SAJDVD Volume 11, Issue 3

SAJDVD

The electronic version of the journal is available at www.diabetesjournal.co.za

The South African Journal of Diabetes & Vascular Disease

September 2014

Volume 11 Number 3

Featured in this issue: Incretins harmful to the pancreas?

Systemic medication and diabetic retinopathy Role of physiotherapy in managing diabetes Paediatric diabetes in adolescents Medicinal plants, renal function and blood pressure The ADVANCE cardiovascular risk model Electrocardiographic abnormalities in subSaharan African diabetics

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Reviews

Ethics Focus

Achieving Best Practice

Psychological considerations in managing diabetes

Diabetes Educator’s Focus

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4

ISSN 1811-6515

THE SOUTH AFRICAN JOURNAL OF HYPE

RINSULINAEMIA

Diabetes & vascular disease VOLUME 11 NUMBER 3 • SEPTEMBER 2014 www.diabetesjournal.co.za

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

CONTENTS

Editorial

99

The role of allied health practitioners in diabetes care and more FA Mahomed

Reviews

100

Incretins: harmful to the pancreas or not?

N Ramsunder

102

The effects of systemic medication on diabetic retinopathy C-H Kruse

104

An overview of the role of physiotherapy in managing diabetes and diabetes-associated conditions H Shanahan

108

Paediatric diabetes with a focus on the adolescent B Dhada, D Blackbeard, G Adams

111

A review of the literature on multidisciplinary interventions in cardiac rehabilitation M Rabilal

115

The effects of medicinal plants on renal function and blood pressure in diabetes mellitus CT Musabayane

121

The ADVANCE cardiovascular risk model and current strategies for cardiovascular disease risk evaluation in people with diabetes AP Kengne

Research Article

126

Prevalence and determinants of electrocardiographic abnormalities in sub-Saharan African individuals with type 2 diabetes A Dzudie, S-P Choukem, AK Adam, AP Kengne, P Gouking, M Dehayem, F Kamdem, MS Doualla, HA Joko, MEE Lobe, YM Mbouende, H Luma, JC Mbanya, S Kingue

Diabetes Peronality

131

Making a difference, one patient at a time P Wagenaar

Patient Information Leaflet

133

Psychological considerations in the management of diabetes O Brown

Production Editor SHAUNA GERMISHUIZEN TEL: 021 785 7178 FAX: 086 628 1197 e-mail: shauna@clinicscardive.com Financial & Production Co-ordinator ELSABÉ BURMEISTER TEL: 021 976 8129 CELL: 082 775 6808 FAX: 086 664 4202 e-mail: elsabe@clinicscardive.com Content Manager MICHAEL MEADON (Design Connection) TEL: 021 976 8129 FAX: 086 655 7149 e-mail: michael@clinicscardive.com Gauteng Contributor PETER WAGENAAR CELL: 082 413 9954 e-mail: skylark65@myconnection.co.za

The South African Journal of Diabetes and Vascular Disease is published four times a year for Clinics Cardive Publishing (Pty) Ltd and printed by Durbanville Commercial Printers/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 EDITOR PO BOX 1013 DURBANVILLE 7551 or info@clinicscardive.com TEL: 021 976 8129 FAX: 086 664 4202 INT: +27 (0)21 976-8129 To subscribe to the journal or change address, email elsabe@clinicscardive.com 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.

SA JOURNAL OF DIABETES & VASCULAR DISEASE

EDITORIAL

The role of allied health practitioners in diabetes care and more FA MAHOMED

T

his edition examines the important role of allied health practitioners in the management of diabetes and also looks at potential risks associated with medication.

Shanahan gives an excellent review of the spectrum of diabetesassociated disease covered by physiotherapy, as well as the principles of management. Areas covered range from neuropathic joints to adhesive capsulitis.

Brown reviews the psychological aspects of diabetes. These are Correspondence to: Dr FA Mahomed Principal endocrinologist, Department of Internal Medicine, Grey’s Hospital, Pietermaritzburg Tel: +27 (0) 33 897-3213 Fax: 086 6474 729 e-mail: Fazleh.Mahomed@kznhealth.gov.za S Afr J Diabetes Vasc Dis 2014; 11: 99

often overlooked in busy practices and hospitals in South Africa, but contribute greatly to quality of life, and need to be detected and managed appropriately. Important topics range from eating disorders to depression and more.

Rabilal looks at the multidisciplinary approach to cardiac rehabilitation. Cardiac complications are common in diabetes, and rehabilitation forms an important part of comprehensive management.

Dhada and colleagues provide valuable insight into their experience in running a paediatric/adolescent diabetes clinic in a resource-limited setting.

Kruse reviews the effect of systemic drugs on diabetic retinopathy.

The effect of erythropoietin, aspirin and other drugs are explained.

These are important clinical considerations.

Ramsunder looks at the debate on benefit or harm produced by incretins. New drugs on the market need to be carefully examined for potential risk. As always, clinicians should assess the risk–benefit ratio when prescribing medication.

15th ANNUAL SA HEART CONGRESS

REGISTRATION & ACCOMMODATION BOOKINGS OPEN SA Heart Congress 2014 will be held in Durban, from 16 – 19 October, with the central theme being ‘Bridging the Divide’. This is the divide that exists between current best practice – and the challenges encountered in implementing these ideals. All medical and allied professionals with an interest in cardiac health are warmly invited by the organising committee to attend.

For more information: EUROPA ORGANISATION AFRICA Tel +27 11 325 0020 Fax: +27 11 325 0028 or 0865 102 208 Email info@eoafrica.co.za

IN SOUTH AFRICA

at the SA Heart Association Congress

Bridging the Divide | 16 - 19 October 2014 International Convention Centre Durban South Africa

Website www.saheart.org/congress2014

WW00035 SAHEART ANN_1/2HA4.indd 1

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

Incretins: harmful to the pancreas or not?

Nikash Ramsunder Introduction Naturally occurring incretins are intestinal hormones that are released in response to food ingestion in order to potentiate the glucose-induced insulin response, and account for 50 to 70% of the total insulin secretion after meal ingestion. Their effects are mediated through binding with specific receptors as well as neural modulation.

GIP and GLP-1 are both rapidly degraded into their inactive metabolites by the enzyme dipeptidyl dipeptidase 4.1 Their physiological actions include: • stimulation of glucose-induced insulin secretion • regulation of metabolism in the adipocytes • promotion of β-cell proliferation • stimulation of insulin gene transcription and hence biosynthesis • suppression of glucagon secretion in the pancreatic islets • exertion of trophic effects on pancreatic β-cell mass, with β-cell proliferation and β-cell neogenesis • inhibition of gastrointestinal secretion and motility, particularly gastric emptying • enhancement of satiety • stimulate somatostatin secretion • improvement of endothelial dysfunction in patients with stable coronary artery disease.

