sajdvd volume 9, issue 3

Diabetes in the young and elderly

Volume 9 Number 3September 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

Hypertension guidelines

The young hypertensive

Social media used by adolescents to advise on diabetes

Childhood anti-obesity programmes

Saxagliptin efficacy in the elderly

Cardiovascular disease in mental illness

Metabolic syndrome in HIV

Effects of medicinal plants in diabetes

Supplements for type 2 diabetes

Risk markers in diabetic Africans

ADA Watch 2012

Hypertension Society congress reports

Managing neuropathic pain

It's theshell that

makes

safer.

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.

Safety-CoatedR

81mgThe ORIGINAL low dose aspirinfor optimum cardio-protection

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 3 • SEPTEMBER 2012www.diabetesjournal.co.za

CONTENTS Editorial

103 Preventing burnout: the inspiration of local meetingsL Lombard

Reviews

104 Hypertension guidelines for type 2 diabetes in South Africa: consensus and controversiesB Rayner

107 Cardiovascular disease and diabetes in people with severe mental illness: causes, consequences and pragmatic managementRIG Holt

112 Diabetes and the metabolic syndrome in HIVP Govender

114 The effects of medicinal plants on renal function and blood pressure in diabetes mellitusCT Musabayane

Diabetes Educator’s Focus

120 Supplements for type 2 diabetes patientsT den Dalk

Diabetes Personality

124 A young diabetic harnesses social media to advise and support others with the conditionP Wagenaar

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

Development Editor: GLENDa HarDYCELL: 071 819 6425FAX: 086 610 3395e-mail: [email protected]

Production EditorSHaUNa GErmISHUIZENTEL: (021) 785-7178FAX: 086 628 1197e-mail: [email protected]

Editorial Assistant and CirculationELSabÉ bUrmEISTErTEL/FAX: (021) 976-8129e-mail: [email protected]

Production Co-ordinatorWENDY WEGENErTEL: (021) 976-4378e-mail: [email protected]

Content ManagermICHaEL mEaDoN (Design Connection)TEL: (021) 975-3785FAX: 0866 557 149e-mail: [email protected]

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.

Articles in this Journal are sourced as per agreement with the British Journal of Diabetes and Vascular Disease

all correspondence to be directed to:

THE EDITorPO BOX 1013DUrbaNVILLE7551or [email protected]

TEL/FAX: (021) 976-8129INT: 2721 976-8129

Full text articles available on:

www.diabetesjournal.co.za via

www.sabinet.co.za

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.

Evidence in Practice

125 Early cardiac risk markers in diabetic African patients

126 Left ventricular remodelling after antihypertensive treatment

Salt intake falling: still too high

127 Can very low-calorie diets reverse diabetes?

Success with childhood anti-obesity programmes

Reports

128 ADA Watch, 2012 update from Philadelphia, USAL Lombard, D Jivan, J Aalbers

134 22nd European meeting on hypertension and cardiovascular protection, London 2012N Rapeport, S Middlemost

135 Southern African Hypertension Society congress report, March 2012 The young hypertensiveG Hardy

136 Southern African Hypertension Society congress report, March 2012 Management of type 2 diabetes in primary healthcareW Mollentze

Drug Trends

137 ORIGIN trial shows safety and efficacy of insulin glargine: no adverse cardiovascular outcomes after a 6.2-year follow up of early insulin use

L Lombard, L Distiller, J Aalbers

141 Managing neuropathic pain: first expert recommendation for South Africa places emphasis on stepwise pharmacological intervention

J Aalbers

144 Saxagliptin efficacy and safety in special patient groups (the elderly and those with renal impairment)J Aalbers

SA JOURNAL OF DIABETES & VASCULAR DISEASE EDITORIAL

VOLUME 9 NUMBER 3 • SEPTEMBER 2012 103

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

S Afr J Diabetes Vasc Dis 2012; 9: 103.

Speaking to colleagues, it is alarming to see how pressurised most healthcare professionals are in the current healthcare environment. This is especially true for our colleagues

in private practice where high patient volumes, administrative burdens, medical funders and health politics are affecting most of us and undermining our morale and excellent healthcare system. We’re stressed out and struggle to find a balance between practice and personal life, including family responsibilities. Many of us battle to stay motivated to do the job we studied so hard for and thought we were called to do.

I have just returned from the annual Centre for Diabetes Education (CDE) conference. It is always worthwhile attending this conference, which is of a very high standard. Conferences such as these are important for updating our knowledge but are so much more than that. It’s also about the interaction between colleagues and friends, sharing the tips and struggles of daily practice and getting re-motivated to once again go out there and do the best we possibly can for our patients.

Personally, I find the inspiration given by excellent talks offered by colleagues at these conferences to be highly motivational and one of the greatest benefits of these gatherings. Some speakers have the gift to inspire their colleagues to another level and help us to once again focus on the importance of our job as healthcare professionals.

It helps us to then inspire our patients to improve their health. After all, this is why we became healthcare professionals, but this noble calling can so easily get engulfed by the burdens of daily practice.

This edition focuses on the young and the elderly and once again contains some excellent articles. Prof Rayner, one our local experts, gives a balanced view on the differences and similarities between the SEMDSA and Hypertension Society guidelines. Although there are only small differences between the guidelines, these two societies could improve their communication in future so as not to give a confusing message to practitioners who are already overloaded with multiple guidelines for many of the different medical conditions they see.

The article by Prof Musabayane on the medicinal value of some African plants in hypertension and diabetic renal disease was

Preventing burnout: the inspiration of local meetingsLANDI LOmBARD

completely new to me and very informative. This is also backed up by some animal studies. Wouldn’t it be exciting if we could find a local plant with a revolutionary medicinal benefit, especially in the field of diabetes?

A detailed report on a lecture by Dr Milton Raff on the manage-ment of painful neuropathy (including diabetic neuropathy) should prove very useful in the management of this very challenging problem. It includes a complete list of pharmacological options.

There are also reports on the European hypertension and cardiovascular protection conference, as well as the American Diabetes Association congress (ADA Watch) and the ORIGIN trial presented at the ADA congress.

For our diabetes educators and dieticians, Talia den Dalk has written a fairly comprehensive article on supplements in diabetes and the science behind it. It is unfortunate that more clinical studies are not available to back up the use of these supplements, which make so much physiological sense.

The most recent ORIGIN trial could unfortunately not support the use of omega-3 supplements in diabetics despite the physiology and previous smaller studies supporting its use. More of these large, prospective trials are necessary to investigate some of the other supplements discussed.

I must bring your attention to our diabetes personality. This is a girl I know well and she is a true inspiration to everybody around her, including me. She has cerebral palsy as well as type 1 diabetes but she always has a smile on her face and an extremely positive attitude towards life, which sometimes can be very humbling.

It's theshell that

makes

safer.

Safety-CoatedR

81mgThe ORIGINAL low dose aspirinfor optimum cardio-protectionHp

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

104 VOLUME 9 NUMBER 3 • SEPTEMBER 2012

REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE

Correspondence to: Brian RaynerDivision of Nephrology and Hypertension, University of Cape Town, Cape TownTel: +27 (0)21 404-3495 e-mail: [email protected]

S Afr J Diabetes Vascular Dis 2012; 9: 104–106

Hypertension guidelines for type 2 diabetes in South Africa: consensus and controversiesBRIAN RAYNER

Introduction

Hypertension is common and integral to the pathophysiology of type 2 diabetes (T2DM). It affects the majority of patients, and is an important modifiable risk factor for both micro-

and macrovascular disease.1

The recent publication of the South African Hypertension Society guideline (SAHS) 20112 and the SEMDSA guideline for the management of type 2 diabetes3 affords us the opportunity to compare the recommendations for treatment of hypertension in T2DM and consider the consensus and controversies arising from the publications.

ConsensusBoth guidelines are unambiguous on emphasising the importance of hypertension as a modifiable risk factor in the patient with T2DM. Blood pressure (BP) reduction is associated with reduction in both micro- and macrovascular complications. Both guidelines emphasise the need for correct BP measurement techniques, the use of combination therapy to achieve the BP goal, use of ACE inhibitors or ARBs for patients with albuminuria, monitoring of renal function and the use of furosemide in preference to thiazides if the estimated glomerular filtration rate (GFR) is reduced. Additionally neither guidelines advocate β-blockers as part of the first-line antihypertensive treatment regimen.

Both guidelines also advocate the use of ambulatory BP monitoring (ABPM) in the assessment of patients, but the SEMDSA guideline restricts this to patients with suspected white-coat or office hypertension. The SAHS guideline advocates the use of ABPM for diagnosis of hypertension, and assessment of white coating, masking, nocturnal BP and response to treatment.

ControversiesThe small differences in the SEMDSA and SAHS guidelines reflect the current controversies articulated in the wider domain. The important differences between the guidelines are shown in Table 1.

BP target and the J curveSeveral studies have influenced the old adage ‘the lower the better in type 2 diabetes’. The ‘lower the better’ BP targets and the J curve are the most controversial issues currently in hypertension literature. In a critical reappraisal of the European Hypertension Guidelines as far back

as 2009, Mancia et al. questioned the target BP < 130/80 mmHg in diabetic patients.4 They concluded that there is a wealth of evidence for treating BP above 140/90 mmHg, but very little to support targets of 130/80 mmHg. However, the target BP has as yet not been adjusted.

This difference in target is highlighted in the SAHS and SEMDSA guidelines. The former suggested < 130/80 mmHg and the latter ≤ 140/80 and ≥ 120/70 mmHg. In the 2006 SAHS guideline, a lower limit of diastolic pressure of 64 mmHg was included, but not in the current guideline.

The guidelines are in agreement with the diastolic pressure target of < 80 mmHg, which was based on the secondary analysis of the HOT study.5 A systolic target has never been established and was extrapolated from clinical trials. However the ADVANCE study recently showed that benefit was achieved down to a target of 134 mmHg.6

In the ACCORD study, patients were randomised to standard versus conventional treatment. The average difference in BP in the first year was 133.5 mmHg in the standard- versus 119.3 mmHg in the intensive-treatment group.7 From the epidemiological perspective there should have been a marked reduction in cardiovascular (CV) events, but the actual results showed no benefit in the primary endpoint compared to standard treatment, albeit with significantly lower stroke rates.

In a recent publication, the results of diabetic and non-diabetic patients from the ONTARGET study were analysed post hoc to determine the effect of BP on outcome.8 At all levels of BP, cardiovascular events were significantly increased in the diabetics. In agreement with the ACCORD study, the risk of stroke in the diabetic patients continued to decrease to achieved systolic BP values of 115 mmHg, with no evidence of an upward J-curve inflection.

In contrast, for the primary outcome (CV death, myocardial infarction, stroke or hospitalisation for congestive heart failure), the nadir of the J curve lay at about 129.6 mmHg (122.1–137.0 mmHg) systolic BP for diabetic patients and 129.0 mmHg (123.9–134.1 mmHg) for non-diabetic patients. Achieving systolic BP of 130 mmHg instead of 140 mmHg reduced the risk for the primary outcome by 3.4% in diabetic patients and 4% in non-diabetic patients; for CV death, 0 and 1.9%, respectively; for myocardial infarction, –3.7 and 0.1%, respectively; and for stroke, 31.4 and 21.7%, respectively.

For diastolic BP, the primary outcome in both diabetic and non-diabetic patients showed the highest risk occurred in subjects with the lowest or highest in-trial diastolic BP (67.2 and 86.7 mmHg, respectively), whatever the systolic BP values. The increase in risk in the lowest diastolic BP quartile was even greater in diabetics than non-diabetics.

In a Cox hazards risk analysis of the subjects with initial systolic BP < 130 mmHg, after adjusting for the baseline variables, the

Table 1. Key differences between the SEMDSA and SAHS guidelines.

• BP target and the J curve• Definition of hypertension in the diabetic patient• Choice of antihypertensive therapy and combination therapy• Hypertension algorithm


SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW

risk of experiencing events was increased in diabetes (HR: 1.29, 95% CI: 1.05–1.58) and in patients with underlying co-morbidities such as coronary artery disease, peripheral vascular disease and renal dysfunction.

The reader also needs to be cognisant of the important limitations of reported BPs in clinical trials, as outlined by Fischer et al. In a systematic review of 1 372 trial reports, there was inconsistency in reporting BP and no study has reported target control in individuals.9 In addition, the limitations of office BP must be clearly stated. The closer the BP is to target, the greater the uncertainty of the ‘actual’ mean BP, taking into account the natural variability of BP, white coating and masking. White coating is increasingly exaggerated in older people.

All practitioners, in assessing BP control in diabetics, older indivi-duals and other high-risk patients should make use of ambulatory and home BP monitoring in addition to office measurements to avoid the pitfalls of both over- and under-treatment of high-risk patients. For example, if an office BP is recorded at 170/100 mmHg, and the white-coat or masking effect is 20/10 mmHg, in both instances the patient requires intensification of treatment as the ‘actual’ mean BP for the white coater would be 150/90 mmHg and for the masker 190/110 mmHg. However if the office BP is recorded at 140/90 mmHg and the white-coat or masking effect is 20/10 mmHg, there is considerable uncertainty. The ‘actual’ mean BP would be 120/80 mmHg for the white coater and 160/100 mmHg for the masker, resulting in completely different clinical decisions regarding the hypertensive management. It is estimated that up to 30% of hypertensives will display white-coat or masking effects.

However, there is a pattern emerging from these studies where stroke shows no J point at current target BP levels but there is a nadir for coronary artery disease and CV death, particularly at a systolic BP of 130 mmHg and diastolic BP of 67 mmHg. This is especially so in high-risk, elderly subjects, which includes diabetics. In the author’s opinion, based on current data, the systolic target should be 130 mmHg (but not below) to balance the competing risks of stroke reduction and increased CV events. In addition, a low diastolic BP < 70 mmHg should be avoided. Greater use of ABPM and home monitoring is advocated to assist in the assessment.

Definition of hypertensionThe SEMDSA guidelines use the definition of hypertension if BP remains > 140/80 mmHg instead of the traditional definition > 140/90 mmHg. This is a small detail but there should be consistency of definition.

Choice of antihypertensive therapy and initiation of treatmentThere are two areas of disagreement here. With regard to the choice of initial diuretic with normal renal function, the SEMDSA guideline recommends a thiazide while SAHS recommends either a thiazide or indapamide. Low-dose hydrochlorothiazide is a weak antihypertensive in monotherapy and has no outcome data at this dose.10 Indapamide on the other hand has been clearly shown in the HYVET study to reduce events as first-line therapy.11 In the author’s opinion, if monotherapy with a diuretic is selected then it should be indapamide. However, in combination therapy, these differences are much less important.

The second important point is that the SAHS guideline recommends combination therapy de novo if the BP is > 20/10 mmHg above goal. This recommendation is based on two important

points. Firstly the average response to any antihypertensive agent is about 10/5 mmHg and 20/10 mmHg for two drugs in combination treatment. Secondly sequential monotherapy has been shown to delay control of BP, but even when combination therapy is instituted, there is ‘failure to catch up’ with patients given initial combination therapy.12

Hypertension treatment algorithmThe hypertension algorithm of the SEMDSA and SAHS guidelines are broadly in agreement, but SEMDSA’s is overly complicated. The SEMDSA guideline makes an important distinction regarding calcium channel blockers (CCBs). Non-dihydropyridine (DHP) CCBs are advocated in combination with ACE inhibitors in the presence of albuminuria, whereas for patients without albuminuria, a DHP CCB is advocated. In contrast the SAHS guideline recommends CCBs as part on mono- or combination therapy without reference to the non-DHP or DHP subclass.

The recommendation for using non-DHP CCBs for proteinuria is based on small studies done by Bakris et al.13 In the much larger Benedict study, verapamil was not shown to prevent new-onset microalbuminuria or the progression of microalbuminuria in patients with type 2 diabetes, whereas the ACE inhibitor trandolopril was clearly effective.14,15 In general, BP control in addition to ACE inhibitors is the most effective strategy to reduce proteinuria and, in the author’s opinion, the antihypertensive should be selected on the basis of tolerability and ability to control BP.

ConclusionsBoth the SEMDSA and SAHS guidelines provide important guidance for treatment of hypertension in diabetes. In their broad perspective they are very similar and perhaps we should not be distracted by the small differences. After all, if we achieved a target BP of < 140/90 mmHg in the majority our patients with diabetes and hypertension, this would be a giant step forward. Perhaps in the future, the two guidelines could be harmonised to avoid these small differences.

ReferencesTight blood pressure control and risk of macrovascular and microvascular 1. complications of type 2 diabetes: UKPDS 38. United Kingdom Prospective Diabetes Study Group. Br Med J 1998; 317: 703–713.Seedat YK, Rayner BL. The South African Hypertension Guideline. 2. S Afr Med J 2012; 102: 57–84.The 2012 SEMDSA guideline for the management of type 2 diabetes. 3. J Endocrin Metabol Diabetes S Afr 2012; 17: S1–S94Mancia G, Laurent S, Agabiti-Rosei E, 4. et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27: 2121–2158Hansson L, Zanchetti A, Carruthers SG, 5. et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351: 1755–1762.ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and 6. indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370: 829–840.ACCORD Study Group. Effects of intensive blood-pressure control in type 2 7. diabetes mellitus. N Engl J Med 2010; 362: 1575–1585.Redon J, Mancia G, Sleight P, 8. et al. Safety and efficacy of low blood pressures among patients with diabetes. Subgroup Analyses From the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial). J Am Coll Cardiol 2012; 59: 74–83.Fischer U, Webb, AJS, Howard SC, Rothwell PM. Reporting of consistency of 9. blood pressure control in randomized controlled trials of antihypertensive drugs: a systematic review of 1372 trial reports. J Hypertens 2012; 30: 1271–1276.



Kaplan NM. The choice of thiazide diuretics: why chlorthalidone may replace 10. hydrochlorothiazide. Hypertension 2009; 54: 951–953. Beckett NS, Peters R, Fletcher AE, 11. et al, HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358: 1887–1898. Brown MJ, McInnes GT, Papst CC, Zhang J, MacDonald TM. Aliskiren and the 12. calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial. Lancet 2011; 377: 312–320. Bakris GL, Mangrum A, Copley JB, Vicknair N, Sadler R. Effect of calcium 13.

channel or beta-blockade on the progression of diabetic nephropathy in African Americans. Hypertension 1997; 29: 744–750.Ruggenenti P, Fassi A, Ilieva AP, 14. et al.; BENEDICT-B Study Investigators. Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial. J Hypertens 2011; 29: 207–216.Ruggenenti P, Fassi A, Ilieva AP, 15. et al.; Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004; 351: 1941–1951.

Diabetes congress diary

Date Conference Venue Contact details to register

OCTOBER 2012

1–5 October 48th EASD Annual Meeting Berlin, Germany www.easd.org

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

Istanbul, Turkey

20–22 October 8th Asian Pacific Society of Atherosclerosis and Vascular Disease

Phuket, Thailand www.apsavd2012.com

DECEMBER 2012

4–6 December 1st American Diabetes Association Middle East Congress: Diabetes Prevention and Treatment

Dubai, UAE

JANURAY 2013

31 January – 3 February 2nd international conference on prehypertension and cardio-metabolic syndrome

Barcelona, Spain www.prehypertension.org

FEBRUARY 2013

24–28 February International congress for endovascular specialists (ICON 2013)

Scottsdale, USA

27 February – 2 March The 6th international conference on advanced technologies and treatments for diabetes

Paris, France http://www2.kenes.com

MARCH 2013

14–16 March 7th international DIP symposium on diabetes, hypertension, the metabolic syndrome and pregnancy

Florence, Italy www2.kenes.com/diabetes-pregnancy/

APRIL 2013

11–14 April 5th international conference on advances in diabetes and insulin therapy

Sofia, Bulgaria http://adit-conf.org/

18–20 April 5th international congress on pre-diabetes and the metabolic syndrome

Vienna, Austria www.kenes.com/prediabetes

27 April – 1 May 15th European congress of endocrinology Copenhagen, Denmark www.ece2013.com

MAY 2013

12–15 May 20th European congress on obesity Liverpool, UK www.easo.org/eco2013/

JUNE 2013

21–25 June 73rd American Diabetes Association scientific sessions (ADA)

Chicago, IL, USA www.diabetes.org

To advertise your conference/meeting, e-mail details and half-page pdf advert to [email protected]



Correspondence to: Richard HoltHuman Development and HealthAcademic Unit, Faculty of Medicine,University of Southampton, UKEmail: [email protected]

Originally in: Prim Care Cardiovasc J 2012; 5: 81–85


Cardiovascular disease and diabetes in people with severe mental illness: causes, consequences and pragmatic managementRICHARD IG HOLT

The prevalence of many physical illnesses is increased in people with severe mental illness and accounts for around three quarters of all deaths; cardiovascular disease

is the commonest cause of death. The level of screening for and management of diabetes and cardiovascular risk factors remains low but a straightforward yet systematic care pathway should go a long way towards reducing the health inequalities experienced by people with severe mental illness.

Schizophrenia and bipolar disorder are psychotic illnesses that may alter perception, thought, affect and behaviour and are characterised by intermittent loss of insight. The lifetime risk of schizophrenia is approximately 1–2% and the figure is somewhat higher for bipolar illness. Schizophrenia and bipolar disorder are often collectively known as severe and enduring mental illnesses.

Severe mental illness is associated with a three-fold increased risk of premature death and it shortens life expectancy by approximately 10–20 years.1 Although suicide accounts for the highest relative risk of mortality, being up to 20-fold commoner than among the general population, a number of physical illnesses also occur more frequently in people with severe mental illness and cause around three-quarters of deaths, with cardiovascular disease being the commonest cause of death.1

Primary healthcare professionals have a major role to play in reducing the burden of physical disease in people with severe mental illness. Contrary to expectation, individuals with severe mental illness attend primary care settings more frequently than the general population and are as motivated about their physical health as the rest of the population, but often lack awareness and fail to prioritise their physical well-being.2 This review will examine the prevalence and aetiology of diabetes and cardiovascular disease in people with severe mental illness, and review the steps that can be taken to address this problem in a pragmatic way.

MethodsPubMed and other electronic databases were searched to identify articles that included the keywords: diabetes, cardiovascular disease, psychosis, schizophrenia, bipolar illness, antipsychotic and each individual antipsychotic drug name.

The article draws on the author’s own clinical and research experience, which included membership of three different committees whose remit was to develop pragmatic guidelines to manage diabetes and cardiovascular risk in people with severe mental illness.

Cardiovascular disease in severe mental illnessCardiovascular morbidity and mortality are increased approximately 2–3-fold overall in people with severe mental illness.1 This increased risk is particularly marked in younger individuals with severe mental illness, in whom the prevalence of cardiovascular disease is 3.6 times higher, compared with a 2.1-fold increase in people who are older than 50 years.3 The rates of cardiovascular disease and mortality have fallen in the general population over the last 20 years but these benefits have not been shared by people with severe mental illness and consequently, the health inequality gap has widened.

Several studies have shown that the prevalence of modifiable cardiovascular risk factors, such as obesity, smoking, diabetes and dyslipidaemia, is also increased in people with severe mental illness and explains much of the excess cardiovascular mortality (Table 1).4

Furthermore, the risk factors appear at younger ages: in the US Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, at baseline more than a quarter of men with schizophrenia

Points for the clinicThe prevalence of diabetes and cardiovascular disease is • increased 2–3-fold in people with schizophrenia or bipolar illnessThe reasons for this include genetic and lifestyle factors as • well as disease- and treatment-specific effectsThere is a need to screen people with severe mental illness • systematically for diabetes and cardiovascular riskThe principles of management are similar to those in the • general population

Table 1. Estimated prevalence of modifiable cardiovascular risk factors in people with schizophrenia and bipolar illness and relative risk compared with the general population. Adapted from De Hert et al.4

Schizophrenia Bipolar illness

Modifiable Prevalence Relative Prevalence Relative risk factor (%) risk (%) risk Smoking 50–80 2–3 54–68 2–3 Dyslipidaemia 25–69 < 5 23–38 < 3 Diabetes 10–15 2–3 8–17 1.5–3 Hypertension 19–58 2–3 35–61 2–3 Obesity 45–55 1.5–2 21–49 1–2 Metabolic syndrome 37–63 2–3 30–49 2–3



aged 20–29 years had the metabolic syndrome, compared with fewer than 10% in the general US population.5 The implication of this finding is that healthcare professionals need to pay attention to cardiovascular risk-factor management in people with severe mental illness from the point of diagnosis rather than waiting until they reach the age of 40 years, when they would be eligible for screening under the NHS Health Check programme.

