLY ANTICOAGULATED4

*AF – Atrial Fibrillation** Best Estimate

REFERENCES: 1. Stats South-Africa. Stats-Online. P0302 - Mid-year population

estimates. Updated 20 July 2010. Available from: http://www.statssa.gov.za/publications/P0302/P03022010.pdf

2. Connor M. Stroke Management in South Africa – Who is responsible? S Afr Psychiatry Rev 2005; 8: 125-126.

3. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fi brillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 2005; 36:1115-9.

4. Gladstone DJ, Bui E,Fang J, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke 2009;40;235-240.



Correspondence to: Dr PF Wessels Consultant: Ampath LaboratoriesPart-time consultant: Department of Medical Oncology, University of PretoriaPrivate practice: clinical hematologist, LCM Hospital, Pretoriae-mail: [email protected]


Anticoagulation therapy in diabetic patientsPF WESSELS

IntroductionDiabetic patients have a high risk of developing arterial disease (coronary artery, cerebrovascular and peripheral arterial disease) and are therefore often given antiplatelet therapy.

Although only retrospective studies1,2 suggest that diabetic patients are also prone to venous thrombo-embolism, many comorbid factors in the diabetic patient, such as heart failure, physical inactivity and atrial fibrillation increase the risk of venous thrombosis. A recent sub-analysis of the RECORD study3 examined the risk of hyperglycaemia during hip replacement, as a risk factor for postoperative venous thrombo-embolism. For these reasons, diabetic patients are also often given anticoagulant therapy.

Pathophysiology of vascular disease in diabetic patientsEndothelial cell dysfunction, smooth muscle cell migration and platelet hyper-reactivity play an important role in arterial disease. Virchow’s triad of endothelial injury, endothelial dysfunction and hypercoagulability (hyper-reactive platelets and increased clotting factors) are important factors in venous thrombosis.

Endothelial cells produce important active substances that lead to decreased vascular tone and blood flow, increased fibrinolysis, activation of endogenous anticoagulants, decreased leucocyte diapedesis and decreased platelet activation. The nitric oxide (NO) produced by endothelial cells also prevents vascular smooth muscle proliferation and migration (thus protecting the cell from atherosclerosis).

Endothelial dysfunction in diabetic patients is due to metabolic abnormalities such as hyperglycaemia, insulin resistance and increased serum free fatty acid levels.

Platelet function in the diabetic patient is also abnormal due to increased GPIb receptors (increased platelet interaction with the ‘glue’ von Willebrand factor) and increased GPIIb/IIIa receptors (increased platelet interaction with fibrin and fibrinogen). Calcium homeostasis is abnormal and NO production decreased in the platelets.

Increased levels of procoagulants (clotting factors) such as FIII (tissue factor), FVII and FII, and a decrease in naturally occurring anticoagulants (thrombomodulin on the endothelial surface activates some of the anticoagulants) lead to hypercoagulability. The fibrinolytic pathway is also abnormal, with decreased fibrinolysis due

to the increased production of plasminogen activator inhibitor-1 (PAI-1).

Atrial fibrillation and diabetes mellitusAtrial fibrillation (AF) is the most common cardiac arrhythmia, and is more prevalent in older patients and men. Risk factors include coronary artery disease and hypertensive heart disease. Since atrial fibrillation is an important risk for stroke and thrombo-embolism, many of these patients are given anticoagulant therapy.

It is important to realise that stroke risk in asymptomatic or paroxysmal AF patients is comparable with that seen in patients with permanent AF.

Management of these patients also includes control of heart rate or rhythm.

The decision to give anticoagulation must be weighed against the risk of bleeding. Either aspirin (antiplatelet effect) or warfarin (anticoagulant) has been used. A risk-scoring system, the CHADS2 score,4 considers congestive heart failure, hypertension, age over 75 years, diabetes mellitus and previous stroke/TIA. A new scoring system (CHA2DS2VASc)5 adds vascular disease (myocardial infarction, peripheral arterial disease or aortic plaque), female gender and an altered age stratification. The HASBLED6 score has been developed to evaluate the risk of bleeding in AF patients.

Taking this latest CHA2DS2VASc scoring system into consideration, the 2010 European Society of Cardiology (ESC) guidelines7 recommend that any patient with AF and diabetes (without any other added risk) should receive either anticoagulation therapy or aspirin (and preferably anticoagulation). If any one other risk factor (e.g. female, 65 years and older, hypertension) is present, oral anticoagulation is definitely recommended. The reason for this is the superiority of warfarin and the newer oral anticoagulants over aspirin. It is also suggested that patients with a CHA2DS2VASc score of 0 receive no antithrombotic therapy.

Warfarin has been used successfully for many years, but most strokes occur in AF patients on warfarin during under-anticoagulated periods. Due to the narrow therapeutic index (INR between 2 and 3), control of oral anticoagulation can be challenging, especially due to the wide variety of drug–drug and drug–food interactions.

Newer oral drugs, the anti-FII drug (acting against clotting factor II) dabigatran (Pradaxa) and the anti-FX drug (acting against clotting factor FX) rivaroxaban (Xarelto) have been extensively tested for stroke prevention in atrial fibrillation patients. In the RE-LY study,8 dabigatran was shown to be more effective than warfarin, with a similar risk of bleeding in dosages of 150 mg twice a day. The 110 mg bd dose of dabigatran showed significantly less bleeding than warfarin, with a similar efficacy. In 2010 the USA Food and Drug Administration (FDA) approved the use of the 220-mg bd dose of dabigatran for atrial fibrillation.

Rivaroxaban (the ROCKET-AF study9) has also been shown to be non-inferior to warfarin, with comparable rates of bleeding but significantly lower rates of intracranial bleeding compared to warfarin. In 2011 the FDA approved rivaroxaban 20 mg once daily for use in patients with AF in the USA. Recently, the results of a

PF Wessels



study of rivaroxaban in acute coronary syndromes10 were published, showing reduced risk of the composite end-point of death from cardiovascular causes, myocardial infarction or stroke with the use of this new drug, although it increased the risk of major bleeding and intracranial haemorrhage, but not the risk of fatal bleeding.

In the AVERROES study, apixaban (another anti-FX drug) was compared with aspirin in patients with AF.11 Apixaban 5 mg twice daily was superior to aspirin, with a similar rate of major bleeding, and was better tolerated than aspirin.

These drugs have not been approved in South Africa yet for use in AF, but have been approved and successfully used as prophylactic agents against deep-vein thrombosis in orthopaedic patients. In view of the newer guidelines worldwide and experience in other countries, many patients with AF and diabetes will probably receive them in the future.

No laboratory testing is necessary with these two new drugs, but routine laboratory assays may be used to determine the presence of the drugs in cases of bleeding. With dabigatran, activated partial thromboplastin time (PTT) and thrombin time (TT) may be used, and in the case of rivaroxaban, prothrombin time (PT) may be used. Specific assays to determine the level of the drug in the blood have been developed, but in view of the predicted response and lack of need for monitoring, these assays are not available in routine laboratories.

No specific antidote is available for these drugs yet, but fortunately both have a short half-life. Fresh, frozen plasma and activated FVII (Novo VII) have been suggested as antidotes in a patient who is bleeding and needs urgent reversal. Ideally, a fast-acting antidote for these newer drugs would be welcomed.

Dabigatran may need dose adjustment if used with amiodarone, and use is not recommended concomitant with quinidine. It should also be used with caution with verapamil, clarithromycin, rifampicin and other potent P-gp inducers. Rivaroxaban should not be used with ketoconazole, itraconazole and HIV protease inhibitors, and should be used with caution with fluconazole, phenotoin, carbamzepine and other strong CUYP3A4 inducers. Considering the many warfarin–drug interactions, these drug interactions are few in number.

Combination therapy with antiplatelet and anticoagulation drugsThe risk of bleeding increases with dual therapy consisting of anticoagulants and antiplatelet drugs. It is even greater with triple therapy where two antiplatelet drugs (aspirin and clopidrigel) and an anticoagulant are used. There are however patients who need this combination of the antiplatelet effect of aspirin (e.g. underlying ischaemic heart disease) with anticoagulant therapy (e.g. valve replacement, high-risk AF patients).

The ESC working group on thrombosis recommends that in patients with atrial fibrillation who are on oral anticoagulants and present with acute coronary syndrome and possibly stenting, the following applies: with a CHADS2 score of 0, patients should

receive dual therapy, and with a CHADS2 score of 1 or more, triple therapy is indicated. INR control must be kept between 2.0 and 2.5 with triple therapy. The duration of triple therapy depends on the HASBLED bleeding risk, as well as type of procedure that has been done.12

The North American perspective13 further suggests that aspirin, if used in combination with oral anticoagulants, should be less than 100 mg and that a proton pump inhibitor (such as pantoprazole) be given for the duration of therapy. It is also suggested that if the newer drug dabigatran is used in combination with antiplatelet therapy, the 110-mg instead of the 150-mg dosage be used. It is recommended that the newer antiplatelet drugs such as prasugrel and ticagrelor not be used with oral anticoagulant therapy.

ConclusionMany new anticoagulant therapies have been developed and have undergone testing in atrial fibrillation. New antiplatelet drugs have also been developed. Many other novel drugs are at present being tested in clinical trials. The time may come when more specific therapy, tailored to each individual patient’s circumstances, will be recommended.

ReferencesPetrauskiene V, Falk M, Waernbaum I,1. et al. The risk of venous thrombo-embolism is markedly elevated in patients with diabetes. Diabetologia 2005; 48: 1017–1021. Stein PD, Goldman J, Matta F,2. et al. Diabetes mellitus and risk of venous thromboembolism. Am J Med Sci 2009; 337: 259–264. Cohn DM, Hermanides J, De Vries JH,3. et al. Stress-induced hyperglycemia and venous thromboembolism following total hip or total knee arthroplasty: Analysis from the RECORD trials. Thromb Haemost 2012; 107(2): 225–231.Gage BF, van Walraven C, Pearce L, 4. et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation 2004; 110 (16): 2287–2292.Lip GYH, Nieuwlaat R, Pisters R, 5. et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach. Chest 2010; 137(2): 263–272.Pisters R, Lane DA, Nieuwelaat R, 6. et al. A novel, user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: The Euro Heart Survey. Chest 2010; 138: 1093–1100.Camm AJ, Kirchhof P, Lip GY, 7. et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369–2429. Connolly SJ, Ezekowitz MD, Yusuf S,8. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151. Patel MR, Mahaffey KW, Garg J,9. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–891.Mega JL, Braunwald E, Wiviott SD, 10. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9–19.Connolly SJ, Eikelboom J, Joyner C. Apixaban in patients with atrial fibrillation. 11. N Engl J Med 2011; 364: 806–817.Lip G, Huber K, Andreotti F, 12. et al. European Society of Cardiology Working Group on Thrombosis. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/ stenting. Thromb Haemost 2010; 103: 13–28.Faxon DP, Eikelboom JW, Berger PB,13. et al. Anti- thrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: A North- American perspective. Thromb Haemost 2011; 106: 572–584.

For your patients with type 2 diabetes on monotherapy

when HbA1c levels begin to rise above 7 %1,2,3

References: 1. DeFronzo RA, et al. Diabetes Care 2009;32:1649–55. 2. Chacra AR, et al. Int J Clin Pract 2009;63(9):1395–406. 3. Hollander P, et al. J Clin Endocrinol Metab 2009;94(12):4810–9.

S3 ONGLYZA® 2.5 (Tablet). Each ONGLYZA® 2.5 tablet contains saxagliptin hydrochloride equivalent to 2.5 mg saxagliptin free base. S3 ONGLYZA® 5 (Tablet). Each ONGLYZA® 5 tablet contains saxagliptin hydrochloride equivalent to 5 mg saxagliptin free base. PHARMACOLOGICAL CLASSIFICATION: A.21.2 Oral hypoglycaemics. Reg. No. ONGLYZA® 2.5 : 43/21.2/0608. Reg. No. ONGLYZA® 5 : 43/21.2/0609. Ref: Reg. No. ONGLYZA® - EPI (28/07/11). ONGLYZA® is a registered trademark of Bristol-Myers Squibb. For full details relating to any information mentioned above please refer to the package insert. Bristol-Myers Squibb (Pty) Limited. Reg. No. 1956/001115/07. 47 van Buuren Road, Bedfordview, 2008, South Africa. Tel: (011) 456 6400. Fax: (011) 4566579/80. www.Bms.com. Date compiled: December 2011

0000 Onglyza A4 Advert.indd 1 1/11/12 9:40:23 AM



Correspondence to: Dr Landi LombardNetcare Kuilsrivier Hospital, Cape TownTel: +27 0(21) 900-6350e-mail: [email protected]

S Afr J Diabetes Vasc Res 2012; 9: 9–12

DPP-4 inhibitors (gliptins) in the management of type 2 diabetesLANDI LOMBARD

IntroductionMost readers of this journal will be aware of the huge pandemic of non-communicable diseases, led by diabetes, particularly type 2. This has been highlighted recently by the World Health Organisation1 and was reported in our recent editorial.2 Unlike the HIV pandemic, where we are past the peak and are controlling and preventing the disease, we have thus far been unsuccessful in making any progress in the escalating diabetes pandemic. The peak is not in sight, parallel to the massive increase in worldwide obesity.

Despite this increase, we as physicians are not faring well in controlling diabetes. Worldwide, targets for managing diabetic patients are not being met.3,4 We therefore urgently need more drugs in our armament to improve the control of diabetes, especially in our own country.

As with the HIV pandemic, the scientific and pharmaceutical industry has responded with many new drugs recently entering the market and many to follow. One of these classes is the dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors). Five of these molecules have been developed (more are currently in development) and most will probably be available in this country. To help clinicians make decisions regarding these molecules, this review will briefly discuss the molecules and assess their special features and differences.

Biochemistry and pharmacodynamicsDPP-4 inhibitors are GLP-1-based (glucagon-like peptide-1) therapy, previously reviewed in this journal.5 The DPP-4 inhibitors act by inhibiting the serine protease DPP-4 enzyme responsible for the rapid breakdown and short half-life of GLP-1.6 The inhibition of this enzyme prevents the metabolic clearance of the molecule and therefore increases the insulinotropic activity of GLP-1.

It is well documented that diabetics have decreased GLP-1 production,7 which to some extent limits the efficacy of the DPP-4 inhibitors. This limitation is because DPP-4 inhibitors can only prolong the effect of the produced GLP-1 and not, as the GLP-1 analogues do, increase or replace production to normal or supra-normal levels. The increased levels of GLP-1 will have positive effects, including blood glucose lowering, as summarised in Table 1.5-9

The DPP-4 inhibitors can be divided into two classes; those which mimic the dipeptide structure (peptidomimetic) of the DPP-4 enzyme, and the so-called non-peptidomimetic class. Five molecules will be discussed. The first three are vildagliptin,10-12 sitagliptin13-15 and saxagliptin16,17 and all are peptidomimetics. The other two are non-peptidomimetics called alogliptin18,19 and linagliptin.20,21 Their structures can be seen in Fig. 1.22

All five of these molecules are competitive, reversible inhibitors of DPPs with a high affinity for DPP-4. Their modes of action differ however. Sitagliptin,1 alogliptin18 and linagliptin20 form non-covalent bonds with the catalytic site. Vildagliptin10 and saxagliptin16 act by a two-step process. A reversible covalent enzyme-inhibitor complex is formed with a slow rate of inhibitor bonding and dissociation, resulting in the enzyme slowly equilibrating between the active and the inactive forms. This explains the much longer duration of action of these drugs compared to their half-lives and this will have implications for their pharmacokinetics.

Many studies have been published on the efficacy and potency of each of these molecules, but only one compared them directly. This study showed that there is very little difference in efficacy, but that potency varied significantly, as measured by IC50.23 There is a marked variation in the half-life of the drugs, as can be seen in Table 2.12,15,17,24,25

The differences in half-life are reflected in the therapeutic doses (ranging from 5 mg for saxagliptin to 100 mg for sitagliptin), and in the dosing frequency (once daily for all, except vildagliptin which is twice daily). Despite the differences in potency, when used at their therapeutic doses, the effects of the inhibitors (extent of DPP-4 inhibition in vivo) are broadly similar. More than 90% inhibition is achieved within 15 minutes of drug administration, with 70–90% inhibition being sustained 24 hours post dose.22 For vildagliptin, the

Table 1. The effects of GLP-1.5-9

1. Delay gastric emptying2. Enhance satiety3. Suppress appetite4. Glucose-dependant improved insulin production by beta-cells 5. Suppress post-prandial glucagon release and hepatic glucose output

(glucose-dependent)6. Improve beta-cell function and mass7. Decrease beta-cell apoptosis (animal studies)8. Enhance beta-cell neogenesis (animal studies)

Fig. 1. The structure of the DPP-4 inhibitors.22



Table 2. Biochemistry, pharmacodynamic and pharmacokinetic profiles of DPP-4 inhibitors.

DPP-4 inhibitor Class Metabolised Excretion Selectivity DPP-4 inhibition t1/2 (h) Dosing

Sitagliptin B-amino acid-based Not Renal High Max 97%> 80% 24 h post dose

8–24 100 mg/day

Vildagliptin Cyanopyrrolidine Hydrolysed in liver, inactivated

Renal, 22% as parent, 55% metabolite

Moderate Max 95%> 80% 12 h post dose

1.5–4.5 50 mg bd

Saxagliptin Cyanopyrrolidine Liver, active metabolite

Renal, ± half as active metabolite

Moderate Max 80%70% 24 h post dose

2–4 parent3–7 metabolite

5 mg/day

Alogliptin Modified pyrimidin-edione

Not Renal > 70% unchanged

High Max 90% 75% 24 h post dose

12–21 25 mg/day

Linagliptin Xanthine based Not Biliary > 70% unchanged

Moderate Max 80% 70% 24 h post dose

10–40 5 mg/day

extent of plasma DPP-4 inhibition drops to around 50% after 24 hours with 50 mg once daily, but the twice-daily therapeutic dosing regimen maintains plasma DPP-4 inhibition at > 80% over the full 24-hour period.10-12

One of the potential problems of these drugs is that DPP-4 is a member of a large family of protease enzymes. The selectivity of the drugs to block only the breakdown of the required DPP-4 enzyme is critical to limit unwanted side effects. It is therefore very important to assess the selectivity of these drugs because inhibition of, for example, DPP-8 and -9 have been linked to unwanted toxicities and side effects, especially on T-cell activation and proliferation.26,27 The selectivity for the enzyme is summarised in Table 2.

Sitagliptin and alogliptin are the most selective of the five molecules discussed and have practically no inhibitory activity on the other members of the family. Vildagliptin and saxagliptin are less selective with regard to inhibition of DPP-8/9 in vitro,28,29

although the significance in vivo is questionable because DPP-8/9 are located intracellularly.

Linagliptin is very selective with regard to DPP-8/9 and is less selective with regard to fibroblast activation protein-α (FAPα). FAPα is an extracellular enzyme which is not generally present in normal adult tissue (although it is expressed in stromal fibroblasts and upregulated during tissue remodelling).30 The clinical relevance of this is not clear because the extent of any FAPα inhibition in vivo with the therapeutic dose of linagliptin in humans has not been reported.

These agents have also been studied for possible drug interactions by assessing their activity against CYP-450 and many other enzymes. No activity could be demonstrated, except for linagliptin which has weak activity against CYP-3A4.21

In general this group of drugs has very few reported drug interactions. Many drug interactions have been studied, including other oral diabetic drugs as well as simvastatin, and none of them had any relevant interactions.12,15,17

However, CYP3A4/5 is important for the activation of saxagliptin, and potent inhibitors of these enzymes (such as ketoconazole) increase the concentration of the parent drug, requiring dose reduction of saxagliptin to half dose when co-administered with these drugs.31 Linagliptin has been shown to be a weak inhibitor of these enzymes and the potential for drug interactions are considered weak, with less than a two-fold increase in drug concentration.21

PharmacokineticsOne of the major benefits of DPP-4 inhibitors is that they can be taken orally (compared to the GLP-analogues), with rapid absorption

and onset of action as quickly as five minutes after ingestion. Their oral bioavailability varies but is generally high.32-35

The volume of distribution of DPP-4 inhibitors varies widely and is greater than the total body water, suggesting wide tissue distribution. Their chemistry suggests that they might not penetrate cell membranes; the only molecule which has been shown to penetrate cell membranes in high concentration is vildagliptin.12,15,24,34 This was shown in rat studies at more than 600 times the human dose and it is unlikely to be relevant for human use.28 Saxagliptin has been shown to have very little potential for membrane permeability, and few data are available on the other drugs.17

These drugs have variable reversible protein binding, but seem not to cross the blood–brain barrier.12,34,36 They do however cross the placenta freely and should not be used in pregnancy and lactation.12,15,17

Three of these drugs, sitagliptin, alogliptin and linagliptin are not metabolised significantly and are predominately eliminated unchanged.22 Although sitagliptin has three active metabolites, their concentration and affinity are low and they are not clinically significant.15 In contrast, vildagliptin and saxagliptin are extensively metabolised. Vildagliptin is predominantly metabolised in the liver by a CYP-450-independent mechanism.12 Saxagliptin is also metabolised by the liver using the CYP3A4/5 enzymes and has an active metabolite which is responsible for 50% of its potency.17

The DPP-4 inhibitors are mainly excreted via the kidneys by an active transport mechanism.22 Sitagliptin is actively excreted in the proximal tubule.37 Alogliptin is renally excreted, mainly unchanged.24,38 Saxagliptin and its main metabolite are also renally eliminated. Vildagliptin is excreted by the kidneys although only 22% is unchanged and the remainder is eliminated as metabolites from liver metabolism.11 Linagliptin is the exception to this rule and will be important in the renally impaired patient because the drug has a high degree of protein binding and is excreted via the hepatic/biliary route, mostly unchanged, in the faeces.21,25

In patients with renal impairment, sitagliptin has been fairly well studied and shown to be reasonably safe, even in moderate renal impairment.39,40 Patients with severe renal impairment have not been as well studied with any of the drugs. Current recommendations are that patients with mild renal impairment (CrCl > 50 ml/min) can use these drugs safely without dose change. In moderate renal impairment (CrCl 30–50 ml/min), halving of the sitagliptin and alogliptin doses is recommended.22,39 In severe renal impairment (CrCl < 30 ml/min), the safest current recommendation would probably be not to use this class until more data become available.



In the USA both sitagliptin and saxagliptin can be used in severe renal impairment, with dose adjustments.22 It would be expected that linagliptin should be safe in the renally impaired because it is not renally excreted, but too little data are available to make a recommendation. This drug is currently not available in South Africa.41

In patients with hepatic impairment, it seems that the pharmacokinetics is not clinically significantly changed. However, vildagliptin is not recommended in these patients.12 The effects of hepatic impairment on sitagliptin and alogliptin were very mild and not significant.15,24 Saxagliptin exposure increased with hepatic impairment and its active metabolite decreased.17 Therefore, saxagliptin should be used with caution in these patients and it is preferable to use one of the safer DPP-4 inhibitors (sita-, alogliptin). Linagliptin is primarily hepatically eliminated and should therefore not be recommended in liver disease. The characteristics of the DPP-4 inhibitors are summarised in Table 2.12,15,17,24,25

Side effectsThese drugs are in general well tolerated with few side effects, largely comparable to placebo in trials.22 Hypoglycaemic risk is low, which make these drugs safe in the elderly and those with cardiovascular disease. Hypoglycaemia only becomes a risk when the drugs are combined with sulphonylureas. They are all weight neutral, which is a further benefit compared to the sulphonylureas.