The incretin mimetics GIP and GLP-1, and dipeptidyl peptidase 4 (DPP-4) inhibitors are a new class of antidiabetic agents first introduced in 2005 (exenatide) and 2007 (sitagliptin), respectively.

The most significant of these benefits that is not found with other antidiabetic treatments are the glucose-dependant nature of their insulinotropic effects and that they are associated with very low rates of hypoglycaemia.2 They have also shown the ability to preserve the remaining β-cells in diabetes and this at one stage provided hope that enhancing GLP-1 could potentially alter the natural progression of diabetes.3 There is no doubt that incretin-based therapies have been shown to be effective as glucose-lowering agents, as GLP-1 receptor agonists demonstrate an efficacy comparable to that of insulin treatment. This was demonstrated in the AMIGO studies where, in a comparison of exenatide and insulin glargine, the lowering of HbA1c levels did not differ between the groups during six and 12 months of treatment.2 However, there is controversy regarding the potential regenerative effects of incretin therapy on pancreatic β-cells, as shown by a study on pancreases from age-matched donors with diabetes mellitus (DM) and treated with incretins, those treated with other Correspondence to: Dr Nikash Ramsunder Department of Internal Medicine, Tygerberg Hospital, Cape Town e-mail: nikashramsunder@gmail.com S Afr J Diabetes Vasc Dis 2014; 11: 100–101

100

therapeutic agents, and non-diabetic control subjects. This study revealed an average increase in pancreatic mass of around 40% in those treated with incretins, showing a marked expansion of the exocrine and endocrine pancreas. The former was accompanied by increased proliferation and dysplasia and the latter by β-cell hyperplasia with the potential for evolution into neuroendocrine tumours.4 This has created concern as to the long-term consequences of using such therapies. Some of these concerns include the potential of these drugs to cause acute pancreatitis and to initiate histological changes to suggest chronic pancreatitis and pancreatic cancer.

Type 2 diabetes mellitus and obesity are known risk factors for acute and chronic pancreatitis and pancreatic cancer, and patients are more prone to developing these compared to the nondiabetic population. Therefore one can assume that there would be an increased incidence of pre-malignant pancreatic lesions. It is therefore important to establish whether these pre-malignant lesions undergo proliferation in response to GLP-1 mimetic therapy and whether such an effect could explain the early reporting of pancreatic cancer observed here.5,6 In animal studies performed on three different species, including mice, rats and monkeys, the GLP-1 agonist liraglutide did not induce pancreatitis macroscopically or microscopically in any of the species when dosed for up to two years and with exposure levels up to 60 times higher than in humans.7 In another study, however, low-grade chronic pancreatitis was noted in most rats treated with exenatide,6 and this is of concern since chronic pancreatitis increases the risk of pancreatic cancer. There have been reports of acute pancreatitis in humans with the use of exenetide, the first of which was in 2006.8,9 Assessment of the US Food and Drug Administration (FDA) adverse events database (AERS) in 20116 showed a six- to 10-fold increase in pancreatitis in patients treated with the DPP-4 inhibitor sitagliptin (131 events) and GLP-1 receptor agonist exenatide (971 events), respectively, in comparison to patients treated with the control drugs rosiglitazone, nateglinide, repaglinide and glipizide (43 events). The reported event rate for pancreatic cancer was 2.9 times higher for exenatide (81 events) and 2.7 times greater for sitagliptin (16 events) when compared with control therapies (13 events).10 A German adverse-events database showed a high incidence of reporting of pancreatic cancer in association with exenatide (11 cases in four years with 15 000–25 000 patients treated annually), with a mean treatment duration of about 12 months. There was no significant increase for the DPP-4 inhibitors.10 As these drugs have been around for a relatively short period of time, these findings must be reviewed with caution. This time period seems too short to induce tumour development, given the observed 10-year interval between tumour induction, growth and clinical diagnosis.9,10 It is also important to consider the limitations of the FDA AERS database, including incomplete data and reporting bias introduced by potential confounders, which influenced the choice of drug therapy, e.g. cigarette smoking, obesity and gender.11 The above analysis shows an increased reporting of pancreatic cancer in association with exenatide, compared with other

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treatments. It may suggest that the apparent increase in pancreatic cancer with GLP-1 mimetic therapy is through the mechanism of chronic inflammation and increased cell turnover.6 A cohort study that included patients without claims of prior pancreatic disease, which initiated exenatide or other antihyperglycaemic drugs between 2005 and 2007, showed that with exenatide (n = 25 719), 40 confirmed cases of acute pancreatitis were found, compared to 254 among the other antihyperglycaemic agents (n = 234 536). The conclusion reached was that exenatide was not associated with an increased risk of pancreatitis when compared with other antihyperglycaemic medications.12 Other retrospective cohort studies of a large medical and pharmacy claims database of 786 656 patients have shown that the incidence of acute pancreatitis in the non-diabetic group, the diabetic group, the exenatide group and the sitagliptin group were 1.9, 5.6, 5.7 and 5.6 cases per 1 000 patient years, respectively. The risk of acute pancreatitis was significantly higher in the combined diabetic group than in the non-diabetic group.13 The risk of acute pancreatitis was similar in the exenatide versus the diabetic control group, and the sitagliptin versus the diabetic control group. No association was found between the use of exenatide or sitagliptin and acute pancreatitis.12,13 Noel et al. also examined the risk for pancreatitis in subjects with type 2 diabetes and they reported a similar increased risk for acute pancreatitis (4.22 cases per 1 000 patient years).14 Pancreas-related events after authorisation of DPP-4 inhibitors have also raised early concerns about their possible association with pancreatitis. Events of acute pancreatitis, including fatal haemorrhagic or necrotising pancreatitis, have been reported in patients receiving sitagliptin, vildagliptin or saxagliptin. In addition, a case–control study suggests an association of sitagliptin with an increased odds ratio of hospitalisation for acute pancreatitis.15-18 These findings need to be looked at with caution in the light of data from randomised, controlled trials that did not verify an association of sitagliptin with acute pancreatitis (n = 1 event per 4 709 patient years) compared with a control group (n = 4 events per 3 942 patient years).19 The incidence of acute or chronic pancreatitis was similar however between patients receiving alogliptin and those on placebo in a randomised control trial of 18 weeks.20,21 Linagliptin was associated with an increased number of cases of pancreatitis compared to placebo. The study showed 11 cases of pancreatitis among patients treated with linagliptin in a dataset of 4 687 patients. There were 15.2 cases of pancreatitis per 10 000 patient-year exposure in patients treated with linagliptin as opposed to 3.7 cases per 1 000 patient-year exposure in patients receiving placebo.22,23 Furthermore, there were 11 reports of pancreatitis out of 5 902 patients treated with allogliptin and five out of 5 183 patients in the control group during the drug’s clinical programme.22

Conclusion There are conflicting data surrounding the latest therapies for diabetes mellitus, which include the GLP-1 mimetics and the DPP-4 antagonists, with some reports suggesting that there is a link between incretin use and pancreatic adverse events. Others suggest that there is no relationship between the two. Current evidence is insufficient to define a causative relationship between the DPP-4 inhibitors and GLP-1 agonists and pancreatic adverse events. There is a need for trials of sufficient size and duration with well-defined parameters, as well as close pharmaco vigilance to evaluate their

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effects on the durability of glycaemic control, the durability and magnitude of weight regulation, their effects on cardiovascular outcomes and long-term trials on safety.