The worldwide prevalence of obesity has increased dramatically over the last three decades, largely driven by changes in diet and physical activity. These demographic changes appear to have affected people with severe mental illness to a greater extent than the general population, as studies that pre-date the 1980s did not consistently report that obesity was commoner in those with severe mental illness.6 By contrast, more recent studies have reported obesity rates that are approximately doubled in people with schizophrenia or bipolar illness. Body composition is also altered in people with severe mental illness: higher waist-to-hip ratios and increased visceral fat have been found even at first presentation of psychosis. Other studies have not replicated these findings, but note marked weight gain and increasing girth during treatment with antipsychotic medication.6

It is estimated that between 10% and 15% of people with severe mental illness have diabetes.4 Type 1 diabetes is not increased and so the 2–3-fold excess is explained by an increase in type 2 diabetes. It is well recognised that approximately 25% of cases of type 2 diabetes are undiagnosed in the general population but this situation is exaggerated in people with severe mental illness, among whom as many as 70% of cases are undiagnosed. This may reflect a reluctance of people with severe mental illness to volunteer their symptoms and the overlap between some symptoms of diabetes and mental illness, which may lead to reduced screening in people with severe mental illness.

The major lipid abnormalities seen in people with severe mental illness are lower levels of high-density lipoprotein (HDL) cholesterol and hypertriglyceridaemia, although not all studies have shown these abnormalities.7

Overall, dyslipidaemia is reported in 25–69% of people with severe mental illness.

Although some studies have reported increased rates of hypertension, this again is not a universal finding, probably reflecting the diverse action of antipsychotics on blood pressure.7 Smoking rates are high in people with severe mental illness, affecting 50–80%.

Antipsychotic medication and cardiovascular diseaseThere are concerns that antipsychotics contribute to cardiovascular risk by inducing weight gain and worsening lipid profile and blood glucose. Weight gain is a well-recognised side effect, affecting between 15 and 72% of patients.6

Although no antipsychotic can be viewed as weight-neutral, the risk of weight gain differs between antipsychotics: mean weight gain is highest with clozapine and olanzapine, there is an intermediate risk of weight gain with quetiapine and risperidone whereas aripiprazole, amisulpride and ziprasidone have little effect on weight. Some first-generation antipsychotics (FGAs), such as chlorpromazine, and other psychotropic medication, such as the antidepressant mirtazapine, are also associated with a high risk of inducing weight gain. Although choice of antipsychotic may be used to predict weight gain, there is marked interindividual variation in treatment-induced weight change. Other factors

associated with weight gain are younger age, lower initial body mass index, family history of obesity, concomitant cannabis use and a tendency to overeat at times of stress.6 The best predictor of long-term weight gain is weight change in the first 4–6 weeks of treatment, emphasising the need for regular weight measurement during the early phase of treatment.

The relationship between antipsychotics and diabetes is complex because of the long natural history of diabetes and the potential confounding effects of other diabetes risk factors in people with severe mental illness.8 Both genetic and lifestyle factors, such as imprudent diet and physical inactivity, may contribute to the increased prevalence of diabetes in people with severe mental illness.

Nevertheless, there are case reports of drug-induced diabetes and diabetic ketoacidosis with each of the second-generation antipsychotics; some of these report that diabetes enters remission when the drug is stopped. A large number of pharmaco-epidemiological studies have indicated that people receiving antipsychotics have a higher prevalence of diabetes and that people receiving second-generation drugs have a small but increased risk of diabetes compared with those receiving first-generation drugs. By contrast, randomised controlled trials have not demonstrated a difference in treatment-emergent diabetes between different antipsychotics or placebo, suggesting that the reasons why individuals with severe mental illness develop diabetes are much more likely to reflect their genetics, lifestyle and illness than their treatment. On the other hand, small increases in blood glucose have been reported, particularly with olanzapine and clozapine, which, if persistent over a lifetime, may translate into meaningful differences in the rates of diabetes.

Antipsychotic treatment is also associated with increases in low-density lipoprotein (LDL) cholesterol and triglycerides and decreased HDL cholesterol. Again, there are differences between drugs, with greater changes generally being seen with those drugs that induce the most weight gain. There may also be other direct mechanisms as hypertriglyceridaemia may occur despite only modest weight gain.

The effect of antipsychotics on blood pressure is variable: although weight gain may lead to increased blood pressure, this may be offset by the adrenergic blockade seen with antipsychotics.7

Although it appears that antipsychotics have an adverse effect on several individual cardiovascular risk factors, it is important to appreciate that this may differ from their effect on cardiovascular events and mortality. A large UK study of more than 46 000 people found that while exposure to first-generation antipsychotics, particularly in high doses, was associated with excess cardiovascular mortality, this increase was not seen in people receiving second-generation antipsychotics.3 Similarly, in a large Finnish study of 66 881 people with schizophrenia, total mortality was lowest in individuals receiving clozapine and olanzapine, with no difference in cardiovascular mortality between drugs.9 These studies are both observational and therefore there may be other explanations or confounders underlying the results, but nevertheless the data are reassuring.

Screening for diabetes and cardiovascular risk factorsThe increased prevalence of cardiovascular disease and its modifiable risk factors in people with severe mental illness provides a strong imperative to screen for diabetes and other cardiovascular risk factors. Although the case for screening does not fulfil all of the criteria laid down by the National Screening Committee, screening



is recommended by a number of national and international guidelines.4, 10-12

Screening should begin prior to the commencement of treatment or as soon as is reasonably possible, 2–3 months later to assess the acute metabolic effects of the antipsychotics and thereafter on an annual basis unless significant treatment changes are contemplated (Table 2). One exception to this timetable is the measurement of weight, which should be performed weekly during the initial phase of treatment.

Cardiovascular risk assessment should include a detailed medical history to assess risk factors, physical examination to include weight and blood pressure, a blood test to assess lipids and glycaemia and an ECG.4 Although waist circumference may provide additional information, this measurement has proven difficult to achieve in the UK. While a fasting blood sample is required to interpret a full lipid profile, there may be merits in taking a pragmatic approach and accepting a non-fasting sample when logistical difficulties prevent the patient attending fasted. The sensitivity and specificity for diabetes, particularly if the glucose measurement is combined with measurement of glycated haemoglobin (HbA1c), do not differ greatly and the 10-year cardiovascular risk assessment employs the total and HDL cholesterol, which are largely unaffected by eating. Although it may be easier to obtain a non-fasting sample, clinicians should not

assume that patients with severe mental illness are unable to attend fasted since several studies have shown that this is feasible.

The latest Quality and Outcomes Framework now includes four indicators for physical health measurements in the mental health domain; these are the recording of body mass index (MH12), blood pressure (MH13), total-to-HDL cholesterol ratio (MH14) and blood glucose (MH15).11 Although MH14 and MH15 are only for those over the age of 40 years, this initiative should improve the monitoring of cardiovascular risk factors in those with psychotic illness.

Current screening practicesIn the National Health Service, where to a large extent care is not offered unless requested, people with severe mental illness may be disadvantaged. The Disability Rights Commission has highlighted that, instead of receiving holistic care, many people with mental illness describe how their physical illnesses are overshadowed by the mental illness, with healthcare professionals concentrating on the latter to the detriment of the former.13 Consequently, many people with severe mental illness are not screened for cardiovascular risk factors. In an audit of 50 in-patients and 50 out-patients of people with severe mental illness in Hampshire, documented evidence that blood pressure had been measured was found in only 32% of case notes, while glucose (16%), lipids

Table 2. Recommended screening based on currently available guidelines

Baseline 2–3 months Annual Target

Medical history, to include ✔ ✔ ✔

family history, ethnicity, smoking, alcohol, diet, exercise

Height ✔

Weighta ✔ Every week during first ✔ BMI < 25 kg/m2

6–8 weeks of treatment and at every clinic visit thereafter but at least quarterly

Blood pressure ✔ ✔ ✔ < 140/90 mmHg

Glucoseb ✔ ✔ ✔ • Fasting glucose < 6.0 mmol/l • Non-fasting glucose < 7.8 mmol/l

Glycated haemoglobinc ✔ ✔ ✔ < 6.0% (42 mmol/mol) if no history of diabetes; target should be individualised for people with diabetes but likely 6.5–7.5% (47–58 mmol/mol)

Lipid profiled ✔ ✔ ✔ • Total cholesterol < 5.0 mmol/l or < 4.0 mmol/l if established CVD or diabetes • LDL cholesterol < 3.0 mmol/l or < 2.0 mmol/l if established CVD or diabetes • 30% reduction in patient starting statins

ECG ✔ ✔ ✔ To assess QTc interval

aAdditional information can be obtained by measuring waist circumference: target in men < 94 cm, in women < 80 cm. Lower values should be sought in people from non-European descendancy;bEither a fasting or non-fasting sample can be used. Fasting samples are more reproducible but may be logistically more difficult to obtain. A formal 75-g OGTT is needed only rarely;cNote HbA1c may be normal in situations where there is a rapid onset of diabetes; dEither a fasting or non-fasting sample can be used. Fasting samples are needed to assess LDL cholesterol and triglycerides but cardiovascular risk can be calculated using total:HDL cholesterol ratio which is largely unaffected by eating. BMI = body mass index; CVD = cardiovascular disease; LDL = low-density lipoprotein; HbA1c = glycated haemoglobin; OGTT = oral glucose tolerance test; HDL = high-density lipoprotein.



(9%) and weight (2%) were assessed even less frequently.14 This was despite a high prevalence of the metabolic syndrome in these patients and a significant number with a 10-year cardiovascular risk of greater than 20%.

The National Institute for Health and Clinical Excellence (NICE) guidance places the responsibility for screening for physical health problems within primary care (Table 3).10 Despite this, there is a lack of clarity among mental healthcare professionals about whose responsibility physical health screening is.15 mental healthcare professionals have also expressed concern about their lack of understanding about what should be measured and when and how to interpret the results. Lack of access to necessary equipment may be a further barrier. Although some people with severe mental illness may never attend their general practice, many do and are willing to undergo screening.16 For those who are seen only within mental health settings, the psychiatry team should ensure that physical health screening is undertaken. Furthermore, there is a responsibility for psychiatry teams to ensure that people with severe mental illness receive physical healthcare from primary care and this should form part of the clinical care plan.10 In order to ensure that patients are not missed, clear communication between primary care and mental health teams is essential.

Assessment of cardiovascular riskCardiovascular risk is usually assessed by the use of locally relevant risk engines. These have not been validated in people with severe mental illness, who are typically younger, have higher blood pressure and are more likely to smoke than the populations used to derive cardiovascular disease risk scoring systems such as Framingham and QRISK. As traditional risk factors only partially explain the excess cardiovascular disease seen in people with severe mental illness, it seems likely that these traditional risk engines will

underestimate cardiovascular risk in people with severe mental illness and so general practitioners should have confidence to treat those identified as at high risk. Pending further research, there is also an argument to consider primary cardiovascular prevention in individuals at intermediate levels of cardiovascular risk who would not routinely reach the National Service Framework or NICE thresholds for treatment.

Managing cardiovascular risk factorsDiabetes and cardiovascular risk factors in people with severe mental illness should be managed along similar lines to the general population despite the additional challenges to ensure that the patient understands the need for lifestyle modification and medication.

SmokingHealthcare professionals should provide smokers with information about the risks of smoking and encourage them to quit. Behavioural counselling and pharmacological approaches, such as nicotine replacement, are suitable for people with severe mental illness.

ObesityThe nihilism that surrounds obesity management has been challenged recently by a number of observational studies and randomised controlled trials in people with severe mental illness.17,18 Trials have shown that non-pharmacological lifestyle interventions lead to ~2.5-kg reductions in mean body weight over 2–6 months,17

while longer observational studies have demonstrated that further weight loss is achievable with on-going support.19

A range of unlicensed pharmacological treatments have been tried to treat or prevent antipsychotic-induced weight gain, with limited benefit.17 There is, however, preliminary evidence from short-term studies that metformin may attenuate weight gain or promote weight loss. While longer definitive trials are needed, the joint European Associations’ position statement recommends that metformin may be considered as a second-line treatment in patients with additional risk factors, such as a personal or family history of metabolic dysfunction.

DyslipidaemiaTarget levels of total cholesterol and LDL cholesterol are the same as those for the general population (< 5.0 mmol/l and < 3.0 mmol/l, respectively) but tighter goals of < 4.0 mmol/l and < 2.0 mmol/l may be appropriate for individuals with established cardiovascular disease or diabetes. No cardiovascular disease outcome trials with statins have been performed specifically in people with severe mental illness but these drugs are as effective in lowering total and LDL cholesterol in this population as in the general population.20

Furthermore, there is no evidence that lipid-lowering medication is associated with suicide or traumatic deaths in people with severe mental illness.

DiabetesThe treatment of diabetes in people with severe mental illness should follow currently available treatment algorithms, although oral anti-diabetes agents that induce less weight gain may have advantages, given the high prevalence of obesity in people with severe mental illness. The additional challenges of managing co-morbid diabetes

Table 3. National Institute for Health and Clinical Excellence (NICE) recommendations regarding management of physical illness in people with schizophrenia10

11.4 Promoting recovery 11.4.1 Primary care 11.4.1.1 Develop and use practice case registers to monitor the physical and mental health of people with schizophrenia in primary care. 11.4.1.2 GPs and other primary healthcare professionals should monitor the physical health of people with schizophrenia at least once a year. Focus on cardiovascular disease risk assessment as described in 'Lipid modification' (NICE clinical guideline 67) but bear in mind that people with schizophrenia are at higher risk of cardiovascular disease than the general population. A copy of the results should be sent to the care coordinator and/or psychiatrist, and put in the secondary care notes. 11.4.1.3 People with schizophrenia at increased risk of developing cardiovascular disease and/or diabetes (for example, with elevated blood pressure, raised lipid levels, smokers, increased waist measurement) should be identified at the earliest opportunity. Their care should be managed using the appropriate NICE guidance for prevention of these conditions. 11.4.1.4 Treat people with schizophrenia who have diabetes and/or cardiovascular disease in primary care according to the appropriate NICE guidance. 11.4.1.5 Healthcare professionals in secondary care should ensure, as part of the Care Programme Approach, that people with schizophrenia receive physical healthcare from primary care as described in recommendations.



and mental illness, however, require close collaboration between mental and physical health services.

Attention must also be paid to preventing diabetes; recent trials have shown that lifestyle intervention programmes involving dietary modification, weight-loss and increased physical activity reduce the incidence of type 2 diabetes. As these programmes share many features with lifestyle weight-loss programmes used in people with severe mental illness, it is hoped that the programmes may also lead to diabetes prevention although this has not been formally assessed. Metformin treatment may also be considered.4

HypertensionThe management of hypertension in severe mental illness should follow the same treatment algorithm as in the general population, with target blood pressure levels of < 140/90 mmHg being recom-mended. Patients should be advised to reduce smoking and salt intake. European and UK guidelines emphasise the need to choose antihypertensive agents best suited to the individual patient’s needs as the achieved blood pressure is more important than the agent used to achieve it.

ConclusionThe increased rates of diabetes and cardiovascular disease in people with severe mental illness provide a clinical imperative to screen and manage cardiovascular disease using a systematic approach. In the past, the physical health needs of people with severe mental illness have largely been ignored, creating significant health inequalities. Although there are additional challenges in the treatment of people with severe mental illness, doing the simple things well is likely to have a significant impact on cardiovascular disease in severe mental illness.

Conflicts of interestProfessor Holt has undertaken lectures for Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Novo Nordisk and Otsuka Pharmaceuticals. He has served on advisory boards for Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline and Novo Nordisk. He has received funding to attend conferences from Astra Zeneca, Eli Lilly, GlaxoSmithKline, Novo Nordisk.

ReferencesBrown S, Kim M, Mitchell C, Inskip H. Twenty-five year mortality of a community 1. cohort with schizophrenia. Br J Psychiatry 2010; 196: 116–21.Buhagiar K, Parsonage L, Osborn DP. Physical health behaviours and health locus 2. of control in people with schizophrenia-spectrum disorder and bipolar disorder: a crosssectional comparative study with people with non-psychotic mental illness. BMC Psychiatry 2011; 11: 104.Osborn DP, Levy G, Nazareth I, Petersen I, Islam A, King MB. Relative risk of 3. cardiovascular and cancer mortality in people with severe mental illness from

the United Kingdom's General Practice Research Database. Arch Gen Psychiatry 2007; 64: 242–9.De Hert M, Dekker JM, Wood D, Kahl KG, Holt RI, Moller HJ. Cardiovascular 4. disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). Eur Psychiatry 2009; 24: 412–24.McEvoy JP, Meyer JM, Goff DC, 5. et al. Prevalence of the metabolic syndrome in patients with schizophrenia: Baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005; 80: 19–32.Holt RI, Peveler RC. Obesity, serious mental illness and antipsychotic drugs. 6. Diabetes Obes Metab 2009; 11: 665–79.Osborn DP, Wright CA, Levy G, King MB, Deo R, Nazareth I. Relative risk of 7. diabetes, dyslipidaemia, hypertension and the metabolic syndrome in people with severe mental illnesses: systematic review and metaanalysis. BMC Psychiatry 2008; 8: 84.Holt RI, Peveler RC. Antipsychotic drugs and diabetes-an application of the Austin 8. Bradford Hill criteria. Diabetologia 2006; 49: 1467–76.Tiihonen J, Lonnqvist J, Wahlbeck K 9. et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009; 374: 620–7.National Collaborating Centre for Mental Health. The NICE guideline on core 10. interventions in the treatment and management of schizophrenia in adults in primary and secondary care CG82. London: The British Psychological Society and The Royal College of Psychiatrists; 2010.NHS Employers. Quality and Outcomes Framework guidance for GMS contract 11. 2011/12: Delivering investment in general practice. http://www.nhsemployers.org/Aboutus/Publications/Documents/QOF_guidance_GMS_contract_2011_12.pdf. 2011. Accessed 8-11-0011.Citrome L, Yeomans D. Do guidelines for severe mental illness promote physical 12. health and well-being? J Psychopharmacol 2005; 19(6 Suppl): 102–09.Disability Rights Commission. Equal Treatment: Closing the gap. A formal 13. investigation into physical health inequalities experienced by people with learning difficulties and mental health problems. London: Disability Rights Commission; 2006.Holt RI, Abdelrahman T, Hirsch M, 14. et al. The prevalence of undiagnosed metabolic abnormalities in people with serious mental illness. J Psychopharmacol 2010; 24: 867–73.Barnes TR, Paton C, Cavanagh MR, Hancock E, Taylor DM. A UK audit of screening 15. for the metabolic side effects of antipsychotics in community patients. Schizophr Bull 2007; 33: 1397–403.Osborn DP, King MB, Nazareth I. Participation in screening for cardiovascular risk 16. by people with schizophrenia or similar mental illnesses: cross sectional study in general practice. Br Med J 2003; 326: 1122–3.Baptista T, ElFakih Y, Uzcategui E 17. et al. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs 2008; 22: 477–95.Alvarez-Jimenez M, Hetrick SE, Gonzalez-Blanch C, Gleeson JF, McGorry PD. Non-18. pharmacological management of antipsychotic-induced weight gain: systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry 2008; 193: 101–07.Holt RI, Pendlebury J, Wildgust HJ, Bushe CJ. Intentional weight loss in overweight 19. and obese patients with severe mental illness: 8-year experience of a behavioral treatment program. J Clin Psychiatry 2010; 7: 800–05.Hanssens L, De Hert m, Kalnicka D, 20. et al. Pharmacological treatment of severe dyslipi-daemia in patients with schizophrenia. Int Clin Psychopharmacol 2007; 22: 43–9.



Correspondence to: Dr Pranessa GovenderDepartment of Nephrology, Internal Medicine, Greys Hospital, Pietermaritzburge-mail: [email protected]


Diabetes and the metabolic syndrome in HIVPRANESSA GOVENDER

When the antiretroviral (ARV) rollout finally began in 2004, it was a huge victory for the health sector and South Africa.1 Almost 10 years later, we find ourselves

facing new challenges in HIV-positive patients. As patients survive longer into middle age with the use of antiretroviral therapy, they are becoming more prone to non-HIV related diseases such as type 2 diabetes, hypertension, dyslipidaemia and an increased risk of cardiovascular disease. In the long term these conditions are associated with significant morbidity and mortality and need prompt diagnosis and treatment.2

There are three categories of diabetic patients in the HIV-positive population:

highly active antiretroviral therapy (HAART)-naïve, HIV-positive • patients who develop diabetes after becoming infected with HIV.Diabetic patients who had diabetes prior to becoming HIV • infected.HIV-positive patients who develop diabetes after antiretroviral • therapy has been initiated.

The time of HIV infection is difficult and almost impossible to determine. Identifying more patients at the onset of HIV infection would allow larger numbers of patients to be recruited and studied for the effects of HIV on glucose homeostasis. There have been several studies on the development of diabetes and insulin resistance secondary to antiretroviral therapy. But there is limited research on a possible link between HIV itself and the consequent development of diabetes.3

Insulin resistance may have an HIV disease-associated compo-nent. Earlier studies show that HIV-infected HAART-naïve patients may have higher rates of insulin clearance and increased insulin sensitivity in peripheral tissues compared to a non-infected person.4

Lipodystrophy occurs usually in patients on particular antiretroviral drugs, but can occur in the ARV-naïve patient. There is evidence that HIV 1 infection contributes to the development of the lipodystrophic phenotype, interfering with some key genes of adipocyte differentiation and mitochondrial function.5

Lipodystrophy presents with fat loss on the face, buttocks, arms and legs. There is also fat accumulation in certain areas. Patients develop hepatic steatosis, central obesity, fat deposits in their upper backs (interscapular fat pad) and increase in breast size. Lipodystrophy does not progress, but usually does not reverse once causative antiretroviral therapy has been stopped. Generalised lipodystrophy is associated with severe insulin resistance and is often accompanied by dyslipidaemia.6

The metabolic syndrome has various definitions and criteria.

Essential components consist of diabetes or impaired glucose tolerance, hypertension, dyslipidaemia (hypertrigyceridaemia and low high-density lipoprotein cholesterol) and obesity–central obesity (increased waist:hip ratio or a body mass index > 30kg/m2). Patients on antiretroviral therapy are at high risk of developing the metabolic syndrome and its complications.7

Antiretroviral therapy is associated with diabetes and impaired glucose tolerance, dyslipidaemia and lipodystrophy. Hence the link between antiretroviral exposure and the metabolic syndrome is not surprising. Other factors besides antiretroviral therapy that predispose patients to diabetes and the metabolic syndrome should be taken into consideration:

the age of the patient (> 50 years increases risk)• obesity, some contributing factors being sedentary lifestyle and • poor dietary habitsethnicity: Asian and the black population are at increased risk• positive family history of diabetes, hypertension, dyslipidaemia.• 4

Antiretroviral therapy involved in the development of diabetes and the metabolic syndromeMost commonly, the most marked effects are caused by nucleotide reverse transcriptase inhibitors (NRTIs), especially stavudine, and protease inhibitors. Protease inhibitors may cause fat redistribution, hyperlipidaemia, insulin resistance and hyperglycaemia. They have varying effects on glucose and lipid metabolism and need to be assessed individually. The mechanisms of these metabolic changes have not yet been fully clarified. There is likely to be a multifactorial aetiology.2

Lopinavir/ritonavir increases fasting triglyceride and free fatty acid levels, but has little or no effect on insulin sensitivity. Indinavir may induce insulin resistance by blocking insulin-mediated glucose disposal by direct blockade of GLUT-4. However there is no effect on lipid metabolism.4, 5

Protease inhibitors are associated with reduced adiponectin secretion and induced expression of interleukin 6. This may contribute to the inhibition of insulin-stimulated glucose uptake.9

Common drugs altering lipid profiles are stavudine, zidovudine, efavirenz, lopinavir/ritonavir and earlier protease inhibitors. Drugs with a cleaner lipid profile are lamivudine, emtricitabine, nevirapine, tenofovir and atazanavir.10

Management of diabetes in the HIV-positive patientMaking the diagnosis with SEMDSA guidelines. No screening • guidelines are in place for patients exposed to antiretroviral therapy. Various factors need to be considered: risk factors, choice of antiretroviral drug in a known diabetic patient, if and when to switch antiretroviral therapy in a patient showing signs of impaired glucose tolerance or insulin resistance.4 Patient education at diagnosis is vital and regular ongoing • education is necessary. These patients are already on antiretroviral therapy and are trying to cope with HIV, antiretroviral therapy and side effects. Adding more medication with further side effects and more responsibility for another condition requires



a good understanding of their diabetes as well as all the other problems encountered in the metabolic syndrome.General measures: modify risk factors such as hypertension • and dyslipidaemia. Check blood pressure quarterly and do an annual lipid profile. Self monitoring of sugar levels where possible. Advise patient to be careful with the sharps they’re using. Check HbA1c level two to four times per annum. Aim to keep HbA1c < 7%.