Vildagliptin was the first of these drugs on the market in South Africa and had been shown to cause increased liver transaminases in some of the trials, especially with the 100-mg once-daily dose, resulting in dose alteration to 50 mg bd. Hence the recommendation of liver-function tests prior to initiation of treatment, and three monthly thereafter for the first year. Liver disease is a contra-indication for its use, although no evidence of adverse liver outcomes were proven.12,42,43

Although earlier reports suggested increased urinary tract infections and nasopharyngitis, this was not confirmed by later analyses.22 No links to cancer or metabolic bone disease could be found. These drugs have also shown no negative cardiovascular symptoms in the available data.43-45 There are no current data to suggest increased risk of pancreatitis.22,43,47,48

Efficacy and useFrom the pharmacodynamic data, we expected to see similar lowering of HbA1c and fasting blood glucose levels when these drugs were compared to each other. The reasons for this include their comparative effects on DPP-4 inhibition. The data are mostly from different trials, not directly comparing the drugs, and showed very little difference between them. There is only one head-to-head study comparing sitagliptin to saxagliptin as add-on therapy, which showed similar HbA1c lowering, with sitagliptin being slightly better at lowering fasting blood glucose levels. This is probably related to the longer half-life of sitagliptin.49

The DPP-4 inhibitors showed significant lowering of HbA1c, postprandial and fasting blood glucose levels in multiple trials across the board. These trials showed the same trends already established with other drugs, i.e. that greater reduction in HbA1c levels is seen in patients with higher baseline levels. Some studies also showed equivalent HbA1c lowering compared to metformin,50,51 sulphonylureas52,53 and the glitazones.54,55 In general, the expected lowering of HbA1c levels from 8% baseline would be about 0.5–

1.0%. If, however, the baseline was 8.5–9.0%, the drugs could lower HbA1c levels by about 1% or more.22

These drugs are very safe and should be used early in type 2 diabetes. When used early, these agents are more efficacious. Their hypoglycaemic risk is very low, side effects are minimal and they are weight neutral. They are fairly well priced. Their well-described mode of action and correction of pathophysiology in type 2 diabetes gives further peace of mind. We are keenly awaiting cardiovascular disease outcome trials.

Our South African/SEMDSA guidelines are currently being rewritten and should be published early in 2012. This will include DPP-4 inhibitors as second-line treatment at primary level, after metformin and lifestyle changes, which will always be first-line treatment. If, however, metformin is not tolerated, DPP-4 inhibitors should be seriously considered as first-line therapy.

ConclusionThe DPP-4 inhibitors are a new class of antidiabetic agents which are here to stay and will probably be used as first- or second-line therapy. The different agents are very similar where safety, tolerability and efficacy are concerned. They do differ in structure, selectivity, half-life, route of elimination, dosing and use in patients with organ dysfunction. Currently we are limited by those registered by the Medicines Control Council, but I am sure that most, if not all, will eventually reach our shores.

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assessment report (EPAR) – scientific discussion. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/januvia/H-722-en6.pdf. Accessed 5 July 2010.Augeri DJ, Robl JA, Betebenner DA, 16. et al. Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005; 48: 5025–5037. European Medicines Agency (EMEA). Onglyza (saxagliptin) – European public 17. assessment report (EPAR) –CHMP Assessment Report. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/onglyza/H-1039-en6.pdf. Accessed 5 July 2010.Feng J, Zhang Z, Wallace MB, 18. et al. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J Med Chem 2007; 50: 2297–2300. Karim A, Bridson WE, Fleck P, 19. et al. Disposition of the dipeptidyl peptidase-4 inhibitor [14C] alogliptin benzoate ([14C]SYR-322) after oral administration to healthy male subjects (Abstract). AAPS Annual Meeting and Exposition, 9–15 November 2007.Eckhardt M, Langkopf E, Mark M,20. et al. 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem 2007; 50: 6450–6453. Blech S, Ludwig-Schwellinger E, Gräfe-Mody EU, Withopf B, Wagner K. The 21. metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos 2010; 38: 667–678. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: 22. a comparative review. Diabetes Obes Metab 2011; 13: 7–18.Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F, Mark M. 23. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther 2008; 325: 175–182. Covington P, Christopher R, Davenport M, 24. et al. Pharmacokinetic, pharmaco-dynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. Clin Ther 2008; 30: 499–512. Heise T, Graefe-Mody EU, Hüttner S, Ring A, Trommeshauser D, Dugi KA. 25. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab 2009; 11: 786–794. He YL, Wang Y, Bullock JM et al. Pharmacodynamics of vildagliptin in patients 26. with type 2 diabetes during OGTT. J Clin Pharmacol 2007; 47: 633–641. Boulton DW, Geraldes M. Safety, tolerability, pharmacokinetics and 27. pharmacodynamics of once daily oral doses of saxagliptin for 2 weeks in type 2 diabetic and healthy subjects (Poster 0606-P). Diabetes 2007; 56(Suppl. 1): A161. Burkey BF, Hoffmann PK, Hassiepen U, Trappe J, Juedes M, Foley JE. Adverse 28. effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited. Diabetes Obes Metab 2008; 10: 1057–1061. Kirby MS, Dorso C, Wang A,29. et al. In vitro enzymologic characteristics of saxagliptin, a highly potent and selective DPP4 inhibitor with “slow binding” characteristic (Abstract). Clin Chem Lab Med 2008; 46: A79. O’Brien P, O’Connor BF. Seprase: an overview of an important matrix serine 30. protease. Biochim Biophys Acta 2008; 1784: 1130–1145. Lankas GR, Leiting B, Roy RS, 31. et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 2005; 54: 2988–2994. Herman GA, Stein PP, Thornberry NA, Wagner JA. Dipeptidyl peptidase-4 inhibitors 32. for the treatment of type 2 diabetes: focus on sitagliptin. Clin Pharmacol Ther 2007; 81: 761–767. He YL, Sadler BM, Sabo R,33. et al. The absolute oral bioavailability and population-based pharmacokinetic modelling of a novel dipeptidylpeptidase-IV inhibitor, vildagliptin, in healthy volunteers. Clin Pharmacokinet 2007; 46: 787–802. Fura A, Khanna A, Vyas V, 34. et al. Pharmacokinetics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and clinical projections. Drug Metab Dispos 2009; 37: 1164–1171.Dittberner S, Duval V, Staab A, Troconiz I, Graefe-Mody U, Jaehde U. 35. Determination of the absolute bioavailability of BI 1356, a substance with nonlinear pharmacokinetics, using a population pharmacokinetic modelling approach (abstract 1110). Poster presented at 16th Annual Meeting of the Population Approach Group in Europe, København, Denmark; June 2007.

Available from URL: http://www.page-meeting.org/?abstract=1110. Accessed 5 July 2010.Fuchs H, Binder R, Greischel A. Tissue distribution of the novel DPP-4 inhibitor 36. BI 1356 is dominated by saturable binding to its target in rats. Biopharm Drug Dispos 2009; 30: 229–240. Herman GA, Stevens C, Van Dyck K, 37. et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 2005; 78: 675–688. Christopher R, Covington P, Davenport M, 38. et al. Pharmacokinetics, pharmaco-dynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects. Clin Ther 2008; 30: 513–527. Bergman AJ, Cote J, Yi B,39. et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care 2007; 30: 1862–1864. Chan JC, Scott R, Arjona Ferreira JC, 40. et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab 2008; 10: 545–555. Graefe-Mody U, Friedrich C, Port A, 41. et al. Linagliptin, a novel DPP-4 inhibitor: no need for dose adjustment in patients with renal impairment (Abstract 822). Diabetologia 2010; 53(Suppl. 1): S326. Press Release, 4th February 2008: Galvus42. ®, a new treatment for patients with type 2 diabetes, receives European approval for label update paving the way for EU launches. Available from URL: http://www.medicalnewstoday.com/articles/95931.php. Accessed 5 July 2010.Ligueros-Saylan M, Foley JE, Schweizer A, Couturier A, Kothny W. An assessment 43. of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of Phase II and II clinical trials. Diabetes Obes Metab 2010; 12: 495–509. Williams-Herman D, Engel SS, Round E,44. et al. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord 2010; 10: 7. Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M, Kothny W. 45. Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large phase III type 2 diabetes population. Diabetes Obes Metab 2010; 12: 485–494. Frederich R, Alexander JH, Fiedorek FT, 46. et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 2010; 122: 16–27. Engel SS, Williams-Herman DE, Golm GT,47. et al. Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis. Int J Clin Pract 2010; 64: 984–990. Dore DD, Seeger JD, Arnold Chan K. Use of a claims-based active drug safety 48. 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. Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and 49. safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev 2010; 26: 540–549.Aschner P, Katzeff HL, Guo H, 50. et al. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes Metab 2010; 12: 252–261. Schweizer A, Dejager S, Bosi E. Comparison of vildagliptin and metformin 51. monotherapy in elderly patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Obes Metab 2009; 11: 804–812. Ferrannini E, Fonseca V, Zinman B, 52. et al. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2009; 11: 157–166. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of 53. the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9: 194–205. Bolli G, Dotta F, Rochotte E, Cohen SE. Efficacy and tolerability of vildagliptin vs. 54. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab 2008; 10: 82–90. Scott R, Loeys T, Davies MJ, Engel SS. Efficacy and safety of sitagliptin when 55. added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2008; 10: 959–969.


RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE

A collaboration between the University of Stellenbosch and the Cape Peninsula University of Technology, investigating the

30-year cardiovascular risk profile of South Africans, has recently been published.1 In particular, South African individuals of mixed ancestry with non-diabetic hyperglycaemia and undiagnosed and self-reported diabetes were assessed.

The urban community of Bellville South, Cape Town provided 583 participants without a history of cardiovascular disease, who were eligible for lifetime estimation of risk for cardiovascular dis-ease. High cardiovascular disease risk (> 20%) was evident in nor-moglycaemic and younger subjects (under 35 years). Significant predictors of cardiovascular disease were found to be sibling his-tory of diabetes, and levels of triglycerides, low-density lipoprotein cholesterol and glycated haemoglobin (p < 0.001).

High lifetime risk of cardiovascular disease in South Africans of mixed ancestry: findings of the Bellville, South Africa pilot study

‘The high lifetime risk in normoglycaemic and younger subjects may be considered a warning that cardiovascular disease might take on epidemic proportions in the near future in this country’

developed for the assessment of cardiovascular disease risk over a 10-year period in general populations. The 10-year time frame of these models has faced criticism as the lifetime risk may be high, whereas the 10-year risk prediction may be low.

An algorithm allowing for 30-year risk assessment has recently been developed. Although this provides a lifetime risk level, criti-cism is that this method oversimplifies the risk and may also lead to overuse of medication. This method is additionally limited by patient-specific issues, such as socio-economic status and ethnic-ity.

Individuals of mixed-ancestry from the Bellville South commu-nity between the ages of 35 and 65 years were randomly selected for the cohort. Trained personnel administered a questionnaire designed to retrospectively obtain information on lifestyle factors such as smoking and alcohol consumption, physical activity, diet, family history of cardiovascular disease and diabetes, as well as demographic considerations. A detailed drug history was obtained and clinical measurement included height, weight, hip and waist circumferences, body fat measurements and blood pressure.

Other than self-reported diabetic subjects, all participants under-went a 75-g oral glucose-tolerance test, with fasting blood glu-cose determinations in all participants. Blood assessments included plasma glucose, glycosylated haemoglobin (HbA1c), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides.

Relationship between dysglycaemia and cardiovascular riskPrevious studies of the South African population have indicated marked geographical and ethnic variations in the prevalence of diabetes. The South African Indian popula-tion has the highest incidence of diabetes, followed by individuals of mixed ancestry. Mortality from cardiovascular disease is two- to four-fold higher in individuals with type 2 diabetes mellitus. The relationship between dysglycaemia and cardiovascular disease is linear, and sometimes starts below the diag-nostic level of diabetes.

The aim of this pilot study was to assess the lifetime cardiovascular disease risk in the mixed-ancestry population of South Africa in individuals with non-diabetic hypergly-caemia, undiagnosed diabetes, known dia-betes and normoglycaemia.

Cardiovascular risk assessment: 10- vs 30-year modelsMathematical equations incorporating major cardiovascular disease risk factors (age, gender, high blood pressure, smoking, dys-lipidaemia and diabetes), as well as models from the Framingham Heart Study and the UK Prospective Diabetes Study have been

Table 1. Cardiovascular disease risk factors used in the equation in different age groups.

Age groups (years)

CVD risk factor 20–30 31–40 41–50 51–60

% males 9.5 16.7 36.50 37.3

% BMI < 25 kg/m2 50 22.95 30.81 20.71

% BMI ≥ 25, < 30 kg/m2 29.17 24.59 25.12 29.80

% BMI ≥ 30 kg/m2 20.83 52.46 44.08 49.49

SBP (mmHg)* 112.7 ± 13.9 113.9 ± 13.7 119.4 ± 17.1 125.6 ± 17.6

TC (mmol/l)* 4.7 ± 1.1 5.1 ± 1.0 5.4 ± 1.1 6.0 ± 1.2

HDL-C (mmol/l)* 1.2 ± 0.26 1.2 ± 0.37 1.3 ± 0.35 1.3 ± 0.36

% smoking 63.27 49.18 47.42 44.72

TRTBP 10.42 12.30 25.59 47.45

Diabetes status

% IFG 2.04 4.96 5.63 3.52

% IGT 2.04 13.22 15.02 20.60

% undiagnosed DM 4.08 5.79 13.62 18.59

% self-reported DM 0 5.79 6.57 14.07

Lipid full (%)# 8.5 ± 6.9 19.4 ± 13.0 35.1 ± 17.6 56.6 ± 18.2

*Replicated measurements, #Mean ± standard deviation.CVD, cardiovascular disease; BMI, body mass index; SBP, systolic blood pressure; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; TRTBP, treatment for blood pressure; IFG, impaired fasting glucose; IGT, impaired glucose tolerance, DM, diabetes mellitus.


SA JOURNAL OF DIABETES & VASCULAR DISEASE RESEARCH ARTICLE

Study outomes

The pattern of cardiovascular disease risk factors used in the 30-year risk calculator is shown in Table 1. It was found that risk of diabetes, hypertension and cardiovascular disease generally increased with age. In this study, diabetic subjects were at significantly higher risk for cardiovascular disease. Significant differences were observed between the estimated cardiovascular disease risk in non-diabetic, normal-weight and obese subjects, with high risk scores still evi-dent in the normal-weight, normoglycaemic individuals.

The criticism that 10-year models underestimate cardiovascular disease risk by allowing for continued progression of sub-clinical atherosclerosis was evident in this study where more than 20% of young, normoglycaemic subjects presented a high risk score. Intra-class correlation between lipid- and body mass index (BMI)-based equations showed that either method could be used for cardio-vascular disease risk estimation. The study also observed a strong association between HbA1c level and cardiovascular disease risk.

Application in practiceResults from this study have important public health implications, as cardiovascular disease is often underestimated in the young. Cardiovascular disease risk can easily be estimated in a primary healthcare setting due to inter-convertibility of lipids and BMI in risk estimation. Interestingly, a significant number of participants were unaware of their diabetic status. So, in addition to improving the primary healthcare system towards a chronic disease management approach, the inclusion of education on cardiovascular disease in school and university curricula may assist in reducing the preva-lence of obesity and the metabolic syndrome.

G Hardy

ReferenceMatsha TE, Hassan MS, Kidd M, Erasmus RT. The 30-year cardiovascular risk profile 1. of South Africans with diagnosed diabetes, undiagnosed diabetes, pre-diabetes or normoglycaemia: the Belville, South Africa pilot study. Cardiovasc J Afr 2012; 23(1): 5–11.

This peer-reviewed journal is available as full text at all tertiary institutions in South Africa, presenting a great opportunity to submit your

good-quality original articles for speedy publication.

Recent user research has shown that some 10 000 annual topic searches were done on the SA Journal of Diabetes & Vascular Disease database,

which contains seven years of published material.

The SA Journal of Diabetes & Vascular Disease aims to provide a forum for specialists involved in the care of people with diabetes, to exchange information,

promote better management and stimulate research in Africa.

This quarterly journal publishes original research and scholarly reviews about prevention and management of diabetes, relating to both general and

specific issues.

The SA Journal of Diabetes & Vascular Disease invites you to submit your articles online only. Read the Instructions to Authors at

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Correspondence to: MA Zaki Chemical Pathology Department, Medical Research Institute, Alexandria University, Egypt Tel: +203 428-2331Fax: +203 428-3719e-mail: [email protected], [email protected]

KM AhmedCardiology and Angiology Unit, Internal Medicine Department, Medical Research Institute Teaching Hospital, Alexandria University, Egypt


Impact of vascular complications on serum levels of soluble RAGE and TNF-α in females with type 2 diabetes

AbstractBackground: Binding of advanced glycation end products (AGEs) to AGE receptors (RAGE), and endothelial dysfunction resulting from oxidative stress and pro-inflammatory cytokines, such as tumour necrosis factor (TNF-α), contribute to the pathogenesis of diabetic vascular complications. A soluble form of RAGE (sRAGE) acts as a decoy receptor in an attempt to decrease cellular binding of AGEs. We aimed to measure sRAGE, TNF-α and the products of lipid peroxidation (thiobarbituric acid-reactive substances: TBARS) in females with type 2 diabetes with and without vascular complications.Methods: Forty-five females with type 2 diabetes (30 with vascular and 15 without vascular complications) were compared to 15 healthy control females. Serum sRAGE and TNF-α were measured with enzyme immunoassays specific for each, while plasma TBARS was determined colorimetrically. Results: Diabetic females with vascular complications had higher mean serum value of both sRAGE and TNF-α, as well as a higher plasma TBARS mean value, compared to the other two groups. The mean sRAGE value was higher in those with both micro- and macrovascular complications compared to those without vascular complications. Serum sRAGE values correlated with duration of diabetes in the whole patient group. Conclusion: A high plasma sRAGE value in the diabetics with vascular complications implicates a possible role of vascular insult in triggering sRAGE production in a trial to overcome AGEs toxicity. The use of RAGE as a potential therapeutic means could benefit the diabetic patients with vascular complications, particularly those presenting with microvascular complications.

Keywords: soluble RAGE, tumor necrosis factor-α, lipid peroxidation products, type 2 diabetes vascular complications

Submitted 18/6/2011, accepted 1/2/2012

MA ZAKI, KM AHMED

Diabetes mellitus, particularly type 2 diabetes, is increasing at an alarming rate.1 Its macro- and microvascular complications are the main causes of morbidity and mortality in diabetics.2 Several mechanisms are proposed for explaining the link between chronic hyperglycaemia and both the onset and progression of diabetic vascular complications, including the non-enzymatic glycation of proteins and lipids, with the resultant formation of irreversible advanced glycation end products (AGEs).3

The AGEs exert their effects on cellular function through interaction with receptors associated with increased oxidative stress, growth, and inflammatory effects, known as receptors for AGE (RAGE).4 Other receptors involved in AGE detoxification include macrophage scavenger receptors class A, type-II (MSR-AII) and class B type-I (MSR-BI),5 AGE receptor-1 [AGE-R1, oligosaccharide transferase-48 (OST-48)], AGE receptor-2 (AGE-R2, 80K-H phosphoprotein) and AGE receptor-3 (AGE-R3, galectin-3).6,7

The RAGE is a signal-transducing receptor for AGEs that mediates diverse cellular responses. Engagement of RAGE amplifies the development of complications, particularly in a ligand-enriched environment.8,9 Being a member of the immunoglobulin superfamily, RAGE is a multi-ligand receptor, expressed by a variety of cell types including endothelial cells, smooth muscle cells, lymphocytes, monocytes and neurons.8,9 Since RAGE recognises tertiary structures rather than amino acid sequences, RAGE has the ability to engage classes of molecules rather than individual ligands.

In diabetic blood vessels, an up-regulation of RAGE and its ligands, particularly AGEs and S100/calgranulins occurs.10 One of the best-documented consequences of RAGE activation is the generation of reactive oxygen species (ROS). Increased ROS is also associated with the formation of AGEs. At sites of vascular inflammation there would be an expectation of increased ROS formation, which would be further enhanced by the activation of RAGE.11

A 50-KDa soluble form of RAGE (sRAGE) exists in circulating blood and extracellular fluids, resulting from either alternative splicing of RAGE mRNA, called endogenous secretory RAGE (esRAGE), or neprilysin-mediated proteolytic cleavage of membrane-bound RAGE, called cleaved RAGE (cRAGE).12,13 Whatever its source, sRAGE exerts cytoprotective properties against the action of AGEs by acting as a decoy receptor that binds ligands, thus preventing them from reaching the cell surface of RAGE and exerting their effects.14

The hyperglycaemia-induced oxidative stress and pro-inflammatory cytokines, such as tumour necrosis factor (TNF-α), have a share in the endothelial dysfunction seen in diabetic vascular complications.15 In addition, both AGEs and TNF-α were shown to enhance RAGE expression in human vascular endothelial cells via activation of the p65/p50 complex of nuclear factor kappa-B.16

Our study aimed to measure serum sRAGE and TNF-α as well as plasma lipid peroxidation products (TBARS) in females with type 2 diabetes presenting with vascular complications, and to correlate them with type of vascular complications.



Methods The study was conducted at the Medical Research Institute Teaching Hospital, Alexandria University, with 60 adult female subjects, 45 of them suffering from type 2 diabetes mellitus. These were divided into 15 patients without clinically manifest vascular complication(s), and 30 with vascular complications. A group of 15 healthy females of matched age and socio-economic status were chosen as a control group.

Written consent was obtained from all females participating in this study. It was approved by the Institute’s ethics committee.

The female patients in the study were selected to be free of intercurrent acute illness, urinary tract infection, end-stage renal disease, malignancy, rheumatoid arthritis, inflammatory bowel diseases such as ulcerative colitis, and neurological diseases such as Alzheimer’s dementia. At the time of this study, all the diabetic females were receiving insulin and oral hypoglycaemic agents and 83% of them received angiotensin converting enzyme (ACE) inhibitors. None received antioxidant treatment.

A detailed history was taken from all subjects and a thorough physical examination was carried out. Twelve-lead standard electrocardiograms and B-mode ultrasonography were done on the common carotid arteries for measuring the carotid intima–media thickness (CIMT).

Laboratory investigations were carried out on all participants. Morning mid-stream urine specimens were obtained for complete urine analysis, along with a quantitative determination of albumin using an immunoturbidimetric assay,17 and calculation of the albumin/creatinine ratio (ACR).18 Concomitant venous blood samples were obtained following a 12-hour fast. Care was taken in the choice of an appropriate anticoagulant.

Whole EDTA blood was used for glycated haemoglobin (HbA1c) determination using an immunoturbidimetric assay.19 A portion of

the serum was used for the determination of concentrations of glucose, urea, creatinine, cholesterol (total, high- and low-density fractions) and triglycerides. Analyses of urine, EDTA whole blood and serum were conducted on the Konelab 30i clinical chemistry analyser (Thermoelectron Corporation, OY Vantaa, Finland). Serodetection of rheumatoid factor was done using the latex agglutination test.20

The rest of the serum sample was stored at –80°C until the time of determination of sRAGE (cat. no. DRG00, R&D systems, Minneapolis, MN) and TNF-α (cat. no. BMS223/3, Bender Med-systems, GmbH), using commercial enzyme immunoassays according to the manufacturers’ instructions. The sRAGE enzyme immunoassay measured the total sRAGE pool resulting from both cleavage and alternative splicing of RAGE. No significant cross-reactivity or interference was observed for EN-RAGE, HMG-1, S100A10, or S100B with sRAGE, as stated by the manufacturer. No significant cross-reactivity or interference was observed for soluble TNF receptors (60 kDa and 80 kDa) with TNF-α, as stated by the manufacturer. The intra- and inter-assay coefficients of variation for sRAGE assays were < 6 and < 8%, while for TNF-α they were < 6 and < 7.4%. The minimum detection limit for sRAGE and TNF-α enzyme immunoassays were 4.12 and 2.3 pg/ml, respectively.