Acknowledgement Dr F Mahomed, head of Department of Internal Medicine, Grey’s Hospital, assisted with this article.

References 1. Gautier JF, Choukem SP, Girard J. Physiology of incretins (GIP and GLP-I) and abnormalities in type 2 diabetes. Diabetes Metab 2008; 34: S65–S72.

2. Nauck AM, Vilsboll T, Gallwitz B, Garber A, Madsbad S. Incretin-based therapies, viewpoints on the way to consensus. Diabetes care 2009; 32(2): S223–S231.

3. Lamont BJ, Andrikopoulos S. Hope and fear for a new class of type 2 diabetes drugs: Is there preclinical evidence that incretin-based therapies alter pancreatic morphology? J Endocrinol 2014; 221(1): T43–T61.

4. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 2013; 62: 2595–2604.

5. Cefalu WT. A critical analysis of the clinical use of incretin-based therapies.

Diabetes Care 2013; 36: 2126–2132.

6. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler P. Pancreatitis, pancreatic and thyroid cancer with glucagon like peptide I-based therapies. Gastroenterology 2011; 141: 150–156.

7. Niels NCB, Molck AM, Lars MW, Lotte BK. The human GLP I analog liraglutide and the pancreas. Evidence for the absence of structural pancreatic changes in three species. Diabetes 2012; 61: 1243–1249.

8. Denker SP, Demarco PE. Exenatide (exendin-4)-induced pancreatitis. A case report. Diabetes Care 2006; 29(2): 471.

9. Spranger J, Stammschulte UGT. GLP-I based therapies: The dilemma of uncertainty.

J Gastroenterol 2011; 141: 20–23.

10. Vangoitsenhoven R, Mathieu C, Schueren B. GLP-I and cancer: friend or foe.

Endocrine Related Cancer 2012; 19: F77–F88.

11. Phillips LK, Prins BJ. Update on incretin hormones. A New York Acad Sci 2012: 1–20.

12. Dore DD, Bloomgren GL, Wenten M, Hoffman C, Clifford CR, Quinn SG, et al. A cohort study of acute pancreatitis in relation to exenatide use. Diabetes Obesity Metab 2011; 13(6): 559–566.

13. Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin, a retrospective observational pharmacy claims analysis. Diabetes Care 2010; 33(11): 2349–2354.

14. Olansky L. Do incretin-based therapies cause acute pancreatitis. J Diabetes Sci Technol 2010; 4(1): 228–229.

15. Girgis C, Champion B. Vildagliptin induced acute pancreatitis. Endocrine Pract 2011; 17: e48–e50.

16. Saraogi R, Mallik R, Ghosh S. Mid acute pancreatitis with vildagliptin use. Indian J Endocrinol Metab 2012; 16: S480–S482.

17. Kunjathaya P, Ramaswami P, Krishnamurthy A, Bhat N. Acute necrotizing pancreatitis associated with vildagliptin. J Oncol Pract 2013; 14: 81–84.

18. Singh S, Chang H, Richards T, Weiner J, Clark J, Segal J. Glucagon-like peptideI-based therapies and the risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. J Am Med Assoc Int Med 2013; 173: 534–539.

19. Engel S, Williams HD, Golm G, Clay R, Machotka S, Kaufman K, et al. Sitagliptin: review of preclinical and clinical data regarding the incidence of pancreatitis. Int J Clin Pract 2010; 64: 984–990.

20. Ligueros MS, Foley J, Schweizer A, Couturier A, Kothny W. An assessment of adverse effects of vildagliptin versus comparators on the liver, spleen, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of phase II and phase III clinical trials. Diabetes Obesity Metab 2010; 12: 495–509.

21. White W, Cannon C, Heller S, Nissen S, Bergenstal R, Bakris G, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. New Engl J Med 2013; 369: 1327–1335.

22. Karagiannis T, Boura P, Tsapas A. Safety of dipeptidyl peptidase 4 inhibitors: a perspective review. Ther Adv Drug Safety 2014; 5: 138–146.

23. Linagliptin assessment report. Eur Med Agency (updated 20 September 2012, Cited 5 June 2014). Available from http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_-_public_assessment_report/human/000771/ WC500115748.pdf

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The effects of systemic medication on diabetic retinopathy Carl-Heinz Kruse The incidence of diabetic retinopathy Of all the complications of diabetes mellitus, diabetic retinopathy (DR) is feared most by patients. These fears are well founded since DR is the third leading cause of irreversible blindness in the world1 and the leading cause among working-age adults.2 As a matter of fact, a diabetic patient is more likely to go blind in the next 14 years3 than die of a motor vehicle accident in his/her lifetime.4 The gold standard for the treatment of diabetic retinopathy has until recently been laser therapy. This modality is useful for halting the progress in both proliferative retinopathy as well as diabetic macular oedema. Recently the use of intravitreal steroid (Triamcinolone) and intravitreal anti-VEGF (Bevacizumab) have shown improved results and have resulted in an overall improvement of vision over laser therapy alone.

Despite these advances, some patients have relentless disease, which sometimes inexorably leads to severe visual impairment despite all treatment. The prevalence of self-rated visual impairment among US adults with diabetes was almost 25%.5 The best management for DR remains prevention and the best way to achieve this in a diabetic patient is meticulous control of blood glucose levels.2 In recent studies, it has also been found that other systemic drugs, often given for the treatment of other conditions, can have deleterious or beneficial effects on the initiation and progression of diabetic retinopathy. This article aims to give a synopsis of the most relevant of these drugs.

Drugs for glucose control Insulin It is apparent that glycaemic medication would have the greatest effect on the initiation and progression of DR. This effect is particularly pronounced at the early stages of DR where good glucose control has a stronger protective effect. Although strict glucose control is almost always beneficial for DR, under certain circumstances it can actually be harmful.