Annual eye examination by an ophthalmologist or optometrist. Foot care: refer to a podiatrist when necessary. Patients with

diabetes and HIV may be prone to peripheral neuropathy. This may be compounded by TB treatment and antiretroviral therapy.

Screen for diabetic nephropathy. These patients may also have HIV-associated nephropathy. Lifestyle modification: dietary modification. Refer patients to a • dietician to provide adequate nutritional support and dietary education. Exercise and weight loss (in the patient with a raised body mass index) have positive effects on metabolic parameters in HIV-positive patients. It may improve blood pressure and lipid profile and increase insulin sensitivity. Cessation of smoking as this is a major risk factor for cardiovascular disease.7,10,11

Drug management of diabetes mellitusThe aim of treatment is to reduce mortality and morbidity of diabetes-related complications.

What are the indications for a lipid-lowering agent? The use of statins should be universal in diabetics. Consider drug interactions with antiretroviral therapy, particularly protease inhibitors. Fibrates are the agents of choice with hypertrigyceridaemia and have some effect against hypercholesterolaemia. They are safe to use with protease inhibitors. Many statins have significant drug interactions with protease inhibitors, leading to elevated levels of statins, resulting in potential toxicity. Pravastatin and low-dose atorvostatin are safe to use with protease inhibitors.

Other important medications include ACE inhibitors or angiotensin receptor blockers (ARBs) which are renoprotective, aspirin10,12,13 and oral hypoglycaemic agents, such as biguanides, thiazolidediones and insulin secretagogues.

Biguanides: Metformin improves insulin resistance or glucose intolerance. There is a possible risk of lactic acidosis, but it is not contra-indicated in patients on antiretroviral therapy. Patients receiving nucleotide reverse transcriptase inhibitor (NRTI) therapy for longer than six months are usually at higher risk for lactic acidaemia. Stavudine, zidovudine and didanosine are the drugs most commonly associated with raised lactate levels. Check renal function first. Educate patients about symptoms of lactic acidosis.

Thiazolidediones increase insulin sensitivity and reduce insulin resistance. Do liver function tests (LFTs) before using pioglitazone or rosiglitazone. Avoid these drugs if LFTs are impaired: > 2.5 upper limit of normal.

Insulin secretagogues such as sulphonylureas may not be effective in severe insulin resistance.

Change to subcutaneous insulin therapy if diabetes remains uncontrolled. Insulin does not have any drug interactions with antiretroviral therapy or other drugs and it is not contra-indicated

in hepatic or renal dysfunction. Insulin is always the safe option if there is any doubt.3,4

Type 1 diabetes is usually more difficult to manage with or without HIV. Most of these patients are adolescents. Various issues need to be addressed. These patients need more extensive counselling, support and the involvement of caregivers. Compliance, substance abuse and sexual issues are some of the points that need to be addressed. A multidisciplinary approach is important where the social worker, caregiver, teachers at school, doctors and many others need to be involved.10,14

ConclusionHIV and diabetes are chronic diseases which significantly impact on a patient’s lifestyle and wellbeing. It can be overwhelming to deal with. One has to understand the glucose disturbances that can occur with antiretroviral therapy, screen patients appropriately for impaired glucose tolerance and diabetes, altering HIV therapy when necessary, and take into account all other metabolic disturbances associated with antiretroviral therapy, which put patients at high risk of cardiac disease. These modifiable cardiovascular risk factors will have a significant impact on healthcare and patients in the near future.14-16

ReferencesNicoli N. South Africa’s ‘rollout’ of highly active antiretroviral therapy: A critical 1. assessment. J Acquired Immune Deficiency Syndr 2006; 43(5): 618–623.Idiculla J, Ravindra’n GD, D’Souza J, Singh G, Furrugh S. Diabetes mellitus, insulin 2. resistance and metabolic syndrome in HIV-positive patients in South India. Int J Gen Med 2011, 4; 73–78.Kalra S, Kalra B, Agrawal N, Unnikrishnan AG. Understanding diabetes in patients 3. with HIV/AIDS. Diabetol Metab Syndr 2011; 3: 2. Spollet GR. Hyperglycaemia in HIV/AIDS. 4. Diabetes Spect 2006; 19(3): 163–166.Giralt M, Domingo P, Guallar JP, Rodriguez de la Concepcion ML, Alegre M, 5. Domingo JC, Villarroya F. HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART- associated lipodystrophy. Antiviral The 2006; 11(6): 729–740.Chow SC, Day LJ, Souza SA, Shikuma CM. Metabolic complications of HIV 6. therapy. Online – HIVInsite May 2006.Jerico C, Knobel H, Montero M, Ordonez-Llanos J, Guelar A, Gimeno JL, 7. et al. Metabolic syndrome among HIV-infected patients. Diabetes Care 2005; 28(1): 132–137.Lee GA, Seneviratne T, Noor MA, Lo JC, Schwarz JM, Aweeka FT,8. et al. The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS 2004; 18(4): 641–649.Kim RJ, Wilson CG, Wabitsch M, Lazar MA, Steppan CM. HIV protease inhibitor-9. specific alterations in human adipocyte differentiation. Obesity 2006; 14(6): 994–1002.Wilson D. HIV and diabetes.10. S Afr J Diabetes Vasc Dis 2011; 8(3): 104–105.Grinspoon S, Carr A. Cardiovascular risk and body fat abnormalities in HIV-11. infected adults. N Engl J Med 2005; 352: 48–62. Aberg JA. Lipid management in patients who have HIV and are receiving HIV 12. therapy. Endocrinol Metab Clin N Am 2009; 38(1): 207–222.Wienbergen H, Senges J, Gitt AK. Should we prescribe statin and aspirin for every 13. diabetic patient? Diabetes Care 2008; 31(2): S222–S225.McCulloch DK. Patient information – Diabetes mellitus type 1: Overview (beyond 14. basics). Uptodate – online.Monroe A. HIV/AIDS and diabetes: Minimizing risk, optimizing care. The body – 15. complete HIV/AIDS resource – online.Young F, Critchley JA, Johnstone LK, Unwin NC. A review of co-morbidity between 16. infectious and chronic disease in sub-Saharan Africa: TB and diabetes mellitus, HIV and metabolic syndrome, and the impact of globalization. Globalization Health 2009; 5.



Correspondence to: Prof CT MusabayaneDepartment of Human Physiology, Faculty of Medicine, University of KwaZulu-Natal, Durban, South AfricaTel : +27 (0) 31 260-7975Fax: +27 (0) 31 260-7132e-mail: [email protected]

S Afr J Diabetes Vasc Dis 2012; 9: 114-119

The effects of medicinal plants on renal function and blood pressure in diabetes mellitusCT mUSABAYANE

Abstract

Diabetes mellitus is one of the most common chronic global diseases affecting children and adolescents in both the developed and developing nations. The

major types of diabetes mellitus are type 1 and type 2, the former arising from inadequate production of insulin due to pancreatic β-cell dysfunction, and the latter from reduced sensitivity to insulin in the target tissues and/or inadequate insulin secretion. Sustained hyperglycaemia is a common result of uncontrolled diabetes and, over time, can damage the heart, eyes, kidneys and nerves, mainly through deteriorating blood vessels supplying the organs. Microvascular (retinopathy and nephropathy) and macrovascular (atherosclerotic) disorders are the leading causes of morbidity and mortality in diabetic patients. Therefore, emphasis on diabetes care and management is on optimal blood glucose control to avert these adverse outcomes.

Studies have demonstrated that diabetic nephropathy is associated with increased cardiovascular mortality. In general, about one in three patients with diabetes develops end-stage renal disease (ESRD) which proceeds to diabetic nephropathy (DN), the principal cause of significant morbidity and mortality in diabetes. Hypertension, a well-established major risk factor for cardiovascular disease contributes to ESRD in diabetes. Clinical evidence suggests that there is no effective treatment for diabetic nephropathy and prevention of the progression of diabetic nephropathy. However, biomedical evidence indicates that some plant extracts have beneficial effects on certain processes associated with reduced renal function in diabetes mellitus. On the other hand, other plant extracts may be hazardous in diabetes, as reports indicate impairment of renal function. This article outlines therapeutic and pharmacological evidence supporting the potential of some medicinal plants to control or compensate for diabetes-associated complications, with particular emphasis on kidney function and hypertension.

Keywords: diabetes mellitus, diabetic nephropathy, medicinal plants, hypertension

Submitted 11/12/11, accepted 6/3/12

IntroductionDiabetes mellitus is a global disease affecting both the developed and developing nations. Epidemiological data suggest that at least one in 20 deaths are attributable to diabetes and related complications, a proportion which increases to at least one in 10 deaths in adults aged 35 to 64 years.1 The figure is considered to be an underestimate since most individuals die from cardiovascular and renal-related complications.2 World Health Organisation data show that the age-standardised death rate for diabetics in South Africa is 85 per 100 000. Death rates in other sub-Saharan African countries range from 21 to 49 per 100 000, compared with 18 in the USA and six per 100 000 in the UK.3

The principal causes of mortality in type 1 and 2 diabetes patients are disorders grouped as microvascular (retinopathy and nephropathy) and macrovascular (atherosclerotic) complications.4,5 Macrovascular diseases account for the majority of deaths in type 2 diabetes patients, and the presence of hypertension is associated with a four- to five-fold increase in mortality.6 A causal relationship between chronic hyperglycaemia and diabetic microvascular disease, long inferred from various animal and clinical studies,7

has now been established by data from the Diabetes Control and Complications Trial (DCCT) controlled clinical study.8

Conventional diabetes therapy using blood glucose-lowering agents such as sulphonylureas, insulin therapy, α-glucosidase inhibitors, peroxisome proliferator gamma (PPAR-γ) agonists and biguanides has limitations. For instance, insulin therapy does not achieve glycaemic control in patients with insulin resistance, and oral hypoglycaemic agents may lose their efficacy after prolonged use. Previous studies elsewhere suggest that insulin is not only ineffective in preventing type 1 diabetes in patients at risk of developing this condition, but it can also cause cardiovascular disease.9,10 Furthermore, conventional drugs are not easily accessible to the general population in developing countries due to socio-economic conditions.11,12 Hence there is an urgent need to find affordable treatments that are effective in slowing the progression of diabetic complications.

Traditional herbal medicine is used by many rural African communities to treat a range of diseases, including diabetes. Anecdotal evidence suggests that diabetic complications are less common in rural populations, attributable to either the beneficial effect of plant medicines or to the fact that other risk factors that aggravate diabetes in the urban context are less present in rural situations. The World Health Organisation not only encourages the use of plant medicines, but also recommended scientific evaluation of the hypoglycaemic properties of plant extracts.13 Estimates indicate that more than 70% of the world’s population uses resources derived from traditional medicine to control diabetes.14 Medicinal plant home remedies are used as crude extracts or standard, enriched fractions in pharmaceutical preparations.

Research summarised in a recent review15 showed that several southern African plant species used by rural communities as traditional medicines had hypoglycaemic effects in streptozotocin-induced (STZ) diabetic rat. Furthermore, some species had



antihypertensive properties.16-19 The impact on the kidney varies, with some species being reno-protective, whereas others had a deleterious effect on kidney function. By identifying the bio-active compound, oleanolic acid (OA), which confers reno-protection, we have been able to demonstrate the effectiveness of this agent in STZ diabetic rats.

The focus of this article is to evaluate current evidence on plant extracts used for the management of hypertension and kidney disease in diabetes. The beneficial as well as deleterious effects of medicinal plants in both conditions are discussed based on reports on plants frequently used in the southern Africa setting. Herein, a medicinal plant is defined as any plant which provides health-promoting characteristics, temporary relief or has curative properties.

Antihypertensive therapy and diabetic renal diseaseDiabetic complications, which include damage to large and small blood vessels, can lead to coronary heart disease, stroke and hypertension, the latter being a well-established major risk factor for cardiovascular disease that contributes to end-stage renal disease (ESRD). Reduction of blood pressure (BP) is therefore an efficient way of preventing or slowing the progression of ESRD. Conventionally, reno-protection is achieved through reduction in BP with antihypertensive regimens.20-23 Several studies, however, document that antihypertensive treatment in diabetes not only improves the quality of life,24-27 but also reduces renal complications.28

The major antihypertensive drug classes widely used include thiazide diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-blockers, central sympatho-lytic agents, calcium channel antagonists and other vasodilators. However, some antihypertensive agents, for example, thiazide diuretics and β-blockers deleteriously influence glycaemic control.29

To date, the most effective treatments for diabetic nephropathy (DN) are the antihypertensive drugs, particularly those that target the renin–angiotensin system (RAS) such as ACS inhibitors, angiotensin-1 receptor antagonists, or their combination.25,30,31 Although these treat-ments may retard the progressive decline in renal function in diabetes, clinical trials suggest that there is no effective treatment for DN.8

For these reasons, novel anti-diabetic therapeutic agents that supplement, substitute or complement the existing modern medications to ameliorate renal function in diabetes constitute novel therapeutic strategies for diabetes. Evidence from biomedical literature suggests that some plant extracts have protective effects against cardiovascular disease in diabetes.32 The following sections evaluate the therapeutic and pharmacological evidence for the use of some of the medicinal plants and their bioactive phytochemicals in cardio-renal related diabetic complications, as well as the potential for nephrotoxicity from other plant extracts.

Natural plants for cardiovascular diseaseSeveral plant extracts with potential therapeutic properties for the treatment of hypertension and complications such as coronary heart disease, angina, arrhythmias and congestive heart failure have been identified.33-36 Traditional medicinal healers in southern Africa have used Helichrysum ceres S moore [Asteraceae] to treat kidney and cardio-respiratory disorders.37 Recent laboratory studies suggest that the hypotensive effects of H ceres leaf extract in anaesthetised male Sprague-Dawley rats could in part be attributed to the extract’s natriuretic and diuretic properties.38 We reported that H ceres ethanolic leaf extract’s hypotensive effects were elicited in part by the direct relaxant effects on cardiac and vascular smooth

muscles.39 The data suggested that lowering of blood pressure was due to reduced peripheral resistance elicited by the extract’s vasodilatatory effects on the vascular smooth muscles, mediated in part via the endothelium-derived factors (EDRF). This suggestion was corroborated by the observations that H ceres leaf extract elicited potent negative inotropic and chronotropic effects in vivo and exhibited vasorelaxant effects in vascular tissue preparations.

We also reported that Ekebergia capensis Sparrm (Meliaceae) leaf extract prevented the development of hypertension in weanling genetically hypertensive Dahl salt-sensitive (DSS) rats, which develop hypertension as they age.19 The in vivo reduction in blood pressure by the extract occurred without significant alterations in the heart rate, suggesting that the in vitro cardiovascular effects of the extract significantly contributed to the hypotensive effects. Indeed, studies showed that the hypotensive effect of E capensis leaf extract was in part mediated via modulation of total peripheral resistance of the vascular smooth muscles, as evidenced by the extract’s elicited dose-dependent vasorelaxations in endothelium-intact and endothelium-denuded aortic ring preparations. It should be noted that lanoxin, one of the cardiac glycosides found in a number of plants, has specific effects on the myocardium.

Kidney function changes in diabetes mellitusSustained hyperglycaemia is the main cause of the changes in kidney function in diabetes mellitus. Hyperglycaemia leads to the increased formation of advanced glycation end-products (AGEs), oxidative stress, activation of the polyol pathway and hexosamine flux, causing inflammation and renal damage.40 AGEs result in the increased production of extracellular matrix proteins in endothelial cells, mesangial cells and macrophages in the kidney.41 Additionally, AGEs have been shown to reduce matrix protein flexibility through cross-link formation of the extracellular matrix proteins, leading to an abnormal interaction with other matrix components.41

Irrespective of all the other structural and functional changes, the mesangial alterations appear to be the main cause of declining renal function in experimental diabetic animal models.42 For example, hyperfiltration, which occurs in the early stages of DN has been attributed to increased mesangial production of vascular permeability factors in response to stretching.43 The subsequent decline in glomerular filtration rate (GFR) as nephropathy progresses may be due to expansion of the mesangial matrix, which compresses the glomerular capillaries, thereby reducing the filtration surface area and impairing the mechanism that maintains the normal glomerular capillary hydrostatic pressure.42 The fall in GFR also reduces the sodium load delivered to the macula densa cells, resulting in enhanced tubulo-glomerular feedback (TGF).44 In turn angiotensin II production increases due to hyper-activation of the renin–angiotensin–aldosterone system,45 causing more reabsorption of sodium and an increase in systemic blood pressure.

The accumulation of AGEs can be prevented by antioxidants such as flavonoids or by preventing the glucose-dependent formation of intermediate products (Amadori, Schiff bases or Milliard products). Indeed, blocking or deleting AGEs’ receptor (RAGE) in experimental animals reversed atherosclerosis.46 Amino guanidine and pyridoxamine, AGEs formation inhibitors, had reno-protective effects in diabetic animals.47,48 Furthermore, inhibition of AGEs effects could be achieved through breaking of the AGEs cross links by drugs such as alagebrium or inhibition of AGE signal transduction.48



Tanaka et al.49 reported that the biguanide metformin, the only example of an approved anti-diabetic from a herbal source, French lilac (Galega officinalis) may be useful in the prevention of the development of AGEs. The Panax quinquefolium (Linnaeus) [Araliaceae] extracts, a phyto-oestrogen derived from Vitis vinifera (Linnaeus) [Vitaceae] (resveratrol), curcumin from Curcuma longa (Linnaeus) [Zingiberaceae] and glycosides from Stelechocarpus cauliflorus (RE Fr) [Annonaceae] have also been reported to inhibit formation of AGEs or RAGE.50-56

Diabetic nephropathyRenal disease is a common and often severe complication of diabetes, with the majority of patients with 18 years’ duration showing signs of diabetic renal involvement.57 In general, about one in three patients with type 1 or 2 diabetes develops ESRD which proceeds to DN, the principal cause of significant morbidity and mortality in diabetes.8 The onset of DN is associated with a progressive rate of decline in renal function, urinary albumin excretion and glomerular filtration rate. For purposes of this discussion, DN is used as a generic term referring to any deleterious effect on kidney structure and/or function caused by diabetes mellitus.

Management of diabetic nephropathyWorld Health Organisation data report age-standardised death rate for diabetics in South Africa is 85 per 100 000 compared with 18 in the USA and six per 100 000 in the UK.3 The principal reason for the high mortality rates in South Africa is renal failure as a result of DN. Some 30 to 40% of diabetics develop nephropathy, which is the leading cause of ESRD.14

DN progresses through five well-defined stages.58 Stage 1 is an increase in GFR, which progresses to the clinically silent stage 2, in which hyperfiltration is associated with hypertrophy. Stage 3, or initial nephropathy, is typified by microalbuminuria, modest increases in blood pressure and a reduction in GFR. Stage 4 sees macroalbuminuria, raised blood pressure and progressive reductions in GFR, leading to stage 5 or ESRD when renal-replacement therapy is required.

ESRD is managed in developed countries by renal replacement therapy (RRT), such as dialysis and transplantation. In developing countries, however, kidney failure rates are double those in the West because access to RRT is severely limited by its high cost to patients.13 The figures are stark: 70% of patients in a Nigerian study were able to afford dialysis for only one month, with less than 2% having sufficient resources to remain on dialysis for more than 12 months.59 Access to RRT is virtually impossible for the rural poor.12

Current conventional diabetes therapy using blood glucose-lowering medications has limitations in averting renal complications. Progression towards ESRD may be slowed in part by strict control of blood sugar levels and blood pressure, a reduction in dietary protein intake and inhibition of the renin–angiotensin system. Consequently, drug developmental strategies should target these metabolic pathways for the prevention of progression to ESRD, which proceeds to DN.

Many patients of sub-Saharan Africa, however, cannot afford these expensive drugs. Hence there is an urgent need to find affordable treatments which are effective in slowing the progression of DN.

Medicinal plants in the management of diabetic kidney diseaseEthno-medicinal plants have traditionally been used for the

treatment of diabetes and its complications. In fact, current pre-clinical and clinical studies have demonstrated that many have beneficial effects on some processes associated with reduced renal function in experimental animals.60-62 The active phytochemicals responsible for their activities have also been identified.

Our research has established the therapeutic and pharmacological properties of a number of ethno-botanical herbs traditionally used in the management of diabetes mellitus by African communities.15 Observations indicate that some herbal extracts contain compounds that could be effective in mild diabetes mellitus or in cases of impaired glucose tolerance (Fig. 1). These are likely to have a positive impact on glucose homeostasis in diabetic patients.

Investigations from our laboratory have also examined whether herbal extracts could lower blood pressure or improve the impaired renal and cardiovascular functions often seen in diabetes. The results suggest that while some extracts such as Hypoxis hemerocallidea corm aqueous extract (APE) had hypoglycaemic effects, they may have deleterious effects on kidney function. Gondwe et al. found that APE increased renal fluid output and electrolyte retention, and reduced glomerular filtration rate,32 neither of which are desirable in diabetes mellitus. In contrast, other studies from our laboratories have shown that Opuntia megacantha leaf extract, which had hypoglycaemic effects, reversed the inability of the kidney to excrete Na+ in STZ diabetes mellitus, suggesting that this plant may be beneficial.17

We undertook a systematic survey of medicinal plants used by rural communities in South Africa and have identified several species with beneficial effects in the prevention of renal complications in diabetes mellitus. These effects were observed with both crude extracts and bioactive compounds isolated from medicinal plants. In particular, we showed that plants such as Sclerocarya birrea [(A Rich) Hochst] [Anachardiaceae], Persea americana (Miller) [Lauraceae], Ficus thonningii (Blume) [Moraceae] and Helichrysium ceres had reno-protective effects (Fig. 2).17,32,38 Initial studies have shown that extracts from these plants ameliorated renal dysfunction in experimental diabetes.

Fig. 1. Oral glucose tolerance test in STZ-diabetic rats showing dose-related reduction in plasma glucose levels following treatment with F thonningii bark ethanolic extracts (FTE, 60–240 mg/kg) comparable to that induced by metformin (500 mg/kg).17 Statistical comparison of the differences between the control and experimental group means was performed using one-way analysis of variance (ANOVA) followed by Tukey-Kramer multiple comparison test. A value of p < 0.05 was considered significant.



Subsequently, we isolated oleanolic acid as the bioactive compound and have shown that it possesses reno-protective effects in experimental diabetes mellitus. Therefore, S cordatum-derived oleanolic acid caused increased renal Na+ excretion in STZ-

Table 1. Partial survey of medicinal plants/plant extracts which affected the cardiovascular and kidney function in diabetes mellitus.