EDTA plasma was used for the determination of thiobarbituric acid-reactive substances (TBARS) using a colorimetric assay, based on the reaction of thiobarbituric acid with a malondialdehyde product of the reactive oxygen species.21

Statistical analysis was done using SPSS version 11.5 (SPSS, Inc, Chicago, IL, USA).22 Data were coded and fed into the SPSS software package. Descriptive measures, namely mean and standard deviation, were done for each variable in every group. Data comparison between groups was done using analysis of variance (ANOVA). Pearson’s correlation coefficient (r) was applied

Table 1. Clinical data in the studied groups, including the frequency of vascular complications of diabetes mellitus in diabetics with vascular complications.

Demographics Control group (I)

Diabetic group

Without vascular With vascular complications (II) complications (III)

p-value

P1 P2 P3Number 15 15 30

Age (years) 39.7 ± 7.8 44.2 ± 8.1 44.1 ± 6.5 NS NS NS

Blood pressure

Systolic (mmHg) 113 ± 8 127 ± 12 140 ± 21 0.033 < 0.001 0.012

Diastolic (mmHg) 77 ± 5 84 ± 9 89 ± 12 0.043 < 0.001 NS

CIMT (mm) 0.64 ± 0.1 0.69 ± 0.1 0.84 ± 0.1 NS < 0.001 < 0.001

DDM (years) - 7.7 ± 4.2 11.2 ± 5.7 0.039

Types of vascular complications in group III Frequency Percentage (%)

Nephropathy 27/30 90

Retinopathy 19/30 63.3

Neuropathy 17/30 56.7

Cardiovascular disease 14/30 46.7

Cerebrovascular disease 4/30 13.3

Peripheral vascular disease 8/30 26.7

CIMT: carotid intima–media thickness, DDM: duration of type 2 diabetes. p < 0.05 was considered statistically significant, p < 0.001 was considered highly significant, NS: not statistically significant. P1: statistical difference between the control and the diabetic group without vascular complications. P2: statistical difference between the control and the diabetic group with vascular complications. P3: statistical difference between the diabetic groups with and without vascular complications.



to our results to test the hypothesis of a linear relation between the studied variables within the same group. A p-value < 0.05 was considered statistically significant.

ResultsThe mean age of all females participating in this study was comparable. The duration of diabetes mellitus in the females suffering from vascular complications was significantly higher than those not suffering from vascular complications, indicating that the process of development of vascular complications in diabetes is determined by the duration of exposure to uncontrolled hyperglycaemia.

The types of vascular complications in the diabetic females were mostly microvascular complications, namely nephropathy (90%), retinopathy (63%) and neuropathy (57%), followed by macrovascular complications, namely cardiovascular disease (47%), peripheral vascular disease (27%) and cerebrovascular disease (13%). The carotid intima–media thickness (CIMT), which monitors the degree of atherosclerosis, was significantly higher in the group presenting with vascular complications when compared to both the control group and those without vascular complications (Table 1).

The mean value of the albumin-to-creatinine ratio (ACR) in the diabetic females with vascular complications was significantly higher than the mean ACR values in both the diabetic females without vascular complications and the control group (Table 2).

Plasma glucose, reflecting momentary changes in glycaemic status and whole blood glycated haemoglobin (HbA1c), reflecting

long-term monitoring of glycaemic control, were significantly higher in both groups of diabetic females compared to the control group, and even more elevated in those with vascular complications compared to those without complications. Urea and creatinine, although showing some significant differences between the groups, were within the reported safe reference intervals.

The lipid profile in the three groups demonstrated significantly higher mean values of total cholesterol, low-density lipoprotein cholesterol and triglycerides, and lower mean values of high-density lipoprotein cholesterol in the diabetic group with vascular complications compared to the control group. There was no statistically significant difference in lipid profile between the two groups of diabetic patients (Table 2).

Markers of oxidative stress measured in this study, namely thiobarbituric acid-reactive substances, showed significantly higher mean values in both patient groups compared to the control group, as well as a significantly higher mean value in the group presenting with vascular complications compared to those without vascular complications (Table 2).

Soluble RAGE in the diabetic group without vascular complications showed a significantly lower mean value compared to the diabetic group with vascular complications and the control group. No significant difference was noted between the control group and the patients with vascular complications (Table 2). On the other hand, soluble TNF-α mean values in the patients with vascular complications were significantly higher compared to the

Table 2. Biochemical and calculated parameters in whole blood, plasma and urine of patients in the studied groups.

Analytes Control group (I)

Diabetic groupp-value

Without vascular complications (II)

With vascular complications (III) P1 P2 P3

Random urine sample

Albumin (mg/l) 9.97 ± 2.04 11.4 ± 3.81 341.9 ± 271.5 NS < 0.001 < 0.001

Creatinine (gm/l) 1.27 ± 0.21 1.09 ± 0.33 1.53 ± 0.75 NS NS 0.019

ACR (mg/gm) 7.99 ± 1.74 11.13 ± 4.16 237.07 ± 186.8 NS < 0.001 < 0.001

Fasting whole venous blood sample

HbA1c (%) 4.92 ± 0.43 7.72 ± 1.64 9.66 ± 1.97 < 0.001 < 0.001 < 0.001

Fasting plasma sample

Heparin plasma

Glucose (mmol/l) 4.95 ± 0.33 8.58 ± 1.98 13.48 ± 3.41 < 0.001 < 0.001 < 0.001

Urea (mmol/l) 3.33 ± 0.83 5.81 ± 1.33 6.31 ± 3.49 NS 0.011 0.014

Creatinine (μmol/l) 71.60 ± 7.96 88.4 ± 14.14 95.47 ± 34.48 NS 0.004 NS

Total cholesterol (mmol/l) 4.40 ± 0.34 4.92 ± 0.67 5.39 ± 0.98 NS < 0.001 NS

HDL–C (mmol/l) 1.42 ± 0.21 1.11 ± 0.21 1.06 ± 0.23 0.001 < 0.001 NS

LDL–C (mmol/l) 2.56 ± 0.28 3.21 ± 0.54 3.57 ± 0.80 0.009 < 0.001 NS

Triglycerides (mmol/l) 0.95 ± 0.25 1.34 ± 0.51 1.60 ± 0.87 NS 0.003 NS

EDTA plasma

TBARS (μmol/l) 1.69 ± 0.52 2.95 ± 1.89 5.73 ± 1.32 0.014 < 0.001 < 0.001

Fasting serum sample

sRAGE (pg/ml) 1261 ± 496 691 ± 537 1279 ± 758 0.025 NS 0.009

TNF-α (pg/ml) 8.45 ± 4.66 11.08 ± 6.64 23.15 ± 23.32 NS 0.009 0.035

p < 0.05 was considered statistically significant, p < 0.001 was considered highly significant, NS: not statistically significant.P1: statistical difference between control group and diabetic group without vascular complications.P2: statistical difference between control group and diabetic group with vascular complications.P3: statistical difference between diabetic patients with and without vascular complications.ACR: albumin-to-creatinine ratio, HbA1c: glycated haemoglobin, A1c fraction, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, sRAGE: soluble from of receptor for advanced glycation end products, TBARS: thiobarbituric acid-reactive substances, TNF-α: tumour necrosis factor-alpha.



mean values in those without vascular complications and the control group (Table 2).

Upon dividing the diabetic females with vascular complications according to the type of vascular complication, serum sRAGE and plasma TBARS mean values were significantly higher in each entity of micro- and macrovascular types of complications compared to the group without vascular complications. As for serum TNF-α, its mean value was significantly higher in those with nephropathy, neuropathy and ischaemic heart disease compared to those without vascular complications (Table 3).

DiscussionAge, male gender and smoking are considered risk factors for the overall risk of coronary artery disease (CAD), a major macrovascular complication of diabetes.23 Only non-smoking female subjects were included in our study to nullify such risk factors. Mogensen reported that 30% of patients with type 2 diabetes had hypertension at the time of diagnosis, and when nephropathy developed, almost 70% had high blood pressure.24 In the present work, 33.33% of the diabetic patients without vascular complications were hypertensive, while in the diabetic patients with vascular complications, 53.33% were hypertensive.

Soluble forms of RAGE are up-regulated in diabetics, particularly those presenting with vascular complications. The serum sRAGE mean value in the diabetic females with vascular complications was significantly higher than the mean in patients without vascular complications (Table 2). Angiotensin converting enzyme (ACE) inhibitors are known to be sRAGE inducers,25 and since 83% of our diabetic females with vascular complications were receiving ACE inhibitors, this could partly explain the rise in serum sRAGE in those with vascular complications. Such high values in the diabetics with vascular complications represent an attempt by the body to overcome the toxic effect of the AGEs present in the affected blood vessels.

The relation of sRAGE to duration of diabetes has been addressed by Challier et al. who observed lack of this association in type 1 diabetes patients.26 We were able to demonstrate a significant

positive correlation (r = 0.434, p = 0.004) between circulating sRAGE and the duration of diabetes in the whole group of diabetic females. The degree of non-enzymatic glycation is determined mainly by glucose concentration and time of exposure. Therefore a longer duration of diabetes with associated hyperglycaemia results in sustained stimulation of the formation of AGEs, with its positive regulatory effect on RAGE expression.27

TBARS, end-products of free radicals, are the most popular molecules used as an indicator of lipid peroxidation.28 Their mean plasma values were significantly higher in both groups of diabetic patients compared to the corresponding control group, and again significantly higher in those with vascular complications compared to those without vascular complications (Table 2).

The long-established role of oxidative stress in accelerated atherosclerosis and its development before late complications become clinically evident indicates that oxidative stress plays a crucial role in the pathogenesis of late diabetic complications.29 This is clearly evident in the positive relation of plasma TBARS with CIMT (r = 0.502, p ≤ 0.001) and urinary ACR (r = 0.437, p = 0.003). Furthermore, significant positive relations of TBARS with both duration of diabetes (r = 0.351, p = 0.018) and HbA1c levels (r = 0.512, p < 0.001) in the whole diabetic group emphasise that prolonged poor glycaemic control potentiates oxidative stress in diabetic patients.

In agreement with studies demonstrating increased serum levels of inflammatory markers such as TNF-α in type 2 diabetes patients, where lack of tight glycaemic control increased their serum levels,30,31 a significantly higher mean serum TNF-α value was noted in the diabetic females with vascular complications compared to those without vascular complications and the control group. Tanaka et al. proposed that increased TNF-α levels in type 2 diabetes patients may worsen diabetic vasculopathy via RAGE gene induction,16 yet no information regarding the effect of TNF-α on sRAGE exists.

Regarding microvascular complications, the diabetic females presenting with nephropathy had higher serum mean values of sRAGE and TNF-α compared to those without microvascular

Table 3. Serum sRAGE, TNF-α, and plasma TBARS mean values in each type of vascular complications present in the diabetic group compared to those without vascular complications.

Patients without vascular

complications

Patients with vascular complications (n = 30)

Nephropathy Retinopathy NeuropathyIschemic heart

disease Peripheral

vascular disease

sRAGE (pg/ml) (n = 15) (n = 27) (n = 19) (n = 17) (n = 14) (n = 8)

Mean± SD

691537

1312772

1420841

1423809

1406966

15541021

p-value 0.006 0.010 0.006 0.027 0.019

TNF-α (pg/ml) (n = 15) (n = 26) (n = 19) (n = 16) (n = 14) (n = 8)

Mean± SD

11.086.64

22.1522.01

25.4025.10

27.2027.10

29.9028.20

21.6020.30

p-value 0.022 NS 0.040 0.023 NS

TBARS (μmol/l) (n = 15) (n = 27) (n = 19) (n = 17) (n = 14) (n = 8)

Mean± SD

3.01.9

5.81.4

5.70.3

6.31.4

6.11.4

6.01.6

p-value < 0.001 < 0.001 < 0.001 < 0.001 0.001

p < 0.05 was considered statistically significant, p < 0.001 was considered highly significant.sRAGE: soluble form of receptor for advanced glycation end products, TBARS: thiobarbituric acid-reactive substances, TNF-α: tumour necrosis factor-alpha.



complications (Table 3). Grossin et al. reported a low serum sRAGE mean value in type 2 diabetics with nephropathy, compared to those without vascular complications, explained by possible true sRAGE consumption in an attempt to neutralise AGEs toxicity.32

Navarro et al. reported in diabetic patients a significant relationship between serum TNF-α levels and both microalbuminuria and urinary proteins.33 Being a pro-inflammatory cytokine, TNF-α is cytotoxic to glomerular, mesangial and epithelial cells, hence inducing significant renal damage independent of alterations in haemodynamic factors or effects of recruited inflammatory cells.34

A significantly higher plasma TBARS mean value was also noted in nephropathy cases. Dave and Kalia demonstrated a higher level of TBARS in diabetic nephropathy patients versus those without nephropathy.35

Retinopathy cases had significantly higher mean values of serum sRAGE and plasma TBARS compared to those without vascular complications (Table 3). Reports were inconsistent regarding the level of serum sRAGE or plasma TBARS in diabetic retinopathy.36,37

Neuropathy cases on the other hand had significantly higher mean serum values of sRAGE and TNF-α compared to those without vascular complications (Table 3).

Haslbeck et al. suggested that activation of the AGE/RAGE/NF-κB axis might contribute to the pathogenesis of diabetic polyneuropathy.38 High TNF-α levels in neuropathy cases could be attributed to the effect of hyperglycaemia, oxidative stress and AGEs on the macrophages in a diabetic state, where activated macrophages infiltrate nerve tissues, with the resultant local production of much TNF-α, resulting in endothelial and nerve fibre damage.39 Plasma TBARS mean value was significantly higher in those with neuropathy compared to those without vascular complications (Table 3). The results of previous studies were inconsistent in that aspect.40,41

Diabetic females suffering from ischaemic heart disease, one of the macrovascular complications of diabetes, had significantly higher levels of serum sRAGE and TNF-α compared to those without vascular complications (Table 3). Nakamura et al. reported a high serum level of sRAGE in diabetic patients with coronary artery diseases.42 Tuttle et al. reported mildly increased serum TNF-α levels in diabetic females with cardiovascular disease.43 Plasma TBARS mean value was significantly higher in our diabetic females with ischaemic heart disease compared to those without vascular complications, an observation also noted by Kesavulu et al.44

The number of diabetic females who suffered the cerebrovascular complications of diabetes was too small to generate valid statistical analysis. Regarding peripheral vascular disease, serum sRAGE and plasma TBARS had significantly higher mean values in diabetic females presenting with this type of macrovascular complication compared to those without vascular complications. Lapolla et al. demonstrated, in their study on type 2 diabetes patients, a higher plasma malondialdehyde level and its strong association with peripheral arterial disease.45

ConclusionThe low serum sRAGE mean value seen in diabetics without vascular complications compared to those with vascular complications implicated a true consumption of this decoy receptor molecule in the neutralisation of AGEs, followed by elimination of complexes via the reticulo-endothelial system, and hence a protective role against the development of AGEs-induced vascular complications. The high serum sRAGE mean level in diabetics with vascular

complications may represent a potential marker of diabetic vascular complications. In addition, in all diabetic females, the significant relation of sRAGE with duration of diabetes makes sRAGE an attractive molecule to be used in follow-up studies to assess its role as a predictor of development of vascular complications. Also, the generalised chronic inflammation seen in diabetics induces the production of pro-inflammatory cytokines such as TNF-α, with the resultant triggering of oxidative stress markers. This is of major importance in determining the degree of vascular damage.

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MaCarthy E, Sharma R, Sharma M. TNF-34. α increases albumin permeability of isolated rat glomeruli through the generation of superoxide. J Am Soc Nephrol 1998; 9: 433–438.Dave GS, Kalia K. Hyperglycemia induced oxidative stress in type-1 and type-2 35. diabetic patients with and without nephropathy. Cell Mol Biol 2007; 53: 68–78.Polak 36. M, Zagorski Z. Lipid peroxidation in diabetic retinopathy. Ann Univ Mariae Curie Skladowska Med 2004; 59: 434–437.Yonekura H, Yamamoto Y, Sakurai S, Watanabe T, Yamamoto H. Roles of the 37. receptor for advanced glycation end products in diabetes-induced vascular injury. J Pharmacol Sci 2005; 97: 305–311.Haslbeck KM, Neundorfer B, Schlotzer-Schrehardtt U, Bierhaus A, Schleicher 38. E, Pauli E, et al. Activation of the RAGE pathway: a general mechanism in the pathogenesis of polyneuropathies? Neurol Res 2007; 29: 103–110.Carrington AL, Litchfield JE. The aldose reductase pathway and nonenzymatic 39. glycation in the pathogenesis of diabetic neuropathy: A critical review for the end of the 20th century. Diabetes Rev 1999; 7: 275–299.Gallou 40. G, Ruelland A, Campion L, Maugendre D, Le Moullec N, Legras B, et al. Increase in TBARS and vascular complications in type 2 diabetes mellitus. Diabetes Metab 1994; 20: 258–264.Turk H41. M, Sevinc A, Camci C, Cigli A, Buyukberber S, Savli H, et al. Plasma lipid peroxidation products and antioxidant enzyme activities in patients with type 2 diabetes mellitus. Acta Diabetol 2002; 39: 117–122.Nakamura 42. K, Yamagishi S, Adachi H, Kurita-Nakamura Y, Matsui T, Yoshida T, et al. Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease. Diabetes Metab Res Rev 2007; 23: 368–371.Tuttl43. e HA, Davis-Gorman G, Goldman S, Copeland JG, McDonagh PF. Proinflammatory cytokines are increased in type 2 diabetic women with cardiovascular disease. J Diabetes Complicat 2004; 18: 343–351. Kesavulu M44. M, Rao BK, Giri R, Vijaya J, Subramanyam G, Apparao C. Lipid peroxidation and antioxidant enzyme status in Type 2 diabetics with coronary heart disease. Diabetes Res Clin Pract 2001; 53: 33–39.Lapolla 45. A, Piarulli F, Sartore G, Ceriello A, Ragazzi E, Reitano R, et al. Advanced glycation end products and antioxidant status in type 2 diabetic patients with and without peripheral artery disease. Diabetes Care 2007; 30: 670–676.

Diary for 2012 cardiovascular congresses

DATE PLACE CONFERENCE

18–21 April Dubai, United Arab Emirates World Congress of Cardiologywww.world-heart-federation.org

17–20 May Berlin, Germany Congress on Cardiac Problems in Pregnancy (CPP 2012)www.cppcongress.com

18-20 May Cape Town International Convention Centre

First annual congress of the Faculty of Consulting Physicians of South Africa www.physician.co.za

27 June Frankfurt, Germany iCi 2012 – Imaging in Cardiovascular Interventionswww.ici-congress.org

28 June Frankfurt, Germany CSI 2012 – Catheter Interventions in Congenital and Structural Heart Disease

19–22 July Sun City, South Africa 13th Annual SA Heart Congresswww.saheart.org

25–29 August Munich, Germany 2012 ESC, European Society of Cardiology Congresswww.escardio.org



Correspondence to: M Hossain Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh e-mail: [email protected]

O Faruque, I Khan, L Ali Research Division, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka, Bangladesh

G Kabir, D SikdarDepartment of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh


Association of serum tumour necrosis factor-α and interleukin-6 with insulin secretion and insulin resistance in subjects with type 2 diabetes in a Bangladeshi populationM HOSSAIN, O FARUQUE, G KABIR, I KHAN, D SIKDAR, L ALI

Abstract Objective: Epidemiological evidence suggests that levels of inflammatory markers, such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), can predict the development of diabetes but the association of these inflammatory markers with the basic pathology of type 2 diabetes is unclear. In the present study we investigated the association of TNF-α and IL-6 with insulin secretion and insulin sensitivity in subjects with type 2 diabetes. Methods: Thirty-seven subjects with type 2 diabetes were studied along with 56 age- and body mass index (BMI)-matched controls. Insulin was measured by ELISA analysis and TNF-α and IL-6 chemiluminescence-based EIA. Results: Fasting serum TNF-α and IL-6 levels were significantly higher in subjects with type 2 diabetes (p = 0.032) than in controls. In binary logistic regression analysis, TNF-α was significantly (p = 0.026) associated with diabetes when age, gender and BMI were matched. In linear multiple regression analysis, it was found that levels of HOMA S (p = 0.010), HOMA B (p = 0.003) and fasting glucose (p = 0.004), and WHR (p = 0.017) were negatively associated with TNF-α in diabetic subjects. In the same analysis, HOMA S (p = 0.013), HOMA B (p = 0.002) and fasting glucose levels (p = 0.001), and WHR (p = 0.038) were positively associated with IL-6 in diabetic subjects. The association of TNF-α was positive with IL-6 (p = 0.001). Conclusion: TNF-α and IL-6 levels were both associated with insulin resistance and insulin secretory defects in patients with type 2 diabetes, and hyperglycaemia seemed to be a major trigger for pro-inflammatory changes in diabetes.

Keywords: TNF-α, IL-6, cytokines, inflammatory marker

Submitted 21/7/2011, accepted 1/2/2012

Chronic inflammation plays an important role in the pathogenesis of type 2 diabetes.1 Recent studies have shown that serum levels of some inflammatory markers are elevated in patients with type 2 diabetes. Therefore, it has been suggested that long-term activation of the immune system is involved in the development of insulin resistance and type 2 diabetes mellitus.2 Tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are two major pro-inflammatory markers or cytokines and they act primarily as autocrine and/or paracrine factors. Studies have shown a relationship between various inflammatory markers, specifically TNF-α, IL-6, C-reactive protein and sialic acid, and the risk of developing type 2 diabetes.3-6

TNF-α is a pro-inflammatory cytokine secreted by several types of cells, such as macrophages, monocytes, neutrophils and T cells. Increased TNF-α synthesis has been shown in adipose tissue derived from obese rodents or human subjects, and TNF-α is considered a contributory factor in obesity-related insulin resistance and the pathogenesis of type 2 diabetes mellitus.7 TNF-α exerts its metabolic effects via multiple mechanisms: the down-regulation of genes that are required for normal insulin action, negative regulation of PPARγ an important insulin-sensitising nuclear receptor, the direct effects on insulin signalling, and induction of elevated free fatty acids via the stimulation of lipolysis.8

By contrast, IL-6 is a monomer of 184 amino acids, an immune protein in the haematopoietin family. It is synthesised by T cells, macrophages and endothelial cells found on a single gene located at 7p21. It is a major pro-inflammatory cytokine and is produced by activated leukocytes, adipocytes and endothelial cells. In vivo infusion of human recombinant IL-6 has shown it to induce gluconeogenesis, subsequent hyperglycaemia and compensatory hyperinsulinaemia.9 The role of IL-6 in insulin resistance is controversial.10 Adipocytes, skeletal muscle cells and hepatocytes are involved in peripheral insulin resistance and glucose homeostasis.

Evidence based on epidemiological studies suggests that inflammatory markers predict the development of diabetes and glucose disorders,3 but the association of these inflammatory markers with the basic pathology of type 2 diabetes is unclear. In a recent study it was claimed that TNF-α and IL-6 are associated with insulin resistance in type 2 diabetes.11 Other studies have shown that levels of these two inflammatory markers are elevated in the pre-diabetic, impaired glucose tolerance (IGT) condition.12,13 In a recent study on Bangladeshi pre-diabetic subjects, it was shown that TNF-α may have a causal relationship with an insulin secretory defect.

The present study was undertaken to determine the relationship of TNF-α and IL-6 with insulin resistance and insulin secretion in Bangladeshi subjects with type 2 diabetes, in order to better understand the mechanism of this deadly disease.



Table 1. Clinical, anthropometric and biochemical characteristics of control and diabetic subjects.