The Early Treatment Diabetes Retinopathy Study (ETDRS)6 clearly showed that improving systemic glucose control reduces the risk of progression to severe visual loss or vitrectomy at five years. Patients with HbA1C levels above 12% had a 39% greater chance of a poor outcome than those with HbA1c levels less than 8.3%.6 The exception to this rule is in patients with non-insulindependent diabetes mellitus (NIDDM), who improve their glycaemic control by changing to aggressive insulin therapy.7 This effect was

Correspondence to: Dr Carl-Heinz Kruse Department of Opthalmology, University of KwaZulu-Natal, Durban e-mail: ruraleye@gmail.com S Afr J Diabetes Vasc Dis 2014; 11: 102–103

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particularly pronounced when the HbA1c levels where dropped by more than 3%; 23% of these patients developed a progression of retinopathy of three or more levels. This effect is termed ‘early worsening’ and occurs in the first two years after initiating insulin therapy.

In most cases, this effect seems to be transient and strict glucose control eventually gives better retinopathy results, especially after the first three years.2,8 Early worsening is therefore not a reason not to aggressively control glucose levels, but close monitoring of the DR before and after initiation of insulin therapy is still warranted.

The introduction of antioxidant supplementation might attenuate this transient insulin-induced worsening of DR.9 If the DR is severe, the intensive insulin therapy should be delayed until laser panretinal photocoagulation has been completed. Rapid development of proliferative DR has been reported in isolated cases where extremely high doses of insulin were given.

Biguanides Metformin not only has cardioprotective effects independent of glucose control but also clinically inhibits inflammation-mediated angiogenesis. The magnitude of this protective effect on DR is yet to be elucidated.

Drugs for hypertension management Controlling blood pressure is in itself a good method of reducing the progression of DR.10 Keeping the blood pressure below 150/85 mmHg reduces the chances of deterioration of DR by two levels in NIDDM by 34% over a nine-year period. A further decrease of diastolic blood pressure to below 75 mmHg did not give added benefit with regard to DR progression.11 Some antihypertensive drugs however seem to have an effect on diabetic retinopathy independent of the antihypertensive effect.12 Blockage of the renin–angiotensin system slows progression of DR in insulin-dependent diabetes. Enalapril and losartan show a 65 and 70% reduction of a two-step progression of DR at five years.13 Importantly, this effect is independent of the changes in blood pressure and is therefore recommended in patients with both diabetes and hypertension.

Candesartan not only slows progression but has been associated with an overall regression of DR.14 This effect was seen in NIDDM patients with mild to moderate retinopathy.

Drugs for lipid control Lowering of serum lipid levels in diabetics with hyperlipidaemia reduces the development of hard exudates and reduces the vision loss from diabetic macular oedema.15 Once again, some of these drugs show an additional advantage on DR independent of the lipid-lowering effect.

Fenofibrate, a PPARα agonist, has been accepted in a number of countries as an effective method to modulate and reduce the progression of DR. Two large trials, the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) and ACCORD (Action to Control Cardiovascular Risk in Diabetes) studies, have

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demonstrated its benefit in DR.16 These two trials together included 21 000 participants, of whom over 10 000 received fenofibrate.

Although these trials primarily looked at cardiovascular effects, both had large retinopathy subsets.

The ACCORD study consistently showed benefit in reducing progression of DR. The FIELD study showed that 40% fewer patients taking fenofibrate had significant DR progression than the control group after five years (10.2 vs 6.5%). Additionally, 30% more patients in the control group required laser therapy than in the fenofibrate group (3.6 vs 5.2%).16

Drugs for anaemia treatment Erythropoietin is a potent ischaemia-induced angiogenic factor during retinal angiogenesis in DR.17 Patients receiving erythropoietin should have their retinopathy closely monitored, especially if in combination with anaemia and kidney disease.

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careful choice of systemic medication, especially for hypertension, hyperlipidaemia, anaemia and cardiac complications management can assist in decreasing irreversible loss of vision in diabetic patients.

References 1.

2.

3.

4.

5.

6.

Drugs for cardiac complications management Both salicylates and digoxin have the theoretical ability to be advantageous in DR. Salicylates Aspirin-like substances may be useful in early DR to slow progression. As early as 1964, the effects of large doses of salicylates on DR have been reported and recent studies show a positive effect on DR in animals. Doses of 2 to 4 mg per day in humans could delay the progression of DR. New advances in nanotechnology imply that salicylates could be formulated as an eye drop for topical use.18 One of the complications of proliferative diabetic retinopathy is that of loss of vision due to vitreous haemorrhage. Systemic aspirin has been proven not to increase this risk19 and neither does warfarin nor heparin.20 Digoxin Digoxin has been found to block hypoxia-induced expression of multiple angiogenic genes and is also a powerful inhibitor of neovascularisation of the retina and choroid layer.21 The FDA has recently begun trials on a topical application.

Anti-angiogenic drugs and steroids Both of these agents only improve DR (proliferative DR as well as macular oedema) when injected intra-ocularly. Systemic administration of both has a negligible effect and steroids can make glycaemic control difficult, and potentially worsen DR.

7.

8.

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10.

11.

12.

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14.

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18.

19.

Conclusion

20.

Although good serum glucose control and regular fundoscopy are most important for managing diabetic retinopathy, there are other strategies we can use to modify the outcome of this disease. A

21.

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Bourne RRA, et al. Causes of vision loss worldwide, 1990–2010: a systematic analysis. Lancet Glob Health 2013; 1: e339–e349.

Abbate M, Cravedi P, Iliev I, Remuzzi G, Ruggenenti P. Prevention and treatment of diabetic retinopathy: evidence from clinical trials and perspectives. Curr Diabetes Rev 2011; 7: 190–200.

Moss SE, Klein R, Klein BEK. The 14-year incidence of visual loss in a diabetic population. Ophthalmology 1998; 105: 998–1003.

Lally S. NSC Releases 2014 edn of injury facts | EHS Works. NSC Releases 2014 edn Inj Facts EHS Works 2014. <http://ehsworks1.blogspot.com/2014/03/nscreleases-2014-edition-of-injury.html> Saaddine JB, et al. Prevalence of self-rated visual impairment among adults with diabetes. Am J Public Health 1999; 89: 1200–1205.

Davis, MD, et al. Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18. Invest Ophthalmol Vis Sci 1998; 39: 233–252.

Henricsson M, Janzon L, Groop L. Progression of Retinopathy after change of treatment from oral antihyperglycemic agents to insulin in patients with NIDDM. Diabetes Care 1995; 18: 1571–1576.

Diabetes Control and Complications Trial Research Group. Progression of Retinopathy with Intensive versus Conventional Treatment in the Diabetes Control and Complications Trial. Ophthalmology 1995; 102: 647–661.