Botanical species Bioactive compounds Antidiabetic advantages Renal function advantages Cardiovascular advantages References

Allium sativum L (garlic) (Alliaceae)

phenolsflavonoids

insulin secretion hepatic glycogen

GFR vasorelaxant, ihypolipidaemic

67, 68

Gongronema latifolium

flavonoids saponins polyphenols

hepatic glycogen anti-oxidant ihypolipidaemic 69

Foeniculum vulgare L (Apiaceae)

phyto-oestrogens iglucose absorption diuretic natriuretic

vasorelaxant 70

Opuntia mega-cantha

phenols, flavonoids (quercetin) taxifolin

iglucose absorption GFR vasorelaxant 71, 72, 73

Syzygium spp phenylpropanoids flavonoids sesquiter-penes oleanolic acid rhamnetin

i hepatic glycogen insulin secretion

GFRanti-oxidant

vasorelaxant 63, 66, 74

Sclerocarya birrea [(A Rich) Hochst] [Anacardiaceae]

flavonoids, alkaloids, triterpenoids, coumarins,ascorbic acid

hepatic glucose utilisation insulin secretion

GFR vasorelaxant 32, 75

Persea americana Mill (Lauraceae) [Avocado]

tannins, saponins flavonoids, alkaloids glycosides

hepatic glycogen insulin secretion

GFR vasorelaxant bradycardiaihypolipidaemic

32, 76, 77, 78

Hypoxis hemerocal-lidea

glycoside hypoxoside β-sitosterol sterolins, cytokinins

insulin secretion reno-toxic iGFR

cardiodepressant bradycardia 79, 80

Ficus thonningii (Blume) [Morarceae]

alkaloids anthraqui-nones flavonoids saponins tannins

hepatic glycogen GFR cardiodepressant vasorelaxantbradycardia

17, 81

Olea europaea L, (Oleaceae)

triterpenes, flavonoids, glycosides

insulin secretion glucose utilisation

GFRanti-oxidant

cardiodepressant vasorelaxantbradycardia

36, 82, 83, 84

Helichrysum ceres S moore[Asteraceae]

polyphenols, tannins, triterpenes saponins

unclear diureticnatriuretic

cardiodepressant vasorelaxant,bradycardia

38, 39

Ekebergia capensis Sparrm(Meliaceae)

saponins alkaloids flavonoids tannins

unclear unclear cardiodepressant vasorelaxantbradycardia

85

Fig. 2. Sub-chronic treatment with F thonningii bark ethanolic extracts (FTE) every third day increased glomerular filtration rate in STZ-diabetic rats.63

induced diabetic rats, which was mediated by an improvement in glomerular filtration rate (Fig. 3).63 Other active agents identified in these plants include polysaccharides, flavonoids, xanthones and peptides.

Fig. 3. Sub-chronic treatment with oleanolic acid (OA, 60 mg/kg bid every third day) increased glomerular filtration rate in STZ-diabetic rats.66



There are various mechanisms by which reno-protection may be achieved, including modulation of AGEs, of the polyol pathway, and of the PKC pathway, and anti-oxidative properties. For example, morroniside isolated from Corni fructus has shown reno-protection in experimental diabetes through a reduction in the production of AGEs.64 Additionally, some plants have been shown to cause an improvement in renal function in experimental diabetes mellitus through inhibition of ET-1 and TGF-β1 and the endothelin-1 receptor A (ETRA).65

Available evidence suggests that some herbal extracts interfere with the concentrating and diluting mechanisms of tubular transport processes in the proximal and distal tubules and/or on other components of tubular cell membranes. Therefore we speculate that oleanolic acid influences renal fluid and electrolyte handling by altering the structural integrity and function of tubular epithelial cells to affect reabsorption and secretion.

Modification of risk factors in diabetes has an impressive impact on morbidity and mortality in diabetic patients. An overview of some of some medicinal plants currently used in diabetic hypertension and kidney disease, together with the possible mechanism(s) is summarised in Table 1.

ConclusionWe describe the therapeutic and pharmacological evidence in support of some of the medicinal plant extracts used in the management of hypertension and kidney disease in diabetes mellitus. Some of these medicinal plant extracts are a potential source of anti-diabetic drugs because of their therapeutic efficacy and anti-diabetic mechanisms reported in experimental animals. However, at present, the cellular/molecular mechanisms of action of these plant extracts remain to be established.

Future research directed at the identification of active components is the only viable option for supporting the efficacy claims for all herbs. In the absence of such standardisation, health practitioners and consumers alike should remain optimistic but wary. Research funding to investigate potentially beneficial effects of medicinal plants is critically important for optimal patient care and safety.

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of four triterpenoids in rat urine after oral administration of total triterpenoids from Ganoderma lucidum . J Pharmaceut Biomed Anal 2007; 43: 1185–1190.Nakagawa T, Goto H, Hikiami H, Yokozawa T, Shibahara N, Shimada Y. Protective 62. effects of keishibukuryogan on the kidney of spontaneously diabetic WBN/Kob rats Jf Ethnopharmacol 2007; 110: 311–317.Mapanga RF, Tufts MA, Shode FO, Musabayane CT. Renal effects of plant-derived 63. oleanolic acid in streptozotocin-induced diabetic rats. Renal Failure 2009; 31(6): 481–491.Yokozawa T, Yamabe N, Kim HY, Kang KS, Hur JM, Park CH, Tanaka T. Protective 64. effects of morroniside isolated from Corni Fructus against renal damage in streptozotocin-induced diabetic rats. Biol Pharm Bull 2008; 31: 1422–1428.Rao NK, Nammi S. Antidiabetic and renoprotective effects of the chloroform 65. extract of Terminalia chebula Retz. Seeds in streptozotocin-induced diabetic rats. BMC Complement Alternative Med 2006; 6: 17.Musabayane C, Tufts MA, Mapanga RF. Synergistic antihyperglycemic effects 66. between plant-derived oleanolic acid and insulin in streptozotocin-induced diabetic rats. Renal Failure 2010; 32: 832–839.Al-Qattan K, Thomson M, Ali M. Garlic 67. (Allium sativum) and ginger (Zingiber officinale) attenuate structural nephropathy progression in streptozotocin-induced diabetic rats. Eur e-J Clin Nutr Metab 2008; 3: e62–e71.Eidi A, Eidi M, Esmaeili E. Antidiabetic effect of garlic (Allium sativum L.) in normal 68. and streptozotocin-induced diabetic rats. Phytomedicine 2005; 13: 624–629.Ugochukwu NH, Cobourne MK. Modification of renal oxidative stress and lipid 69. peroxidation in streptozotocin-induced diabetic rats treated with extracts from Gongronema latifolium leaves. Clin Chim Acta 2003; 336: 73–81.El-Hilaly J, Hmammouchib M, Lyoussi B. Ethnobotanical studies and economic 70. evaluation of medicinal plants in Taounate province (Northern Morocco). J Ethnopharmacol 2003; 86: 149–158 Tabassum M, Mumtaz M, Haleem MA. Electrolyte content of serum, erythrocyte, 71. kidney and heart tissue in salt induced hypertensive rats. Life Sci 1996; 59: 731–747.Bwititi P, Musabayane CT, Nhachi CFB. Effects of72. Opuntia megacantha on blood glucose and kidney function in streptozotocin diabetic rats. J Ethnopharmacol 2000; 69(3): 247–252.Bwititi PT, Machakaire T, Nhachi CB, Musabayane CT. Effects of73. Opuntia megacantha leaves extract on renal electrolyte and fluid handling in streptozotocin (STZ)-diabetic rats. Renal Failure 2001; 23: 149–158.Prince PS, Menon VP, Pari L. Hypoglycaemic activity of74. Syzigium cumini seeds: effect on lipid peroxidation in alloxandiabetic rats. J Ethnopharmacol 1998; 61: l–7.Braca A, Politi M, Sanogo R, Sanou H, Morelli I, Pizza CN. Chemical composition 75. and antioxidant activity of phenolic compounds from wild and cultivated Sclerocarya birrea(Anacardiaceae) leaves. J Agric Food Chem 2003; 51(23): 6689–6695.Afzal M, Khan NA, Ghufran A, Iqbal A, Inamuddin M. Diuretic and nephroprotective 76. effect of Jawarish Zarooni Sada – a polyherbal unani formulation. J Ethnopharmacol 2004; 91(2–3): 219–223.Yasir M, Das S, Kharya MD. The phytochemical and pharmacological profile of77. Persea americana Mill. Phcog Rev 2010; 4: 77–84.Owolabi MA, Coker HAB, Jaja SI. Bioactivity of the phytoconstituents of the 78. leaves of Persea americana. Journal of Medicinal Plants Research 2010; 4(12): 1130–1135.Musabayane CT, Xozwa K, Ojewole JAO. Effects of 79. Hypoxis hemerocallidea (Fisch. & C.A. Mey) [Hypoxidaceae] corm (African Potato) aqueous extract on renal electrolyte and fluid handling in the rat. Renal Failure 2005; 27(5): 763–770.Ojewole JAO. Antinociceptive, anti-inflammatory and antidiabetic properties of 80. Hypoxis hemerocallidea Fisch. & C.A. Mey. (Hypoxidaceae) corm [African Potato] aqueous extract in mice and rats. J Ethnopharmacol 2006; 103(1): 126–134.Usman H, Abdulrahman F, Usman A. Qualitative phytochemical screening and 81. in vitro antimicrobial effects of methanol stem bark extract of Ficus thonningii (Moraceae). Afr J Tradit Complement Altern Med 2009; 6(3): 289–295.Benavente-Garcia O, Castillo J, Lorente J, Ortuno A, Del Rio JA. Antioxidant 82. activity of phenolics extracted from Olea europaea L. leaves Food Chem 2000; 68: 457–462.Bennani-Kabchi N, Fdhil H, Cherrah Y, El Bouayadi F, Kehel L, Marquie G. 83. Therapeutic effect of Olea europea var. oleaster leaves on carbohydrate and lipid metabolism in obese and prediabetic sand rats (Psammomys obesus) Ann Pharm Fr 2000; 58: 271–277.Al-Azzawie HF, Alhamdani MS. Hypoglycemic and antioxidant effect of oleuropein 84. in alloxan-diabetic rabbits Life Sci 2006; 78: 1371–1377.Fitzpatrick DF, Hirschfield SL, Ricci T, Jantzen P, Coffey RG. Endothelium-dependent 85. vasorelaxation caused by various plant extracts. J Cardiovas Pharmacol 1995; 26: 90–95.


SA JOURNAL OF DIABETES & VASCULAR DISEASE

S Afr J Diabetes Vasc Dis 2012; 9: 120–123

Talia den DalkDietician, Somerset Weste-mail: [email protected]

Diabetes Educator’s Focus

SUPPLEMENTS FOR TYPE 2 DIABETES PATIENTS

T hese days, many diabetes patients are opt-

ing to go the natural route to enhance lon-

gevity and to improve their general health

and well-being. Complementary medicine is often

used by type 2 diabetes patients to improve their

health and blood glucose control. In Canada, a re-

cent survey found that 75% of people with diabetes

used non-prescribed supplements (herbal, vitamin,

mineral or others) and alternative medications.

Overall, research indicates that most people who

use complementary alternative therapies do so in

addition to, rather than in place of, conventional

medical treatment. The aim of this article is to ex-

amine some of these alternative therapies and the

evidence regarding the use of supplements in type

2 diabetes.

MultivitaMin/Mineral and anti-oxidant preparationsAs with nearly all biochemical processes, glucose

metabolism and insulin signaling require cofactors

and vitamins, which are essential in the diet. Defi-

ciencies in any of these micronutrients have the

potential to impair glucose metabolism and cause

insulin resistance. Clinical evidence supporting this

hypothesis is mounting regarding the metabolic ef-

fects of specific deficiencies, including vitamin D,

chromium, biotin, thiamine and vitamin C.

Modern agriculture and food-processing techniques

result in a relative reduction in the micronutrient con-

tent of common foods. Despite an excess of dietary

calorie intake, obese individuals have relatively high

rates of micronutrient deficiencies (Table 1).

No health professional organisation promotes the

regular use of multivitamins or individual nutrients

without considering first the quality of a person’s

diet. However, individuals with poor nutrient intake

from diet alone, and those who consume low-calorie

diets and avoid certain foods (such as strict vegetar-

ians or wheat avoidance) might benefit from taking

multivitamins.

Several medical studies support the use of daily

multivitamins while following a calorie-restricted eat-

ing plan for weight loss. As type 2 diabetes patients

are often overweight, they will be encouraged to lose

weight by means of calorie-restricted eating plans.

These patients should consider the use of multi-

vitamins in order to meet daily nutrient requirements

and to prevent worsening of existing nutritional de-

ficiencies.

Table 1. The prevalence of micronutrient deficiency in type 2 diabetes and obesity.

Micronutrient Type 2 diabetes (%) Obesity (%)

Thiamine 17–17 15–29

Vitamin B12 22 3–8

Vitamin C – 35–45

Selenium – 58

Zinc – 14–30

Vitamin D 85–90 –

Chromium 20–40 –

– Prevalence data not available.


SA JOURNAL OF DIABETES & VASCULAR DISEASE EDUCATOR’S FOCUS

Taking a basic multivitamin that provides nutrients approximating

recommended intakes should pose no safety risks to healthy people.

However, individuals who take multivitamins and other supplements

and eat a healthy and/or fortified diet might consume some nutrients in

excess, increasing the possibility of adverse affects.

When choosing multivitamin preparations, find one that is tailored

to age, gender and other situations (e.g. pregnancy). Multivitamins for

men usually contain no iron, for example, whereas those for seniors

contain more calcium, vitamin D and vitamin B12.

Patients and clinicians should ensure that all vitamins are present in

dosages meeting 100% of the RDA. Patients who need supplementa-

tion of calcium or magnesium might need to take these supplements

separately from their multivitamins, as the required dosage is relatively

large.

vitaMin dVitamin D is a fat-soluble vitamin that is naturally present in very few

foods, added to others, and is available as a dietary supplement. It is pro-

duced endogenously when ultraviolet rays from sunlight strike the skin

and trigger vitamin D synthesis.

Vitamin D obtained from sun exposure, food and supplements is bio-

logically inert and must undergo two hydroxylations in the body for activa-

tion. High rates of vitamin D insufficiency have been reported in obese

individuals and in diabetics.

The following are risk factors for vitamin D deficiency:

high skin pigmentation: 50-fold reduction •

elderly, institutionalised or housebound people•

lack of exposure to sunlight •

– geographic location: research indicates a worldwide vitamin D

deficiency

– time of day and calendar season

present 10:00 to 15:00, blocked by ozone•

sunscreen use, protective clothing•

– SPF 8 = 97.5%

– SPF > 15 = 99%

obesity•

renal and liver disease•

multiple or short-interval pregnancies•

medications: anticonvulsants, rifampicin, cholestyramine, anti-retro-•

viral usage.

The prevalence of vitamin D insufficiency (defined as < 30 mg/dl) in

type 2 diabetes individuals ranges from 80 to 90%.

Several studies are providing evidence that the protective effect of

vitamin D on the heart could be via the renin–angiotensin hormone sys-

tem, through the suppression of inflammation, or directly on the cells

of the heart and blood vessel walls. In the Framingham Heart study,

patients with low vitamin D concentrations (< 15 ng/ml) had a 60%

higher risk of heart disease than those with higher concentrations.

The Framingham study found that subjects with low vitamin D con-

centrations (< 15 ng/ml) were twice as likely to have a heart attack

than those with high concentrations (> 30 ng/ml). In another study,

which followed men and women for four years, patients with low vita-

min D concentrations (< 15 ng/ml) were three times more likely to be

diagnosed with hypertension than those with high concentrations (>

30 ng/ml).

Research indicates that replenishing vitamin D in patients with type

2 diabetes was found to improve insulin secretion, peripheral insulin

sensitivity and glycosylated haemoglobin levels

supplementation guidelines for vitamin dVitamin D supplementation is the most practical means of address-

ing vitamin D insufficiency. I would recommend that any type 2 diabetes

patient considering supplementation of vitamin D to have his/her blood

level of vitamin D checked first. The dosage of vitamin D supplementation

depends on the blood level; 1 000 IU calciferol a day raises serum 25(OH)

D by 20 ng/ml (25 nmol/l), and is given for six weeks.

Vitamin D analogues: 1-calcidol or Calcitriol are ineffective to correct

vitamin D deficiency. For deficiency < 20 ng/ml (< 25 nmol/l):

• Calciferol10000 IUdaily or60000 IUweekly foreight to12

weeks

OR

• Calciferol 300000 IUmonthly for threemonths (intramuscular

injection), followed by the same dose once or twice a year (severe

malabsorption).

For insufficiency, 20–29 ng/ml (25–50 nmol/l) or maintenance therapy

following deficiency:

• Calciferol1000–2000IUdailyor10000IUweekly

• VitaminD3 supplementation of at least 800–1000 IU/day ap-

pears to be appropriate year-round for all women

• Besttakeninconjunctionwithadietaryfatsource,i.e.avocado.

ChroMiuMChromium has long been of interest for its possible connection to vari-

ous health conditions. Among the most active areas of chromium re-

search are its use in supplement form to treat diabetes, lower choles-

terol levels, promote weight loss, and improve body composition.

Chromium is an essential micronutrient and also a toxic metal. Chro-

mium is essential for the proper metabolism of carbohydrates, fat and

protein in the body. Chromium improves insulin sensitivity by means

of increasing insulin binding to cells, increasing insulin receptor

numbers, and activation of insulin receptor kinase, leading to increased

insulin sensitivity.


EDUCATOR’S FOCUS SA JOURNAL OF DIABETES & VASCULAR DISEASE

Chromium is widely distributed in foods but most provide only small

amounts (< 2 mcg) per serving. Meat and wholegrain products as

well as some fruit, vegetables and spices are relatively good sources,

whereas foods high in simple sugars are low in chromium.

The absorption of chromium in the digestive tract is low, ranging from

0.4 to 2.5% of the amount consumed. Vitamin C and niacin enhance the

absorption of chromium from the diet.

The body’s chromium content may be reduced under several condi-

tions. Diets that are high in simple sugars (> 35% of calories) can in-

crease chromium excretion in the urine. Infection, acute exercise, preg-

nancy and lactation, and stress increase chromium losses and can lead

to deficiency, especially if chromium intakes are already low.

Chromium deficiency impairs the body’s ability to use glucose to meet

its energy needs and raises insulin requirements. It has therefore been

suggested that chromium supplements might help to control type 2 dia-

betes or the glucose and insulin responses in persons at high risk of

developing the disease.

Recent studies have shown that chromium reduces HbA1c levels by

0.6% in type 2 diabetes and reduces fasting glucose levels by 1 mmol/l.

There is less weight gain in patients who use chromium in combination

with diabetes treatment than with treatment alone. Chromium has more

consistent effects in those with poorer glycaemic control, patients who

are insulin resistant, and those who are chromium deficient.

Suggested dosages in type 2 diabetes can range from 200–1 000

mcg/day. Few serious adverse effects have been linked to high chromium

intake, so the Institute of Medicine has not established a tolerable upper

intake level. Chromium supplements are available as chromium chloride,

chromium nicotinate, chromium picolinate, high-chromium yeast and

chromium citrate, some of which have poor bioavailability.

My choice of supplement is chromium nicotinate. I often prescribe

chromium with meals due to its appetite-reducing effects, which would

therefore help weight-loss patients keep to their eating plans.

MagnesiuMThere is an increased interest in the role of magnesium in the prevention

and management of disorders such as hypertension, cardiovascular dis-

ease and diabetes. Magnesium plays an important role in carbohydrate

metabolism. It may influence the release and activity of insulin, the hor-

mone that helps control blood glucose levels.

Low blood levels of magnesium (hypomagnesaemia) are frequently

seen in individuals with type 2 diabetes. Hypomagnesaemia may worsen

insulin resistance, a condition that often precedes diabetes, or may be a

consequence of insulin resistance.

Individuals with insulin resistance do not use insulin efficiently and

require greater amounts of insulin to maintain blood sugar within normal

levels. The kidneys possibly lose their ability to retain magnesium during

periods of severe hyperglycaemia (significantly elevated blood glucose

levels). The increased loss of magnesium in the urine may then result in

lower blood levels of magnesium.

In older adults, correcting magnesium depletion may improve insulin

response and action. It is postulated that magnesium may improve the

action of insulin and decrease blood glucose levels, particularly in the

elderly, where there is a definite decline in magnesium intake and in-

crease in magnesium secretion.

The recommended amount of magnesium per day is 300–420 mcg. The

following foods have high amounts of magnesium: green leafy vegetables,

wholegrain, high-bran cereals, nuts and seeds, legumes, and bananas. The

indications for supplementation are:

uncontrolled diabetes as magnesium is lost in the urine when glu-•

cose rises above 8 mmol/l

diabetics with uncontrolled hypertension •

diabetics using certain medications such as diuretics (Lasix, thiaside •

diuretics) or antibiotics (gentamicin, amphotericin)

older diabetics; with aging, magnesium intake decreases and mag-•

nesium excretion increases.

Doctors can evaluate the magnesium status when these medical prob-

lems occur and determine the need for magnesium supplementation.

Oral magnesium supplements combine magnesium with another sub-

stance such as a salt. Examples of magnesium supplements include

magnesium oxide, magnesium sulfate and magnesium carbonate.

Elemental magnesium refers to the amount of magnesium in each

compound. The amount of elemental magnesium in a compound and its

bioavailability influence the effectiveness of the magnesium supplement.

Bioavailability refers to the amount of magnesium in food, medications

and supplements that is absorbed in the intestines and ultimately avail-

able for biological activity in the cells and tissues. Enteric coating (the

outer layer of a tablet or capsule that allows it to pass through the stom-

ach and be dissolved in the small intestine) of a magnesium compound

can decrease bioavailability.

In a study that compared four forms of magnesium preparations,

results suggested lower bioavailability of magnesium oxide, with sig-

nificantly higher and equal absorption and bioavailability of magnesium

chloride and magnesium lactate. This supports the belief that both the

magnesium content of a dietary supplement and its bioavailability con-

tribute to its ability to restore deficient levels of magnesium.

thiaMineThiamine is an essential micronutrient that acts as a co-factor for several

key enzymes in glucose and amino acid metabolism. Thiamine deficiency

leads to a relative reduction in the function of specific metabolic path-

ways and can lead to endothelial dysfunction and potentially worsen type

2 diabetes.


SA JOURNAL OF DIABETES & VASCULAR DISEASE EDUCATOR’S FOCUS

Thiamine is absorbed in the proximal small bowel, mainly through ac-

tive transport. The recommended daily intake of thiamine is 1.2 mg, ap-

proximately 0.5 mg per 1 000 kcal consumed.

Important food sources of thiamine include pork, red meat, wheat germ,

eggs, fish and legumes. Thiamine is virtually absent in food products con-

taining refined carbohydrates such as milled rice and simple sugars, yet

the metabolism of these foods requires relatively high amounts of thia-

mine and may lead to depletion. In subjects on thiamine-deficient diets,

total body thiamine stores can be depleted within two to three weeks.

Severe deficiency of thiamine can lead to wet or dry ber-beri or Wer-

nicke encephalopathy, depending on the tissues involved. Moderate

deficiency of thiamine may affect glucose metabolism and impact on

diabetes and related complications.

The prevalence of thiamine deficiency has been reported in 17 to 79% of

diabetic patients, although these studies include both type 1 and 2 diabetes

patients. Evidence for the effect of thiamine supplementation to reduce the

risk and severity of type 2 diabetes has been demonstrated in a number

of studies.

Hyperglycaemia results in the overproduction of oxygen free radicals,

which contributes to the progression of diabetes. The development of

complications during diabetes is also associated with oxidative stress. The

cardiovascular complications such as coronary artery disease, peripheral

vascular disease and stroke have been closely related to oxidative stress

during diabetes.

Cultured endothelial cells demonstrate reduced production of reactive

oxidative species and improved function in high glucose concentrations

in the presence of thiamine. Both of these characteristics are expected

to reduce the risk of diabetic complications and possibly reduce the risk

of diabetes itself.

In a double-blind, cross-over trial, the administration of benfotiamine,

a lipid-soluble thiamine analogue, improved endothelial function, reduced

markers of oxidative stress and reduced levels of advanced glycosylated

end-products following a test meal in type 2 diabetes patients.