Parameters Controls (n = 56) Type 2 diabetes (n = 37)

Age (years) 38 ± 6 42 ± 6

Body mass index (kg/m²) 25.4 ± 3.9 24.3 ± 3.0

Waist-to-hip ratio 0.90 ± 0.05 0.94 ± 0.04* (p = 0.004)

Neck circumference (cm) 35.4 ± 3.0 36.2 ± 2.8

MUAC (mm) 296 ± 28 275 ± 57

Triceps (mm) 14.4 ± 5.2 11.4 ± 3.4* (p = 0.03)

Body fat mass (%) 29.2 ± 6.2 27.6 ± 25.8

Systolic blood pressure (mmHg)

114 ± 8 121 ±16

Diastolic blood pressure (mmHg)

76 ± 8 83 ± 8* (p = 0.008)

Fasting glucose (mmol/l) 5.1 ± 0.4 8.0 ± 2.0* (p = 0.004)

2-hour glucose (mmol/l) 5.8 ± 1.1 15.9 ± 3.5* (p = 0.004)

Triglycerides (mg/dl) 149 (52–376) 222 (54–532)* (p = 0.008)

Total cholesterol (mg/dl) 188 (90–261) 210 (161–278)* (p = 0.01)

HDL cholesterol (mg/dl) 31 (18–59) 30 (17-42)

LDL cholesterol (mg/dl) 127 (45–194) 135 (85–175)

Fasting insulin (pmol/l) 50 (7–155) 67 (25–145)

HOMA B 99 (21–187) 50 (13–141)* (p = 0.004)

HOMA S 88 (29–554) 61 (30–160)* (p = 0.04)

TNF-α (pg/ml) 9.9 (4.8–28.9) 12.3 (5.8–45.1)* (p = 0.03)

IL-6 (pg/ml) 2.8 (1.1–10.6) 4.0 (1.9–22.5)* (p = 0.03)

*p < 0.05, significantly different compared to controls when using Student’s t-test.MUAC = mid-upper arm circumference; HOMA B = B-cell function and HOMA S = insulin sensitivity, assessed by homeostasis model assessment; TNF-α = tumour necrosis factor-alpha; IL-6 = interleukin-6.

Table 2. Binary logistic regression analysis of TNF-α and IL-6 adjusted for confounding factors (using control as reference).

Group Factors B SE p-value Exp (B)

Type 2 diabetes TNF-α 0.103 0.047 0.026 1.109

BMI 0.048 0.065 0.461 1.049

Age 0.137 0.051 0.007 1.147

Gender –0.063 0.756 0.933 0.939

Constant –8.539 3.442 0.013 0.000

Type 2 diabetes IL-6 0.155 0.092 0.094 1.167

BMI –0.178 0.102 0.080 0.837

Age 0.182 0.056 0.001 1.200

Gender –0.293 0.707 0.679 0.746

Constant –3.406 2.997 0.256 0.033

MethodsThis retrospective analytical case–control study was conducted in the Research Division, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka. A group of 37 subjects with type 2 diabetes was selected from the outpatient department of BIRDEM. A group of 56 age-, gender- and body mass index (BMI)-matched healthy subjects without a family history of diabetes was selected as controls from among the circle of friends of the diabetic subjects, considering them to be of the same socio-economic status. Written consent was obtained from all volunteers.

A clinical history was taken by a registered physician using a self-administered, pre-designed questionnaire. Anthropometric measurements were carried out using standard methods. The measurement of height and weight was done with light clothes and without shoes. The weighing scale was calibrated daily with a known standard weight. Triceps, waist, hip and mid-upper arm circumference circumferences were measured with the tape measure provided by the nutritionist. Body fat mass (%) was measured using a body fat monitor, HBF 302, Omron Corp, Japan. Blood pressure was taken with a standard blood pressure machine after a 10-min rest.

After overnight fasting, subjects were requested to come on a pre-scheduled morning for the fasting blood sample. Subjects

were then given 75 g anhydrous glucose dissolved in 250 ml water. Blood was taken by venepuncture in the fasting condition and two hours after glucose loading.

Serum glucose, total cholesterol, triglyceride, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels were determined by enzymatic colorimetric methods using commercial kits (Randox Laboratories Ltd, UK). Serum insulin levels were determined using the enzyme-linked immunosorbent assay (ELISA) method (Linco Research Inc, USA). Serum TNF-α and IL-6 concentrations were measured by the solid-phase, enzyme labelled, chemiluminescent immunometric assay (IMMULITE, DPC). Using HOMA-CIGMA software, insulin secretory capacity (HOMA B) and insulin sensitivity (HOMA S) were calculated from fasting glucose and fasting insulin levels.14

SPSS (Statistical Package for Social Science) software for Windows version 10 (SPSS Inc, Chicago, Illinois, USA) was used for statistical analysis. Data are expressed as mean ± SD (standard deviation), median (range), and/or percentage (%), as appropriate. A p-value was assessed by ANOVA or Mann-Whitney U-test (as appropriate). Logistic and multiple regressions were done among the parameters. A two-tailed p-value of < 0.05 was considered statistically significant.

ResultsSubjects with type 2 diabetes had significantly higher waist-to-hip ratios (WHR) (p = 0.004), triceps skin-fold thickness (p = 0.03), diastolic blood pressure (p = 0.008) but not systolic blood pressure, than the controls. Fasting serum triglyceride (TG) and total cholesterol levels were significantly higher in the diabetic subjects compared to controls (p = 0.008 and 0.01, respectively). No significant differences in HDL and LDL cholesterol levels were shown in the diabetic subjects compared to the controls. HOMA B and HOMA S were significantly lower in the diabetic (p = 0.004, p = 0.04) subjects compared to controls. The diabetic subjects had significantly higher levels of serum TNF-α (p = 0.032) and IL-6 (p = 0.032) than the controls (Table 1).

On binary logistic regression analysis (Table 2), it was found that TNF-α was positively associated (p = 0.026) with the diabetic subjects when the controls were used as the reference value, and age, gender and BMI were adjusted for. Such an association of IL-6 with the diabetic state was not evident.



On multiple regression analysis (Table 3), considering TNF-α and IL-6 as dependent variables, HOMA B, HOMA S and fasting glucose levels, and WHR showed a significant negative association, and IL-6 showed a significant positive association with TNF-α, adjusting for the confounding factors in the diabetic subjects. HOMA B, HOMA S, TNF-α and fasting glucose levels, and WHR showed a significant positive association with IL-6, adjusting for the effects of the confounding factors in the diabetic subjects.

DiscussionType 2 diabetes mellitus is associated with increased inflammatory markers. Insulin resistance is a common feature of type 2 diabetes. It has been shown that inflammatory cytokines such as TNF-α and IL-6 have been linked to insulin resistance.15 The underlying mechanisms of the development of insulin resistance are not clear, but a key mechanism by which TNF-α was thought to induce insulin resistance involved serine phosphorylation of the insulin receptor substrate-1 (IRS-1).16 TNF-α level has been shown to be increased in patients with type 2 diabetes mellitus. However, whether it is involved in the development of type 2 diabetes mellitus and whether elevation of TNF-α precedes the onset of type 2 diabetes mellitus is not clear.

Recently it was shown that inflammation contributes to insulin resistance in obese and diabetic patients.17 Inflammatory molecules such as TNF-α and IL-6 may therefore play an important role. It was found that diabetic patients had elevated levels of TNF-α,18 which reinforces this hypothesis.

In our study, serum TNF-α levels were significantly higher in the diabetic subjects than in the controls. Other studies have documented that serum TNF-α concentrations were higher in subjects with impaired glucose tolerance than in those with normal glucose tolerance.11,19,20 A Korean study found no elevation in serum TNF-α concentrations in pre-diabetic patients compared to controls.21 Spranger et al. showed that baseline levels of TNF-α were significantly elevated among type 2 diabetes subjects (2.08 pg/ml) compared to controls (1.78 pg/ml, p = 0.002).22

Our study shows similar patterns of association in the type 2 diabetes subjects. Moreover on binary logistic regression analysis, TNF-α was significantly (β = 0.102, p = 0.039) associated with diabetes when TNF-α and IL-6 were considered as covariates. On multiple linear regression analysis it was found that levels of HOMA S (β = –0.45, p = 0.010), HOMA B (β = –0.945, p = 0.003) and fasting glucose (β = –0.796, p = 0.004), and WHR (β = –0.379, p = 0.017) were negatively associated with TNF-α in the diabetic subjects.

In our study we found that serum IL-6 levels were significantly higher in the diabetic subjects compared to controls. In addition, IL-6 was not significantly associated with diabetes when TNF-α and IL-6 were considered as covariates using binary logistic regression analysis. With multinominal regression analysis it was shown that HOMA S (β = 0.411, p = 0.013), HOMA B (β = 0.885, p = 0.002) and fasting glucose (β = 0.865, p = 0.001) levels, and WHR (β = 0.311, p = 0.038) were positively associated with IL-6 in the diabetic subjects.

Other studies have documented that serum IL-6 concentrations were higher in subjects with impaired glucose tolerance than in those with normal glucose tolerance,11,19,20 while a Korean study found no elevation in serum IL-6 concentrations in pre-diabetic Korean women compared to controls.21 A study on Italian Caucasians has shown that impaired glucose tolerance and type 2 diabetes, but not impaired fasting glucose levels were associated with elevated IL-6 levels.13 This discrepancy was most likely due to racial differences, environment, geographical condition and nutritional status.

The major weakness of our study was small sample size. Due to funding constraints we were limited in the number of patients in our study.

ConclusionFrom our study, it can be concluded that levels of TNF-α were associated with insulin resistance in subjects with type 2 diabetes. Hyperglycaemia appeared to be a major trigger for the pro-inflammatory changes in diabetes.

Table 3. Multiple linear regression analysis of different factors affecting TNF-α and IL-6 versus type 2 diabetes subjects.

Group Factors Standardised coefficients Unstandardised coefficients β SE β t p-value

TNF-α vs

type 2 diabetes

(Constant) 1180.937 314.606 3.754 0.001

HOMA B –2.127 0.618 –0.945 –3.440 0.003

HOMA S –1.229 0.430 –0.558 –2.861 0.010

IL-6 –3.655 0.528 0.903 6.924 0.001

F_GLU –32.952 10.150 –0.796 –3.246 0.004

BMI 0.736 3.658 0.062 0.201 0.843

WHR –755.628 288.776 –0.579 –2.617 0.017

IL-6 vs

type 2 diabetes

(Constant) –259.714 74.416 –3.490 0.002

HOMA B 0.492 0.141 0.885 3.481 0.002

HOMA S 0.273 0.100 0.711 2.725 0.013

TNF-α 0.193 0.028 0.903 6.924 0.001

F_GLU 8.838 2.098 0.865 4.212 0.001

BMI –0.125 0.841 –0.059 –0149 0.883

WHR 153.346 68.821 0.511 2.228 0.038

Standardised coefficient (β) was calculated by multiple linear regression analysis using SPSS 11.5.



AcknowledgementWe acknowledge the Diabetic Association of Bangladesh and the International Program in the Chemical Sciences (IPICS), Uppsala University, Sweden for the financial support of this study.

ReferencesPickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune 1. system? Diabetologia 1998; 41: 1241–1248.Caballero AE. Endothelial dysfunction, inflammation, and insulin resistance: A 2. focus on subjects at risk for type 2 diabetes. Curr Diab 2004; 4: 237–246.Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, 3. et al. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 1999; 353: 1649–1652.Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, 4. interleukin 6, and risk of developing type 2 diabetes mellitus. J Am Med Assoc 2001; 286: 327–334.Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE, Tracy RP. 5. The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes 2001; 50: 2384–2389.Freeman DJ, Norrie J, Caslake MJ, Gaw A, Ford I, Lowe GD, 6. et al. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 2002; 51: 1596–1600.Hotamisligil, GS. Tumor necrosis factor alpha inhibits signaling from the insulin 7. receptor. Proc Natl Acad Sci USA 1994; 91: 4854–4858Chen KT, Chen CJ, Gregg EW, Imperatore G, Narayan KM. Impaired fasting 8. glucose and risk of diabetes in Taiwan, follow up over three years. Diabetes Res Clin Pract 2003; 60(3): 177–182.Stith RJL. Endocrine and carbohydrate responses to interleukin-6 in vivo. 9. Circulatory Shock 1994; 44: 210–215. Carey AL, Bruce CR, Sacchetti M, Anderson MJ, Olsen DB, Saltin B, 10. et al. Interleukin-6 and tumor necrosis factor-alpha are not increased in patients with type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness. Diabetologia 2004; 47: 1029–1037. Miyazaki Y, Pipek R, Mandarino LJ, De Fronzo RA. Tumor necrosis factor alpha 11. and insulin resistance in obese type 2 diabetic patients. Int J Obes Relat Metab Disord 2003; 27: 88–94.

Konukoglu D, Hatemi H, Bayer H, Bagriacik N. Relation between serum 12. concentrations of interleukin-6 and tumor necrosis factor-α in female Turkish subjects with normal and impaired glucose tolerance. Horm Metab Res 2006; 38(1): 34–37.Cardellini M, Andreozzi F, Laratta E, Marini MA, Lauro R, Hribal ML, 13. et al. Plasma IL-6 levels are increased in subjects with impaired glucose tolerance but not in those with impaired fasting glucose in a cohort of Italian Caucasians. Diabetes Metab Res 2007; 23(2): 141–145.Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment 14. (HOMA) evaluation uses the computer program. Diabetes Care 1998; 21: 2191–2192.Hotamisligil GS. Inflammatory pathways and insulin action. 15. Int J Obes Relat Metab Disord 2003; 27(suppl 3): S53–S55.Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-16. mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996; 271: 665–668.Sun Y, Liu S, Ferguson S, Wang L, Klepcyk P, Yun SJ, Friedman EJ. Phospho-17. enolpyruvate carboxykinase overexpression selectively attenuates insulin signaling and hepatic insulin sensitivity in transgenic mice. J Biol Chem 2002; 277: 23301–23307.Roden M, Petersen KF, Shulman GI. Nuclear magnetic resonance studies of 18. hepatic glucose metabolism in humans. Recent Prog Horm Res 2001; 56: 219–237. Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, 19. et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans; Role of oxidative stress. Circulation 2002; 106: 2067–2072.Muller S, Martin S, Koenig W, Hanifi-Moghaddam P, Rathmann W, Haastert 20. B, et al. Impaired glucose tolerance is associated with increased serum concentrations of interleukin-6 and co-regulated acute-phase proteins but not TNF-a or its receptors. Diabetologia 2002; 45: 805–812.Choi KM, Lee J, Lee KW, Seo JA, Oh JH, Kim SG, 21. et al. Comparison of serum concentrations of C-reactive protein, TNF-alpha and IL-6 between elderly Korean women with normal and Impaired Glucose Tolerance. Diabetes Res Clin Pract 2004; 64: 99–106.Spranger J, Kroke A, Möhlig M, Ristow M, Boeing H, Pfeiffer AFH. Role of TNF-22. alpha in the development of type 2 diabetes: Preliminary results of a population-based, prospective study. Exp Clin Endocrinol Diabetes 2002; II: 194.

Diary for 2012 diabetes congresses

DATE PLACE CONFERENCE

19–22 April Bantry Bay, South Africa SEMDSA/NOFSA Congresswww.semdsa.org.za

5–9 May Florence, Italy European Congress of Endocrinology

8–12 June Philadelphia, USA 72nd American Diabetes Association Scientific Sessions

24–26 July Johannesburg, South Africa CDE Centres for Diabetes and Endocrinology

10–13 October Istanbul, Turkey ISPAD 2012 – 38th Annual Meeting of the International Society for Pediatric and Adolescent Diabetes

4–6 December Dubai, United Arab Emirates 1st American Diabetes Association Middle East Congress ‘Diabetes Prevention and Treatment’

It's theshell that

makes

safer.

Safety-CoatedR




EVIDENCE IN PRACTICE SA JOURNAL OF DIABETES & VASCULAR DISEASE

Apixaban, an oral direct factor Xa inhibitor, significantly reduced stroke and systemic embolism compared to

warfarin in patients with atrial fibrillation (AF) and at least one risk factor for stroke, according to results from a major study.

The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomised 18 201 patients with AF and at least one additional risk factor for stroke to apixaban (5 mg twice daily; 2.5 mg in selected patients) or warfarin (dosed to achieve a target INR of 2.0–3.0).

Results, reported during a hot-line session at European Society of Cardiology and published in the New England Journal of Medicine, showed that apixaban reduced the relative risk of stroke or systolic embolism by 21% (p = 0.01) and all-cause mortality by 11% (p = 0.047). The predominant effect on stroke prevention was on haemorrhagic stroke, which was 49% lower with apixaban than warfarin (p < 0.001), along with an effect on ischaemic or uncertain stroke that was 8% lower with apixaban than with warfarin (p = 0.42, NS).

Apixaban was superior to warfarin for the primary safety outcome of major bleeding, which was reduced by 31% compared to warfarin (p < 0.001). Major or clinically relevant non-major bleeding was reduced by 32% (p < 0.001).

‘These are important findings because they show when compared to warfarin, itself a very effective treatment to prevent stroke, apixaban resulted in an additional 21% relative reduction in stroke and systemic embolism,’ said lead investigator Christopher Granger, Professor of Medicine at Duke University, Durham, USA. ‘There is an enormous unmet need in terms of treatment of patients at risk of stroke associated with atrial fibrillation,’ says Professor Granger. ‘Only about half of patients who should be treated are being treated. The disparity exists because warfarin treatment has several limitations.’

Adverse events were similar in the apixaban (81.5%) and warfarin (83.1%) groups, as were serious adverse events (35.0% with apixaban and 36.5% with warfarin). Discontinuation of study drug was significantly less common with apixaban (25.3% of patients, 3.6% due to death) than with warfarin (27.5% of patients, 3.8% due to death; p = 0.001).

Originally from PCCJ 2011; 4(4): 141.

Apixaban is superior to warfarin in reducing stroke or systemic embolism in atrial fibrillation

SAJDVD recommended actionApixaban is not yet licensed for stroke prevention in patients withAF in South Africa, but this study shows that the oral agent is moreeffective than warfarin without the need for anticoagulationmonitoring. It is also safer, with a substantially lower risk of alltypes of bleeding and lower rates of discontinuation.

ReferenceGranger CB, Alexander JH, McMurray JJV, et al. Apixaban versuswarfarin in patients with atrial fibrillation. N Engl J Med 2011 Aug28; doi 10.1056/NEJMoa1107039. ESC 2011. Hot Line 1.http://www.escardio.org/congresses/esc-2011/congressreports/Pages/706-4-ARISTOTLE.aspx

Ambulatory blood pressure monitoring (ABPM) is the most cost-effective way to diagnose hypertension. Studies have shown

that the average blood pressure over 24 hours is a better predictor of long-term cardiovascular outcome than blood pressure (BP) measured during a standard clinic appointment. About one person in four with a raised reading in clinic will not have a raised ambulatory recording.

The new study compared the cost-effectiveness of BP measurements in the clinic, home and over 24 hours. The researchers found that ambulatory monitoring was the most cost-effective strategy in men and women of all ages.

Diagnosis using ambulatory readings after an initially high clinic reading confirms genuine cases of hypertension, and prevents treat-ment of patients whose ambulatory readings suggest their BP is normal.

The authors concluded that ambulatory monitoring improves health, increases quality of life, and reduces costs and that ambulatory monitoring should be seriously considered for most people before the start of antihypertensive treatment. Senior author of the analysis, Professor Richard McManus (University of Birmingham) said: ‘Ambulatory monitoring allows better targeting of BP treatment to those who will receive most benefit. It is already undertaken in some general practices and while implementation on a wide scale will need to be phased in to allow training and acquisition of new equipment, it is cost saving in the long term as well as more effective and so will be good for patients and doctors alike.’


SAJDVD recommended actionAmbulatory BP measurement is now the recommended approach in assessing people with hypertension. Primary care practices should take active steps to introduce this approach into their practice.

ReferenceLovibond K, Jowett S, Barton P, et al. Cost-effectiveness of options for the diagnosis of high blood pressure in primary care: a modelling study. Lancet 2011; DOI:10.1016/S0140-6736(11)61184-7

Ambulatory BP measurement: most cost-effective way to diagnose hypertension


SA JOURNAL OF DIABETES & VASCULAR DISEASE EVIDENCE IN PRACTICE

Carefully manage discontinuation of low-dose aspirinThe risk of non-fatal myocardial infarction

(MI) or death from coronary heart disease increases by nearly 50% in patients with a history of ischaemic events who discontinue low-dose aspirin therapy in primary care.

Although low-dose aspirin is standard treatment for the secondary prevention of cardiovascular disease, up to half of long-term users stop therapy. Discontinuation has been linked with increased risk of ischaemic events and death in secondary care. This study evaluated the risks in primary care.

Data from the Health Improvement Network database of > 3 million patients in primary care in the UK identified 39 513 people aged 50–84 with prescriptions for aspirin for secondary prevention of cardiovascular outcomes. They were followed for an average of 3.2 years to identify any cases of non-fatal MI or death from coronary heart disease.

Of these patients, 876 experienced MI and 346 died from coronary heart disease. Compared with current users, people who had recently stopped taking

SAJDVD recommended actionLow-dose aspirin prophylaxis plays a vital role in secondary prevention of cardiovascular dis-ease. This primary care study supports the results of previous studies in secondary care. Primary healthcare professionals should encourage patients with a history of cardiovascular events to continue with their long-term aspirin prophylaxis. Efforts to improve adherence with therapy should be ongoing.

ReferenceGarcia Rodriguez L, Cea-Soriano L, Martin-Me-rino E, Johansson S. Discontinuation of low dose aspirin and risk of myocardial infarction: case-control study in UK primary care. BMJ 2011;343: doi:10.1136/bmj.d4094http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139911/?tool=pubmed

were about four more cases of non-fatal MI among patients who discontinued treatment with low-dose aspirin (recent discontinuers) compared with patients who continued treatment.


aspirin had a significantly increased risk of non-fatal MI or death from coronary heart disease combined [rate ratio (RR) 1.43, 95% CI: 1.12–1.84) and non-fatal MI alone (RR 1.63, 95% CI: 1.23–2.14]. There was no significant association between recently stopping low-dose aspirin and the risk of death from coronary heart disease (RR 1.07, 95% CI: 0.67–1.69). For every 1 000 patients, over a period of one year there

15-minute daily exercise significantly improves health

Even limited exercise of about 15 minutes per day results in a reduced risk of all-cause mortality of 14% and life expectancy

was extended by three years. Previously the health benefits of leisure-time physical activity have been well known, but it was unclear whether less exercise than the recommended 150 minutes per week (30 minutes x 5) would be beneficial.

In a study of over 400 000 people in Taiwan with an average follow-up of eight years, participants were divided into five categories of exercise volume: inactive, or low, medium, high, or very high activity. Hazard ratios (HR) for mortality risks and life expectancy were calculated for each group compared with the inactive group.

Compared with individuals in the inactive group, those in the low-volume activity group (an average of 92 min-

SAJDVD recommended actionThese data provide primary care professionals with strong encouragement for convincing their patients that even small amounts of physical activity can bring significant health benefits, including a substantial reduction in mortality.

Reference

Wen C-P, Wai J, Tsai M, et al. Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study. Lancet 2011, DOI:10.1016/S0140-6736(11)60749-6.

utes exercise per week/about 15 minutes a day) had a 14% reduction in risk of all-cause mortality, a 10% reduced risk of all-cancer mortality, and a three-year longer life expectancy.

Every additional 15 minutes of daily exercise beyond the minimum amount of 15 minutes a day further reduced all-cause mortality by 4% and all-cancer mortality by 1% (0.3–4.5). These benefits were applicable to all age groups and both genders, and to those with cardiovascular disease risk factors. Individuals who were inactive had a 17% increased risk of mortality compared with individuals in the low-volume activity group.

The authors commented: ‘This low-volume of physical activity could play a central part in the war against non-communicable diseases, reducing medical costs and health disparities.’



EVIDENCE IN PRACTICE SA JOURNAL OF DIABETES & VASCULAR DISEASE

Rivaroxaban reduces stroke in atrial fibrillationRivaroxaban, a direct factor Xa inhibitor, may

provide more consistent and predictable anticoagulation than warfarin in patients with atrial fibrillation (AF) who are at increased risk of stroke.

The ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was a double-blind multicentre trial in which 14 264 patients with non-valvular AF at increased risk for stroke were randomly assigned to treatment with rivaroxaban 20 mg or dose-adjusted warfarin.

The study demonstrated that rivaroxaban was non-inferior to warfarin in prevention of stroke or systemic embolism. In the primary analysis, the primary endpoint of ischaemic/

SAJDVD recommended actionRivaroxaban may provide an oral alternative to war-farin in the prevention of stroke in patients with AF. It is not currently licensed in Europe for this indica-tion. Xarelto® (rivaroxaban) is licensed for prevention of venous thromboembolism in adults undergoing elective hip or knee replacement surgery.

Reference

Patel M, Mahaffey K, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; published online 10 August, 10.1056/NEJMoa1009638.

PRIMARY ENDPOINT IN INTENTION-TO-TREAT POPULATION

Rivaroxaban Warfarinpatients (n) Events (n) Event rate* patients (n) Events (n) Event rate* HR (p value) 7 081 269 2.1 7 090 306 2.4 0.88 (0.75– 1.03) p < 0.001*n/100 patient-years

haemorrhagic stroke or systemic embolism occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio [HR] in the rivaroxaban group, 0.79; 95% CI, 0.66 to 0.96; p < 0.001 for non-inferiority). In the intention-to-treat analysis, the primary endpoint occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (HR 0.88; 95% CI: 0.74–1.03; p < 0.001 for non-inferiority; p = 0.12 for superiority).

There was no significant between-group difference in the risk of major bleeding although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. Major and non-major clinically relevant bleeding occurred in 1 475 patients in the rivaroxaban

group (14.9% per year) and in 1 449 in the warfarin group (14.5% per year) (HR 1.03; 95% CI: 0.96 –1.11; p = 0.44), with significant reductions in intracranial haemorrhage (0.5% vs 0.7%, p = 0.02) and fatal bleeding (0.2% vs 0.5%, p = 0.003) in the rivaroxaban group.

Rivaroxaban is currently licensed for pre-vention of venous thromboembolism in adults undergoing elective hip or knee replacement surgery.


Metformin usage may protect women against pancreatic cancer

SAJDVD recommended actionExtended-release metformin, which also reduces gastrointestinal side effects and improves patient adherence,3 could be considered earlier for at-risk women with a clinical history predisposing to the development of type 2 diabetes, based also on reducing cancer risk.

In a case–control study of 2 800 patients with newly diagnosed pancreatic cancer,

the risk of developing pancreatic cancer was significantly reduced in women receiving metformin therapy for a few years.1

Pancreatic cancer is relatively rare as far as cancers go, but it progresses quickly. Most people do not survive more than a couple of years after diagnosis. Research has sug-gested that people with pancreatic cancer may have an increased risk of diabetes, but it is unclear how diabetes and the drugs used to treat it may affect pancreatic cancer risks in previously cancer-free people.

To help answer that question, Dr Chris-toph Meier of the University Hospital, Basel in Switzerland and his colleagues consulted a database of more than eight million people in the UK, including about 2 800 who were diagnosed with pancreatic cancer between 1995 and 2009. For each of those people, they found another six of the same age and gender that didn’t have pancreatic cancer, to serve as a comparison group.

Using records from primary-care doc-tors, the researchers determined how many people in the pancreatic cancer and cancer-free groups had previously been diagnosed with diabetes and were on an antidiabetes drug, such as metformin or sulfonylureas,

which included glimepiride and glyburide.One in nine people with pancreatic

cancer had a prior diagnosis of diabetes, compared to about one in 12 in the cancer-free comparison group. According to their medical records, 2% of people with pan-creatic cancer had been taking metformin long-term before they were diagnosed, compared to 1.6% of the group without cancer – a difference that could have been due to chance.

But when the researchers separated the records by gender, they found that signifi-cantly fewer women with a new diagnosis of pancreatic cancer had been taking met-formin for at least a few years, compared to cancer-free women. That was after the researchers had already taken into account whether women were overweight or obese and if they smoked or drank alcohol.

The association in one gender but not the other was ‘somewhat unexpected’, according to Meier’s team, and there is no clear biology-based way to explain why met-formin might help protect women against pancreatic cancer, but not men.

The findings were reversed for insulin and sulfonylureas in the study population. Significantly more people with pancreatic cancer had a history of long-term use of

those drugs than cancer-free people.Importantly, metformin is the first-line

oral medication recommended for type 2 diabetes. A recent review of two clinical trials using metformin has shown the poten-tial of using higher doses of metformin to improve control in diabetic patients without increasing gastrointestinal effects.2

ReferencesBodmer, 1. et al. Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis. Am J Gastroenterol, online 31 Jan 2012.Hirst J, Farmer A, Ali R, Roberts NW, Stevens RJ. 2. Quantifying the effect of metformin treatment and dose on glycaemic control. Diabetes Care 2012; 35: 446–454.Jabbour S, 3. et al. Extended release metformin – increased GI tolerability, with once-daily dosage – improve patient adherence – increase glucose control. Postgrad Med 2011; 123(1): 15–23.

SA JOURNAL OF DIABETES & VASCULAR DISEASE


Keep and Copy SeriesPatientinformationleaflet

IMPROVING WARFARIN CONTROL: CAN WE ACHIEVE 70% TIME IN THERAPEUTIC RANGE IN SOUTH AFRICA?

S Afr J Diabetes Vasc Dis 2012; 9: 29–30. Warfarin is used for the management and

prevention of venous thrombo-embolism (deep-vein thrombosis and pulmonary

embolus) as well as arterial thrombo-embolism.Lifelong therapy with warfarin is required for the

prevention of systemic embolism in patients with atrial fibrillation and prosthetic heart valves. During warfarin initiation, the loading dose is usually 5 or 10 mg. The therapeutic response is measured by the international normalised ratio (INR) and the dose is adjusted accordingly.

Warfarin has a narrow therapeutic range and therefore drug monitoring is essential. The target INR depends on the indication for warfarin treatment. The target therapeutic range for venous thromboembo-lism is 2–3, whereas for double valve replacement, it is 2.5–3.5. An INR < 2 is usually associated with thrombotic events and an INR > 4 with haemorrhagic events.1

However, the wide inter-individual variability in therapeutic response poses a major challenge to clini-cians. This response is determined by genetic as well as clinical factors (age, gender, body mass index, co-morbid illnesses) accounting for 30–55% variability.2,3

In South Africa, good INR control, referred to as the time in therapeutic range (TTR) has been shown to be poor. Patients are only protected for about 50% of the time, according to a study undertaken at Groote Schuur Hospital’s prothrombin clinic,4 and the in-ternational RE-LY study, which also included South African patients.

Initiatives to improve control that hold promise are focused on establishing (1) an anti-coagulation man-agement service which can be nurse, pharmacist or

laboratory service led, and (2) empowering patients

with a self-monitoring device and clear information

on interactional medication and foods that may alter

their warfarin control.

ESTABLISHING AN ANTI-COAGULATION MANAGEMENT SERVICEWhile prothrombin clinics have been established

in some South African hospitals, there is an unmet

need to make the practice of anticoagulation care

more patient-centred, particularly for the elderly who

are most vulnerable to strokes.

PATIENT SELF-MONITORINGPortable, hand-held prothombin time (PT/INR) me-

ters, such as the CoaguChek (R) XS system for pa-

tient self-testing, enable patients to test their clotting

time at home in about a minute, using a small drop

of blood from a simple finger stick. Currently in the

United States, less than 5% of patients on blood thin-

ners perform self-testing, according to the Centers

for Medicare and Medicaid Services.

Studies suggest that anticoagulation patients who

self-test may experience fewer complications overall

than those who do not, because self-testing may in-

crease patient time in the therapeutic range.5 Studies

also suggest that PT/INR self-testing is just as accu-

rate as finger-stick testing performed by a healthcare

professional and conventional testing performed on

a laboratory analyser.6-8

All patients on anticoagulant medication need a

prescription from their doctor for a self-testing meter

and supplies, before being able to monitor their own

clotting time at home. Patient self-testing is also de-


PATIENT INFORMATION LEAFLET SA JOURNAL OF DIABETES & VASCULAR DISEASE

signed to augment, not eliminate, testing and therapy management that is overseen by a doctor. Patients who self-test must notify their doctors of clotting time results so they can make the proper adjustments to their medication.

Patients interested in finding out more about self-testing their PT/INR should talk to their doctors.

For more information on the CoaguChek XS system for patient self-testing, visit www. ASmartWayToTest.com.

INTERACTION WITH OTHER MEDICATIONS: AN EASY FORMAT FOR PATIENT EDUCATIONUsing broad classes of drugs and including common entities that either enhance or reduce warfarin’s anti-coagulant efficacy, clinicians can sim-plify patient education. The A–S list below could be useful.

Enhancers of warfarin efficacyAlcohol: occasional large intake of alcohol is likely to enhance briefly •the effects of warfarin, but more importantly, regular immoderate intake potentiates warfarin activity, especially if liver functions are compromised. Anabolic steroids potentiate warfarin effects.•Analgesics•

− Non-steroidal anti-inflammatory type (NSAIDs): the anti-aggregatory effects of the NSAIDs on platelets are likely to play a major role in adding to the anticoagulant activity of warfarin. Their effects are largely dose dependent, and aspirin is a prominent offender. It seems that meloxi-cam, nabumetone and naproxen are much less inclined to interact in this manner. It should be noted that extensive use of topical NSAIDs may also enhance warfarin efficacy.

− Paracetamol, once thought to be unlikely to interact with warfarin, is now known to be a major potentiator of the anticoagulant effect. How-ever, low, single or infrequent therapeutic doses of paracetamol are documented as unlikely to have any anticoagulant-potentiating activity.

− Opioids: propoxyphene and tramadol may well enhance the ef-ficacy of warfarin, but careful observation for such effects is needed with all high-dose prolonged use of opioids.

Anaesthetics of the inhalational type: broadly speaking, great caution •is recommended when these agents are utilised in persons receiving warfarin. Note that propofol may reduce the efficacy of warfarin.Anti-arrhythmics: notable in this category are amiodarone, disopyra-•mide, propafenone and quinidine.Anti-infective agents: in this very large category (including quinine), •most potentiate warfarin. However, cloxacillins, rifampins, griseofulvin, ribavirin and terbinafine reduce the activity of warfarin.Anticonvulsants: while most enhance warfarin efficacy, the barbiturate •type, cabamazepine and phenytoin may reduce the activity of warfarin.

Antidepressants: those that are selective serotonin re-uptake inhibitors •are the most likely culprits from among the antidepressant category.Antithyroid agents have been implicated in enhancing, but also in di-•minishing warfarin efficacy. Antidiabetic agents (oral): especially the sulphonylurea types.•Antiplatelet agents: all chemical entities with antiplatelet activity, in-•cluding fish oil concentrates and many herbal substances, such as ginseng, ginkgo biloba, aloe, dandelion, cranberry and garlic should be avoided.Beta-blockers: atenolol and propranolol are the most frequent offend-•ers in this category, but others may not be exempt.Botanicals: a vast variety of botanical/herbal preparations potentiate •the activity of warfarin by their coumarin-type activity and/or via their antiplatelet effects. Significant effects usually are associated with regu-lar use.Corticosteroids: prolonged high doses.•Fibrates: such as fenofibrate.•Gastric acid suppressants: cimetidine and the azole-type proton-pump •inhibitors are the major offenders.Statins: simvastatin, lovastatin and possibly fluvastatin enhance war-•farin activity, while the effects of pravastatin are likely to be unpredict-able.

Reducing warfarin’s efficacyThese include antacids (non-absorbable), antihistamines (many), an-•tipsychotics (many), barbiturates, carbamazepine, chlordiazepoxide, cloxacillins, griseofulvin, meprobamate, oral contraceptives, phenytoin, rifampins, selective oestrogen receptor modulators, spironolactone, St John’s wort, thiouracils, trazodone, ubiquinone (co-enzyme Q10), vita-

min C (high dosage), vitamin K, and food items rich in vitamin K.

ReferencesSchwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, 1. et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008; 358: 999–1008.D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio 2. V, et al. A polymorphism in VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005; 645–649.Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and 3. VKORC1- Rational and perspectives. Thromb Res 2007; 120: 1–10.Stnley A, Ntsekhe M Commerford PJ. An audit of an anti-coagulation clinic at 4. a tertiary hospital. Poster presentation, Department of Medicine Research Day Groote Schuur Hospital, University of Cape Town, South Africa. Oct 2008.Kortke H, Minami K, Breymann T, 5. et al. INR self-management after mechanical heart valve replacement: ESCAT. Z Kardiol 2001; 90(6): 118–124.CoaguChek XS system package insert. Indianapolis, Roche Diagnostics 6. Corporation, 2006.Bussey HI, Chiquette E, Bianco TM, 7. et al. A statistical and clinical evaluation of finger stick and routine laboratory prothrombin time measurements. Pharmacotherapy 1997; 17(5): 861–866.Kaatz SS, White RH, Hill J, 8. et al. Accuracy of laboratory and portable monitor international normalized ratio determinations. Comparison with a criterion standard. Arch Intern Med 1995; 155: 1861–1867.


SA JOURNAL OF DIABETES & VASCULAR DISEASE REPORT

In a new direction for SANOFI, the general manager, John Fagan pointed out that not

only is diabetes a key focus area for SANOFI, ‘but we also need to go beyond traditional pharmaceutical research and development in our focus. Together with clinicians, we need to think about the patient first, then about the product, and do competent research and development to meet patients’ unmet needs’, he said. This approach is reflected in the Diabetes Division’s new slogan, ‘Going beyond, together’.

In the special briefing at the recent SANOFI specialist meeting held in Cape Town, John Fagan noted that the South African Gov-ernment’s National Health Insurance devel-opment looks more cautious, planned, and inclusive of the private sector than initially thought, which offers opportunities for both state- and privately funded healthcare organ-isations to improve patient care.

‘The ORIGIN outcome trial with strong South African patient recruitment, which looks at early insulin therapy with glargine, will likely present first results at the 2012 American Diabetes Association (ADA) meet-ing and is an important diabetes care mile-stone for Sanofi’, he concluded.

The incretins: so much attention at international meetings that a review in South Africa is timeousDr Larry Distiller, co-ordinator of this special-ist meeting, set the pace of thorough review of topics presented at the meeting, by cau-tioning clinicians to evaluate incretin usage critically. ‘It is clearly time to review these agents, both the GLP-1 agonists and the DPP-4 inhibitors, as their international status grows and they become more available on the South African market’, he noted.

‘The defining characteristic of these two classes of agents are the supra-physiological levels of GLP-1s attained by exenatide or liraglutide treatment (the GLP-1 agonists), and the physiologically stable levels of GLP-1s attained by the use of DPP-4 inhibitors. The actions of the injectable GLP-1 agonists are therefore generally more powerful than that of the oral DPP-4 inhibitors. The incretins’ enhancement of glucose-induced insulin secretion and the restoration of the gluca-gon-suppression response are particularly rel-evant, as glucagon is certainly the forgotten hormone of type 2 diabetes’, he said.

Referring to exenatide (twice daily), also to the more powerful once-weekly dosage not yet available in South Africa, and liraglu-tide (once daily), Dr Distiller noted that their promise is partially fulfilled by the fact that the reduction in level of HbA1c (0.8–1% reduction depending on baseline HbA1c level) is maintained over a two- to three-year period and there is a progressive and prob-ably meaningful weight loss.

‘There is considerable interest in the non-glycaemic potential benefits of GLP-1 agonists with regard to their neuroprotec-tive and cardioprotective effects.’ A real-life study in medically insured patients, the Life-Link study, has recently shown a 16% reduc-tion in cardiovascular events in patients on exenatide’, Dr Distiller noted.1

‘With regard to the ultimate promise of these agents, the increased proliferation and reduced apopstosis of β-cells, which was shown in early experimental laboratory studies, there is some evidence from HOMA studies that, for example, liraglutide is β-cell sparing, compared to thiaglitazides (TZDs) and basal insulin. At this juncture, liraglu-tide appears the better option in this class

of agents, but this situation is dynamic and may change with the advent of once-weekly exenatide’, Dr Distiller noted.

‘With regard to the DPP-4 inhibitors’, Dr Distiller said ‘they work; they are mild and do not change the world, but they do work. They are weight neutral, drop HbA1c levels on average by 0.7% and there is a sugges-tion that they preserve β-cell function. Over-all their cardiovascular effects are not yet as well researched as the GLP-1 agonists’, he noted.

With regard to when to use these agents, Dr Distiller noted that early use when there is still β-cell function is taken up in many algo-rithms, as an alternative for sulphonylureas with metformin; also in combination with insulin, following acceptable trials, and reg-istration for use of the particular agent with insulin.

As DPP-4 receptors are widespread in the body, and despite claimed specificity of these inhibitors, Dr Distiller noted a gen-eral acceptance that these drugs have a subtle effect on the immune-surveillance system, leading to increased incidence of bronchitis, for example. With regard to the GLP-1 analogues and their risk of pancrea-titis, pancreatic and thyroid cancer, there is an alert but not yet an alarm, despite the much-commented article on post-marketing surveillance’,2 he concluded.

From promise to gold standardDr Joshi, emeritus professor of Medicine, MEDUNSA‘Metformin has truly been established as the foundation, first-line therapy for type 2 dia-betes’, Prof Joshi noted. Derived from the Galega officinalis plant, galegine produced hypoglycaemia in sheep but was found to

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be too toxic for humans, leading to the pro-duction of dimethyl biquanide (metformin) and other biquanides, such as phenformin. Early use in the United States focused on phenformin, a pro-drug that was later with-drawn as it was the main culprit for the lactic acidosis observed in the 1950s.

The UKPDS study of type 2 diabetes and the global use of metformin are intrinsically related, although earlier clinical studies3 had shown that metformin works in poorly con-trolled diabetics, primarily, it was thought, by re-sensitising tissues to insulin. ‘In a nut-shell, today we regard the principle actions of metformin as increasing sensitivity of the liver to circulating glucose load, and reduc-ing gluconeogenesis and improving insulin sensitivity peripherally. The loss of adipose tissue and its anorectic action in today’s world is an additional valued benefit’, Prof Joshi noted.

With relevance to current knowledge, metformin also acutely increases the plasma levels of GLP-1, not by DPP-4 inhibition but by stimulating GLP-1 production. ‘Met-formin has a synergistic action with the incretins, giving an increased effect when used together, compared to when either agent is used alone’, Prof Joshi noted.

An important principal to note is that the reduction of cardiovascular events with oral anti-diabetic agents takes a long time to show results. ‘In metformin’s case, vascular protection was measurable only after chronic exposure of at least six years. Patience should be exercised with regard to this aspect; and the newer oral agents prob-ably require studies in excess of five years to evaluate their cardio-protective benefits’, Prof Joshi cautioned. ‘The side effects of diarrhoea and nausea occur initially in 20% of patients, but over time and with the use of slow-release tablets, this can be greatly reduced’, he added.

The known side effect of low vitamin B12 levels and vitamin B12 deficiency occur in 10 to 30% of patients after long-term metformin use (vitamin B12 levels: deficiency < 150 pmol/l, low levels 150–220 pmol/l). ‘Well-defined studies are needed in our populations and this is a clinical priority for local research’, Prof Joshi pointed out. ‘In principle, after a patient has been on met-formin for 10 to 12 years, vitamin B12 levels should be tested once a year, and if found to be low, a single dose of 1 000 mg vita-min B12 should be given. This could be com-bined with calcium as it facilitates vitamin B12 absorption, as shown in initial study find-ings’, Prof Joshi said.4

The use of metformin in type 1 diabetes patients with high insulin usage is growing. Studies have shown that we could reduce doses of insulin by about 10% in patients with type 1 diabetes. A reduction in insulin doses of about 20 to 30% are observed in type 2 diabetics on higher doses of insulin.

Does exercise improve or impede glycaemic control in type 1 diabetes?Andrew Heilbrunn began his fascinating pres-entation on the impact of exercise on glycae-mic control in the type 1 diabetes patient, by referring to the findings of Ralph Paffen-barger’s 36-year follow-up study in the 1993 article in New England Journal of Medicine, ‘The Harvard Study.5 Findings indicated that there was a dose response to exercise with a percentage reduction in risk of death from certain chronic illnesses, including cardiovas-cular disease and diabetes.

Up to a point, increased energy expendi-ture correlated with a reduction in risk of mortality. It was found that those with the highest levels of fitness had the lowest risk of cardiovascular death, in particular. The unfit non-diabetic person has twice the car-diovascular risk of the physically active indi-vidual. The unfit type 2 diabetes patient is a ‘time-bomb’.

Ming Wei concluded his 15-year study (n = 1 200 type 2 diabetes patients) in 2000, by suggesting that the type 2 diabe-tes patient would benefit more from regular exercise than any other chronically ill patient. Data from a seven-year follow-up type 1 dia-betes patient cohort study indicated that the mortality rate was 50% lower in the type 1 diabetes patient who burned 2 000 calories per week, opposed to those burning less than 1 000 calories per week.

The evident benefit of exercise on risk of mortality raises the question of how much exercise is appropriate to bring about physiological changes to decrease mortality. Answers to this question have ranged from 75 minutes per day, to 60 to 85% aerobic capacity for 30 to 60 minutes, to 60 min-utes of moderate-intensity exercise (a brisk walk).

For the type 2 diabetes patient, the latest ADA and Society for Endocrinology, Metabo-lism and Diabetes of South Africa (SEMDSA) guidelines recommend a minimum of 150 minutes’ exercise per week, combining mod-erate-intensity aerobic exercise and strength/resistance training. One would think that these guidelines would be suitable for the

type 1 diabetes population. However, a large percentage of type 1 diabetes patients prefer to participate in marathons, high-intensity ball sports, body building, and some may chal-lenge themselves with recreational climbing and diving. A fair number of these patients do not realise that there is a complex rela-tionship between exercise and type 1 diabe-tes, and exercise may lead to hypoglycaemia or hyperglycaemia. This raises the question ‘Does regular exercise improve or impede blood glucose control in type 1 diabetes?’

There are numerous theories as to why exercise may improve insulin sensitivity, increase muscle blood flow, increase insulin binding by muscle receptors, and increase insulin-regulating glucose transporters. How-ever, the primary theory and benefit occurs during the 12 to 24 hours post exercise; the time for glycogen replenishment. During the course of exercise, liver and muscle gly-cogen stores are used as an energy source. Post exercise, the liver and muscle draw glu-cose from the blood to replenish the stores used during exercise. This process requires little insulin and is enzyme initiated.

Regular chronic exercise/training has a different effect to a single session of exer-cise and the literature suggests that patients with type 1 diabetes should exercise daily or on alternate days to improve their insulin sensitivity. However, with cessation of regu-lar activity, insulin sensitivity is rapidly lost.

In the non-diabetic, insulin levels decrease with the onset of exercise. This allows for an increase in counter-regulatory hormones, in particular glucagon. This response leads to hepatic glucose production, and the subse-quent increase in blood glucose is met by glucose uptake in the muscle. Due to this precise neuro-endocrine function, blood glucose levels remain stable under most exercise conditions.

In type 1 diabetes, the pancreas does not regulate insulin levels in response to exercise and there may be impaired glucose counter-regulation, making normal fuel regulation nearly impossible. Therefore the type 1 dia-betes patient is at risk of becoming hypogly-caemic or hyperglycaemic, dependent to a great extent on the levels of circulating insulin and the duration and intensity of the exercise.

Fear of hypoglycaemia is the primary factor affecting the attitude of patients towards exercise. According to Remi-Rabasa Lohret, 2008, those individuals who best understood how insulin works in their body were shown to be less fearful of physical activity and hypoglycaemia. Furthermore,



those individuals with the greatest fear of physical activity had the poorest control of their diabetes.