Wu H, et al. Supplementation with antioxidants attenuates transient worsening of retinopathy in diabetes caused by acute intensive insulin therapy. Graefes Arch Clin Exp Ophthalmol 2012; 250: 1453–1458.

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 1998; 317: 703–713.

Estacio Ro, Jeffero BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000; 23(Suppl 2): B54–64.

Teuscher A, Schnell H, Wilson PW. Incidence of diabetic retinopathy and relationship to baseline plasma glucose and blood pressure. Diabetes Care 1988; 11: 246–251.

Mauer M, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 2009; 361: 40–51.

Sjølie AK, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial.

Lancet 2008; 372: 1385–1393.

Chew EY, Klein ML, Ferris FL, III, et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy: Early Treatment Diabetic Retinopathy Study (ETDRS) report 22. Arch Ophthalmol 1996; 114: 1079–1084.

Wong TY, Simó R, Mitchell P. Fenofibrate – a potential systemic treatment for diabetic retinopathy? Am J Ophthalmol 2012; 154: 6–12.

Watanabe D, et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med 2005; 353, 782–792 (2005).

Das S, Bellare JR, Banerjee R. Protein based nanoparticles as platforms for aspirin delivery for ophthalmologic applications. Colloids Surf B Biointerfaces 2012; 93: 161–168.

Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin treatment on diabetic retionopathy: ETDRS Report number 8. Ophthalmology 1991; 98: 757–765.

Silva PS, Cavallerano JD, Sun JK, Aiello LM, Aiello LP. Effect of systemic medications on onset and progression of diabetic retinopathy. Nat Rev Endocrinol 2010; 6: 494–508.

Yoshida T, et al. Digoxin inhibits retinal ischemia-induced HIF-1α expression and ocular neovascularization. FASEB J 2010; 24: 1759–1767.

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An overview of the role of physiotherapy in managing diabetes and diabetes-associated conditions Heidi Shanahan

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lthough physiotherapists usually encounter diabetes as a secondary condition in patients during the evaluation and treatment of movement, functional and musculoskeletal disorders, physiotherapy is both a curative and preventative discipline that employs a holistic approach to healthcare.

Physiotherapists in South Africa can utilise their knowledge of therapeutic exercise and preventative care, so contributing to addressing the challenges of non-communicable disease and the increasing burden this is placing on healthcare resources.1 Involvement in primary healthcare embraces health promotion, which encourages the patient to share responsibility for optimal health outcomes and adopt beneficial behavioural changes and a healthy lifestyle, and to better self-manage his/her condition.

Physiotherapists may encounter patients with impaired glucose tolerance or insulin resistance (pre-diabetes), early diabetes with no or minimal vascular changes, and more advanced disease with several vascular complications, as well as complications that include involvement of the musculoskeletal system. Some of these musculoskeletal conditions are commonly seen by physiotherapists, who may not be aware of the impact of diabetes on the condition.

Micro- and macrovascular complications affect several organs including the muscle, skin, heart, brain and kidneys.

Even though conditions such as diabetic neuropathy, retinopathy, nephropathy and cardiovascular and peripheral vascular diseases may not be the reason for the physiotherapy intervention, it is important for the physiotherapist to be aware of the underlying vascular deficits when providing treatment for musculoskeletal and movement disorders. In addition, physiotherapists can play an important role in the care of people with diabetes because interventions such as exercise prescription and promoting increased physical activity can assist in alleviating symptoms, slow metabolic progression to overt type 2 diabetes and reduce morbidity and mortality associated with these complications.2

Musculoskeletal manifestations of diabetes Assessment and management of the patient should include questions regarding the presence of diabetes and glycaemic control, and relevant patient education and exercise prescription, as well as referral for review to other disciplines (e.g. dietitian, podiatrist) if necessary.

Adhesive capsulitis This is also known as frozen shoulder, and has been reported as having greater incidence among patients with insulin-dependent diabetes, Correspondence to: Heidi Shanahan Physiotherapy Department, Grey’s Hospital, Pietermaritzburg e-mail: heidi.shanahan@kznhealth.gov.za S Afr J Diabetes Vasc Dis 2014; 11: 104–107

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with increased frequency of bilateral shoulder involvement.3,4 The condition is characterised by three phases: painful (pain is dominant), adhesive (stiffness dominates), and resolution, which may take two to three years to complete. Adhesive capsulitis is considered to be a self-limiting condition, but many patients never regain normal shoulder mobility.

Physiotherapy treatment of adhesive capsulitis aims to relieve pain, maintain or improve active and passive range of motion (ROM) and restore function. The modalities include exercise, electrotherapy, mobilisation techniques and hydrotherapy.

Carette et al.5 concluded that a single intra-articular injection of corticosteroid administered under fluoroscopy combined with a simple home exercise programme was effective in improving shoulder pain and disability in patients with adhesive capsulitis.

Adding supervised physiotherapy provided faster improvement in shoulder range of motion. When used alone, supervised physiotherapy was of limited efficacy.

Patients with greater disability levels, more co-morbidities, high fear and anxiety levels, lower educational levels, and those who have less social support may benefit more from formal supervised physiotherapy.5,6 Patient education about the progression of restricted motion and extended time to recovery is an important aspect of treatment.

Carpal tunnel syndrome The symptoms of parasthesia over the median nerve’s cutaneous distribution may be caused by compression of the median nerve in the carpal tunnel, by diabetic neuropathy, or a combination of both.3 About 5–8% of patients with carpel tunnel syndrome have diabetes, and it is more common in women than men.

Physiotherapy treatment of carpal tunnel syndrome with ultrasound can provide satisfying short- to medium-term effects in patients with mild to moderate idiopathic carpal tunnel syndrome.7 Digital flexor tendon-mobilising techniques have been shown to be helpful in the management of pre- and postoperative carpal tunnel patients.8 In addition, physiotherapists and occupational therapists can offer advice on task modification and ergonomics, which will often control mild or moderate symptoms of carpal tunnel syndrome.

The pressure in the carpal tunnel is lowest in neutral wrist flexion extension range, with the pressure rising significantly as the wrist is moved into flexion or extension. Splints that hold the wrist in the neutral position are often helpful in controlling symptoms of mild to moderate severity.8 Depuytren’s contracture This is palmar or digital thickening, tethering or contracture of the hands. In patients with diabetes, the middle and ring finger are more commonly affected, compared with the fifth finger in patients without diabetes. Physiotherapy intervention comprises a hand therapy programme with the aim of optimising ROM,

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improving grip strength and maintaining or improving function.