Long-term studies investigating the use of thiamine supplementation

in diabetic patients have not been performed. The potential exists for

thiamine supplementation to modify the course of diabetes by modulation

of glucose metabolic pathways. Given high rates of thiamine deficiency in

diabetic patients, supplementation may be considered.

ReferencesVia M. The malnutrition of obesity: micronutrient deficiencies that promote diabetes. 1. Int Scholarly Res Network 2012, Article ID 103472, doi:10.5402/2012/103472.Ford ES, Tsai J, Li C, Zhao G. Associations between concentrations of vitamin D 2. and concentrations of insulin, glucose, and HbA1c among adolescents in the United States. Diabetes Care 2011; 34: 646–648.Nahas R, Moher M. Complementary and alternative medicine for the treatment 3. of type 2 diabetes. Can Fam Physician 2009; 55: 591–596.Lukaczer D. Nutritional support for insulin resistance: a summary. 4. Appl Nutr Sci Rep 517 7/01 Rev. 5/02. Dakhale GN, Harshal V, Chaudhari, Shrivastava M. Supplementation of vitamin C 5. reduces blood glucose and improves glycosylated hemoglobin in type 2 diabetes mellitus: a randomized, double-blind study. Adv Pharmacol Sci 2011, Article ID 195271. doi:10.1155/2011/195271.Ming-Hoang Lai J. Antioxidant effects and insulin resistance. Improvement of 6. chromium combined with vitamin C and E supplementation for type 2 diabetes mellitus. Clin Biochem Nutr 2008; 43: 191–198.Wiernsperger N, Rapin JR. Trace elements in glucometabolic disorders: an update. 7. Diabetol Metab Syndr 2010; 2: 70. http://www.dmsjournal.com/content/2/1/70.Manya K, Champion B, Dunning T, Manya, 8. et al. The use of complementary and alternative medicine among people living with diabetes in Sydney. BMC Complement Alternative Med 2012; 12: 2. http://www.biomedcentral.com/1472-6882/12/2.Psaltopoulou T, Ilias I, Alevizaki M. The role of diet and lifestyle in primary, 9. secondary, and tertiary diabetes prevention: a review of meta-analyses. Rev Diabet Stud 2010; 7: 26–35.Lecube A, Baena-Fustegueras JA, Fort JM, Pelegrı D, Hernandez C, Simo R. 10. Diabetes is the main factor accounting for hypomagnesemia in obese subjects. Plos 1 2012; 7(1): e30599.Giovannucci E, Leu M. Vitamin D: epidemiology of cardiovascular risks and 11. events. Clin Endocrinol Metab 2011; 25: 633–646.Makariou S, Liberopoulos EN, Elisaf M, Challa A, Makariou S, 12. et al. Novel roles of vitamin D in disease: What is new in 2011? Eur J Int Med 2011; 22: 355–362.

It's theshell that

makes

safer.

Safety-CoatedR





S Afr J Diabetes Vasc Dis 2012; 9: 124.

Diabetes Personality

A YOUNg DIABETIc hARNESSES SOcIAL MEDIA TO ADvISE AND SUPPORT OThERS wITh ThE cONDITION

Eighteen-year-old Claire Potgieter is a poster

girl for a positive attitude. She lives with di-

abetes and also has cerebral palsy, but she

chooses to look on the bright side and use her expe-

riences to support and guide other young diabetics.

To this end, she created a Facebook page earlier this

year called Sweet Enough Diabetics, through which

she dispenses advice and encouragement.

She was initially diagnosed with diabetes a while

after undergoing an operation to lengthen her ham-

strings. Her doctor thought that the impact of the op-

eration might have been responsible for ‘bringing the

diabetes to the surface’.

‘Right from the start, I saw it as an adventure and

was not too fazed by the need for constant testing

of my blood glucose levels and injections of insulin’,

she recalls. ‘The only thing I wanted was not to have

to spend time in hospital again.’ At the time, Claire

and her family lived in Springs.

A few years later they moved to Cape Town, an

experience Claire found traumatic. Unhappy and

distressed, she admits she briefly ‘lost the plot’ and

stopped caring about her glucose

levels. ‘But it was maybe only for a

week or two. I quickly realised that

it just wasn’t worth it not to take

care of myself. Others, however,

remain in this space for much

longer periods and it’s my hope

that I can help some of them to

understand that it’s not worth eat-

ing badly and making the condi-

tion worse.’

Today, Claire describes her condition as more or

less stable. ‘I’m on insulin and my glucose levels

are more or less okay. I’m not where I hope to be

just yet, but I will get there’, she says.

Since 2006, Claire has been in the care of endo-

crinologist Dr Landi Lombard. In 2010 she joined the

Kuils River branch of the Centre for Diabetes and

Endocrinology, which is headed up by Dr Lombard’s

wife, Claudia. ‘Sweet Enough Diabetics was actually

Claudia’s idea and she encouraged me to start it.

I had always wanted to reach out and help, and to

share my experiences with others in the same boat.

This seemed like a great way to do it’, says Claire.

The forum is still in its infancy, but is slowly

growing. ‘If someone posts that they’re having a

bad day, I’ll respond with words of encouragement,

reassuring them that even if it seems dark at the

moment, the sun will come out again and life can

be good. It’s a wonderful feeling when I get an an-

swer back telling me that my words made the writer

feel better and reassured him that he is not alone.’

Claire likes the fact that she’s also made some new

friends through Sweet Enough Diabetics.

Claire remains adamant that having diabetes is ‘re-

ally not that bad’. ‘I count it as a blessing. There are

some wonderful people like Claudia and Landi who

I might never have met otherwise. They’ve enriched

my life’, she concludes. She also credits her parents,

brother, sisters and friends, as well as her faith in God,

with having played a significant part in supporting her

through the changes diabetes has brought in her life.

Peter Wagenaar


SA JOURNAL OF DIABETES & VASCULAR DISEASE EVIDENCE IN PRACTICE

It is well known that diabetes is associated with concentric left ventricular (LV) remodelling, and that LV hypertrophy is particularly

common in patients afflicted with both type 2 diabetes and hypertension. The co-existence of diabetes and other cardiovascular risk factors such as hypertension and obesity may contribute to the association of diabetes with subclinical cardiac target-organ damage. In the LIFE study, concentric LV remodelling was associated with three and eight times increased risk, respectively, of stroke and cardiovascular death after 4.8 years of follow up.

An increased prevalence of congestive heart failure and stroke has been noted among black diabetic patients. Recent publications arising out of sub-Saharan Africa report an increase in the prevalence of diabetes, hypertension and other cardiovascular risk factors, as well as a high prevalence of LV hypertrophy. The Strong Heart study indicates that increased relative wall thickness (RWT) and LV hypertrophy are more prevalent in diabetic African-Americans than in diabetic Caucasians, with earlier development of cardiac end-organ damage. However, there is a dearth of data on LV geometry in diabetic populations from sub-Saharan Africa.

A study by Chillo and colleagues attempted to determine the prevalence and covariates of abnormal LV geometry among type 1 and 2 diabetic out-patients of African origin and made a welcome contribution to current knowledge on diabetic heart disease in this population.1 Of particular importance to resource-limited settings where echocardiography is not freely available, this study indicates that a simple algorithm using routine clinical and laboratory tests (type of diabetes, presence of hypertension, obesity and albuminuria) may be used to identify 75% of high-risk diabetic patients with increased RWT.

Results indicate that abnormal LV geometry is common in diabetic sub-Saharan African patients; the most prevalent form of which is concentric remodelling, associated with reduced LV myocardial contractility and delayed diastolic relaxation. In the total study population, the prevalence of concentric remodelling, eccentric hypertrophy and concentric hypertrophy was 32, 8.3 and 23.7%, respectively.

Abnormal LV geometry was found in 40% of type 1 diabetes patients, most commonly concentric remodelling (30%). Chillo et al.1 explain the interesting finding of concentric LV hypertrophy being most common in patients with type 2 diabetes (36.7%), but entirely absent in type 1 diabetes study patients, by drawing attention to the low prevalence of hypertension among the group with type 1 diabetes.

Hypertension is a strong covariate of having both LV hypertrophy and increased RWT. In the study, all type 1 diabetes patients with LV hypertrophy (10%) displayed eccentric LV hypertrophy and also had albuminuria, identifying albuminuria as a main covariate of LV hypertrophy. From this, Chillo et al. raise the question whether drugs that inhibit the renin–angiotensin system will prevent progression to LV hypertrophy among type 1 diabetes patients.

Age and systolic blood pressure were the primary confounders of difference in LV structure between type 1 and 2 diabetes patients. Hypertension, in particular isolated systolic hypertension, increased in prevalence with aging, mainly as a consequence of

Early cardiac risk markers in diabetic African patients

DefinitionsHypertension was defined as blood pressure ≥ 140/90 mmHg • or use of antihypertensive medications. Microalbuminuria was defined as a urinary albumin:creatinine • ratio (UACR) > 30 mg/g and macroalbuminaria as UACR > 300 mg/g. LV hypertrophy was considered present when LV mass • indexed for height (LVMI) exceeded 49.2 g/m2.7 in men and 46.7 g/m2.7 in women. RWT was calculated as end-diastolic posterior wall • thickness:end-diastolic LV internal radius ratio. RWT was considered increased if ≥ 0.43. LV geometric patterns were considered normal if LVMI and • RWT were both normal. Concentric remodelling was defined as the combination of normal LVMI and increased RWT, whereas the combination of LV hypertrophy and normal RWT defined eccentric hypertrophy. Concentric LV hypertrophy was indicated in the presence of both LV hypertrophy and increased RWT.

arterial stiffening imposing increased load on the left ventricle. Older age was particularly associated with increased RWT, and with LV hypertrophy when hypertension co-existed.

Overall, increased RWT was present in 58% of the study patients. Although higher RWT was significantly associated with older age and higher blood pressure in this study, independent associations between increased RWT and measures of systolic and diastolic LV function were found irrespective of presence or absence of LV hypertrophy or hypertension. This emphasises the need to further stratify patients according to the different LV geometric patterns, rather than by presence or absence of LV hypertrophy alone. This is particularly important in the context of African diabetes, as concentric remodelling was found to be the most common abnormal LV geometric pattern.

Other significant findings of this study also associated higher RWT in type 2 diabetes patients with lower serum high-density lipoprotein (HDL) cholesterol, but not with triglyceride-to-HDL cholesterol ratio. No independent association between gender and measures of LV geometry was indicated, contrasting with findings of the ARIC (Atherosclerosis Risk in Community) study conducted in an African-American population.

In conclusion, Chillo et al.1 found that a 76% chance of having cardiac target-organ damage existed in the type 2 diabetes patients with any of the risk factors of obesity, hypertension or albuminuria, as well as in the type 1 diabetes patients having any two of these three risk factors.

ReferenceChillo P, Lwakatare J, Lutale J, Gerdts E. Increased relative wall thickness is a 1. marker of subclinical cardiac target-organ damage in African diabetic patients. Cardiovasc J Afr, published online 20/3/12.


EVIDENCE IN PRACTICE SA JOURNAL OF DIABETES & VASCULAR DISEASE

Left ventricular remodelling after antihypertensive treatment

Salt intake falling: still too highReducing dietary salt intake has major health benefits and significant

cost savings, but a new review shows that salt intake is still 9–12 g per day.

Reduction of salt intake in the population to the recommended level of < 5–6 g per day could result in improvements similar to the provision of clean water and drains in the late nineteenth century. The review also recommends that salt intake in patients with heart failure should be reduced to < 5 g per day.

A meta-analysis of randomised salt-reduction trials suggests that a reduction of 6 g/day in salt intake would reduce stroke by 24% and coronary heart disease by 18%.

Originally from PCCJ 2011; 4(4): 142.

SAJDVD recommended actionThis review suggests that ongoing encouragement by healthcare workers to their patients to reduce salt added during cooking and to reduce the con-sumption of prepared foods will reap benefits. This approach, together with the food industry reducing salt content in prepared foods, will result in signifi-cant improvements in public health.

ReferenceHe F, Burnier M, Macgregor G. Nutrition in cardiovascular disease: salt in hyper-tension and heart failure. Eur Heart J 2011; doi:10.1093/eurheartj/ehr194

There is a substantial body of evidence that suggests left ventricular (LV) geometric patterns may refine the ability to predict cardiovascular

events beyond LV hypertrophy (LVH). The change in geometry of the heart in hypertensive LVH is heterogeneous. Concentric remodelling occurs in some patients, where increases in wall thickness are out of proportion to the chamber diameter. Eccentric LVH may occur in others, with wall thickness increases in parallel with chamber diameters.

From this, it is evident that an important goal of hypertensive therapy is to reduce the prevalence of concentric and eccentric LVH, and LV remodelling. One year of antihypertensive therapy may normalise LV structure in 51% of hypertensive patients of European descent.

A study by Libhaber and colleagues examined whether similar effects could be achieved in Africans, who have a high prevalence of concentric LVH and LV remodelling. LV relative wall thickness is higher in groups of African ancestry than in other patient populations. Included in the study aims was to identify the ability of 13 months of antihypertensive therapy to normalise LV structure in hypertensives of African ancestry.

Results evaluated from 103 hypertensive patients in the Baragwanath Hypertension study revealed that after more than a year of stepwise antihypertensive therapy, the proportion of patients with normal LV mass or geometry did not significantly increase. Despite 64% of patients achieving clinic blood pressure control and 47% achieving 24-hour blood pressure control by 13 months of therapy, 25% of patients remained with concentric LVH and 25% with eccentric LVH. Moreover, concentric remodelling increased from 12 to 23% (p < 0.05).

These residual abnormalities in LV structure were noted despite antihypertensive therapy resulting in a decreased LV M-mode echocardiogram and relative wall thickness. The results were unable to show a relationship between residual LV structural changes and control of clinic and 24-hour blood pressure.

This study reported similar results to those of the LIFE study (patients of European descent) in terms of mean decrease in LV relative wall thickness at one year of antihypertensive therapy, however LV structural abnormalities still persisted in the Baragwanath study population, with a reported increase in concentric remodelling. This suggests that concentric LVH is difficult to normalise in the hypertensive African population.

Confounding considerations when comparing these results to those encountered in the LIFE study included the higher proportion of patients with increased baseline concentric LVH and a higher mean baseline LV relative wall thickness. This was consistent with previously reported ethnic disparities in concentric LV modelling, as well as with the high prevalence of obesity in the study sample.

Other considerations raised by Libhaber et al. included the large proportion of female participants, social demographic factors resulting in low 13-month retention rates, and the inability to draw conclusions as to whether the results of this study apply to all antihypertensive agents.

Source: Libhaber EN, Norton GR, Libhaber CD, et al. Prevalence of residual left ventricular structural changes after one year of antihypertensive treatment in patients of African descent: role of 24-hour pulse pressure. Cardiovasc J Afr 2012; 23(3): 147–152.


SA JOURNAL OF DIABETES & VASCULAR DISEASE EVIDENCE IN PRACTICE

Childhood obesity-prevention programmes, emphasising improved nutrition and physical activity levels, are generally effective and

worth the investment, according to a new Cochrane Review.1 This review of 55 studies updates an earlier Cochrane report from 2005 and includes studies that used a controlled study design, with or without randomisation, and involved interventions lasting 12 weeks or more.

Success with childhood anti-obesity programmes

Effective childhood obesity strategiesSchool curricula that place an emphasis on healthy eating, • physical activity and body imageIncreasing opportunities for physical activity and movement • skills during the school weekImproving nutritional quality of school-supplied food• Establishing environments and cultural practices within • schools that support physical activity, and children eating healthier foods throughout the dayOffering professional development to support teachers and other • staff in implementing health-promotion strategies and activitiesSupporting parents and home activities that focus on activ-• ity, eating more nutritious foods, and spending less time on screen-based activities.

SAJDVD recommended actionThis large systemic review demonstrates the importance of investing in childhood obesity-prevention strategies, and in particular those that seek to change both the surrounding environment and the behaviour of individuals.

Reference

Waters E, de Silva-Sanigorski A, Hall BJ, 1. et al. Interventions for preventing obesity in children. Cochrane Database Syst Rev 2011; 12: CD001871. www.ncbi.nlm.nih.gov/pubmed/22161367.Armstrong ME, Lambert EV, Lambert MI Physical fitness of South African 2. primary school children 6-13 years of age: discover vitality health of the nation study. Percept Mot Skills 2011; 113(3): 999–1016.Harmse B, Kruger HS. Significant differences between serum CRP levels in 3. children in different categories of physical activity: the PLAY study. Cardiovasc J Afr 2010; 21(6): 316–322.

Type 2 diabetes can be reversed by an extremely low-calorie diet, according to a Diabetes UK study that challenges current

thinking that diabetes is an inevitably progressive disease. The study in 11 volunteers (aged 49.5 ± 2.5 years, BMI 33.6 ± 1.2 kg/m2) showed that cutting food intake to only 600 calories a day for two months reversed their type 2 diabetes and seven of these patients remained free of diabetes three months after the study closed.

The participants’ diet consisted of liquid diet drinks and non-starchy vegetables. They were matched to a control group of people without diabetes and then monitored over eight weeks.

Can very low-calorie diets reverse diabetes?

SAJDVD recommended actionThis small study with close medical supervision suggests that beta-cell func-tion and hepatic insulin sensitivity can be normalised using intensive calorie reduction alone. The study offers hope for type 2 diabetes patients, although patients should not be encouraged to lose weight in this extreme way until further studies are undertaken.

ReferenceLim E, Hollingsworth K, Aribisala B, et al. Reversal of type 2 diabetes: normali-sation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011;[Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/ 21656330

KEY IMPROVEMENTS IN TYPE 2 DIABETESFOLLOWING INTENSIVE DIETARY INTERVENTION

At 1 week At 8 weeks

Fasting plasma glucose normalised Hepatic triacylglycerol contentin the diabetic group (from 9.2 ± 0.4 fell from 12.8 ± 2.4% in theto 5.9 ± 0.4 mmol/l; p = 0.003). diabetic group to 2.9 ± 0.2%by week 8 (p = 0.003). Pancreatic triacylglycerolInsulin suppression of hepatic decreased from 8.0 ± 1.6%glucose output improved from to 6.2 ± 1.1% (p = 0.03) 43 ± 4% to 74 ± 5% (p = 0.003 vs baseline; controls 68 ± 5%).

Insulin production from their pancreas and fat content in the liver and pancreas were studied.

After one week, pre-breakfast blood glucose levels had returned to normal (from 9.2 ± 0.4 to 5.9 ± 0.4 mmol/l; p = 0.003) in the intervention group. MRI scans revealed that pancreatic fat had fallen from an elevated level (8%) to normal (6%). The pancreas also regained its normal ability to make insulin and as a result, postprandial blood glucose levels steadily improved. After the study, the participants ate normally but had received advice on portion size and healthy eating.

Originally from PCCJ 2011; 4(4): 142.

Results were assessed according to change in body mass index (BMI) and showed that, with only a few exceptions, the programmes were generally effective in reducing adiposity. Children in intervention groups overall showed a standardised mean difference in adiposity (measured as BMI or standardised BMI) of –0.15 kg/m². The effects according to age subgroups were –0.26 kg/m² for ages zero to five years; –0.15 kg/m² for ages six to 12 years; and –0.09 kg/m² for ages 13 to 18 years.

‘There is now compelling evidence that strategies can be implemented to halt the growing rates of obesity in children’, said lead author Elizabeth Waters from the University of Melbourne, Australia. ‘We know that doing nothing is likely to result in increases of overweight and obesity, particularly in countries where the prevalence continues to rise.’

A recent study in South Africa,2 of physical fitness in primary school children aged six to 13 years, showed the need for encouraging fitness in school children, and proposed the re-introduction of sport, particularly in schools in which African children predominate.

An interesting study of C-reactive protein (CRP) levels, undertaken on African children in a South African township, showed that higher exercise levels related to lower serum CRP levels and a reduced likelihood of becoming overweight.3


ADA WATCH SA JOURNAL OF DIABETES & VASCULAR DISEASE

TABLE OF CONTENTSCLINICAL REVIEWHypoglycaemia and cardiovascular risk ................ 128

Differentiating between GLP-1 receptor agonists ... 128

Differentiating between GLP-1 receptor agonists ... 128

Focus on basal insulin ......................................... 129

New bolus insulins .............................................. 130

Preserving beta-cells ............................................ 130

Bariatric surgery: gastric bypass ........................... 130

Islet cell transplantation: numbers still small, but some success ............................................. 130

FOCUS ON QUALITY OF CARE How to improve diabetes outcomes: a systematic

review of strategies that work, presented as part of the ADA/Lancet symposium .................. 131

NHANES casts spotlight on risk of diabetes from exposure to tobacco smoke (passive smoking) .. 131

Baroreflex sensitivity (BRS) in type 2 diabetes improves on statin therapy (low-dose atorvastatin) ..................................................... 131

Global survey finds one in four type 2 diabetes patients do not take basal insulin as prescribed and more than a third suffer from hypoglycaemia ................................................. 131

ORIGIN trial shows safety and efficacy of insulin glargine: no adverse cardiovascular outcomes after a 6.2-year follow up of early insulin use ... 131

‘Real-world’ study of liraglutide versus twice-daily exenatide and DPP-4 inhibitors ......................... 132

BARI 2D study adds insights on glycaemic control strategies and peripheral neuropathy ............... 132

SYMPOSIUM ON SLEEP DISORDERS AND DIABETESSleep duration and quality and diabetes risk ........ 132

Sleep apnoea and diabetes risk ........................... 132

Mechanisms of insulin resistance in sleep apnoea .. 132

SYMPOSIUM ON THE EFFECTS OF BARIATRIC SUR-GERY ON MATERNAL AND OFFSPRING OUTCOMES

Effects of restrictive and malabsorptive bariatric surgery on reproductive-age women: fertility, metabolic effects and contraception................. 132

Approach to managing the post-bariatric patient during pregnancy, including impact on pre- gestational and gestational diabetes and hypertension .................................................... 132

New lessons in hypertension and diabetes: an update on clinical trials and clinical guidelines . 133

Alternative markers of glycaemia in the ARIC study . 133

2012 update FroM philadelphia, usaAmerican Diabetes Association Congress 8–12 June 2012Contributors: Dr l lombard, Dr D Jivan, J Aalbers

SUMMARIES

ADA WATCH

CLINICAL REVIEWHypoglycaemia and cardiovascular riskSimon Heller elaborated on the possible mechanisms of increased cardiovascular risk caused by hypoglycaemia. Data were shown that hypoglycaemia caused a pro-longed QT, therefore increasing the risk of ventricular rhythm disturbances as well as increased platelet aggregation for sev-eral hours after the hypoglycaemic event. It also decreased spontaneous thromboly-sis after a serious hypoglycaemic event (this effect has been shown to last up to seven days). Hypoglycaemia has also been strongly linked to bradydysrhythmias, with an increased relative risk of nearly nine-fold for bradycardia. It therefore also increases the risk of sudden death.

Exenatide twice daily versus glimepirideIn an ADA/Lancet symposium, Prof Guntram Schernthaner presented the EUREXA study, comparing exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabe-tes who failed metformin therapy. This was an open-label, randomised, controlled trial comparing 10 µg bid of exenatide versus glimepiride in a titration dose.

Failure was diagnosed as an HbA1c level > 7% on two consecutive occasions, or an HbA1c level > 9% on one occasion. Patients (515) were randomised to the exenatide group, of whom 203 achieved failure of this treatment, while in 514 patients in the glimepiride group, 262 reached the end-point of failure of this therapy. Exenatide was therefore shown to be non-inferior to glimepiride for the time-to-treatment failure.

The groups were well matched, although there was quite a large dropout percent-age during the study. At baseline, the HbA1c level was 7.43% on average. At 24

weeks, the Kaplan-Meier curves diverted in favour of exenatide. At the end of the study, 41.4% of the patients on exenatide failed the treatment, while 53.8% of those on glimepiride failed.

If the starting HbA1c level was ≤ 7.3%, exenatide and glimepride showed the same results, but when the HbA1c level was above 7.3%, the exenatide was superior; 44.8% of the patients on exenatide could achieve an HbA1c level of < 7%, compared to 30.8% on glimepiride at the end of the study.