The literature suggests that type 1 dia-betes patients are more lightly to develop hypoglycaemia when participating in low-intensity, long-duration events, due to the fact that they circulate their insulin more efficiently and they may have a blunted counter-regulatory hormonal response.

In an interesting observation, Robitaille, 2007, found that type 1 diabetes patients in the fed state used less liver and endogenous glucose and significantly more muscle glycogen when exercising for 30 to 60 minutes, in comparison to non-diabetic controls. This may have implications for post-exercise glycogen replenishment and hypoglycaemia.

Tansey et al.6 explained that performing low- or moderate-intensity endurance-type exercise postprandially resulted in an 86% chance of developing hypoglycaemia if the patient’s blood glucose level was below 7.0 mmol/l before the exercise.

In McMahon’s euglycaemic clamp studies in 2007, she found that patients perform-ing endurance-type activities at 16:30 had a biphasic need for glucose infusion. The majority of glucose infusions were required during the 45 minutes of exercise and for 45 minutes post exercise. Further glucose infusion was required seven to 11 hours post exercise, which equated to between 02:00 and 04:00.

Dealing with the glucose needs during activity is not too difficult. However, dealing with the late hypoglycaemia occurring in the early morning has always been a challenge. The literature suggests that hypoglycaemic events can be reduced by exercising before breakfast and using rapid-acting insulin, as the patient will be slightly insulin-resistant at this time.

According to Riddel, 2006, exercise late in the day may lead to nocturnal hypogly-caemia, which may be unnoticed during sleep in the majority of individuals. The incidence of hypoglycaemia may be as high as 26% on the night of exercise in adoles-cents and children. This may be due to a child or adolesant’s low glycogen-carrying capacity and blunted counter-regulatory response, and the onset of sleep may also be a factor.

The risk of hypoglycaemia can be man-aged by increasing carbohydrate intake before, during and after exercise. The rate of intake is dependent on body mass and the energy expenditure of the exercise.

Mr Heilbrunn recommends the article by Grimm and colleagues.7 This study indicates that depending on the intensity and dura-tion of exercise, patients should take in 15 to 100 g of carbohydrate per hour during exercise, if exercise is performed at the peak effect of insulin action. Furthermore, daily insulin dosages should be decreased by 20 to 30% if exercising for one hour or more.

Hyperglycaemia may be common in exer-cises such as squash, high-intensity spinning or high-intensity resistance training, due to an excessive counter-regulatory hormonal response. In the non-diabetic, circulating counter-regulatory hormones decrease rap-idly post exercise and insulin levels increase, allowing for rapid glycogen replenishment and therefore a rapid decrease in glucose levels.

Most type 1 diabetes patients choose to exercise during the tail effect of their insu-lin action, or they will decrease their insulin dosage in order to avoid hypoglycaemia. Therefore the post-exercise insulin levels may be low. With high post-exercise circu-lating counter-regulatory hormones and low insulin levels in the type 1 diabetes patient, the counter-regulatory response remains high and the patient’s blood glucose levels may remain high for a number of hours post exercise. Competition days and extra carbo-hydrates will exacerbate the problem. It is suggested that one to two units of insulin prior to exercise and/or after exercise may counteract this hyperglycaemic effect.

Improvement of HbA1c level with exercise has not been firmly established. The blood glucose response to exercise is not always predictable. Cardio-respiratory, metabolic and perceptual effort may be altered in type 1 diabetes and this may impair exercise per-formance.

In Herbst’s cross-sectional, multi-centre analysis of 2006, the frequency of activity had a significant influence on glycaemic control without increasing the risk of severe hypoglycaemia. Furthermore, patients who exercised on a regular basis planned their insulin and carbohydrate adjustments more efficiently than patients exercising sporadi-cally.

In Bernadini’s study in 2004, it was observed that children participating in more than 360 minutes of competitive sport a week had significantly better glycaemic con-trol than those children exercising less than 60 minutes per day.

Mr Heilbrunn felt that although there are many guidelines and books to refer to, our physiological understanding can help

guide individuals, but it cannot replace the importance of individuals monitoring their own blood glucose response to a particular exercise.

He concluded by saying, ‘type 1 diabetes patients who exercise regularly report that they feel better, sleep better, have more energy and are more self-disciplined’. Ide-ally, patients should be exercising daily, or on alternate days, to maximise insulin sensi-tivity. Furthermore, ‘patients who exercised on a regular basis planned their insulin and carbohydrate adjustments more efficiently than patients exercising sporadically. This would aid the prevention and management of hypoglycaemia.’

Review of 2001 type 2 diabetes guidelinesSEMDSA is in the process of reviewing guidelines for the management of type 2 diabetes. Dr Amod explained that this revi-sion has been driven by two primary fac-tors. He says, ‘Currently in South Africa, many different guidelines are referred to… there is a need for an integrative national approach.’ Also, new data has emerged on a number of considerations that affect the management of the diabetic patient since the 2008 primary-care guidelines were for-mulated. These include diagnosis of type 2 diabetes, blood pressure and lipid targets, hypoglycaemic risks, weight loss and bariat-ric surgery, and the dismissal of some new and some old therapeutic agents.

Dr Amod highlighted that many risk fac-tors give rise to the widespread prevalence of type 2 diabetes and that on the whole, diabetes is a poorly managed disease with fewer than half of patients achieving target control levels. He emphasised that diabetes is not a homogeneous disease. He argues that the highly variable pathogenesis of type 2 diabetes and the varying degrees of dis-ease manifestation are compounded by fur-ther variability within the individual patient dependant on duration and stage of his/her disease. This implies that many patients are inadequately managed at some point(s) along the timeline of their disease, in both public and private health systems.

A rigidly uniform therapeutic approach with limited therapeutic options will have limited success in managing the ever-in-creasing diabetic population. The major-ity of diabetic patients are treated at the primary-care level and there is a need to assess current therapeutic strategies, with the goal of improving blood glucose con-trol. It is thought that the earlier inclusion



of safe agents will improve adherence and reduce the need for home glucose monitor-ing. This in turn would limit the number of patients needing up-referral to secondary and tertiary care. Dr Amod also pointed out that increasing evidence of caloric restriction improving insulin resistance and β-cell func-tion raises the question of including weight-loss therapies in guidelines for the treatment of the diabetic patient.

In essence, Dr Amod emphasised that the source mechanism of diabetic disease should be the first consideration when determining therapeutic options to be employed in the management of the patient.

Contributors to the guideline review include endocrinologists and diabetelogists, as well as members of DESSA, DSA, FCPSA, CMSA and the National Department of Health. Observers from funders and the pharmaceutical industry were also included. The draft document is currently up for comment, to be finalised early in 2012.

Early bariatric surgery benefits derive from acute caloric restrictionDr Laura Blacking, Gauteng, presented an unbiased view of bariatric surgery, drawing from recent surgical reviews, which contrast early and long-term results, together with a cluster of established and emerging surgical techniques.

Not giving up on the ‘lifestyle works’ concept, a small new study of acute calorie restriction (600 kCal/day)8 was cited as pro-viding exciting evidence that the unexpected early remission results from bariatric surgery are explained by this phenomenon.

‘In this study from Newcastle-upon-Tyne, UK, Dr Lim and co-workers showed reversal of insulin resistance, and β-cell normalisation in overweight/obese (BMI 33.6 ± 1.2 kg/m²) patients with type 2 diabetes of less than four years’ duration and not yet on insulin therapy when exposed to a 600-kCal/day diet for eight weeks. ‘These patients still had pancreatic function, as did the patients who benefitted most on a long-term basis from bariatric surgery’, Dr Blacking noted.

In a recent study9 of factors influencing the durability of remission of type 2 diabe-tes after Roux-en-Y gastric bypass, the study found that while early remission of type 2 diabetes occurred in 89% of post surgery patients, durable remission over a five-year period occurred in 57% of patients. Durable resolution of type 2 diabetes was greatest in patients who were fairly well controlled on diet or oral hypoglycaemic agents.

‘This study emphasises that durable remission correlated most closely with an early stage of type 2 diabetes’, Dr Black-ing stressed. ‘In our experience, motivated patients with weight loss also do better from alternative therapies, such as hypno-therapy with virtual gastric banding’.

‘In my view, we need to target the brain to achieve successful weight loss’, Dr Black-ing stressed. ‘The requirement from interna-tional guidelines is insufficiently emphasised that successful bariatric surgery requires a lifelong commitment to lifestyle change and follow up by a multidisciplinary team is essential. We need centres of excellence that offer this level of multidisciplinary care at both a pre- and post-operative level’, she concluded.

The long memory of diabetes: epigenetics provides new insightsDiabetes complications under the spotlight‘Epigenetics provides us with an insight as to how the environment interacts with our genomes and emphasises the fact that our behaviour may impact both on our own lives as well as future generations.’

Dr Brian Kramer, CDE, Johannesburg, reviewed the development of the concept of the long-term hyperglycaemic memory of diabetes, as first explored in dogs by Dr RL Engerman, an ophthalmologist from the University of Wisconsin, USA.10 He observed that progression of retinopathy continued during good glycaemic control following a period of profound, poor glycaemic con-trol.

‘This memory effect has also been shown in diabetic patients in the DCCT-EPIC study. This emphasises the need for early metabolic control in both type 1 and type 2 diabetes if we are hoping to reduce dia-betic complications’, Dr Kramer noted. The explanation for the ongoing damage relates to both the role of advanced glycation end-products (AGES), which continue to drive the production of reactive oxygen species, and to the altered up or down regulation of genes due to changes in the epigenetic environment.

The abnormal genetic regulation relates to histone functioning, which is exposed to the altered cellular environment. ‘Tightly packed methylated histones restrict the

availability of the DNA to be transcripted, while the acetylated histones allow unfold-ing, gene transcription and the production of gene products’, Dr Kramer explained.

Research has shown that stress, nutri-tion, smoking and alcohol consumption can also change the environment of the histones; changes that can be passed on to generations of cells. ‘Our investigation of polymorphisms is probably misplaced and the epigenetic environment may provide a new target for better therapeutic agents’, Dr Kramer noted.

Even transient periods of 15 minutes of hyperglycaemia are sufficient to alter the epigenetic environment. Chronic exposure also alters the balance of histone methylase and demethylase enzymes, changing the genetic environment and gene expression.11

‘We really need better markers of glycae-mic control than HbA1c level, which does not describe exposure to glycaemia as well as we would like’, Dr Kramer concluded.

Peripheral neuropathy: focusing on painful, diffuse, distal, symmetric polyneuropathy (DSM)Dr Kaplan, Cape Town, presented a review of the physiology of pain with a special empha-sis on painful diabetic neuropathy. He then discussed clinical and therapeutic aspects of treating neuropathy, and particularly painful diabetic neuropathy.

Diabetic neuropathy occurs in 30 to 60% of diabetic patients, varying from 54 to 59% in type 1 diabetes patients and some-what lower in type 2 patients (37–54%). In 50% of cases of diabetic neuropathy, pain is present, which can occur early, even in patients with impaired glucose tolerance. The incidence of painful diabetic neuropa-thy progresses with duration of the diabe-tes, with a peak after 15 years.

Distal symmetric polyneuropathy is the most common form of neuropathy. Typi-cally, it starts as a loss of sensation, affect-ing the feet more than the hands. As the neuropathy progresses, pain may become the dominant symptom. Often, pain occurs in the setting of a normal clinical examina-tion. It is important to exclude other causes of neuropathy and pain, such as claudica-tion, osteoarthritis and fibromyalgia.

‘It is important to note that there may be few signs to relate to the patient’s complaint of pain – examination of patient reflexes such as vibrational, temperature, sensory and soft touch measures may be normal’, Dr Kaplan said. ‘Typically, patients complain of

‘Sugar and high-fat foods are as addic-tive as alcohol and smoking.



burning feet, especially at night, and lanci-nating pain is also a useful descriptor.’

At the very outset, it is important to try and assess the severity of pain, using the variety of severity scales available. A pain diary may also be useful, and a detailed medical history and psychosocial assessment is essential.

In treating pain, there are numerous guidelines that the clinician can follow, for example, the ADA, NICE or South African SEMDSA guidelines. ‘There is no single drug panacea that works in every patient all the time. In fact there are significant unmet needs for drugs directed at the underlying nerve pathology’, Dr Kaplan noted.

Most commonly, we start with a tricyclic antidepressant and progress to other avail-able modalities. Ideal starting therapy would be the use of duloxetine or pregablin. ‘Of concern however is that these agents are not inexpensive and are not covered by medical aids. We need to initiate a process whereby painful diabetic neuropathy is included in the list of chronic conditions requiring full pay-ment under the prescribed minimum benefits (PBM) legislation’. Dr Kaplan advocated.

Tramadol may be a useful adjuvant but should be used with caution with drugs from the group of selective serotonin reuptake inhibitors, as there may be an added sero-tonergic action. Anti-epileptic drugs are also useful. Dr Kaplan discussed these classes of drugs and outlined the potential of some newer agents.

In conclusion, Dr Kaplan noted that pre-vention is better than cure and clinical trials have shown that a reduction in HbA1c level of 1% can reduce the prevalence of diabetic neuropathy by up to 30%. Once neuropathy is present, tight control of the blood sugar level also helps to reduce the severity of the symptoms, and more so in type 1 than type 2 diabetes.

The individualisation of therapy for haemochromotosisHepcidin, the ‘ultimate’ iron regulatory hor-mone, is the key determinant for assessing

the frequency with which venesection ther-apy should be used to treat haemochroma-tosis. ‘Assays for this protein will soon be available’, noted Prof Peter Jacobs.

Prof Jacobs, emeritus professor, UCT, has been involved in the early clinical assessment of iron overload since the 1960s, in associa-tion with Prof Tom Bothwell and others. He presented a view of this fascinating jour-ney from clinical assessment to the recent determinations of the aberrant genes of iron absorption. In addition to mutations in the HFE gene, defects in four additional genes have been found to cause hereditary haemo-chromatosis: hepcidin, transferrin receptor 2 (TFR2), haemojuvelin (HJV) and ferroportin.12

‘In the 1950s, Bothwell and others pub-lished the first report of the juvenile occur-rence of haemochromatosis. We now know that this early clinical appearance which leads to early cardiovascular abnormalities is due to a defective haemojuvelin gene. Similarly, other manifestations reflecting a series of clinical syndromes can now be related to the individual genetic abnormal-ity, which ultimately affects hepcidin levels’, Prof Jacobs explained.

For the clinician today, Prof Jacobs advised the following:• Imaging studies with MRI can be very

helpful in assessing iron stores in the liver, pancreas and heart tissues.

• Early diagnosis and multidisciplinary sup-port for the haemochromatosis patient involving an endocrinologist, biochemist and cardiologist is essential to prevent organ damage. Sole-practice support of a haemochromatosis patient is unwise.

• Advice to patients should be based on the underlying genetic abnormality so as to re-assure patients concern-ing their and their children’s on-going risk. The University of Stellenbosch is involved in the local genetic studies and Prof Jacobs urged that clinicians should make use of these services to build up a picture of our South African environ-ment.

• Fifty per cent of patients will be symp-tomatic of diabetes, as iron selectively destroys the β-cells of the pancreas.

• The prevalence of haemochromatosis is 1.3% in affected families; six times the prevalence in the general population.

• Therapeutic use of proton pump inhibi-tors, dietary and lifestyle modifications, and iron chelates are not helpful.

• Venesection should be managed, to bal-ance the loss of iron (venesection activates intrinsic mechanisms of iron absorption in the diet). Hepcidin measurement will in future be definitive in the balancing of a venesection programme.3

ReferencesBest JH, Rubin RR, Peyrot M, Li Y, Yan P, Malloy J, 1. Garrison LP. Weight-related quality of life, health utility, psychological well-being, and satisfaction with exenatide once weekly compared with sitagliptin or pioglitazone after 26 weeks of treatment. Diabetes Care 2011; 34(2): 314–319Elashoff M, Matveyenko AV, Gier B, Elashoff R, 2. Butler PC. Pancreatitis, pancreatic and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011; 141(1): 150–156. Epub 2011, February 18.Rambert P, Canivet J, Herve R. [Sugar diabetes and 3. Addison’s disease. Study of 2 cases.] Ann Endocrinol (Paris) 1961; 22: 269–281. Liu KW, Dai LK, Jean W. Metformin-related vitamin 4. B12 deficiency. Age Ageing 2006; 35(2): 200–201.Paffenbarger RS Jr, Hyde RT, Wing AL, Lee IM, Jung 5. DL, Kampert JB. The association of changes in physical-activity level and other lifestyle characteristics with mortality among men. N Engl J Med 1993; 328: 538–545.Tansey MJ, Tsalikian E, Beck RW, Mauras N, Buckingham 6. BA, Weinzimer SA, et al; Diabetes Research in Children Network (DirecNet) Study Group. The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes. Diabetes Care 2006; 29(1): 20–25. Grimm JJ, Ybarra J, Berné C, Muchnick S, Golay A. 7. A new table for prevention of hypoglycaemia during physical activity in type 1 diabetic patients. Diabetes Metab 2004; 30: 465–470.Lim EL, Hollingsworth KG, Aribisala BS, 8. et al. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54(10): 2506–2514. Epub 2011, June 9.Chikunguwo SM, Wolfe LG, Dodson P, Meador 9. JG, Baugh N, et al. Analysis of factors associated with durable remission of diabetes after Roux-en-Y-gastric bypass. Surg Obes Relat Dis 2010; 6(3): 254–259. Epub 2009, November 10.Engerman RL, Kern TS. Progression of incipient 10. diabetic retinopathy during good glycaemic control. Diabetes 1987; 36(7): 808–812.Brasacchio D,11. et al. Hyperglycaemia induces a dynamic co-operativity of histone methylase and demethylase enzymes associated with gene-activating epigenetics marks that co-exist in the lysine trial. Diabetes 2009; 58(5): 1229–1236.Suinkels DW, Fleming RE. Novel observations in 12. hereditary hemochromatosis: potential implications for clinical strategies. Maematologica 2011; 96(4): 485–488.

‘He who understands pain, understands medicine’ – William Osler

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1

Reference:1. IMS MIDAS WorldWide Data - June 2010

Proprietary Name: Levemir®. Scheduling Status: S3 Composition: Insulin detemir 100 units /ml. Indication: Treatment of insulin requiring patients with diabetes mellitus.Registration Number:38/21.1/0084. For full prescribing information refer to package insert approved by the medicines regulatory authority.

Proprietary Name: NovoMix® 30. Scheduling Status: S3 Composition: soluble insulin aspart/protamine crystallised insulin aspart 100 units/ml in the ratio of 30/70. Indication: Treatment of insulinrequiring patients with diabetes mellitus. Registration Number: 35/21.1/0031. For full prescribing information refer to package insert approved by the medicines regulatory authority.

Proprietary Name: NovoRapid®. Scheduling Status: S3 Composition: 100 units insulin aspart/ml. Indication: Treatment of insulin requiring patients with diabetes mellitus.Registration Number: 34/21.1/0160. For full prescribing information refer to package insert approved by the medicines regulatory authority.

Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. PO Box 783155, Sandton, 2146. Tel: (011) 202 0500 Fax: (011) 807 7989 www.novonordisk.co.za NN/DUO/3582/08/10/ver2



TABLE OF CONTENTSINTRODUCTION AND OVERVIEW .......................... 37

Patients’ bill of rights ............................................ 37

GETTING TO THE HEART OF DIABETIC CARDIOVASCULAR DISEASE .............................. 37

Relationship between adiponectin and carotid IMT ........................................................ 38

Oxidative stress and vascular complications of diabetes ......................................................... 38

Visceral fat and cardiovascular risk in a Chinese study .................................................... 38

Gastrectomy and atheroscerlosis progression ........ 38

Sagittal abdominal diameter a better predictor of arterial stiffening than waist circumference .... 38

Raised adiponectin in orthostatic hypotension in diabetes ......................................................... 39

Vascular stiffening response in type 2 diabetes ...... 39

ADVANCE model better predictor of cardiovascular risk in diabetes ............................ 39

Further results from global A1chieveTM study of insulin usage in type 2 diabetes ..................... 39

LATE-BREAKING CLINICAL TRIALS Data show insulin degludec/insulin aspart

combination significantly reduced hypoglycaemia in type 1 and 2 diabetes patients ............................................................. 40

Pooled analysis: fewer major adverse cardiovascular events in type 2 diabetes patients treated with sitagliptin ........................................................... 40

Flat and stable blood glucose lowering shown with once-daily insulin degludec in both type 1 and 2 diabetes patients ................................................ 40

2011 UPDATE FROM DUBAI, UNITED ARAB EMIRATESInternational Diabetes Federation Congress 4–8 December 2011Contributors: Prof b Joffe, Dr A Kengne, J Aalbers

SUMMARIES

IDF WATCH

INTRODUCTION AND OVERVIEWProf BJ Joffe, CDE Centre, Houghton, JohannesburgIn keeping with previous International Dia-betes Federation congresses, the Dubai meeting presented an exciting and varied series of lectures and symposia. This paral-leled the diverse and unique architecture of the city.

Preceding the official start of the congress was a Novo-Nordisk-sponsored programme titled Advances in metabolic science and therapies. It focused on the glucagon-like peptide-1 (GLP-1) agonists, liraglutide in particular, for the treatment of the obesity–pre-diabetes–diabetes continuum, as well as the potential future use of ultra-long-acting insulins such as insulin degludec (see Late-breaking clinical trials, page 4).

The congress began with a symposium dealing with reform in a post-United Nations diabetes world summit. Dr Richard Smith, former editor of the British Medical Journal, gave a thought-provoking review on new health strategies for dealing with diabetes. He stressed that we should concentrate on pre-diabetes, to prevent its progression to diabetes (his personal viewpoint). This should involve mainly lifestyle modification, with patients being encouraged to ‘take charge’ of their own medical problems.

Following this was a debate on best strat-egies to prevent diabetes in high-risk indi-viduals. Dr Fronzo (USA) was of the opinion that early intervention must include drugs such as metformin, pioglitazone, acarbose and, for future use, exenatide and liraglu-tide. Dr Tuomiletho (Finland) however was against the use of drugs – but rather advo-cated lifestyle changes, including diet and exercise.

Diabetic neuropathy was the subject of a cutting-edge symposium in which the importance of early diagnosis was again emphasised. The usual clinical tests are too crude and techniques such as lower-limb skin biopsy and corneal confocal microscopy for detecting a fall-out in small nerve fibre

density were demonstrated. Gastroparesis is a frequently overlooked autonomic mani-festation and is difficult to manage. Pyloric botox injections were even suggested.

A debate on whether blood pressure should be lowered as much as possible in diabetic patients aroused considerable interest. A blood pressure target of below 140/80 mmHg was generally regarded as reasonable, with the ideal hypotensive agents including ACE inhibitors, diuretics, calcium antagonists, and even the almost obsolete drug, reserpine.

The final topic attracting interest was the metabolic memory hypothesis. This hinges on the theory that alternative met-abolic pathways of intracellular glucose metabolism remain dormant if tight gly-caemic control is instituted and initiated in diabetic subjects, thereby reducing the risk of microvascular complications developing several years down the line, irrespective of later control. However, the reverse situation similarly applies.

Patients’ bill of rightsThe IDF traditionally focuses on the patient–caregiver interface and this year’s meet-

ing in Dubai also raised the profile of the diabetic patients’ bill of rights. Education for Society noted that the role of a young generation of patients is essential to the building of public awareness, according to Amir Karman Tayar, diabetologist and chair of the IDF for the Middle East and North Africa Region.

The contributions of Ibn Sina or Avicenna (980–1037), a Persian, born in Afshana near Bukhara in today’s Uzbekistan, who described diabetes in his 14-volume The Canon of Medicine, was cited among the early contributions to today’s understanding of diabetes from the Middle East region.

GETTING TO THE HEART OF DIABETIC CARDIOVASCULAR DISEASEDr A Kengne, Medical Research Council, Cape TownThis cardiovascular session, co-chaired by Profs A Chait and R Eckel (USA), took place in the Sheikh Maktoum A auditorium and included eight presentations, dominated by studies conducted in Asia, with a single African contribution.