Occupational therapy intervention may also include splinting to assist with maintenance of ROM. In diabetics, the contractures are usually mild and rarely require surgery.3 Flexor tenosynovitis This has a higher incidence in diabetic patients and people with impaired glucose tolerance. A corticosteroid injection into the affected tendon sheath is often curative.3 Ultrasound over the affected tendon may help to ease the symptoms.

Diffuse idiopathic skeletal hyperostosis (DISH) This is also known as ankylosing hyperostosis and is characterised by new bone formation, particularly in the thoracolumbar spine.

It occurs with greater frequency in the diabetic population than in non-diabetics, and has a higher prevalence in type 1 compared with type 2 diabetes. DISH is often asymptomatic and diagnosed as an incidental radiographic finding. Physiotherapy treatment would be symptomatic and include electrotherapy and exercise programmes.3 Neuropathic (Charcot’s) joints Limited joint mobility (diabetic cheiroarthropathy) and diabetic amyotrophy are seen more often in type 1 diabetics. Charcot’s joints occur as a result of diabetic peripheral neuropathy. The weightbearing joints are most commonly affected. The use of walking aids and orthotics can reduce impact on the affected joints, assist with reduction of pain when walking and improve mobility.

Diabetic cheiroarthropathy is characterised by thick, tight skin mainly on the dorsum of the hand, and flexion deformities of the metacarpophalangeal and interphalangeal joints. In the early stages, slight pain and parasthesias develop, with pain increasing slowly.

3,9 Physiotherapy (and/or occupational therapy) intervention would comprise a hand therapy programme with the aim of optimising ROM, improving grip strength and maintaining or improving function, as well as instruction on skin care.

Diabetic amyotrophy is characterised by muscle weakness and wasting, and proximal lower limb muscle pain. The shoulder girdle is less commonly affected. Most cases improve gradually with stabilised glycaemic control.3

Effects of micro- and macrovascular complications Diabetic peripheral neuropathy (DPN) This is associated with both vascular and non-vascular mechanisms of diabetes. Altered lower limb sensation and pain may be encountered in the evaluation and treatment of balance and movement disorders. When associated with impaired vascular function, peripheral neuropathy can contribute to the development of lower limb ulceration.2 Transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS) and acupuncture have all been proposed as modalities that may relieve the pain and discomfort associated with DPN. 10-13 Spinal cord involvement This may occur at a subclinical stage of DPN, which suggests that the metabolic insult of diabetes has a generalised effect on the nervous system.14 Spinal cord involvement may be a reason for poor responses to treatment modalities for pain associated with DPN.

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Cardiac autonomic neuropathy This can include clinical abnormalities such as resting tachycardia, exercise intolerance and slow heart rate recovery after exercise.2 The patient’s perceived exertion should be used as a measure of effort for exercise prescription, rather than relying on heart rate responses.

Diabetic retinopathy (DR) DR is a leading cause of visual disability and blindness in people with diabetes. The most significant factor in the development and progression of DR appears to be hyperglycaemia.2 Vision loss has a psychological impact as well as negatively impacting on diabetes self-management skills. An intensive multidisciplinary rehabilitation programme offering exercise training, instruction in diabetes selfmanagement techniques for the visually impaired, and group support early in the course of vision loss may be of clinical benefit.15 Orientation and mobility (O&M) trainers are a scarce but valuable resource for advising and training both the visually impaired patient and their caregivers.

Diabetic nephropathy This typically first manifests as microalbuminaria, which progresses to renal failure and end-stage renal disease. Physiotherapy renal rehabilitation programmes and exercise are recommended to improve patient functional performance, exercise tolerance and quality of life.16 Cardiovascular disease (CVD) CVD risk factors are common in diabetes, but diabetes appears to be an independent risk factor for CVD. Insulin resistance is also linked with increased risk for CVD. Increased physical activity and moderate to high levels of cardiorespiratory fitness is generally recommended as an intervention, which assists with reduction and control of central adiposity, dyslipidaemia, hyperglycaemia and hypertension, so benefitting cardiovascular health and reducing mortality.17,18 Cerebrovascular disease Diabetes is an independent risk factor for stroke across all ages.

In the SASPI study of stroke prevalence in rural South Africans, the risk factor associated with diabetes mellitus was 12%, after hypertension (71%) and current alcohol use (20%).19 Diabetes affects the cerebrovascular circulation by increasing the risk of intracranial and extracranial atherosclerosis.

The challenges of accessing physiotherapy and occupational therapy rehabilitation in rural areas and the lack of resources impact negatively on the level of independent function that is achieved by the stroke patient. Decreased functional abilities compounded by cognitive disabilities associated with stroke can negatively impact on diabetes self-care.

Peripheral vascular disease (PVD) PVD is characterised by occlusion of the lower limb arteries, which causes intermittent claudication and pain, especially with exercise and activity. Severe disability and functional impairment is associated with PVD and diabetes.

Exercise training in people with PVD has been shown to be beneficial to improving walking distance and time, time to claudication and pain, and quality of life. In addition, a person who has better exercise tolerance and muscle power will be more likely to achieve good functional outcomes post amputation.2

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Physiotherapists frequently treat patients with diabetes-related amputations. Rehabilitation may be challenging in the patient with poor glycaemic control as wound healing may be delayed, and vascular impairment, DN or ulceration of the intact limb affects weight bearing and functional gait. The physiotherapist must be aware of the condition of the wound and stump, as preparation of the stump for prosthesis may damage fragile skin and subcutaneous tissue. Resource limitations add to the challenges associated with rehabilitation of amputees.

There are fewer than 800 medical orthotists and prosthetists registered to practice in South Africa, of whom a minority practice in the public health sector. Combined with financial restraints, this leads to long waiting lists and delays in the provision of artificial limbs.

Considerations in the implementation of physical activity and exercise Barriers to participation in exercise are a factor in low activity levels.

Barriers to physical activity and exercise have been reported in diabetic patients attending two urban clinics in Gauteng, including both personal and environmental barriers such as health (e.g. arthritis, foot problems, breathlessness, diabetes), laziness, socioeconomic circumstances (e.g. caring for dependants), perceived adequate exercise (e.g. household chores, gardening), suitable venue, safety, understanding the benefit of exercise.20,21 The physiotherapy departments at public health institutions are well positioned to promote exercise in communities with limited resources. Establishment of a diabetes exercise group would offer the diabetic patient a safe venue, access to regular exercise and information sessions, and a supportive environment that promotes self-management. Those unable to attend supervised exercise groups can be prescribed an exercise programme that they implement unsupervised in their home setting.