A 5.4-kg weight difference was shown over the follow-up period of three years in this study, favouring exenatide. The exenatide group lost an average of 3.9 kg, while the glimepiride group gained 1.5 kg.

Incidents of hypoglycaemia were much more common in the glimepiride group, as could be expected. The glimepiride group had 5.3 hypoglycaemic incidents per patient years, compared to 1.52 hypogly-

caemic events per patient years in the exenatide group.

The only criticism of the trial was that glimepiride was not titrated to full strength in many of the patients, which could have optimised HbA1c levels in some of these patients.

Differentiating between GLP-1 receptor agonistsIn a session on incretin-based therapies, Philip Knop gave a talk on GLP-1 receptor agonists, asking whether they are all the same. All the molecules were discussed and the differences were pointed out.

Exenatide in a twice-daily dose (known in South Africa as Byetta) has a half-life of 2.5 hours. The peak after injection is about two hours. It mainly gets excreted via the kidneys and gives a better postprandial


SA JOURNAL OF DIABETES & VASCULAR DISEASE ADA WATCH

glucose lowering than many of the other GLP-1 analogues.

Liraglutide, known in South Africa as Vic-toza, has a half-life of between 11 and 13 hours, with a peak after nine to 12 hours. It is broken down in the body and does not get excreted via the kidney. It is marketed as a once-daily dose and these two drugs have been on the market for some time. Comparative trials have been published.

Exenatide once a week, which is not currently available in South Africa, is dosed at 2 mg per week. The half-life is more than 24 hours. It is excreted by the kidneys. It has a better effect on the fasting blood glu-cose, compared to exenatide twice a day. Gastrointestinal side effects appear to be less than with the twice-daily dosing. Anti-bodies develop against both formulations of exenatide in about 50% of patients, but this does not seem to impair the action to a large extent.

Another molecule discussed was lix-isenatide 20 µg per day, which has a half-life of between 1.5 and three hours, with a peak after two hours. Apparently the side effects are less, but also the weight loss is less impressive compared with exenatide. This molecule needs further study.

In the pipeline is albiglutide, another GLP-1 analogue, which has a half-life of between six and eight days and a peak after about five days. It achieves less weight loss than the other analogues, and fewer side effects, particularly nausea. It is a large molecule, consisting of two copies of GLP-1 fixed to each other with an albumin tail. The lack of weight loss may be because it does not cross the blood-brain barrier.

Once-a-week exenatide versus liraglutide was studied. Exenatide was shown to have a slightly better HbA1c lowering, as well as a slight weight benefit but with more nausea and vomiting, compared to liraglutide.

The conclusion was that there are many GLP-1 analogues, which differ markedly regarding the backbone, some of them being exendin based and some GLP-mol-ecule based, with slight changes or side chains attached. They vary markedly in size and pharmakokinetics and therefore there is a difference in the clinical response and side-effect profiles, as seen with other classes of drugs. Further study is required.

Focus on basal insulinIn a session on insulin, Prof Jeremiah Boli from Italy gave an excellent overview of

basal insulin. He commenced with NPH insulin, which gives a peak of insulin after four to six hours of subcutaneous injection, often causing night-time hypoglycaemia, especially in type 1 diabetes patients.

There is marked inter- as well as intra-patient variability, which hampers titra-tion of the dose. The duration of action is too short and therefore twice-daily dosing is needed. Prof Boli stated that this insu-lin should definitely not be used for type 1 diabetes patients, and preferably not in type 2 diabetes.

Glargine insulin is a peakless soluble insulin with less variability than NPH and gives 24-hour cover in most patients. It is the best insulin for type 1 diabetes and superior to NPH due to its lower risk for hypoglycaemia.

Detemir is also a soluble insulin with even less variability than glargine, but shorter duration, less potency unit for unit, and therefore often bigger doses are needed for insulin-resistant patients. It is used in a twice-daily dose in type 1 diabe-tes patients. Its hypoglycaemic risk is low and obese patients require more units per kilogram body weight to achieve control.

Insulin degludec was offered as a poten-tially favourable long-acting insulin. It is injected as a di-heximer and forms multi-heximers under the skin after injection. It is then slowly released, giving very long action, with a half-life of about 25 hours, good 24-hour cover and no clear indication of accumulation. There is a low hypogly-caemic risk, low variability and the insulin shows good pharmakokinetics.

Insulin degludec produced a similar HbA1c level to that of glargine in comparative trials. It had a low hypoglycaemic risk of 1.5 events per patient years, versus glargine of 2.5 events per patient years. This was equivalent to a relative risk reduction for hypoglycaemia of 25% in one study, and 18% in another, versus glargine. The absolute risk reduction however was small. Insulin degludec gives more flexibility for time of dosing because of the long half-life.

Another interesting insulin that was dis-cussed was the lispro polyethylene glycol formulation, also known as pregilated lispro. A study was presented on 137 type 1 diabetes patients, showing that this insu-lin was superior to glargine. The patients lost weight and there was an increase in low-density lipoprotein (LDL) cholesterol levels. HbA1c lowering was superior in a few cases. Hypoglycaemia was slightly increased. There was an increase in liver

enzymes and this was a worrying potential side effect that needs further clarification.

A second study of pregilated lispro on fewer than 95 patients also showed weight loss, with fewer hypoglycaemic incidents than with glargine, and equivalent HbA1c lowering. This insulin has potential but the reasons for the weight loss as well as the changes in liver enzyme levels should be investigated.

In another talk in the same symposium, Dr Luigi Menaghini presented new bolus insulins and discussed normal human insu-lin, which showed a 15 to 25% inter- and intra-patient variability. It needs to be taken between 30 and 45 minutes before meals and has a delayed peak, often leading to hypoglycaemia.

Analogues have been shown to cause fewer incidents of hypoglycaemia than the old insulins. They have a small benefit in HbA1c levels and are much safer. They work more effectively if given 15 to 20 minutes before meals.

An enzyme hyaluronidase has been shown to enhance the action of insulin analogues by as much as 200% and pro-duces a much quicker action if given with a short-acting analogue. This option is being investigated currently.

Inhaled insulin was discussed and many are still in phase 2 trials. Technosphere’s insulin is apparently closest to coming on the market. Inhaled insulin produces a better fasting glucose level. It was com-bined with gargine in a basal-bolus regi-men. Incidents of hypoglycaemia were the same compared to subcutaneous insulin. It was mainly the ease of use and patient satisfaction that was found to be supe-rior.

Chronic cough was a notable side effect, especially in the early weeks of usage, but this tended to clear with con-tinued use. However, lung-function tests have shown decreased FEV1 and diffusion capacity in the lungs and this needs fur-ther clarification before inhaled insulin will become a reality.

A trial was presented of glargine plus inhaled insulin compared to NovoMix twice a day. It showed equal HbA1c lowering, less weight gain, and better fasting glu-cose levels. Hypoglycaemic incidents were equivalent but coughing was a side effect.

In previous studies of inhaled insulin, there was a trend towards more incidents of lung cancer in patients who had smoked previously. These drugs cannot be used in current smokers and have the potential to



increase lung cancer in previous smokers. This aspect needs further study.

New bolus insulinsJulio Rosenstock presented different combi-nation therapies in his discussion on co-for-mulations. He answered in the affirmative the question whether there is a place for co-formulations. The main reason for the use of co-formulations is to simplify insulin usage.

He prefers basal insulin plus boluses, either one or more, according to the require-ments of the patients. He supported this with a comparative study comparing pre-mix insulin, which gave a 1.8% reduction in HbA1c level with an average of 7 kg weight gain and more incidents of hypoglycaemia, compared to a basal-plus-one regimen, which gave a –2.1% reduction in HbA1c level in type 2 diabetes patients, with a 5.2-kg weight increase. A basal-plus-three (full basal–bolus) gave a 6.9-kg weight increase with a 2.2% reduction in HbA1c level.

Dr Rosenstock stated that if one can get away with a basal-plus-one regimen in a type 2 diabetes patient, one will probably have the best reduction in HbA1c level with the least weight gain. The pre-mix regimen gives less flexibility and more incidents of hypoglycaemia.

In the future, combinations of GLP-1 analogues with degludec insulin are in the pipeline and they will probably be given as a once-daily dosing, with additional short-acting insulin if necessary. This has been compared to NovoMix and has been shown to cause fewer incidents of hypogly-caemia.

Dr Rosenstock also discussed the use of hyaluronidase with short-acting insulin, improving the onset of action and shorten-ing the duration of action of short-acting analogues. He also discussed the possibil-ity of using pramlintide with lispro insulin, which gives less weight increase and even some weight loss with equivalent diabetes control.

Further combinations, which will be used in the future, are basal insulin plus GLP-1 analogue and metformin. Dr Rosen-stock feels this combination has the poten-tial to lower HbA1c levels as well as promote weight loss.

Preserving beta-cellsIn a diabetes-care symposium, a study was

presented by Dr Ildiko Lingray on preserva-tion of beta-cell function after 3.5 years of follow up after a short period of intensive diabetes therapy. Newly diagnosed type 2 diabetes patients were randomised and put on three months of intensive insulin therapy, with normalisation of HbA1c levels. After three months they were randomised to triple oral therapy with gliburide (according to glucose levels), metformin (1 g bid) and pioglitazone (45 mg), versus NovoMix-30, twice a day with metformin 1 g bid.

All the patients were confirmed to be GAD antibody negative in 42 months of follow up after a three-month randomi-sation period. Failure or endpoint was defined as reaching an HbA1c level of 8% and the study was analysed with intention-to-treat analysis.

Fifty-eight patients were randomised, 29 to each group. The initial HbA1c level was 10.6 ± 2.8%. This was brought down within three months to 5.9% on average (in the normal range) and then randomisa-tion took place. The patients on the insulin gained 4 kg over the period, whereas those on the triple therapy gained 10 kg.

The patients’ beta-cell function was assessed after the treatment period and the conclusion was that early glycaemic nor-malisation with combination therapy pre-served beta-cell function. This was better in the patients in the insulin group.

Bariatric surgery: gastric bypassProf J Cummings focused on the Roux-Y gastric bypass, reporting on follow up of a group of patients who had had the procedure. Between 80 and 85% remission of type 2 diabetes had occurred after the gastric bypass. Remission occurred before the weight loss. The Roux-Y gastric bypass showed better remission of diabetes than comparative weight loss with other methods.

Prof Cummings also discussed a Swedish obesity study with 20-year follow up after gastric bypass. The benefits of the bypass surgery were not related to the degree of obesity. There was a clear lowering in ghre-lin levels and an increase in GLP-1 release. Since food enters the small intestine more quickly after gastric bypass, it appears that the gut has control of not only insulin release, but also insulin sensitivity.

He reported on six patients who had had gastric bypass with six years of follow

up. Their body mass index was between 30 and 35 kg/m2, which was lower than usual. The average duration of diabetes was 13 years and 40% of the patients were on insulin.

The average HbA1c level was 9.7% before treatment. It dropped to 6.5% and was stable over the follow up of six years. Remission of diabetes of 88% occurred. There was > 400% increase in insulin sensitivity and beta-cell function and a recovery of C-reactive protein-measured insulin release after meals. Dyslipidaemia also improved, as did the blood pressure levels.

One of the conclusions was that the duration of diabetes was not related to the remission rate and that even people who had longstanding diabetes could go into remission. Long follow-up periods of the patients are useful to assess these proce-dures.

Islet cell transplantation: numbers still small, but some successDr M Rickels reported on the outcome of islet cell transplants at the largest centres in the world, 27 centres in total, between 1999 and 2010. There were 677 cases of islet cell transplantation and the patients were assessed on insulin independence.

The results confirmed C-reactive protein production > 0.3 ng/ml and an HbA1c level < 6.5%, with preferably normal fasting glucose levels and the absence of hypogly-caemia. Of the patients, 85% had islet cell transplants and 50% also had renal trans-plants. There was no mortality associated with the islet cell transplants.

From 1999 to 2003, only 20% of these patients were insulin independent. With follow up from 2004 to 2006 this increased to 37%, and from 2007 to 2010 it had improved to 44%. In the best centres, the latest results for insulin independence could be as high as 60% with the newest immunosuppressive regimens, the reason for improved outcomes.

However, small numbers of patients are currently receiving the transplant. In the three years from 2007 to 2010, only 208 islet cell transplants were done in all 27 centres, making this largely experimen-tal therapy, done in brittle type 1 diabetes patients with recurrent hypoglycaemia and many complications.

Dr Landi Lombard



FOCUS ON QUALITY OF CARE How to improve diabetes out-comes: a systematic review of strat-egies that work, presented as part of the ADA/Lancet symposiumThis meta-analysis emphasised that initia-tives aimed at improving health systems and involving patients in their care offered the greatest improvement in glycaemic control in more than 140 published clinical trials. The measures used to determine quality improvements, referred to as quality-of-care indicators, included blood pressure con-trol, LDL-cholesterol levels, medication use and monitoring for diabetes complications (retinopathy, renal and foot screening).

Expanded statin usage and smoking-ces-sation programmes also resulted in clinically important benefits (see the BARI 2D and statin usage studies below). Interestingly, the value of the benefits of education and training of healthcare practitioners differed depending on how poor overall glycaemic control was at baseline. For example, clinicians’ educa-tion, and audit and feedback mechanisms achieved improvements when baseline HbA1c levels were > 8%, while this strategy was less effective when HbA1c levels were < 8%. Inter-ventions targeting patients were beneficial at any level of HbA1c control.

The second most important quality-of-care improvement strategy was intervening across the entire system of chronic disease management, which achieved the second-largest benefit irrespective of baseline HbA1c

level. The authors noted that their review could only address the type of intervention, not how to deliver it. This remains the realm of experienced healthcare practitioners.Source: Tricco AC, et al. Effectiveness of quality improve-

ment strategies on the management of diabetes: a sys-

tematic review and meta-analysis. e-published Lancet 9

June 2012. DOI: 10.1016/50140-6736(12).60480-2.

NHANES casts spotlight on risk of diabetes from exposure to tobacco smoke (passive smoking)This US National Health and Nutrition Examination Survey (NHANES) used the objective measure of serum cotinine levels in never-smokers to assess diabetes risk. The study found that higher cotinine levels were positively associated with occurrence of diabetes (404 patients) in this cohort of 3 151 patients.Source: Omayma O, et al. The association of serum

cotinine levels and diabetes in never smokers (Abstract

16-OR: abstract of oral presentation).

Baroreflex sensitivity (BRS) in type 2 diabetes improves on statin therapy (low-dose atorvastatin)Little is known on the effect of statin therapy on BRS. This study examined the effects of low-dose atorvastatin over a period of a year. Atorvastatin significantly reduced total cholesterol levels (27.3%) as expected, as well as triglyceride levels. Normal BRS was significantly improved in atorvastatin patients, while diet had no influence on BRS values.Source: Grigoropoulon P, et al. Long-term atorvastatin

administration improves baroreflex sensitivity in sub-

jects with type 2 diabetes and dyslipidaemia (Abstract

47-OR).

Global survey finds one in four type 2 diabetes patients do not take basal insulin as prescribed and more than a third suffer from hypoglycaemia One in four people with type 2 diabetes had missed or had not dosed their basal insulin correctly in the previous 30 days, according to a new global survey funded by Novo Nordisk. The GAPP2™ (Global Attitudes of Patients and Physicians) survey also found that more than a third experi-enced hypoglycaemia. The data were pre-sented at the late-breaking poster session of the 72nd scientific sessions.

Key findings from the GAPP2Tm survey included:

Dosing irregularities are not uncommon • in people with type 2 diabetes taking basal insulin. In the previous 30 days, 22% had missed a dose, 24% had mis-timed a dose by more than two hours and 14% had reduced a basal insulin dose. Self-treated hypoglycaemia remains a • significant management challenge in type 2 diabetes and 36% of those sur-veyed had experienced an event in the previous 30 days.There is a correlation between hypogly-• caemia and dosing irregularities. Those who had missed a basal insulin dose in the previous 30 days were signifi-cantly more likely to report self-treated hypoglycaemia over the same period as well (41 compared to 34%).

‘A considerable proportion of people with type 2 diabetes are missing or mis-timing their long-acting insulin’, said lead researcher and health psychologist Dr Meryl Brod of the Brod Group. ‘The chal-

lenges of addressing dosing irregularities and self-treated hypoglycaemia are critical for improving patient care as they greatly impact on the achievement of optimal gly-caemic control.’Source: Brod M, Barnett AH, Rana A, Peyrot M.

GAPP2TM: Global survey finds in the last month one

in four type 2 diabetes patients do not take basal insu-

lin as prescribed and over a third suffer hypoglycaemia

(Abstract: 2012-LB-5579-Diabetes).

ORIGIN trial shows safety and effi-cacy of insulin glargine: no adverse cardiovascular outcomes after a 6.2-year follow up of early insulin useThe ORIGIN trial, a large trial in patients with high cardiovascular risk and dysglycae-mia, using an intervention of initial basal insulin (glargine) in impaired fasting glu-cose (IFG), impaired glucose tolerance (IGT) or early-stage type 2 diabetes, has shown no cardiovascular benefits or adverse car-diovascular outcomes. However, a reduc-tion of progression to diabetes did occur in patients with IFG or IGT who were treated with insulin, actively targeting normogly-caemia of < 5.3 mmol/l, compared to those treated with standard care and mainly oral agents.

Importantly, the long-term use of insu-lin glargine was shown to be efficacious in lowering glucose levels safely over the six-year period. There was no increase in the incidence of cancer or cardiovascular events in the more than 5 000 patients treated over this extended period.

The trial showed that better glucose con-trol was achieved using a daily injection of basal insulin (with or without oral agents) in high-risk patients who self-titrated their insulin dosage to a fasting plasma glucose (FPG) level of < 5.3 mmol/l compared to those offered standard care. However, in both groups, a mean HbA1c level of ≤ 6.5% was achieved over the duration of the study.

In those in the glargine arm of the study, the median insulin dose rose from 0.31 U/kg by year one to 0.40 U/kg by year six. Importantly, 83.6% (5 230 patients) were adherent to their insulin glargine therapy at year six; 19% did however permanently discontinue their insulin therapy. In the standard-care group, 11% of patients were using insulin at the end of the study.

With regard to the co-primary compos-ite: cardiovascular outcomes of death from cardiovascular causes, non-fatal myocardial



infarction (MI) or stroke, and secondly, the composite of these events plus either a revascularisation procedure or hospitalisa-tion for heart failure, there was no signifi-cant difference between the two groups.

The incidence of a first episode of severe hypoglycaemia was a modest 1.00 per 100 person-years in the insulin glargine-treated group, and 0.31 per 100 person-years in the standard-care group (p < 0.001). Partic-ipants in the insulin glargine group gained a median of 1.6 kg, whereas the standard-care group lost a median of 0.5 kg.Source: 1. The ORIGIN trial investigators. Basal insu-

lin and CV and other outcomes in dysglycemia. N

Eng J Med. Epub 11/6/2012. DOI: 10.1056/NEJ-

Moa1203858.

2. Cardiovasc J Afr e-alert, Origin trial, 15 June 2012.

‘Real-world’ study of liraglutide versus twice-daily exenatide and DPP-4 inhibitorsNew ‘real-world’ data showed that liraglu-tide injection provided greater reduction in HbA1c levels compared to exenatide and DPP-4 inhibitors, with weight loss and cost-effectiveness, when used in routine primary care, according to current UK type 2 diabetes treatment guidelines. The study presented at the 72nd annual scientific sessions also shows that more patients appeared to favour a drug with a liraglutide-like profile, which is given by injection, over a drug with a sitagliptin-like profile, which is given orally.

‘This study shows us that the results we’ve seen with liraglutide in clinical trials are reflected in day-to-day, real-world use’, said Marc Evans, study investigator from Llandough Hospital, Cardiff, Wales. ‘Key to managing diabetes is choosing treatments that patients will adhere to in order to get the best outcomes.’

The study analysed data from 1 114 type 2 diabetes patients from primary care practices in the UK and assessed the clinical efficacy and patient preference with regard to liraglutide, exenatide and DPP-4 inhibi-tors. Key findings from the study were:

The results showed that greater reduc-• tion in HbA1c level was seen in patients treated with liraglutide compared to exenatide or DPP-4 inhibitors (1.23 ± 0.14%, 0.79 ± 0.19% and 0.72 ± 0.23%, p < 0.05, n = 1 114). Significantly greater weight loss was • seen in patients treated with liraglutide (n = 256) compared to DPP-4 inhibitors (n = 710) (–3.9 ± 5.7 vs –0.8 ± 3.1 kg,

p < 0.05). Greater weight loss was seen in patients treated with liraglutide (n = 256) compared to exenatide (n = 148) (–3.9 ± 5.7 vs –2.9 ± 5.8 kg).More patients expressed a preference • for a drug with a liraglutide-like profile over one with a sitagliptin-like profile (62.5 vs 37.5%, p < 0.05). The calculated life years gained per • patient were 0.12, 0.08 and 0.07 years for those receiving liraglutide, exenatide or a DPP-4 inhibitor, respectively, com-pared to their respective baselines. Based on observed treatment effects, • the United Kingdom Prospective Dia-betes Study (UKPDS), 68 risk equations were applied over a 20-year time hori-zon to calculate cost effectiveness. The observed cost/QALY (quality-adjusted life years) vs baseline for patients receiving liraglutide, exenatide or a DPP-4 inhibitor was £16 505, £16 648 and £20 661, respectively. Costs were calculated using the most commonly prescribed DPP-4 inhibitor, sitagliptin.

BARI 2D study adds insights on glycaemic control strategies and peripheral neuropathyThe BARI 2D study which showed similar long-term cardiovascular outcomes whether the glycaemic control strategy was insulin-sensitising (IS) or insulin-providing (IP) has now shown that IS therapy significantly reduced the cumulative diabetic peripheral neuropa-thy in the four-year follow-up period.Source: Busui RP, et al. Impact of glycaemic control

strategies on the incidence of DPN in the Bypass Angi-

oplasty Revascularisation Investigation 2 Diabetes (BARI

2D) cohort.

J Aalbers

SYMPOSIUM ON SLEEP DISORDERS AND DIABETES

Sleep duration and quality and diabetes riskDr E Tasali, Chicago, USA, showed evidence to suggest that decreased sleep duration or quality may increase diabetes risk. Habitu-ally short sleep duration or quality (low levels of slow-wave sleep) increases sympa-thetic nervous system activity, which leads to insulin resistance and, in the long term, may compromise beta-cell function to cause type 2 diabetes mellitus.

Sleep apnoea and diabetes riskDr N Punjabi, Baltimore, USA, concluded that, independent of other risk factors, obstructive sleep apnoea increases the risk of developing type 2 diabetes mellitus.

Mechanisms of insulin resistance in sleep apnoeaDr O’Donnell, Pittsburgh, Pennsylvania, presented data from animal studies on the mechanism of insulin resistance in sleep apnoea. These studies suggest that increased sympathetic nervous system activity, frag-mented sleep causing dysregulation of the hypothalamic–pituitary axis, endothelial dys-function and alterations in cytokine and adi-pokine release are all putative mechanisms for insulin resistance in sleep apnoea.

SYMPOSIUM ON THE EFFECTS OF BARIATRIC SURGERY ON MATER-NAL AND OFFSPRING OUTCOMES

Effects of restrictive and mal-absorptive bariatric surgery on reproductive-age women: fertility, metabolic effects and contraceptionDr Melinda Maggard-Gibbons, associate professor of Surgery at UCLA discussed the effects of restrictive and malabsorp-tive bariatric surgery on reproductive-age women. While the literature suggests that there is an improvement in fertility post-bariatric surgery, there are not enough data to draw a conclusion about the impact of bariatric surgery on in-vitro fertilisation suc-cess. There is a concern about the absorp-tion of the oral contraceptive pill in patients who have undergone bariatric surgery, and additional barrier methods of contracep-tion are suggested.