Relationship between adiponectin and carotid IMTSerum adiponectin, one of the most com-monly occurring adipokines, has been shown to be associated with cardiovascu-lar disease and related risk factors. In the first communication of this series, Dr Paul Lee, on behalf of his colleagues from the University of Hong Kong (China), presented the results of their study on the association of serum adiponectin with carotid intima–media thickness (IMT), a well-known surro-gate marker of cardiovascular disease.

Participants were 269 adults (132 men), all members of the Hong Kong Cardio-vascular Risk Factors Prevalence Study 2 (CRISPS 2) cohort. CRISPS 2 was a commu-nity-based cohort study conducted from 2000 to 2004 as a follow up of a repre-sentative community-based survey (CRISPS 1) carried out from 1995 to 1996.

Serum adiponectin, IMT and cardiovas-cular risk factors were measured at base-line. Mean age of participants was 53 ± 12 years; 91 had hypertension and 33 had dia-betes. Median (interquartile range) baseline adiponectin level was 5.28 mg/l (3.29–7.93). During the first five years of follow up, carotid IMT significantly increased from 0.62 mm (0.52–0.73) to 0.67 mm (0.57–0.78) (p < 0.001).

In linear regression analysis, after adjust-ment for several baseline covariates, the investigators found a modest association between low baseline adiponectin levels and IMT thickening (β = –0.092, p = 0.039).

The investigators concluded that meas-uring adiponectin level would improve cardiovascular disease risk stratification at the community level. The study was how-ever based on a small sample size, and the investigators did not use measures of global performance to assess the contribution of adiponectin level to risk prediction.

Oxidative stress and vascular complications of diabetesThere is accumulating evidence on the important role of oxidative stress on vas-cular complications of diabetes mellitus. Dr Iso gave a talk on behalf of her colleagues from the School of Medicine, Toho Univer-sity in Japan, on components of oxidative stress associated with carotid IMT in people with diabetes.

In all, they included 52 diabetic patients (17 women) with acceptable levels of control of blood glucose and blood pres-

sure on a cross-sectional basis. They were non-smokers and had non-ongoing acute or chronic inflammatory disease, kidney impairment or liver disease.

Urine levels of 8-hydroxydeoxygua-nosine (8-OHdG, a marker of oxidative DNA damage) and 8-epiprostaglandin F2a (PGF2-a, a marker of lipid peroxida-tion), both makers of oxidative stress, were measured together with inflammatory markers [high-sensitivity C-reactive protein (hs-CRP)] and other clinical and biological parameters. Maximum IMT (max-IMT) was measured by ultrasonography. Mean age and duration of diabetes were 52 and five years, respectively.

In univariate linear regression analysis, age and PGF2-a were the main charac-teristics associated with max-IMT. These associations were borderline in multivariate analysis.

The authors concluded that in diabetic subjects with acceptable metabolic con-trol, oxidative stress may be implicated in the progression of atherosclerosis in people with diabetes. This claim however was based on a small sample size and border-line association in a cross-sectional design.

Visceral fat and cardiovascular risk in a Chinese studyBody fat is a determinant of cardiovascular disease risk, and there are suggestions that the distribution of body fat may contribute differentially to this risk. This presentation from a group of researchers from Shanghai Jiao Tong University in China was delivered by Dr Ma on the contribution of visceral fat accumulation to carotid IMT in a group of 1 005 Chinese adults. Carotid IMT was quantified by ultrasonography, and visceral (VFA) and subcutaneous fat (SFA) were characterised through magnetic resonance imaging.

In multiple regression analysis, waist cir-cumference (an indicator of body fat dis-tribution) was associated with IMT while body mass index, a measure of the overall fat mass, was not. Similarly, VFA, a more accurate indicator of body fat distribution, was associated with IMT, while SFA was not.

The authors suggested that their find-ings were in agreement with reports from other studies in the USA and Korea, and concluded that VFA was effective in identi-fying atherosclerosis in both lean and obese individuals. Since other more reliable meth-

ods for quantifying atherosclerosis already exist, this study extends previous findings from other settings to China and confirms the thesis of differential contribution of body fat distribution to disease risk.

Gastrectomy and atheroscerlosis progressionThis presentation was from a group of investigators from the Centre for Diabe-tes and Endocrinology of Kitano Hospital in Osaka (Japan) and was delivered by Dr Wada. They investigated the effects of gas-trectomy on progression of atherosclerosis in adults with diabetes.

They recruited 157 patients with type 2 diabetes, among whom 20 had undergone a gastrectomy at least five years previously for cancer eradication. Carotid IMT and other clinical and biological parameters were assessed.

Participants with gastrectomy had higher systolic blood pressure, and lower HbA1c and LDL cholesterol levels, compared to those without gastrectomy. Other clini-cal characteristics were similar between the two groups. Mean carotid IMT was significantly lower in the gastrectomised group than in those without gastrectomy (p = 0.04). This difference persisted in some subgroup analyses (smokers, patients with hypertension), but not in all. Subgroup analyses however, were based on small numbers.

The authors concluded that in addition to the known beneficial effects of gast-rectomy on glucose tolerance, this pro-cedure may also have a favourable effect on the progression of atherosclerosis. The study, as recognised by the investigators, was cross-sectional and based on a small sample size.

Sagittal abdominal diameter a better predictor of arterial stiffen-ing than waist circumferenceOstgren and his collaborators from Linkop-ing University in Sweden demonstrated a finding suggesting that sagittal abdomi-nal diameter (SAD) was a better predictor of arterial stiffening than waist circumfer-ence (WC) in people with diabetes. This was based on 255 participants with type 2 diabetes, members of the CARDIPP cohort (CArdiovascular Risk factors in people with Diabetes – a Prospective study in Primary care).



Arterial stiffness was measured by pulse wave velocity (PWV) and participants were followed for four years between 2006 and 2010. They had acceptable metabolic control both at baseline and during follow up.

In multivariate linear regression analy-sis, they found that SAD, not WC or body mass index (BMI) was significantly asso-ciated with PWV at baseline. Likewise, during follow up, change in SAD and BMI, but not WC were associated with four-year change in PWV.

In general, SAD is much easier to meas-ure than WC and may show less variability across populations than WC.

Raised adiponectin in orthostatic hypotension in diabetesOthostatic hypotension (OH), a frequent complication of diabetes mellitus, is asso-ciated with increased risk of mortality. Related mechanisms are still ill understood. This exploratory study was undertaken by Terasawa and co-workers from Dokkyo Medical University Koshigaya in Japan.

They hypothesised that serum high-molecular weight (HMW) adiponectin (the most commonly occurring adipokine, and a determinant of cardiovascular disease and mortality) might be elevated in patients with type 2 diabetes and orthostatic hypo-tension. They also investigated the asso-ciations of orthostatic hypotension with variables of coagulation⁄fibrinolysis and with arterial stiffness

They recruited a group of 105 type 2 diabetes patients (30 with OH), in whom the quantified HMW adiponectin level and many other clinical and biological param-eters were assessed. Serum total and HMW adiponectin levels were higher in patients with OH than in those without. They also had worse renal function and a lower hae-matocrit, which may possibly be explained, at least in part, by the high levels of adi-ponectin.

In multivariate linear regression analysis, systolic blood pressure, HDL cholesterol, haematocrit, prothrombin and brachial pulse-wave velocity were the main deter-minants of HMW adiponectin. The study was cross-sectional and therefore pre-cluded speculation about causal relation-ship. The authors however suggested that the presence of OH is probably an indicator of a clustering of cardiovascular risk factors including HMW adiponectin.

Vascular stiffening response in type 2 diabetesThis study by Penno and co-workers from Azienda Ospedaliero Universitaria Pisana in Italy focused on the single and joint effects of diabetes mellitus and hypertension on carotid and peripheral vascular stiffness. They recruited 114 subjects, including 14 normotensive non-diabetics, 37 hyperten-sive non-diabetics, 20 non-hypertensive diabetics and 39 hypertensive diabetics.

Pulse wave velocity (PWV) was meas-ured by applanation tonometry, and carotid IMT and lumen diameter were assessed by ultrasonography. Peripheral PWV was simi-lar between the four groups, while aortic PWV, carotid stiffness index, carotid IMT and lumen diameter differed and were higher in participants with diabetes or hypertension, compared with their non-diabetic or normotensive counterparts.

In mutually adjusted regression analysis, both hypertension and diabetes were asso-ciated with high aortic PWV. In addition, diabetes was associated with high IMT, while hypertension was associated with high carotid stiffness and diameter.

The authors concluded that type 2 dia-betes and hypertension are characterised by discrete differences in the vasculature stiffening response. This, however, was based on a very small number in a cross-sectional analysis.

ADVANCE model better predictor of cardiovascular risk in diabetesThe use of global cardiovascular risk models is increasingly recommended as an appro-priate basis for initiation and intensification of cardiovascular risk-reduction therapies in people with diabetes. However, those models specific to people with diabetes and developed only recently have not been extensively tested.

In the last presentation in this series, Dr Kengne, on behalf of the ADVANCE inves-tigators, shared their validation studies of the ADVANCE risk model. ADVANCE is the largest global trial of cardiovascular pre-vention in people with diabetes. Dr Kengne and his colleagues used the four to five years’ follow-up data of the trial to develop a model for predicting major cardiovascular disease based on 10 predictors.

They subsequently applied their model to participants from the DIABHYCAR study, a trial of ramipril for the prevention of kidney disease in people with diabetes,

conducted in 16 countries around the Mediterranean. The model had an accept-able performance with a c-statistic of 0.69, equivalent to what was obtained when the model was tested on the ADVANCE cohort (internal validation).

The ADVANCE model also largely did better than two popular Framingham equations. Based on a four-year risk thresh-old of ≥ 8% (equivalent to a 10-year risk of 20%), the ADVANCE model identified the 39% of the DIABHYCAR participants in whom 66% cardiovascular disease events were recorded.

Based on this performance, the investi-gators concluded that the ADVANCE risk model is appropriate for cardiovascular risk stratification in contemporary populations with diabetes who are already receiving many risk-reducing therapies. It would be interesting if this acceptable performance was demonstrated in other validation stud-ies, and that the uptake of the model be shown to improve decision making and the outcomes of care.

Further results from global A1chieveTM study of insulin usage in type 2 diabetes J Aalbers, Special Assignments EditorThe A1chieveTM study was the largest-ever observational study on the use of insulin therapy in patients with type 2 diabetes. The baseline data involving almost 70 000 patients were presented for the first time at the 2011 American Diabetes Association (ADA) meeting in June last year.

The study was a non-interventional 24-week observational study of type 2 dia-betes patients, including both insulin users and non-insulin users, who were started on insulin detemir (Levemir®), insulin aspart (NovoRapid®) or biphasic insulin aspart 30 (NovoMix 30®) in 28 countries across four continents.

Of importance to our region is that the study concentrated on less well-resourced and newly developed countries. It could well be the pivotal study of insulin manage-ment in type 2 diabetes, providing unique data that are more applicable to Africa than that from other studies such as the UKPDS.

The highlights of data presented at the IDF is summarised in this report and will be extensively covered in future issues of the South African Journal of Diabetes and Vas-cular Disease.



In an evaluation of the factors influenc-• ing early insulin initiation, a deteriora-tion of HbA1c levels of 1% increased the probability of early insulin use by 6%. Higher baseline postprandial glu-cose (PPG) levels also predicted earlier insulin use, but higher baseline fasting plasma glucose (FPG) levels had the opposite effect.Interestingly and perhaps a reflection • of inappropriate care, the presence of micro- or macrovascular complications did not favour the introduction of insu-lin.The negative association with higher • FPG levels and positive association with raised BMIs require further explana-tion.Optimisation of insulin therapy in • patients on basal insulin was, for the most part, with premix insulin, rather than switching to a multiple-injection regimen.In the real-life clinical setting, switch-• ing from biphasic human insulin (BHI) to biphasic insulin aspart 30 (BIAsp 30) allowed patients to significantly lower their HbA1c levels and enabled more patients to achieve HbA1c values less than 7% without increasing the risk of hypoglycaemia.Adding mealtime insulin (insulin aspart) • is usually an opportunity for markedly improving the health of people with type 2 diabetes who are already on basal insulin.Results in this real-life clinical situation • suggest that when transferring from insulin glargine with or without oral glucose-lowering agents, use of insu-lin detemir may offer the opportunity to improve glucose control with fewer major, minor and nocturnal hypogly-caemic events.

LATE-BREAKING CLINICAL TRIALS

Data show insulin degludec/insulin aspart combination significantly reduced hypoglycaemia in type 1 and 2 diabetes patientsA soluble co-formulation of insulin deglu-dec and insulin aspart (IDegAsp) was associated with a 58% lower rate of confirmed hypoglycaemic episodes in people with type 2 diabetes compared to biphasic insulin aspart 30 (BIAsp 30), when dosed twice daily.1 The unique way in which insulin degludec/insulin aspart

works, with the basal insulin component providing an ultra-long and steady action profile, plus a bolus boost of insulin aspart, provides a simple way to introduce meal-time dosing at any meal.

In this phase 2 study, the overall occur-rence of confirmed hypoglycaemia was lower with IDegAsp than with BIAsp 30 during the day as well as at night (noctur-nal events, occurring between midnight and 06:00). Improvements in FPG were also seen, with levels significantly lower in the IDegAsp group than the BIAsp 30 group (6.4 vs 7.5 mmol/l). The study also found that IDegAsp was well tolerated and pro-vided comparable overall glycaemic control to BIAsp 30 (mean HbA1c at week 16: 6.7 vs 6.7%).1

‘The unique way in which IDegAsp works, with the basal insulin component providing an ultra-long and steady action profile, plus a bolus boost of insulin aspart, provides a simple way to introduce mealtime dosing at any meal’, said Dr Alan Moses, corporate vice president and chief medical officer of Novo Nordisk. ‘These benefits, along with the lower risk of hypoglycaemia and improved FPG shown in these studies, are very promising for people living with type 2 diabetes.’

In addition, a phase 3 study, also pre-sented, showed that rates of hypogly-caemia at night were lowered by 37% in people with type 1 diabetes using once-daily IDegAsp at any meal (with additional insulin aspart doses for the remaining meals), compared to those using insulin detemir once daily plus insulin aspart at all main meals.2

IDegAsp, in development by Novo Nordisk, will, pending approval, be the only soluble insulin combination of ultra-long-acting basal insulin degludec and rapid-acting insulin, insulin aspart. Clinical studies have shown it provides an optimal glycaemic control with significantly less nocturnal hypoglycaemia compared to premix insulin.3

Insulin degludec has a unique, slow rate of absorption which provides a flat and stable action profile.4,5 In several clinical trials, insulin degludec has demonstrated effective glycaemic control and improve-ments in both HbA1c and FPG levels.6-9 It has also demonstrated a significantly lower rate of nocturnal hypoglycaemia when compared to insulin glargine.6,8

Both insulin degludec and insulin deglu-dec/insulin aspart were submitted to the European Medicines Agency (EMA) and the

US Food and Drug Administration (FDA) earlier this year for regulatory review.

Pooled analysis: fewer major adverse cardiovascular events in type 2 diabetes patients treated with sitagliptinIn a pooled analysis also presented at the IDF congress, a lower incidence of reported major cardiovascular events (MACE) was observed in patients with type 2 diabetes treated with sitagliptin compared to those treated with a sulphonylurea (SU).

In this analysis of cardiovascular (CV) safety data from three previously pub-lished, randomised, blinded clinical stud-ies, which included patients with type 2 diabetes who had been randomised to either sitagliptin 100 mg/day (n = 1 226) or an SU (glipizide or glimepiride, n = 1 225) as monotherapy or add-on to met-formin, there were no reports of a major adverse CV event (ischaemic events and CV deaths) in the sitagliptin group, whereas 11 patients in the SU group were reported to have experienced at least one major adverse CV event.

‘Although a retrospective, pooled anal-ysis with distinct limitations, this analysis shows that patients with type 2 diabetes treated with sitagliptin had fewer major adverse cardiovascular events compared to patients treated with sulphonylureas’, said Barry J Goldstein, MD, PhD, vice president, Diabetes and Endocrinology, Merck. ‘These data are important, but prospective stud-ies are needed. Results of a previously pub-lished pooled analysis of 19 clinical trials to evaluate the safety and tolerability of sitagliptin did not show an increased risk of CV events with sitagliptin 100 mg/day compared to placebo or other medicines.’

Flat and stable blood glucose lowering shown with once-daily insulin degludec in both type 1 and 2 diabetes patientsA double-blind, cross-over trial in type 2 diabetes patients has shown that once-daily insulin degludec has a flat and stable blood glucose-lowering effect over 24 hours. Dosages of 0.4, 0.6 and 0.8 U/kg were evaluated at steady state in 49 type 2 diabetes patients.

For all dose levels, mean 24-hour glu-cose infusion rate (GIR) profiles were flat and stable, while on ending therapy, con-



Sponsored by Novo Nordisk

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

trol was retained for a terminal half-life of 25 hours. Insulin degludec was well toler-ated and there were no safety concerns.

A second study was presented at the IDF following the earlier published observa-tion that insulin degludec has less within-subject variability than insulin glargine in treating type 1 diabetes patients. This study evaluated whether this reduced variability was constant over the 24-hour period at steady state.

Using euglycaemic glucose clamps on the sixth, ninth and twelfth days of treat-ment, area-under-the-curve (AUC) evalu-ations of glucose infusions over 24 hours showed less variability with insulin deglu-dec than with insulin glargine, perhaps due to the slow release of IDeg monomers from the soluble multi-hexamers that form after subcutaneous injection.10,11

ReferencesNiskanen Initial, 1. et al. IDegAsp, a soluble insulin combination of ultra-long-acting insulin degludec and insulin aspart, in type 2 diabetes: comparison with biphasic insulin aspart 30. NN data on file (1792) IDF abstract P-1437. Hirsch initial, 2. et al. BOOST™ T1 IDegAsp, a soluble insulin combination of ultra-long-acting insulin degludec and insulin aspart, used once daily in basal-bolus treatment with insulin aspart in type 1 diabetes. NN data on file (3594) IDF abstract P-1438. Vaag A, 3. et al. IDEGASP, a soluble insulin combination of ultra-long-acting insulin degludec and insulin aspart, in type 2 diabetes: comparison with biphasic insulin aspart 30. Poster 1040, presented at European Association for the Studies of Diabetes (EASD), Lisbon, September, 2011. Heise T, 4. et al. Insulin degludec: two fold longer half-life and a more consistent pharmacokinetic profile compared to insulin glargine. NN data on file (1993) IDF abstract P-1444. Kurtzhals P, 5. et al. Multi-hexamer formation is the underlying basis for the ultra-long glucose

lowering effect of insulin degludec. Poster 1049, presented at European Association for the Studies of Diabetes (EASD), Lisbon, September, 2011. Garber A, 6. et al. Insulin degludec improves long-term glycaemic control with a lower rate of hypo-glycaemia vs. insulin glargine in type 2 diabetes. NN data on file (3582) IDF abstract P-1442. Heller S, 7. et al. Induced hypoglycaemia in type 1 diabetes: enhanced counter-regulatory hormone response with insulin Degludec versus insulin glargine. NN data on file (3538) IDF abstract D-0723. Home PD, 8. et al. Poster 941, presented at European Association for the Studies of Diabetes (EASD), Lisbon, September, 2011. Atkin SL, 9. et al. Oral presentation, abstract 112, presented at European Association for the Studies of Diabetes (EASD), Lisbon, September, 2011. Nosek L, 10. et al. Ultra-long-acting degludec has a flat and stable glucose-lowering affect. Poster P-1452, IDF congress, 2011.Heise T, 11. et al. Ultra-long-acting insulin degludec has consistently lowered pharmacodynamic variability than insulin glargine over 24 h at steady state. Poster P-1453, IDF congress, 2011.

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In-hospital diabetes management of non-critical care patients

Dr Graham Ellis

There are two vital measures to ensure better in-hospital care of patients experi-encing hyperglycaemia. First, all patients admitted to hospital should have non-fast-ing blood glucose levels measured. If above 7.8 mmol/l, an HbA1c determination should be done to assess undiagnosed diabetes. Second, the nursing staff needs to be edu-cated and informed on the standard proto-col for the general medical ward (non-critical care patients) so that they can implement and manage patients appropriately.

‘The in-hospital management of hyper-glycaemia suffers from a dearth of evidence, however, and good clinical trials are few. As a result, expert guideline committees world-wide have used clinical experience to guide their therapeutic choices’, Dr Ellis pointed out.

‘The hyperglycaemic patient may be cat-egorised as: diabetic, or with undiagnosed diabetes prior to admission, or as a patient suffering from stress hyperglycaemia, which returns to normal after the crisis is past’, Dr Ellis noted. ‘On admission, an HbA1c level higher than 6.5% would indicate an undi-agnosed diabetic’, he added.

Stress hyperglycaemia (> 7.8 mmol/l) is commonly seen (32–38%) in patients admitted to general hospital wards. The prevalence among critically ill patients is higher: 41% in patients with acute coro-nary syndromes (ACS), 44% in heart failure patients and 80% in patients who undergo interventional cardiac surgery.

‘Lessons from strict or intense glucose control in critically ill patients have influ-enced clinical care of the non-critically ill patient’, Dr Ellis noted. ‘In both these groups of patients, intensive glucose control has disappointingly not improved mortality, or occurrence of stroke or myocardial infarc-tion, but has led to an increase in hypogly-caemia, with adverse consequences.’

The recent guidelines for the manage-ment of hyperglycaemia, issued in January 2012 by the American Diabetes, Endocrine and Heart Association,1 provide comprehen-sive guidelines for hospitalised type 2 diabe-tes patients in the non-critical care setting. ‘Useful targets are set for a fasting blood glucose level of 5.6–7.8 mmol/l and a non-

The diabetologist/cardiologist debate: a meeting of the minds

fasting level of less than 10 mmol/l. Obvi-ously in patients with terminal illness or high risk of hypoglycaemia, the target can be set less stringently to less than 11 mmol/l’, Dr Ellis noted.

The clinician has the option of oral ther-apy: metformin and sulphonylurea therapy with caution in the elderly, and DDP-4 inhibitors, which are rendered less efficient in patients who are not eating. ‘Insulin is however key to therapy. We should bury the sliding scale, as a number of studies, includ-ing the Rabbit 2 trials,2,3 have shown better results with a basal-bolus approach using glargine (once daily) and glulisine before meals’, Dr Ellis noted.

‘Generally the sliding scale of insulin usage has resulted in patients not receiving enough insulin to reach the set targets. Hospitalisa-tion is a great time to initiate insulin therapy in our type 2 diabetes patients as nursing and clinical support is available’, Dr Ellis noted.

The protocol for the ward management of non-critically ill patients involves a step-wise approach: (1) stopping oral medica-tion, and (2) assessing the patient’s insulin needs based on age, blood glucose levels, body mass index and renal function, initially using 0.2–0.5 U/kg, to a maximum of 70 U to reach target blood glucose levels of 7.8–11.1 mmol/l.

The insulin dose should be given as 50% basal insulin, using Levemir (once daily or bid), Lantus (daily) or NPH (bid) insulin. The balance is given in three equally divided doses before each meal if the patient is eating. If the patient is not eating, blood glucose levels should be measured four to six hourly and the dosage adjusted. Supple-mentary insulin may need to be given if the glucose levels are not at target.

‘We need to take special care not to cause hypoglycaemia (< 3.9 mmol/l) as this is a marker of adverse outcomes. If a hypogly-caemic level is recorded, reducing insulin by 20% is a useful guide. Risk of hypogly-caemia is raised in the older ill patient with impaired renal function and patients stop-ping or reducing glucocorticoid (cortisone) therapy’, Dr Ellis warned.