Mshuqane et al. undertook a study at Bethlehem regional hospital in the Free State, which allocated diabetic patients to one of three groups, namely walking under supervision, cycling under supervision or walking unsupervised (at home). Although the study groups were small, all groups showed improvement in serum glucose levels and exercise capacity over the three-month study period.22 Patients who are unable or unwilling to take part in physical activity of adequate duration, intensity and frequency may benefit from participation in relaxation classes, which have been shown to improve perception of health and general well-being, and reduce stress and anxiety, which may have positive benefits for diabetes self-management.23

Guidelines for implementation of effective and safe exercise programmes Pre-exercise evaluation For moderate-intensity aerobic or resistance exercise, stress testing is not routinely necessary. Previously sedentary patients with multiple CVD risk factors should be assessed before an exercise programme is prescribed, and the patient’s age, activity levels and the presence of other conditions should be noted and considered when developing an exercise programme.

Objective measures such as the six-minute walk test, resting and recovery pulse rates, body mass index and the Borg scale score (perceived exertion) should be recorded during the initial assessment. These measures should be considered when structuring

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personalised programmes and rates of progression of activity.

These baseline scores may be useful to measure future progress and motivate the patient to continue with the programme.

Exercise prescription: type, duration and frequency To improve glycaemic control, assist with weight maintenance and reduce risk of CVD, the physical activity should be distributed over at least three days/week, with no more than two consecutive days without physical activity.17,18 At least 150 min/week of moderate-intensity aerobic physical activity (50–70% of maximum heart rate) and/or at least 90 min/ week of vigorous aerobic exercise (70% of maximum heart rate) should be done. Resistance exercise should be done three times a week, targeting all major muscle groups, progressing to three sets of eight to 10 repetitions at a weight that cannot be lifted more than eight to 10 times.17,18 Factors to consider during exercise prescription Concerns have been expressed about the safety of high-intensity resistance exercise in middle-aged and older people at risk of CVD. The main concern is that the acute rise in blood pressure (BP) associated with lifting a weight may provoke myocardial infarction, stroke or retinal haemorrhage.18 However, as an acute rise in BP can also be associated with aerobic exercise and activities of daily living, CVD risk should not be regarded as a contra-indication.

Until the insulin-dependent patient knows his/her usual glycaemic response to the activity, blood glucose levels should be determined before, after, and several hours after completing a session of physical activity in order to prevent hypoglycaemia.

If pre-exercise glucose levels are less than 6.6 mmol/l, additional carbohydrate can be ingested. Doses of insulin can be reduced before exercise sessions of physical activity, or both strategies can be implemented. However these strategies must be personalised and blood glucose levels monitored.17,18

Conclusion Physiotherapists aim to restore normal function or minimise dysfunction and pain and prevent recurring injuries and disabilities.

One of the core skills used by physiotherapists is exercise prescription, which benefits many aspects of health. Physiotherapists are in a position to impact on the prevention, control and management of diabetes and diabetes-associated conditions.

References 1.

Frantz JM. Physiotherapy in the management of non-communicable diseases: Facing the challenge. S Afr J Physiothery 2005; 61: 8–10.

2. Cade WT. Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther 2008; 88: 1322–1335.

3. Smith LL, Burnet SP, McNeil JD. Musculoskeletal manifestations of diabetes mellitus. Br J Sports Med 2003; 37: 30–35.

4. Pearsall AI. Adhesive capsulitis. eMedicine 2008. Accessed 20/05/2014.

5. Carette S, Moffet H, Tardif J, Bessette L, Morin F, Fre´mont P, et al. Intraarticular corticosteroids, supervised physiotherapy, or a combination of the two in the treatment of adhesive capsulitis of the shoulder. Arthritis Rheumatism 2003; 829–838.

6. Kelley MJ, McClure PW, Leggin BG. Frozen shoulder: evidence and a proposed model guiding rehabilitation. J Orthopaed Sports Phys Ther 2009; 39: 148.

7. Ebenbichler GR, Resch KL, Nicolakis P, Wiesinger GF, Uhl F, Ghanem A, Fialka V. Ultrasound treatment for treating the carpal tunnel syndrome. Br Med J 1998; 316: 731–735.

8. Burke FD, Ellis J, McKenna H, Bradley MJ. Primary care management of carpal tunnel syndrome. Postgrad Med J 2003; 79: 433–437.

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Hoffman S, Hislop M. Diabetes mellitis. In: Brukner P, Khan K (eds). Clinical Sports Medicine, 3rd edn. Australia: McGraw-Hill, 2009: 841–849.

Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies.

Diabetes Care 2004; 27: 1475–1486.

Pieber K, Herceg M. Electrotherapy for the treatment of painful diabetic peripheral neuropathy: a review. J Rehabil Med 2010; 42: 289–295.

Gersh MR, Wolf SL, Rao VR. Evaluation of transcutaneous electrical nerve stimulation for pain relief in peripheral neuropathy, a clinical documentation. Phys Ther 1980; 60: 48–52.

National Institute for Health and Care Exellence (NICE) Guidelines. Percutaneous electrical nerve stimulation for refractory neuropathic pain (IPG450). Issued March 2013.

Selvarajah D, Wilkinson ID, Emery CJ, Harris ND, Shaw PJ, Witte DR, et al. Early involvement of the spinal cord in diabetic peripheral neuropathy. Diabetes Care 2006; 29: 2664–2669.

Bernbaum M, Albert SG, Duckro, PN. Psychosocial profiles in patients with visual impairment due to diabetic retinopathy. Diabetes Care 1988; 11: 551–557.

Gray PJ. Management of patients with chronic renal failure: role of physical therapy. Phys Ther 1982; 62: 173–176.

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17. The 2012 SEMDSA guideline for the management of Type 2 diabetes. Physical activity and type 2 diabetes mellitus. J Endocrin Metab Dis S Afr 2012; 17(suppl): S18–S19.

18. A consensus statement from the American Diabetes Association. Physical activity/exercise and type 2 diabetes. Diabetes Care 2006; 29: 1433–1438.

19. Connor M, Bryer A. Stroke in South Africa. Cape Town: Medical Research Council, 2006. http://www.mrc.ac.za/chronic/cdlchapter14.pdf (accessed 6 May, 2014).

20. Van Rooijen AJ, Rheeder P, Eales CJ, Molatoli HM. Barriers to and expectations of performing physical activity in female subjects with type 2 diabetes. S Afr J Physiother 2002; 3–11.

21. Nel C, Van Rooijen AJ, van der W, Viljoen I, Steenkamp EM, Mamadi S. Physical activity levels in male and female diabetic patients at the Pretoria Academic Hospital, South Africa. S Afr J Physiother 2007; 63: 2–6.

22. Mshuqane N, Cohen D, Kalk JK. Effects of an exercise programme on noninsulin dependant diabetes mellitus. S Afr J Physiother 2004; 60: 26–30.