Approach to managing the post-bariatric patient during pregnancy, including impact on pre-gestational and gestational diabetes and hypertension Eyal Sheiner, an obstetrician from Israel, described an approach to managing the post-bariatric patient during pregnancy. Pre-pregnancy weight loss and careful pre-conception screening of patients for nutritional deficiencies is the ideal. There were lower rates of hypertensive emergen-cies, diabetes and gestational diabetes in



women who conceived after undergoing bariatric surgery compared to women who did not have bariatric surgery, suggesting that bariatric surgery has at least a protec-tive effect on maternal complications.

New lessons in hypertension and diabetes: an update on clinical trials and clinical guidelinesPeter Nilsson critically appraised the current guidelines regarding the treatment of hyper-tension in patients with diabetes. It is proven that lowering blood pressure reduces the risk for stroke. In the UKPDS, lowering blood pres-sure also led to a reduction in retinopathy.

Most guidelines advocate treating blood

pressure at 140/80 mmHg or higher, or at a lower blood pressure in the presence of target-organ damage. While the ADA guideline advocates treating blood pressure to below 130/80 mmHg in diabetes, it is of concern that randomised, controlled studies and observational studies show either no benefit or harm (increased coronary heart disease risk) if the systolic blood pressure goal is below 130 mmHg.

Refer to the new 2012 SEMDSA guidelines for the management of type 2 diabetes.

Alternative markers of glycaemia in the ARIC studyQuartiles of glycated albumin, fructosamine

and 1.5 anhydroglucitol (AG) levels were assessed for utility as risk factor markers for the development of diabetes in a subset of patients from the ARIC study. Upper quartiles of glycated albumin and fructos-amine levels and the lowest quartile of AG levels were associated with diabetes risk. The value of these markers for predicting long-term outcome should be assessed in further studies, this Baltimore study recom-mended.Source: Jurascheck SP, et al. Alternative markers of gly-caemia and risk of diabetes in the Atherosclerosis Risk In Communities (ARIC) study. (22 OR, abstract for oral

presentation).

Dr D Jivan

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


CONFERENCE REPORT SA JOURNAL OF DIABETES & VASCULAR DISEASE

22nd European meeting on hypertension and cardiovascular protection, London 26–29 April 2012

Following the release of the updated NICE (British Hypertension Society) guidelines

last year and the South African guidelines recently, this meeting presented an opportunity to hear opinion leaders analyse, debate and discuss the best way to detect and manage hypertension in the 21st century.

Regarding treatment, the issue of diuretics was highlighted. The NICE guidelines advocate the use of thiazide-like diuretics (indapamide) and chlorthalidone. The South African guidelines also advocate these agents; however the choice of diuretic still includes low-dose hydrochlorothiazide. Prof Franz Messerli, an eminent American opinion leader, was asked what is used in his country and the answer was thiazides, often in fixed combination.

The lesson is to use the thiazides with caution, be aware of the metabolic side effects and understand that the agents now advocated have been shown to have better outcomes data. Prof G Bakris stressed the need to ensure that patients are not hypokalaemic, as this contributes to vasoconstriction of vessels and resistant hypertension. It is important to correct potassium levels before adding in more therapy.

A focus of the meeting was renal nerve denervation (RDN) in resistant hypertension. Prof M Esler gave the Bjorn Folkow award lecture titled ‘The clinical physiology of the sympathetic nervous system: no longer a promissory note in hypertension’. He highlighted the pathophysiology of the sympathetic nervous system and why surgical splanchnicectomy, done from 1934 to 1960, did not work.

Renal denervation using radiofrequency laser is a minimally invasive percutaneous procedure characterised by short recovery times and the absence of systemic side effects. It appears that this technique will be considered an adjunctive therapy in the future. The European Society of Hypertension position paper, ‘Renal denervation – an interventional therapy of resistant hypertension’, intends to facilitate a better understanding of the effectiveness, safety, limitations and issues still to be addressed with RDN.

The meeting covered issues of cardiovascular protection. The cardio–ankle vascular stiffness index (CAVI) is a non-invasive technique used in Japan to assess

arterial stiffness. It is expressed as a ratio between the internal pressure in blood vessels (blood pressure) and changes in vascular diameter, and measures pulse-wave velocity between the heart and femoral artery. The clinical implications are whether it will be a useful tool to assess arterial disease independent of blood pressure levels. There is also an association between CAVI and atherosclerosis. All the work has previously been done in Asians and Japanese, and data were presented on the reliability of this index in a cohort of 4 000 Swiss subjects. Of note is that the index increases with age and women have a lower score than men.

A workshop dedicated to Bill Kannel, father of the Framingham study, was delivered by co-workers. Prof S Franklin, nephrologist, discussed the five seminal articles published regarding blood pressure, ageing and cardiovascular disease, and highlighted findings that changed our understanding of the disease. Prof D Levy, involved with cardiovascular gene therapy, highlighted the genotype and phenotype genome-wide association data from this study.

Although it was predicted in June 2000 that within 10 years one would be able to find out what particular genetic conditions patients have, the individual single-nucleotide polymorphisms identified do not really contribute to the magnitude of hypertension. Those identified for systolic hypertension only contribute to a 1-mmHg increase, and diastolic to 0.5 mmHg. There are associations with stroke risk and left ventricular mass but no association with renal markers of hypertension.

Regarding the Framingham scoring system for cardiovascular risk assessment, it was fascinating to hear how the scoring system was developed. Prof RB D’Agostino, mathematician and statistician, discussed the validation of this score in the non-Framingham population; the transportability and external validation, which allows one to use it for other populations such as non-Caucasians. It has also been validated for non-US populations such as the Chinese.

Hypertension in the elderlyThe VALISH trial enrolled patients with isolated systolic hypertension (age range

70–84 years). These patients were divided into two groups. In one group, target systolic blood pressure was < 140 mmHg whereas in the second group the target systolic blood pressure was between 140 and 149 mmHg. They found no difference in outcome with strict versus less strict blood pressure control (< 140 vs 140–149 mmHg).

There was some discussion about the J-shaped curve regarding diastolic blood pressure in elderly patients. The data suggest that if diastolic blood pressure is lowered to < 80 mgHg in patients who have coronary heart disease at baseline, there is an increase in cardiovascular mortality.

Prior to blood pressure measurement, patients must have rested for at least five minutes and the readings are repeated. In the elderly, particular emphasis should be placed on standing blood pressure.

The HYVET trial recruited patients over the age of 80 years with a systolic blood pressure of > 160 mmHg. Patients were eligible for the trial if the systolic blood pressure was > 160 mmHg but not if the standing systolic blood pressure was < 140 mmHg. In this study, target blood pressure was < 150/80 mmHg. Active treatment with indapamide-based therapy was associated with a significant reduction in total mortality (25%), cardiovascular mortality (35%), stroke mortality (60%) and heart failure (50%).

The JATOS trial, published in Hypertension Research in 2008, confirmed that a systolic blood pressure of < 140 mmHg was associated with more deaths in those over the age of 75 years. It was finally concluded that the target blood pressure in the very elderly is 150/80 mmHg. Currently, there are no data on the optimal blood pressure goal in patients with mild hypertension (140–160/< 90 mmHg) as trials have only recruited patients with a systolic blood pressure > 160 mmHg.

Blood pressure variabilityThis refers to visit–visit variability, within-visit variability, as well as variability over a longer period of time such as a week or a month. The greater the variability in blood pressure, the higher the risk. No specific number was given for the cut-off measure which predicted higher versus lower variability.

A good technique to assess variability


SA JOURNAL OF DIABETES & VASCULAR DISEASE CONFERENCE REPORT

entailed home blood pressure monitoring with three successive measurements a day, over a period of seven days. The greater the variability in readings, the higher the risk.

Recent data published in the Lancet in 2010 confirmed that visit–visit variability in systolic blood pressure is a strong predictor of stroke, independent of mean systolic blood pressure. Increased residual variability

in systolic blood pressure in patients with treated hypertension is associated with a high risk of vascular events.

To most effectively prevent stroke, blood pressure-lowering drugs should reduce mean blood pressure without increasing variability. Ideally they should do both.

Summary from conference report, Cardiovasc J Afr 2012; 23(4): 232–234.

DR NAOMI [email protected] physician, Milpark Hospital, Johannesburg

DR SHIRLEY MIDDLEMOST [email protected], Hermanus MediClinic, Western Cape

Hypertension is increasingly becoming a health concern in the younger

population. Prof Rayner illustrated this point by comparing data from the 1970s, when hypertension in children was extremely rare and almost always prompted investigation to search for an underlying secondary cause, with current statistics.

Recent American studies have shown that the prevalence of childhood hypertension has risen as high as 4.5%. The Harvard Alumni study assessing coronary heart disease mortality in normal subjects and those with pre-, primary and secondary hypertension found that 5–15% of adolescents displayed secondary hypertension.

Factors contributing to childhood hypertension‘The current epidemic of obesity is the key issue in childhood hypertension’, said Prof

Southern African Hypertension Society congress report, March 2012 The young hypertensive

Prof Brian RaynerHead of Division of Nephrology, Groote Schuur Hospital and University of Cape Town Active research interests are therapy of hypertension, mutations in the ENaC, genetic determinants of

salt sensitivity, HIVAN, vascular calcification and chronic kidney disease, primary aldosteronism and the genetics of severe hypertension in blacks.

Rayner. Obesity is defined as a body mass index > 85th percentile, leading to a rise in leptin levels and heart rate and also linked to insulin resistance. He noted that a definite relationship between blood pressure and fasting insulin has been observed.

A number of other factors are also strongly linked to the rise in childhood hypertension, including low birth weight and predisposing genetic factors (family history of risk factors or hypertensive disease). Also contributing are reduced nephron number (Barker-Brenner hypothesis) and elevated uric acid.

There are multiple health concerns around elevated blood pressure in child-hood. Childhood blood pressure (especially systolic) tracks blood pressure into adulthood. Elevated blood pressure is associated with subclinical cardiovascular disease and is a significant driver of overall mortality, cardiovascular mortality and coronary heart disease.

Assessing hypertension in the childKey pointers to primary hypertension in the child include adolescence, obesity, and a family history of hypertension, cardiovascular disease and type 2 diabetes. Pre-hypertension and hypertension were defined as a blood pressure persistently above the 90th and 95th percentiles, respectively. Adult norms of blood pressure should be used from 18 years of age.

Prof Rayner advised that assessment of blood pressure should be based on frequent measures; full 24-hour ambulatory monitoring is ideal to avoid misdiagnosis.

Clinical examination should evaluate for potential secondary causes of hypertension, particularly use of illicit drugs (cocaine, tik) and oral contraceptives, and chronic kidney disease.

Other investigations advised included a dipstick for urine, and creatinine assessment, as well as kidney ultrasound. Blood tests (electrolyte, uric acid and fasting glucose levels, lipogram), an electrocardiogram and an echocardiogram were also considered important.

Treatment of childhood hypertension Lifestyle modification, Prof Rayner empha-sised, forms the basis of treatment of the pre-hypertensive or hypertensive child. Weight loss and increased exercise are of particular importance.

The use of therapeutic agents should be considered in those children with sympto-matic hypertension, secondary hypertension, organ damage and type 1 and 2 diabetes. Also consider those with persistent hyper-tension despite lifestyle modification.

There are some concerns over the use of diuretics in the young, but the use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), calcium channel blockers and beta-blockers has been safely established. Prof Rayner did comment that weight gain and poor exercise tolerance arising from beta-blocker use predisposes the patient to type 2 diabetes.

G Hardy


CONFERENCE REPORT SA JOURNAL OF DIABETES & VASCULAR DISEASE

Prof Willie MollentzeHead of Department of Internal Medicine, Faculty of Health Sci-ences, University of the Free State. He is interested in the epidemiology and clinical management of diabetes as well as geriatric medicine.

Of the 340 million people with diabetes globally, 80% are found in developing

countries. Diabetic complications are the third leading cause of death; and two-thirds of those with type 2 diabetes face cardiovascular disease as the cause of mortality. Prof Mollentze briefly described the four main categories of diabetes; types 1 and 2, gestational diabetes and the eight different sub-categories arising from chronic pancreatitis.

Diabetes is a heterogeneous disorder with variable pathogenesis. Using rigid guidelines with limited therapeutic agents is not successful, as more than half of the patients fail to reach clinical targets. Ideally, care should be organised around the diabetic individual, incorporating a multi- and interdisciplinary team focused on self-care management. Initial evaluation of a type 2 diabetes patient, whether established or newly diagnosed, presents a unique opportunity to individualise a comprehensive care plan.

The World Health Organisation accepts a diabetes diagnosis from an HbA1c level ≥ 6.5%; however Prof Mollentze does not recommend this as a standard test, as point of care is not a good indicator. There is also the question of other anaemic considerations affecting the result.

A superior diagnostic method is provided by a 75-g oral glucose tolerance test (OGTT), particularly in those high-risk individuals with a family history of diabetes. A fasting plasma glucose (FPG) ≥ 5.6% and < 7.0% and a RPG? ≥ 5.6 and < 11.0% is considered diagnostic of diabetes. Improved diagnostic levels require the proper equipping of primary care clinics and appropriate staff training.

Lowering of HbA1c levels to ≤ 7% reduces the long-term development of microvascular complications in the diabetic patient. Early intensive glycaemic control also translates to a reduction in macrovascular disease.

Regular exercise is strongly advised, preventing the onset of type 2 diabetes in high-risk individuals through improving glucose control, reducing cardiovascular risk and promoting weight loss. The American Diabetes Association (ADA) recommends 150 minutes of moderate aerobic activity in a week, spread out over three days, with no more than two consecutive days elapsing without exercise.

Nutritional therapy is also integral to the lifestyle changes required of type 2 diabetes patients. Counselling should ideally be given by a registered dietician.

Referring to the ADA therapeutic guide-lines, Prof Mollentze indicated that met-formin (unless contra-indicated) should be initiated concomitantly with lifestyle changes and nutritional intervention in newly diag-nosed type 2 diabetes patients. Should the HbA1c target level not be met within the first six months, a second agent from a different class (e.g. sulphonlyurea) should be added. He stated that each class of non-insulin agent added to initial therapy can decrease HbA1c levels by 0.9–1.1%.

The ADA and the Canadian Diabetes Association recommend that newly diag-nosed patients with an HbA1c level > 9% or with marked hyperglycaemia should be con-sidered for insulin therapy from the outset, with or without the use of other agents. One should be vigilant in looking for signs of hypoglycaemia that may result from the use of insulin and insulin secretagogues.

In special circumstances, Prof Mollentze advised alternative therapies that could be considered, including acarbose and the newer incretin-based agents, GLP-1 agonists and DPP-4 inhibitors. As an aside, he mentioned a recent FDA warning on the concerns of increased cardiovascular mortality with the use of rosiglitazone, and also raised the association of increased risk of bladder cancer with the use of pioglitazone.

Cardiovascular risk factors of type 2 diabetes patients may be managed with low-dose aspirin. Prof Mollentze indicated that low-dose aspirin may be beneficial in diabetics for the primary prevention of cardiovascular disease, as well as a secondary-prevention strategy in those with a history of cardiovascular disease. Aspirin is not recommended for those diabetic adults at low cardiovascular risk.

Guidelines for lipid management include total cholesterol < 4.5 mmol/l, low-density

lipoprotein cholesterol < 2.7 mmol/l and high-density lipoprotein cholesterol > 1.0 mmol/l in men or > 1.2 mmol/l in women. Prof Mollentze emphasised that statin therapy should only be added after lifestyle interventions have been tried, unless there is pre-existing kidney disease or the patient is older than 40 years of age, has been diabetic for more than 10 years, and exhibits additional cardiovascular risk.

At diagnosis, one-third of diabetic patients present with hypertension. This may rapidly progress to renal failure unless treated aggressively. Treatment goals for hypertensive diabetics are a blood pressure of < 130/80 mmHg. Should blood pressure targets not be met with initial lifestyle inter-vention, pharmacological therapy should be considered. This includes an ACE inhibitor or an ARB (if the ACE is not tolerated), a calcium-channel blocker or a thiazide-type diuretic.

Diabetes is the leading cause of chronic kidney disease (CKD). Approximately 40% of diabetic patients will develop CKD, highlighting the need for screening at the time of diabetes diagnosis. Diabetic nephropathy usually progresses from sub-clinical disease and is characterised by persistent proteinuria.

Referral for specialist renal care is necessary when there is a progressive loss of renal function, estimated glomerular filtration rate (eGFR) < 30 ml/min, acute renal failure > 60 mg/ml and failure to reach blood pressure targets. Diabetic adults with persistent albuminuria should be given an ACE inhibitor to delay progression of CKD by either preventing or delaying a progressive decline in eGFR.

Prof Mollentze advises follow-up testing of serum creatinine and potassium levels within two weeks of a patient being initiated on an ACE inhibitor or ARB. Referral to a nephrologist should be considered when there is a chronic, progressive loss of renal function, despite the recommended interventions.

Also common among diabetics is retinopathy. Of diabetic patients, 40% have diabetic retinopathy and 8% have sight-threatening retinopathy. Screening should be performed annually or in the case of an abnormality. Few South African primary healthcare workers are adequately trained to screen diabetic retinopathy; many patients need to be referred to a skilled professional for screening. Tight glycaemic control, and

Management of type 2 diabetes in primary healthcare


SA JOURNAL OF DIABETES & VASCULAR DISEASE CONFERENCE REPORT

treatment of elevated blood pressure and lipids levels to target may prevent or delay diabetic retinopathy.

Type 2 diabetes patients are also at great risk of neuropathy; one large cohort indicated 59% of patients with a form of neuropathy. Regular examination of the skin and bone are required to detect foot ulcers and for the assessment of neuropathy and microvasculature. Painful polyneuropathy

is difficult to treat, with a number of pharmacological agents recommended for use. Adequate counselling may prevent the development of foot ulceration.

In conclusion, Prof Mollentze recom-mended that an annual examination include assessment of, among others:

HbA• 1c levelserum lipid profile• blood pressure•

weight, body mass index and waist • circumferencethe feet• microalbumin level• serum creatinine level.•

G Hardy

Source: Mollentze WF. What the primary healthcare worker needs to know about the management of type 2 diabetes. S Afr Fam Pract 2012; 54(2): S20–S22.

Drug TrendsORIGIN trial shows safety and efficacy of insulin glargine: no adverse cardiovascular outcomes after a 6.2-year follow up of early insulin use

The ORIGIN trial, a large trial in patients with high cardiovascular risk and dysglycaemia,

using an intervention of initial basal insulin (glargine) in impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or early-stage type 2 diabetes, has shown no cardiovascular benefits or adverse cardiovascular outcomes. However a reduction of progression to diabetes did occur in patients with IFG or IGT who were treated with insulin, actively targeting normoglycaemia of < 5.3 mmol/l, compared to those treated with standard care and mainly oral agents.1

Importantly, the long-term use of insulin glargine was shown to be efficacious in lowering glucose levels safely over the six-year period. There was no increase in the incidence of cancer or cardiovascular events in the more than 5 000 patients treated over this extended period.

The trial showed that better glucose control was achieved using a daily injection of basal insulin (with or without oral agents) in high-risk patients who self-titrated their insulin dosage to a fasting plasma glucose (FPG) level of < 5.3 mmol/l compared to those offered standard care. However, in both groups, a mean HbA1c level of ≤ 6.5%

was achieved over the duration of the study. In those in the glargine arm of the study,

the median insulin dose rose from 0.31 U/kg by year one to 0.40 U/kg by year six. Importantly, 83.6% (5 230 patients) were adherent to their insulin glargine therapy at year six; 19% did however permanently discontinue their insulin therapy. In the standard-care group, 11% of patients were using insulin at the end of the study.

With regard to the co-primary composite cardiovascular outcomes of death from cardiovascular causes, non-fatal myocardial infarction (MI) or stroke, and secondly, the composite of these events plus either a revascularisation procedure or hospitalisation for heart failure, there was no significant difference between the two groups.

Compared to standard care, insulin glargine, titrating towards normoglycaemia, had a neutral outcome with regard to cardiovascular outcomes. There was also no significant difference with regard to micro-vascular events. Of particular importance was that there was no significant difference in the incidence of any cancer, death from cancer or cancer at specific sites (Table 1).

The incidence of a first episode of severe

hypoglycaemia was a modest 1.00 per 100 person-years in the insulin glargine-treated group, and 0.31 per 100 person-years in the standard-care group (p < 0.001). Participants in the insulin glargine group gained a median of 1.6 kg whereas the standard-care group lost a median of 0.5 kg.

Reduction in progression to diabetesIn the sub-population of 1 456 participants without diabetes, but with IFG/IGT and other cardiovascular risks at randomisation, 737 were assigned to insulin glargine and 719 to standard care. Those assigned to insulin glargine were 28% less likely to develop diabetes, as defined by oral glucose tolerance tests performed on 65% of this cohort.

Dr Landi Lombard, specialist physician, diabetologist, Kuilsriver, Cape Town and editor of the South African Journal of Diabetes and Vascular Disease attended the American Diabetes Association meeting and commentedThe ORIGIN trial had two main arms. The first assessed the use of 1 g of omega-3 fatty acid supplementation in this cardio-vascular high-risk group, versus placebo. This was based on many previous trials showing potential benefit, and the GISSI trial showing statistically significant benefit of this therapy in post-myocardial infarction patients, with a 15% reduction in all-cause mortality.

A recent meta-analysis supported these results and showed a 9% cardiovascular mortality benefit. Unfortunately this was not supported in the ORIGIN trial, which showed

Table 1. Cancer incidence in the ORIGIN trial.

Insulin glargine Standard care

Cancer by site Hazard ratio n (%) n (%)

Breast 1.01 28 (0.4) 28 (0.4)

Lung 1.21 80 (1.3) 66 (1.1)

Colon 1.09 76 (1.2) 70 (1.1)

Prostate 0.94 88 (2.1) 89 (2.2)

Melanoma 0.88 15 (0.2) 17 (0.3)

Other 0.95 233 (3.7) 245 (3.9)

Amended from supplementary data, reference 1.

Insu l in G larg ine

I n s u l i n G l u l i s i n e

Powerful PartnersIn glycaemic control.

Insu l in G larg ine24-hour basal coverage. Day af ter day.

I n s u l i n G l u l i s i n eT h e s p e e d y o u n e e d . W h e n y o u n e e d i t .

SCHEDULING STATUS: S3 PROPRIETARY NAME (and dosage form): LANTUS® (solution for injection). COMPOSITION: Each ml of the solution for injection contains 3.64 mg of the active ingredient insulin glargine, corresponding to 100 U human insulin. REGISTRATION NUMBER: 34/21.1/0248. NAME AND BUSINESS ADDRESS OF THE APPLICANT: sanofi-aventis south africa (pty) ltd, 2 Bond Street, Midrand, 1685.

Reg. No. 1996/10381/07.

SCHEDULING STATUS: S3 PROPRIETARY NAME AND DOSAGE FORM: APIDRATM solution for injection. COMPOSITION: 1 ml contains 3,5 mg insulin glulisine, corresponding to 100 U human insulin. REGISTRATION NUMBER:

A38/21.1/0506 NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: sanofi-aventis south africa (pty) ltd, 2 Bond Street, Midrand, 1685. Reg. No. 1996/10381/07.

APPLICANT: sanofi-aventis south africa (pty) ltd, 2 Bond Street, Midrand, 1685. Reg. No. 1996/10381/07. ZA.GLA.09.04.13

EURO

RSC

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96/E


no benefit. The absence of benefit was found in both primary and secondary outcomes and also in all the subgroup analyses. This is obviously very disappointing, with only a very small reduction shown in triglyceride levels. There is no positive take-home message here and I cannot recommend the use of omega-3 fatty acids in this study population.

The second arm of the study assessed insulin glargine versus standard care for IFG, IGT or early diabetes in high-risk cardiovascular patients. This arm of the study was unfortunately also negative. No cardiovascular benefits could be shown for the primary or secondary endpoints despite a 3% per year event rate.

These results were very disappointing and suggest no cardiovascular benefits from early insulin initiation in high-risk patients with early diabetes. This strategy can therefore also not be recommended for cardiovascular protection, but should be used on merit for diabetes control. However, it is important to note is that the early use of insulin glargine targeting normoglycaemia of < 5.3 mmol/l had no adverse effect with regard to cardiovascular outcomes.