Ageing and type 2 diabetes

Dr Sophia Rauff

The physiological changes of ageing and the pathology of diabetes are cumulative. Dr

Sophia Rauff, an endocrinologist and cur-rently a specialist in the Department of Geri-atrics, University of KwaZulu-Natal noted that type 2 diabetes is a growing problem in older patients (defined by the World Health Organisation as those over the age of 60 years).

The need to individualise therapy to each older patient was stressed. In the case of the frail older patient, particularly when tar-geting glucose control, one should seek to avoid hypoglycaemia, and an HbA1c level of 8% would be an acceptable target. In the older patient, angiography frequently shows worse atherosclerotic disease than the dura-tion and severity of diabetes may suggest. Emphasis was placed on early introduction of primary prevention measures.

With regard to blood pressure measure-ment in the older patient, there is clinical value in using the standing blood pressure rather than sitting blood pressure, as ortho-static hypotension can lead to damaging falls in the elderly. The HYVET trial,4 using a low-dose diuretic (inadapamide sustained release 1.5 mg daily) and perindopril (2–4 mg) achieved excellent results with an on-treatment reduction in mortality. Of inter-est is that the open-label extension of the HYVET trial has recently been published and the benefits of reduction in total and cardio-vascular mortality were retained5 in patients on sustained therapy (achieved blood pres-sure of 146/76 mmHg).

The results of this study of blood pressure control in the active, free-living elderly show that benefits are derived early (within one year) and sustained on treatment for a fur-ther year. People over 80 years should have their blood pressure checked regularly, and if they have sustained levels over 160 mmHg these should be treated to a target of 150 mmHg.5

Reasonable targets for the frail older patient are fasting plasma glucose values of 7.0–8.9 mmol/l, HbA1c levels of 7.5–8.5% and blood pressure of < 150/< 90 mmHg – Dr Sophia Rauff

Contrast nephropathy Dr Graham Cassel

There is an increase in demand for radio-logical tests such as CT scans with contrast,



due to an increase in the size of the ageing population and an increase in incidence of cardiovascular disease. There is also an increase in the complexity of procedures and patients (more co-morbidities).

Contrast-induced acute kidney injury is defined as an impairment of renal func-tion (or increase in serum creatinine levels > 25%) within three days of contrast admin-istration, with no other discernible cause. A risk score can identify high-risk patients prior to the procedure. This includes elements such as diabetes, contrast volume, serum creatinine level above 132 mmol/l, anaemia and hypotension. Also important are age, dehydration, and the use of high osmolar contrast media. Consequences include renal impairment that peaks four to five days after contrast administration, longer hospital stay, increased cardiac morbidity, increased risk of death and greater risk of longer-term mor-tality.

Estimated or measured glomerular filtra-tion rate (GFR) can be used to calculate a safe dose of contrast medium [twice the GFR (in ml) is a safe dose; maximum to be used is four times the GFR]. Strategies to prevent contrast nephropathy: withdraw nephrotoxic drugs (NSAIDS, aminoglyco-sides, etc), stop diuretics 48 hours before the procedure, volume expansion over 12 hours pre-procedure with normal saline, limit the dose of contrast, use iso-osmolar contrast, not high osmolar. Bicarbonate and N-acetyl cysteine usage is of uncertain ben-efit but can be used, and even diluting the contrast medium. Doctors need to be aware of and vigilant for this condition.

Modern approach to anticoagulant and antithrombotic therapyDr Darryl Smith

Clopidogrel has been tried and tested in millions of patients with acute coronary syndromes over the last 10 years and the clinical relevance of genetically based clopi-dogrel non-responders is not clinically sig-nificant, except in patients at high risk of stent thrombosis. This pragmatic view, pre-sented by Dr Darryl Smith (Johannesburg), did however carry the caveat of using the newer agents, prasugrel or ticagelor, in spe-cific patient groups.

‘Prasugrel could well be the drug of choice in younger patients at higher risk of thrombotic events, also in diabetic and STEMI patients, and in those with stents and a history of recurrent events. Caution is however required when considering the

use of prasugrel in patients with prior cer-ebrovascular events or transient ischaemic events, those older than 75 years and those with a low body weight of less than 60 kg. Prasugrel in the TRITON-TIMI 38 trial was more effective than clopidogrel in reducing cardiovascular events but at a slightly higher bleeding risk’,6 he noted.

Ticagrelor, not yet available in South Africa, is a very effective drug. It is not a pro-drug and its action is both of shorter dura-tion and reversible. ‘It does however cause dyspnoea and bradycardia, which restricts its use in patients with this cardiac symp-tom’, Dr Smith added.

‘We also need to note that there were significant mortality benefits with ticagrelor in the PLATO study, achieved with a minimal increase in bleeding.’ Dr Smith noted that while aspirin remains the cornerstone of anti-thrombotic therapy, the newer agents such as clopidogrel, prasugrel or ticagre-lor should be used in addition to aspirin to reduce platelet aggregation.

‘The field of anti-coagulation is excep-tionally difficult to review in a brief presenta-tion’, Dr Smith said. However, it is generally accepted that greater anti-coagulation effi-cacy comes at the price of increased bleed-ing. ‘This generalisation has been disproved by the ARISTOTLE7 trial of apixaban in atrial fibrillation (AF), which achieved a significant reduction in stroke and systemic embolism without an increased bleeding risk. This may well be the shape of things to come: more effective protection from coagulation-related events by agents that are also safer to use’, he added.

‘Warfarin is extremely effective but it is difficult to use, particularly in the frail elderly who are at high risk of AF-related stroke or systemic embolism. Registraries show that less than 55% of these patients are put on warfarin, because of concerns around bleeding’, Dr Smith noted.

‘In the prevention of AF-related events, the use of the CHA2DS2-VASc to define risk of an embolic event, and the HASBLED score to define risk of bleeding, can help to individualise therapies using the three new agents, dabigatran, rivaroxaban and apixa-ban’, Dr Smith argued. Use of these agents as front-line therapy for the prevention of AF-related vascular events is currently under vigorous debate.8,9

Complicating the use of these agents is the differing doses required for the same agent in different conditions. For example, rivaroxaban in acute coronary syndromes was trialed at 2.5 mg bid versus 5 mg bid,

but the recommended dose for atrial fibril-lation patients is 20 mg daily. This is also true for dabigatran, which has a different dose in knee- and hip-replacement surgery compared to its dosage in the prevention of vascular complications of AF.

Finally a lack of head-to-head studies makes the clinician’s task of therapeutic selection more difficult. These drugs offer a great deal of promise, as shown in the AF clinical trials against well-controlled war-farin (some three to six patients saved per 1 000), which could be even larger in the real world of poor warfarin control’, Dr Smith concluded.

Aspirin should be continued as anti-thrombotic therapy in high-risk patients undergoing surgery when clopidogrel is discontinued – Dr Darryl Smith

The incretins: so much attention at international meetings that a review in South Africa is timeous

Dr Larry Distiller

Dr Distiller, co-ordinator of this specialist meeting, set the pace in a thorough review of topics presented at the meeting by cautioning clinicians to evaluate incretin usage critically. ‘It is clearly time to review these agents, both the GLP-1 agonists and the DPP-4 inhibitors as their international status grows and they become more avail-able on the South African market’, he noted.

The defining characteristics of these two classes of agents are the supra-physiological levels of GLP-1s, attained by exenatide or liraglutide treatment (the GLP-1 agonists), and the physiologically stable levels of GLP-1 attained by the use of DPP-4 inhibi-tors. ‘The actions of the injectable GLP-1 agonists are therefore generally more pow-erful than the oral DPP-4 inhibitors. The incretins’ enhancement of glucose-induced insulin secretion and the restoration of the glucagon-suppression response are particu-larly relevant, as glucagon is certainly the forgotten hormone of type 2 diabetes’, he said.

Referring to exenatide (twice daily) and the more powerful once-weekly dosage not yet available in South Africa, and to liraglu-tide (once daily), Dr Distiller noted that their promise is partially fulfilled by the fact that the reduction in HbA1c levels (0.8–1% reduc-tion depending on baseline HbA1c level) is maintained over a two to three-year period



Diabetic dyslipidaemia: new therapies Prof Derick Raal

A typical diabetes lipogram: small, dense LDL-C, low HDL-C and high triglyceride • levels.Statin’s main effect is reduction of LDL-C levels.• Fibrate’s main effect is reduction of triglyceride and increased HDL-C levels.• Niacin reduces triglyceride and raises HDL-C levels.• There is still a substantial residual risk of cardiovascular disease, even when the LDL-C • level has been greatly reduced.Triglycerides: no clear cardiovascular risk (if one corrects for other factors). FIELD and • ACCORD LIPID trials showed no cardiovascular benefit with the addition of fibrate to statin therapy.HDL-C has multiple physiological functions. Low HDL-C levels have a clear associa-• tion with increased cardiovascular risk. New drugs target HDL-C.Niacin raises HDL-C levels, decreases carotid intima–media thickness but does not • reduce cardiovascular events (AIM-HIGH study). Side effects are a problem.Reconstituted high-density lipoprotein (rHDL) intravenous infusions can reverse • atheroma in the acute setting.Cholesterylester transfer protein (CETP) inhibitors: torcetrapib raises HDL-C levels, • but increases death rate. New drugs in this class are being developed.More aggressive lowering of LDL-C levels is still the best way of reducing cardiovas-• cular risk. One should aim for very low levels (< 1.8 mmol/l in high-risk patients). For every 2 mmol/l lowering of LDL-C levels, there is a 40% reduction in cardiovascular event rate.New therapy to lower LDL-C levels will soon be available as PSK9 inhibitors•

and there is a progressive and probably meaningful weight loss.

‘There is considerable interest in the non-glycaemic potential benefits of GLP-1 agonists with regard to their neuro- and cardioprotective effects. A real-life study in medically insured patients, the Life-Link study, has recently shown a 16% reduc-tion in cardiovascular events in patients on exenatide.’ Dr Distiller noted.

‘With regard to the ultimate promise of these agents, the increased proliferation and reduced apoptosis of β-cells, which was shown in early experimental laboratory studies, there is some evidence from HOMA studies that, for example, liraglutide is β-cell sparing compared to TZDs and basal insu-lin’. ‘At this juncture, liraglutide appears the better option in this class of agents, but this situation is dynamic and may change with the advent of once-weekly exenatide’, Dr Distiller noted.

With regard to the DPP-4 inhibitors, Dr Distiller noted ‘they work, they are mild, and do not change the world; but they do work. They are weight neutral, drop HbA1c levels on average by 0.7%, and there is a suggestion that they preserve β-cell function. Overall, their cardiovascular effects are not yet as well researched as the GLP-1 agonists’, he noted.

With regard to when to use these agents,10 Dr Distiller noted that early use when there is still β-cell function is taken up in many algorithms as an alternative for sulphonylureas with metformin. They are also used in combination with insulin, fol-lowing acceptable trials and registration for use of the particular agent with insulin.

As DPP-4 receptors are widespread in the body, and despite the claimed specificity of these inhibitors, Dr Distiller noted a general acceptance that these drugs have a subtle effect on the immunosurveillance system, leading to increased incidence of bronchitis, for example.

With regard to the GLP-1 analogues and their risk of pancreatitis, pancreatic and thy-roid cancer, there is an alert but not yet an alarm, despite the much-commented article on post-marketing surveillance’,11 he con-cluded.

Is type 2 diabetes a cardiovascular risk equivalent?Dr AD Horak, Dr Hoosen Randeree

A stimulating debate concluded the pres-entations, with Dr AD Horak (Cape Town) presenting the view that diabetes is worse than a cardiovascular risk equivalent, while

Dr Hoosen Randeree (Parklands Hospital, Durban) felt that diabetes is less than a car-diovascular risk equivalent because future risk is confounded by the patient’s ethnicity, age, gender and age of onset of diabetes. The type of therapy used in the treatment of type 2 diabetes also confounds the assess-ment of the condition as a cardiovascular risk equivalent.

The conclusion of the participants was that the clinician needs to focus on those diabetic patients who will benefit most from preventative therapy, so as to reduce the cardiovascular and vascular consequences of type 2 diabetes.

Dr F Mohamed and J Aalbers

ReferencesUmpierez GE,1. et al. J Clin Endocrinol Metab 2012; 97(1): 16–36.Umpierez GE, 2. et al. Diabetes Care 2011; 34(2): 256–261.Umpierez GE, 3. et al. Diabetes Care 2007; 30(9): 2181–2186.Bloch MJ,4. et al. J Clin Hypertens 2008; 10(6): 501–503.Beckertt N, 5. et al. Br Med J 2011 doi.10.1136/bmj/ol7541.Hochholzer W, Wiviott SD, 6. et al. Circulation 2011; 123(23): 2681–2689.Aristotle committees and investigators. 7. N Engl J Med 2011; 365(11): 981–982.Granger CB, Armaganijan LV. 8. Circulation 2012; 125(1): 159–164.Ansell J. 9. Circulation 2012; 125(1): 165–170. Best JH, Rubin RR, Peyrot M, Li Y, Yan P, Malloy J, 10. Garrison LP. Diabetes Care 2011; 34(2): 314–319.Elashoff M, Matveyenko AV, Gier B, Elashoff R, 11. Butler PC. Gastroenterology 2011; 141(1): 150–156. E-pub 2011, Feb 18.

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DRUG TRENDS SA JOURNAL OF DIABETES & VASCULAR DISEASE

Gabi Steenkamp and Celynn Erasmus, both registered dieticians, have recently released Fast food for Sustained Energy (published

by Tafelberg Publishers). It is a beautifully illustrated and easy-to-follow, realistic guide for people who need to eat healthily on the go.

Enjoy take-away foods such as pizzas, hamburgers, bacon and eggs (and even muffins) in the right portion size and with the right accom-paniments, and you can still be healthy, full of energy and keep your weight under control.• Tips about snacking from tuck shops, trolleys and vending

machines.• General ideas for smart snacking.• Tips for food at office meetings.• Innovative and easy recipes for breakfast, lunch and dinner that you

can prepare or assemble quickly at home or at the office.• All about meals in a glass.• Shopping lists to ensure you have healthy food available so that you

can enjoy the right food with little effort.

With fun tips on how to take the deprivation out of dieting, Fast food for Sustained Energy is an ideal resource to enable you to educate your patients on correct eating.

Also available in Afrikaans as Kos in ’n Kits vir Volgehoue Energie.

Book reviewFast food for Sustained Energy Gabi Steenkamp and Celynn Erasmus

To win a copy of Fast food for Sustained Energy, valued at R250, in English and Afrikaans, e-mail Wendy on [email protected] with your name, language preference, speciality and postal address by 1 May 2012.

You are cordially invited to an exciting potpourri of plenary talks, poster presentations and meet-

the-professor sessions on diabetes, osteoporosis and general endocrinology, presented by a large

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SA JOURNAL OF DIABETES & VASCULAR DISEASE DRUG TRENDS


In 2000 there was an estimated 171 million people worldwide living with diabetes,

and this number is predicted to increase by the year 2030 to 366 million people. It is estimated there will be a 162% increase in the incidence of diabetes in Africa, which sadly, will further erode already depleted financial and human resources.

Type 2 diabetes mellitus is a complex metabolic disease, which is characterised by hyperglycaemia (due to defective insulin secretion, insulin action or both) and also hyperglucagonaemia, with resultant dis-turbances in carbohydrate, fat and protein metabolism. The exact aetiology of this dis-ease is unknown, however interplay between genetics and environmental factors (obesity, sedentary lifestyle) are considered to play a critical role in its pathogenesis.

Type 2 diabetes accounts for 90% of the diabetic population, and the majority of these individuals die of cardiovascular disease. The underlying reason for this pan-demic is obesity, which accounts for 80 to 95% of type 2 diabetes. Obesity also exacer-bates hypertension and atherogenic dyslipi-daemia. Therefore, management of weight gain in diabetes is paramount.

The United Kingdom Prospective Diabe-tes Study (UKPDS) clearly demonstrated that over time, most of the currently available antidiabetic drugs (including insulin) are associated with weight gain, which further

Drug TrendsLiraglutide, an incretin mimetic

increases the cardiovascular risk. This may also serve as a deterrent for tight glycaemic control.

Another impediment to intensive gly-caemic control is hypogylcaemia, which although seldom occurring in type 2 diabe-tes patients, still remains a major concern. The 2010 National Health and Nutrition Examination survey (NHANES 111) revealed that only 44.6% of diabetics have reached target HbA1c levels below 7%.

By nature, type 2 diabetes is a progressive disease, which is characterised by declining β-cell function, with a resultant reduction in production of insulin. As most antidiabetic drugs rely on endogenous insulin production, they ultimately become ineffective, except for insulin therapy, which needs intensification.

It is against this background that newer therapies are being developed. These target-specific pathogenic mechanisms with a potential of halting or delaying progression of the disease, providing glycaemic control with reduced or no risk of hypoglycaemia, and are weight neutral or, better still, lead to weight reduction.

Incretin physiologyIncretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulino-tropic polypeptide (GIP) are naturally occur-ring hormones. GLP-1 and GIP are secreted by the L cells in the distal part of the small

intestine and colon, and the K cells in the duodenum and upper jejunum, in response to oral glucose ingestion. They then bind to a G-protein-coupled receptor on the pan-creatic β-cells, where they lead to insulin release and glucagon suppression in a glu-cose-dependent manner.

This accounts for up to 70% of insulin production (the so-called incretin effect). This then primarily restores first-phase insu-lin secretion (deficient in type 2 diabetes) and targets postprandial hyperglycaemia, an independent cardiovascular risk (DECODE study).

Incretin hormones have a very short half-life of one to two minutes as they are quickly degraded by the enzyme dipeptidyl pepti-dase-4 (DPP-4). Incretin receptors are ubiq-uitous and found in many organs, including the heart, brain, kidneys, gut, lung, nerves and endothelial cells, where GLP-1 exerts different effects as described below:

In the brain: promotes satiety and alters • food preference to healthier food. In the gut via the vagus nerve: leads to • delayed gastrointestinal motility, associ-ated with marked weight loss (average of 3 kg).In the kidneys: a natriuretic effect by • modulating NA+/H+ exchange, which has a hypotensive effect.In the heart: causes an increase in pulse • rate, a condition of as yet unproven clini-

Fig. 1. Change in HbA1c level. Fig. 2. Proportion reaching HbA1c level < 7%.

DRUG TRENDS SA JOURNAL OF DIABETES & VASCULAR DISEASE


Fig. 3. Change in weight. Fig. 4. Change in systolic blood pressure.

cal significance. It has been shown to improve left ventricular heart function in patients with myocardial infarction, improve endothelial function and reduce systolic blood pressure.In the pancreas: proven to preserve • β-cells (in rodents) by having anti-apoptotic properties and cause β-cell regeneration. This is of course a difficult phenomenon to prove in humans, but would make GLP-1 ideal in the very early stages of dysglycaemia (pre-diabetes). GLP-1 also inhibits glucagon release from cells, responsible for maintaining hepatic glu-cose output by promoting glycogenolysis and gluconeogenesis, thereby causing fasting hyperglycaemia.

Type 2 diabetes is regarded as an incretin-deficient state and therefore restoration of hormonal levels to normal would be one of the physiological means of controlling dys-glycaemia, with the advantages mentioned above.

LiraglutideLiraglutide is a GLP-1 analogue with 97% linear amino acid sequence homology to human GLP-1, and a fatty acid side chain for binding to albumin. It has a half-life of 13 hours, making it ideal for once-daily subcu-taneous injection. Produced by recombinant DNA technology in yeasts, liraglutide has been available in Europe since 2009 and in the USA and Japan since January 2010. In South Africa, we are currently awaiting reg-istration.

In a series of phase III clinical studies called the LEAD program (with more than

4 400 patients), liraglutide was used as monotherapy and in combination with one or two oral antidiabetic agents, in different dosages (0.6, 1.2 or 1.8 mg). Liraglutide was measured against active comparators, including insulin, and against placebo. The results of these studies are summarised in Figs 1–4.

Blood pressure reduction was independ-ent of weight loss. There was no statisti-cal difference in diastolic blood pressure changes. There was an increase in pulse rate of about two to four beats per minute in the liraglutide group; the clinical significance of this finding is not yet known. There was also a reduction in fasting and postprandial blood glucose, as well as improvement in β-cell function (HOMA-B).

Type 2 diabetes is a known risk factor for Alzheimer’s disease and in a small study using mice, liraglutide was shown to cross the blood–brain barrier, where it prevented memory loss, loss of synapses and deteriora-tion of synaptic plasticity in the hippocam-pus. There was also an overall reduction in the β-amyloid plaque count in the cortex and a reduction in inflammatory response, as measured by activated microglia. These are some of the key neurodegenerative developments found in Alzheimer’s disease, suggesting liraglutide as a possible treat-ment in the future.

Common side effects of liraglutide were mainly gastrointestinal (diarrhoea, nausea, vomiting, constipation) occurring within the first four weeks of treatment, and mostly transient. There was also an increase in episodes of pharyngitis. There

was no associated increase in the incidence of pancreatitis or thyroid malignancies, or any other biochemical, haematological or fundoscopical changes.

My recommendatons for liraglutide positioningIt makes physiological sense to start liraglu-tide very early in the dysglycaemic course (pre-diabetes). The next alternative would be to add it to those who are failing with metformin treatment, instead of adding sulphonylurea, especially in obese patients. Price unfortunately will always be a factor.

The other alternatives are:Obese insulin-resistant patients on high • dosages of insulin who, by adding GLP-1 analog, will get weight loss and reduc-tion in insulin dosage.Patients with very low glomerular filtra-• tion rate < 30 ml/min where metformin is contraindicated.As third-line treatment for patients on • metformin and sulphonylurea, with a body mass index > 35 kg/m2 and HbA1c level < 7.5%.Anybody with co-morbid disease where • other drugs are contraindicated.

ConclusionAn ultimate antidiabetic drug should be effi-cacious in terms of reducing HbA1c levels, with no hypoglycaemia, no weight gain, and preferably weight loss. Ideally it should be a tablet. I believe we are slowly moving towards this goal. Dr Duma Khutsoane, specialist endocrinologist, Bloemfontein Mediclinic.

Do more than lower blood glucose.

Grab diabetesby the rootsTM

For people with type 2 diabetes

Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. 2nd Floor, Building A, 345 Rivonia Boulevard, Edenburg, Rivonia, Sandton 2128, South Africa. Tel: (011) 202 0500 Fax: (011) 807 7989 www.novonordisk.co.za NN/DUO/5281/January/2012/ver1

References:1. Nauck M, et al; for the LEAD-2 Study Group. Effi cacy and Safety Comparison of Liraglutide, Glimepiride, 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(1):84-90. 2. Gallwitz B, et al. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract. 2010;64(2):267-276. 3. Garber A, et al; on behalf of the LEAD-3 (Mono) Study Group. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes, Obes Metab. 2011; 13: 348-356. 4. Chang AM, et al. The GLP-1 Derivative NN2211 Restores ß-cell Sensitivity to Glucose in Type 2 Diabetic Patients After a Single Dose. Diabetes. 2003;52:1786-1791.

Proprietary Name: Victoza®. Scheduling Status: S4 Composition: Liraglutide 6 mg/ml. Indications: As an adjunct to diet and exercise to achieve glycaemic control in patients with type 2 diabetes mellitus. Registration Number: 43/21.13/0781. For full prescribing information refer to package insert approved by the medicines regulatory authority.

Victoza® is the fi rst and only human GLP-1 analogue with 97 % homology to natural GLP-1

Reductions in HbA1C1-3

Reductions in weight1-3

Reductions in systolic blood pressure1-3

Improvements in beta-cell function4

GOING BEYONDTHE EXPECTED IN

DIABETES MANAGEMENT

We are committed to developing personalized solutions integrated across therapies, devices and services. Partnership is our path to achieving this goal, enabling people with diabetes to make the most of life everyday.

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Documents

SAJDVD Volume 9, Issue 1