There were however two positive outcomes/conclusions from this part of the trial. The first was the safety of glargine insulin, which this study has now proven beyond any doubt to be a safe insulin. Glargine now has more safety data than most other medicines and much more than

any other insulin (10 years), with no sign at all to suggest increase in cancer risk. The risk of hypoglycaemia in the study was also fairly low and weight gain was only 1.6 kg over the 6.2 years of average follow up.

The second positive outcome was that the glargine group slowed progression from dysglycaemia to diabetes in the subgroup with IGT and IFG (n = 1 456), with a 28% risk reduction despite a 1.6-kg weight gain. The question remains if this would be a cost-effective intervention to consider in these patients, and further study will be required.

As in the UKPDS study, an 8.5-year extension of follow up proved to be invaluable with regard to microvascular outcomes. In that light, a further two years of follow up has already been announced, which might generate further interesting data. Currently, I don’t think this strategy can be used in general practice as routine management.

Dr Larry Distiller, Centre for Diabetes Education, Houghton, JohannesburgIt is probably not surprising that there was no demonstrable reduction in cardiovascular outcomes in patients on glargine insulin compared to the standard-care group. Firstly, although these were ostensibly ‘new-onset’ diabetes patients, all were at high risk, with documented cardiovascular disease at the time of selection, and, as

with the ADVANCE, ACCORD and VADT trials, one would not expect a reversal of cardiovascular event rates in just seven years in patients with documented vascular disease.

Secondly, the difference in HbA1c levels achieved between the standard-care and glargine group was just 0.3%, with both groups achieving mean HbA1c levels ≤ 6.5%. Unless one was to anticipate a specific protective effect of insulin itself, one would not anticipate a different outcome between the two groups based on differences in glycaemic control alone.

The positive aspects of this study are that tight glycaemic targets are achievable with-out increasing cardiovascular mortality, even in high-risk patients, and that glargine insulin can be used safely as a therapeutic option in both high-risk and recently diagnosed diabetes. The weight gain documented and the amount of hypoglycaemia experienced is acceptable and not excessive.

It is unlikely that the outcomes reported in this trial will have any significant impact on the current approaches to the management of diabetes in the clinical setting.

Dr Landi Lombard, Dr Larry Distiller, Julia Aalbers

1. The ORIGIN trial investigators. Basal insulin and CV and other outcomes in dysglycemia. N Eng J Med. Epub 11/6/2012. DOI: 10.1056/NEJMoa1203858.

Lantus®: our commitment to safetyIntroductionAs an ethical pharmaceutical company with a long-standing commitment to diabetes, the safety and wellbeing of people with diabe-tes is of paramount importance to Sanofi. Lantus® (insulin glargine [rDNA] injection) is already supported by a wealth of available data1 resulting from more than 80,000 patients enrolled in clinical trials and over 47 million patient-years2 of treatment exposure to insulin glargine, which showed no increased cancer risk with Lantus®.1

Nevertheless, the company is committed to contributing to the generation of knowledge on the safety of insulin, including insulin glargine. Further to the debate on the poten-tial relationship between insulin and cancer since 2009, and the safety of insulin glargine in this context, we are taking an active stance

to provide accurate and meaningful scientific information.

To this effect, Sanofi is working closely with prominent scientists, health authorities (EU, U.S. and others), scientific associations (including the American Diabetes Association) and the American Cancer Society.At the American Diabetes Association 72nd Scientific Sessions, we released new results of a large-scale epidemiological program to evaluate cancer risk in diabetes and generate comprehensive insulin glargine exposure data from large databases.

Sponsored by Sanofi and conducted by inde-pendent researchers in the northern European countries, at Kaiser Permanente in Northern and Southern California, and at the University of North Carolina in the United States, it is the largest obser-vational program designed for this purpose to date.

Lantus® and cancer risk allegationsThe role of (any) insulin and its potential relation to cancer has been a matter of scien-tific debate, where some studies published since 2009 have shown an association and others have not.

In June 2009, Diabetologia published four papers suggesting a possible relation-ship between insulin analogs, such as insulin glargine, and an increased risk of cancer. The publications generated debate and concern over the safety of such insulin treatments.

Limitations of the Diabetologia papersIn January 2011, the U.S. Food and Drug Administration (FDA) announced that it had reviewed the four published papers and deter-mined that the evidence presented was incon-clusive.3 Methodological limitations included:

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SA JOURNAL OF DIABETES & VASCULAR DISEASE DRUG TRENDS

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Insufficient information on patients’ prior • and subsequent use of insulin productsInadequate control of confounding risk • factors for cancer (e.g. smoking, family history of cancer and obesity)Insufficient duration of patient follow-up•

In light of the shortcomings in study design, the FDA did not conclude that insulin glargine increased the risk of cancer and the review determined that prescription of insulin glargine by healthcare professionals and its use by people with diabetes should remain unchanged.3

Drug regulatory agencies in the U.S. (FDA), the EU (EMA) and others have conducted a review of insulin glargine data and have not required changes in the package insert regard-ing its use.3,4 These agencies have recom-mended that patients maintain their treatment as prescribed. The ADA/ACS Consensus state-ment on this matter concludes that further research is needed to clarify these issues.5

The Sanofi Epidemiological ProgramRationaleIn September 2009, the company announced it was collaborating with independent experts on an epidemiological program aimed at generat-ing methodologically-robust information on a potential association between cancer risk and insulin treatment options.

The epidemiological program comprises three major studies designed to overcome the methodological limitations of the Diabetologia papers and to provide further evidence about the safety of insulin glargine with respect to oncol-ogy outcomes.

The three studiesNorthern European (Prescription) database • studyU.S. database study (Northern and Southern • California Kaiser-Permanente Diabetes Registries)International Study of Insulin and Cancer • (ISICA)

The studies have been designed independ-ently of the company by the lead investigators and endorsed by the EMA and FDA. They use state-of-the-art biostatistical methodology with protocols that have been discussed with a senior-level Biostatistics Advisory Group and European regulators.

ResultsAt the American Diabetes Association’s (ADA) 72nd Scientific Sessions, Sanofi announced results from the U.S. and Northern European observational database studies providing further evidence that there was no increased risk of cancer in people with diabetes treated with insulin glargine, compared to those treated with other insulins.

These findings reinforce the established safety profile of insulin glargine, complement-ing the existing wealth of data already availa-ble. Endorsed by the EMA and FDA, the epide-

miological program is the largest observational program designed for this purpose to date.

Northern European database studyThe Northern European Study, conducted in Denmark, Finland, Norway, Scotland and Sweden is the largest study of its kind compris-ing 447,821 people with diabetes using insulin, over 1.5 million person-years of observation.

The average follow-up time is longer than any other follow-up study, at 3.1 years for those on insulin glargine and 3.5 years for other insulins. This study looked at the risk for all cancers, as well as individually for breast, lung, pancreas, colorectal and prostate cancers.

The study was led by Peter Boyle, President of the International Prevention Research Institute based in Lyon, France.

In answering the primary hypothesis, among all users of insulin, and similarly among users of human insulin, this observational study found:

no evidence of an increased risk of breast • cancer in women, prostate cancer in men and colorectal cancer in men and womenno evidence of an increased risk in users of • insulin glargine vs. other insulins relative to the pre-specified secondary hypothesis (risk of all forms of cancer combined) and the exploratory hypothesis (risk of lung or pancreatic cancer)in conclusion, the study showed no increased • risk for cancer in association with the use of insulin glargine compared to users of other insulins.

The Committee for Medicinal Products for Human Use (CHMP) in Europe expressed that the Northern European study results add impor-tant knowledge for understanding the safety of insulin glargine.

U.S. study (Kaiser-Permanente Collaboration)The main analyses of this U.S. database study (using the Northern and Southern California Kaiser Permanente diabetes registries included 115,000 patients with median duration of 1.2 years for glargine use and 1.4 years for neutral protamine Hagedorn (NPH) among all insulin users (insulin glargine and NPH insulin). They examined cancer risk in people treated with each of these insulins as well as those who had switched from one to the other.

Results from the U.S. database study, led by John Buse, former President of the ADA, and Director of the Diabetes Care Center at the University of North Carolina, were also presented at ADA 2012:The main analyses among all insulin users (insulin glargine and NPH insulin) showed:

no association between use of insulin • glargine and increased risk of breast cancer, prostate cancer or colorectal cancer (prima-ry endpoints)no association between insulin glargine use • and increased risk of all cancers combined (secondary endpoints)In the sub-analysis of NPH insulin users • switching to insulin glargine:

no association with an increased risk of • breast, prostate, colorectal or all cancers combinedAmong new users of insulin:• no association between insulin glargine use • – or duration of insulin glargine use – and risks for prostate, colorectal or all cancers combined.

In a sub-analysis using one specific methodol-ogy (counting of dose), there was a suggestion of a very modest increase of breast cancer in patients with two or more years of insu-lin glargine use. When another methodology was adopted (counting of prescriptions), no such suggestion existed. Principal Investigator Laurel Habel, PhD, Research Scientist at the Kaiser Permanente Northern California Division of Research, noted that results of their study should be viewed cautiously, given the relatively short duration of glargine use and the large number of associations examined.

Additionally, the U.S. database study was complemented by findings from researchers at the University of North Carolina, using the healthcare database MedAssurant (43,306 patients on glargine and 9,147 on NPH; mean duration of treatment: 1.2 years for glargine group and 1.1 years for NPH group). There was no evidence of an increased risk for cancer, and specifically for breast cancer.

As with the results of the Northern European Study and data from the U.S. Kaiser Permanente, the MedAssurant study showed no association between use of insulin glargine and increased risk of the cancers evaluated among all insulin users tested.

International Study of Insulin and CancerAdditional results are expected from another observational study, the International Study of Insulin and Cancer (ISICA), led by Lucien Abenhaim, Professor of Public Health at the University of Paris and former Director General for Health in France, which will be completed in 2012.

References1. Home P, Lagarenne P. Combined randomised controlled

trial experience of malignancies in studies using insulin glargine. Diabetologia 2009: 52(9): 2499–2506.

2. Safety Monitoring Report, April 2012.3. US Food and Drug Administration. FDA drug safety

communication: update to ongoing safety review of Lantus® (insulin glargine) and possible risk of cancer. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm239376.htm. Date accessed: June 2012.

4. European Medicines Agency 2009. European Medicines Agency update on safety of insulin glargine – update. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2009/11/news_detail_000066.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac058004d5c1. Date accessed: June 2012.

5. Giovannucci E et al. Diabetes and Cancer. A consensus report. Diabetes Care 2010: 33(7): 1674–1685

Press release from Sanofi. Released at ADA 72nd congress, Philadelphia, USA, 2012

SA JOURNAL OF DIABETES & VASCULAR DISEASE DRUG TRENDS


Managing neuropathic pain: first expert recommendation for South Africa places emphasis on stepwise pharmacological intervention

Neuropathic pain, initiated or caused by a primary lesion or disease in the

peripheral or central nervous system, is best treated by first defining the aetiology, then treating the primary cause such as diabetes or rheumatoid arthritis, and thirdly, initiating appropriate and adequate doses of pain-relieving medication. ‘Frequently, patients are referred to us at the Pain Clinic with appropriate pain-relieving therapy, but at very timid doses’, Dr Milton Raff, Christiaan Barnard Memorial Hospital said at the recent FCPSA Congress.

In his presentation, Dr Raff dealt with the basics of the physiology of pain, stressing the transmission mechanism of pre-synaptic neurons releasing neurotransmitters, reaching the receptor on the post-synaptic neuron in onward transmission to the spinal cord, cortex and the limbic brain, which integrates pain awareness with subjective factors such as fear, anxiety and sleep disturbance. ‘At each physiological level, we have agents to target the pain mechanism (Table 2). We must appreciate that one aetiology does not cause one symptom but causes a cluster of symptoms that are shared with other aetiologies, requiring more than one therapeutic approach’, Dr Raff noted.

With regard to neuropathic pain, there are four main drug classes that can be used: carbamazepine as a sodium channel blocker plus anti-depressants; the alpha-2 delta-ligands (pregabalin and gabapentin); SNRIs; and opioids. ‘The difficulty is that there are no predictors to guide choice and no-head-to-head studies to compare agents’, Dr Raff pointed out. This has led to the development of a stepwise pharmacological approach of using agents, first developed by Dickenson,1 and latterly followed by international agencies such as the European Federation of Neuroscience guidelines.2

Recent South African guidelines have been published,3 with input from an expert panel consisting of specialists from the fields of psychiatry, neurology, neurosurgery, anaesthesiology, family medicine and basic science (Table 1). The expert panel makes the following recommendations:

First-line therapy is the alpha-2 delta-• ligands (pregabalin or gabapentin), TCAs (tricyclic antidepressants) or the SNRIs (duloxetine and venlafaxine).

Table 1. Summary of therapeutic agents for peripheral and diabetic neuropathy in South Africa

Contraindications/precautions/drug interactions Other benefits

α2 δ-ligands

Pregabalin No significant drug interactions Linear pharmacokinetics Dose reduction required in renal insufficiency

Improvement of sleep disturbance Anxiolytic

Gabapentin Dosage reduction required in renal insufficiency No clinically significant drug interactions

Improvement of sleep disturbance

SNRIs

Duloxetine Contraindicated in severe hepatic impairment, end-stage renal disease, alcohol abuse, concomitant use of tramadol and mAOIs Low initial doses for mild to moderate hepatic and renal impairment Caution required in patients with history of mania, seizures, acute narrow-angle glaucoma Glucose monitoring required as worsening glycaemic control seen in diabetic patients Drug interactions with tramadol, TCAs, SSRIs and SNRI. Inhibition of metabolism of drugs metabolised by CYP2D6 Suicide risk (black-box warning, in line with other antidepressants)

Improvement of major depressive disorder and generalised anxiety disorder

Venlafaxine Caution required in patients with cardiac disease Risk of hypertension, hence regular blood pressure monitoring required Lower dose may be necessary in patients with renal impairment (GFR = 10–70 ml/min) or cirrhosis of the liver Use with caution in patients with history of seizures and history of mania Drug interactions with tramadol, TCAs, SSRIs and SNRIs. Inhibition of metabolism of drugs metabolised by CYP2D6 Suicide risk (black-box warning, in line with other antidepressants)

TCA: amitrip-tyline

Contraindicated with MAOI use, antihypertensives, patients with myocardial infarction/heart block, untreated narrow-angle glaucoma Use with caution in patients with glaucoma, cardiovascular disease, especially in elderly patients, hyperthyroidism, impaired liver function, epilepsy, urinary retention, prostatic hypertrophy, constipation, mania

Improvement of major depressive disorder

Tramadol High risk of addiction and abuse, psychomotor impairment possible Use with caution in patients with history of substance abuse, suicide risk, seizure disorder and in elderly patients because of risk of confusion Contraindicated with concomitant use of SSRI, SNRI, TCA

Rapid onset of analgesic benefit

Strong opioids High risk of addiction and abuse, psychomotor impairment possible Use with caution in patients with history of substance abuse, suicide risk and in elderly patients because of risk of confusion Contraindicated with concomitant use of SSRI, SNRI, TCA

Rapid onset of analgesic benefit

SNRIs = serotonin–noradrenalin reuptake inhibitors; MOAIs = monoamine oxidase inhibitors; TCAs = tricyclic antidepressants; SSRIs = selective serotonin reuptake inhibitors.



Table 2. Pathophysiological targets in pain management

1. Peripheral activation (mainly prostaglandin mediated)

NSAIDS, COXibs

2. Factors affecting transmission e.g. increased sodium channels

Carbamazepine, lignocaine

3. Conduction via afferent neurons to dorsal horn (alpha-2 delta subunit)

Pregabalin, gabapentin

4. Dorsal horn receptors (NMDA receptors)

Ketamine (anaesthesia)Gabapentinoids

5. Spinal cord (COX-3 mediated and other mediators)

NSAIDS, paracetamol

6. Brain (µ, κ, δ receptors)

Opioids

7. Modulation of the feedback mechanism (sero-tonin and noradrenaline mediated)

TramadolSNRIs (selective noradrenaline reuptake inhibitors)SSRIs (selective serotonin reuptake inhibitors)

New South African guidelines for the management of neuropathic pain are available on the South African Medical Journal website: www.samj.org.za/index.php/smj/article/download/5472/4036.

Second-line therapy consists of a combi-• nation of these drugs.Third-line therapy involves the use of • tramadol and the opioids (morphine, oxycodone, fentanyl).

‘Interestingly, our so-called proven use of tricyclic antidepressants with their known wide spectrum of side effects is based on a very small study of 79 cases’, Dr Raff said.

‘Gabapentin works, despite a host of side effects including dizziness, somnolence and peripheral oedema. Pregabalin is effective, but it is essential to use a therapeutically adequate twice-daily dose, between 75 and 150 mg bid’, Dr Raff noted.

Duloxetine at a dosage of 60 mg daily is the

recommended dose and there is more evidence for its use in painful diabetic neuropathy (PDN) than there is for venlafaxine use.

Oxycodone in controlled-release format is now available in South Africa. ‘It can however take up to four weeks to provide pain relief and patients must be prepared for this treatment delay’, he noted. ‘Tramadol has adequate but not large studies supporting its third-line use.’

The therapeutic rationale for post-herpetic neuralgia (PHN) is treatment with gabapentin, pregabalin, TCAs, and strong opioids as they have evidence of efficacy for PHN. The first-, second- and third-line therapy is therefore essentially the same for PNP and DPN.

Trigeminal neuralgia therapy options are sparse with only carbamazepine and oxcarbazepine achieving positive outcomes.

Therapy for central neuropathic pain from spinal cord injuries and stroke is a neglected field with few clinical trials. South African guidelines suggest carbamazepine, pregabalin or amitryptiline but note that there is limited supporting evidence in this category of patients.

‘Non-pharmacological treatments, if they work for the patient, should be positively regarded by the attending physician’, Dr Raff concluded.

J Aalbers

Dickenson AH, 1. et al. Pharmacological treatment of peripheral neuropathic pain conditions based on shared commonalities despite multiple aetiologies. Pain 2005; 113(3): 251–254.Ahal N, 2. et al. EFNS guidelines on the pharmacological treatment of neuropathic pain. 2010 revision. Eur J Neurol 2010; 17: 1113-e88.Chetty S, Baalbergen E, Bhigjee AI, Kamerman 3. P, Ouma J, et al. Clinical practice guidelines from management of neuropathic pain: expert panel recommendations for South Africa. S Afr Med J 2012; 102(5): 312–325.

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Uncontrolled blood sugar levels may give rise to considerable health concerns, including keto-acidosis and vascular damage

affecting the heart, kidneys, eyes and nerves. Monitoring of blood sugar throughout the day is an integral part of diabetes care, enabling the person with diabetes to make good food choices, as well as to recognise and avoid hypo- and hyperglycaemic events. Blood sugar levels also affect the balance of physical activity and the use of diabetic medication.

Those individuals taking multiple insulin injections or using an insulin pump should monitor their blood sugar levels several times a day. It is recommended that blood sugar levels are checked upon waking, before meals or large snacks and one to two hours thereafter, and also before and within minutes after physical activity. Levels may have to be checked more often when diabetes medication is being dose-adjusted or changed to another agent, when the patient is under increased stress, when there are changes in routine regarding eating or physical activity, or when the patient is ill.

Effective monitoring of blood sugar requires a reliable, accurate device that suits the patient’s needs. Cipla recently launched the Solus V2 Blood Glucose Management System, a device with many compelling features. A finger-prick blood sample is required and the rapid result (6 seconds) is more reliable due to the use of code-free testing. A 500-test memory allows for 7-, 14-, 28-, 60- and 90-day averages.

The Solus V2 has a large-screen display and the additional benefit of being fully audible (the only audible blood glucose meter in South Africa). This is an extremely helpful feature for visually impaired and blind patients with diabetes, as diabetic retinopathy affects up to 80% of those with diabetes for 10 years or longer.

The audible technology reduces the potential for error in the visually impaired and gives them the ability to independently check their blood sugar levels as needed. It also walks the user through every phase and function of the meter, explaining error messages and telling users when there is an insufficient amount of blood on the test strip, thereby avoiding false-low results.

The Solus V2 Blood Glucose Management System starter pack includes one meter, 10 lancets, 10 strips, a lancing device and the control solution. Sold separately are lancets in packs of 100 and strips in packs of 50. Helpful video tutorials are available on the Solus V2 website (www.solusmeters.co.za) and Cipla has provided the additional support of the Solus V2 helpline (0800-499-994) monitored by a registered nurse Mondays to Fridays from 08:30 to 17:00.

Helping patients to help themselvesA new audible glucose meter ideal for visually impaired and blind diabetic patients



Saxagliptin efficacy and safety in special patient groups (the elderly and those with renal impairment)

medications such as the DPP-4 inhibitors, which improve metabolic

control without increasing the risk of hypoglycaemia, are important additions to the treatment of older patients whose susceptibility to hypoglycaemia increases with age. Saxagliptin, a potent selective DPP-4 inhibitor, has been shown to be pharmacokinetically safe in patients over the age of 65 years, compared to younger healthy subjects.1

In a pooled population of older patients from five randomised, double-blind placebo trials, saxagliptin 5 mg daily lowered HbA1c levels from a baseline of 8.1% by –0.73 ± 0.16% compared to patients on other oral therapies who were not given saxagliptin.2

While this study consisted of patients mainly in the 65- to 75-year age group and without impaired renal function or significant cardiovascular disease, it is important that HbA1c and postprandial glucose levels were safely and effectively lowered in these patients without any weight gain. The incidence of reported and confirmed hypoglycaemia was very low and there were no clinically meaningful interactions with other anti-diabetic medications or agents commonly used to treat hypertension or hyperlipidaemia.

Renally impaired type 2 diabetes patientsKidney disease is common among type 2 diabetes patients, with approximately 20 to 30% of patients developing renal damage ranging from microalbuminuria to overt nephropathy and ultimately renal disease.

In a double-blind placebo-controlled phase III study with parallel groups, the efficacy and safety of saxagliptin was tested in patients with moderate, severe or end-stage renal disease (ESRD) over a period of 12 weeks, with follow up for a further 40 weeks (these results are not yet available). In the first phase, the 12-week study3 patients were randomised to saxagliptin 2.5 mg once daily or placebo on top of their normal diabetes therapy, which included oral agents and insulin.

In the patients with moderate and severe renal impairment, saxagliptin continued to lower HbA1c levels to targeted reductions. In the ESRD subgroup, saxagliptin did not lower HbA1c levels more than placebo (those treated with their standard anti-diabetic therapy), likely because HbA1c levels can be falsely low in patients with ESRD because of uraemia-induced changes in haemoglobin structure.

Saxagliptin therapy in patients in the moderate renal impairment group

(creatinine clearance rate: CrCl ≥ 30 to < 50 ml/min according to the Cockroft-Gault equation) showed HbA1c reductions of (–0.64 vs –0.55%), whereas severely impaired patients’ HbA1c levels dropped by 0.95 vs –0.50% in the placebo group. Overall, saxagliptin was well tolerated with a similar incidence of hypoglycaemia in both treatment groups (20 vs 22.4% for saxagliptin vs placebo).

While hypoglycaemia was more frequent in renally impaired patients, the majority of events were mild in intensity. Renal function was not adversely affected during the 12-week period in the saxagliptin-treated group compared to the normal-therapy (placebo) group.

This study is important as it included type 2 diabetes patients with more advanced disease and those with multiple concomitant diseases, many of whom were on insulin.

J Aalbers

Boulton DW, Goyal A, li L, 1. et al. The effects of age and gender on the single-dose pharmacokinetics and safety of saxagliptin in healthy subjects. Diabetes Care 2008; 57(Suppl 1): Abstract 164.Doucet J, Chacra A, Maheux P, Lu J, Harris S, 2. Rosenstock J. Efficacy and safety of saxagliptin in older patients with type 2 diabetes mellitus. Curr Med Res Opin 2011; 27(4): 863–869.

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

Trusted, Simple, Safe

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

sajdvd volume 9, issue 3

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faculty of medicine

centre of diabetes

diabetes supplements

internal medicine

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university of natal

university of yaounde

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