23. Van Rooijen AJ, Rheeder P, Eales CJ, Becker PJ. Effect of exercise versus relaxation on health-related quality of life in black females with type 2 diabetes mellitus.

S Afr J Physiother 2005; 61: 7–14.

Effects of intensive glycaemic control on ischaemic heart disease

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ow can three landmark trials of intensive versus standard glucose-lowering strategies – ADVANCE, ACCORD and VADT – raise more questions than they answer? This was the conundrum a recent post hoc analysis of the studies looked to address.

All three studies did not meet their primary objective of reducing cardiovascular events, despite achieving significantly lower HbA1c levels; in the ACCORD study, the data-monitoring committee prematurely stopped the intensive-strategy arm due to an excess rate of cardiovascular death. These results flew squarely in the face of conventional wisdom that lowering HbA1c to ‘normal’ levels would improve cardiovascular outcomes, similar to the clearly proven benefit of reducing microvascular complications. Each trial has subsequently published numerous analyses that have tried, mostly unsuccessfully, to explain why mortality, in particular, did not decrease, or in the case of ACCORD even increased, with a more intensive glycaemic strategy.

What is interesting is that across these studies, there does appear to be a consistent signal that improved glycaemic management may reduce coronary artery events. This observation was first noted over a decade ago in the UKPDS study, in which more intense glycaemic control reduced the rate of myocardial infarction (MI).

The ACCORD investigators now report a consistent reduction of about 15–20% in non-fatal MI, unstable angina and coronary revascularisation in the intensive-therapy arm. The benefit became more apparent during the longer follow-up period, suggesting a legacy effect. Interestingly, when controlling for achieved HbA1c level, the benefit was attenuated, which implies that better glycaemic control may be causal in reducing ischaemic events.

It is important to remember that this is a post hoc analysis and still cannot reconcile the higher rates of death in the intensive-strategy arm. But it raises the possibility that there may be

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strategies that can both safely lower glucose and reduce cardiovascular events. How you improve glycaemic control may be as important as the actual HbA1c target. The score of ongoing cardiovascular outcome trials of novel antihyperglycaemic agents will likely provide further insight into this clinical dilemma.

The researchers assessed 10 251 adults aged 40–79 years with established type 2 diabetes, mean HbA1c concentration of 67 mmol/ml (8.3%) and risk factors for ischaemic heart disease enrolled in the ACCORD trial. Participants were assigned to intensive or standard therapy [target HbA1c < 42 or 53–63 mmol/ml (< 6.0 or 7.0–7.9%), respectively]. They assessed fatal or non-fatal MI, coronary revascularisation, unstable angina and new angina during active treatment (mean 3.7 years) plus a further mean of 1.2 years.

Raised glucose concentration is a modifiable risk factor for ischaemic heart disease in middle-aged people with type 2 diabetes and other cardiovascular risk factors. MI was less frequent in the intensive- than in the standard-therapy group during active treatment [hazard ratio (HR) 0.80, 95% CI: 0.67–0.96; p = 0.015] and overall (HR 0.84, 95% CI: 0.72–0.97; p = 0.02).

Findings were similar for combined MI, coronary revascularisation and unstable angina (active treatment HR 0.89, 95% CI: 0.79–0.99, overall HR 0.87; 95% C: 0.79–0.96) and for coronary revascularisation alone (HR 0.84, 95% CI: 0.75–0.94) and unstable angina alone (HR 0.81, 95% CI: 0.67–0.97) during full follow up. With lowest achieved HbA1c concentrations included as a time-dependent covariate, all hazards became non-significant.

Source Lancet, early online publication, 1 August 2014, doi:10.1016/S0140-6736(14) 60611-5. http://www.diabetesincontrol.com/articles/53-/16753-effects-of-intensiveglycemic-control-on-ischemic-heart-disease.

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Paediatric diabetes with a focus on the adolescent Barnesh Dhada, David Blackbeard, Gayle Adams

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oth type 1 and type 2 diabetes mellitus in children and adolescents is increasing worldwide. While new cases are diagnosed in South Africa annually, the true incidence is not known.

The International Society for Paediatric and Adolescent Diabetes (ISPAD) in conjunction with the International Diabetes Federation (IDF) set out a comprehensive, evidence-based standard of care guideline in 2011.1 The goal of diabetes care is to achieve optimal glycaemic control in order to achieve good quality of life by preventing and treating complications. However, successful implementation of all aspects of care is complex.

In local operational research in a paediatric diabetes clinic at a tertiary level in KwaZulu-Natal, we have identified the following ‘mediating variables’ that often play a positive and/or negative role in patient care: self-efficacy of child and caregiver; family functioning for support and supervision; psychosocial interventions for the individual, family and group; a cohesive multidisciplinary team (MDT) for consistency of care; material and socio-cultural resources and support; and mental health and stress exposures for the child–caregiver dyad.

We have found that working as an MDT to tease out the complexity and use the expertise of each team member is an advantage, with the patient at the heart of the team’s efforts.2 In this situation, diabetes education for patients and all MDT members remains vital to empower all, especially the patients and their families.

The diagnosis of type 1 diabetes mellitus is based on clinical features of weight loss, polyuria, polydipsia and glycosuria. The majority of patients in our setting present for the first time with the life-threatening early complication of diabetic ketoacidosis; many having seen a doctor in the preceding weeks to months with the classic clinical features. Without a high index of suspicion and simple bedside diagnostic tests, a random blood glucose level indicating hyperglycaemia and urine dipstix for ketonuria, this relatively easy diagnosis is often missed.3 The underlying pathophysiology is a variable rate of autoimmune-based pancreatic islet beta-cell destruction, with deficient insulin production leading to hyperglycaemia. The subsequent dehydration and acidosis with ketone body formation from the oxidation of fats to meet cellular energy needs complete the clinical picture. Exogenous insulin administration and correction of the dehydration and electrolyte disturbances are essential to break this fatal cycle.

Correspondence to: Barnesh Dhada Department of Paediatrics, Grey’s Hospital, Pietermaritzburg and Department of Paediatrics and Child Health, University of KwaZulu-Natal, Durban e-mail: Barnesh.Dhada@kznhealth.gov.za David Blackbeard Department of Clinical Psychology, Grey’s Hospital, Pietermaritzburg Gayle Adams Department of Dietetics, Grey’s Hospital, Pietermaritzburg S Afr J Diabetes Vasc Dis 2014; 11: 108–110

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Type 2 diabetes mellitus, hyperglycaemia with peripheral insulin resistance is increasing, especially among adolescents. Major risk factors include a family history of type 2 diabetes, and the increasing obesity/metabolic syndrome pandemic. Clinical features of insulin resistance are obesity, acanthosis nigricans, dyslipidaemia, features of ovarian hyperandrogenism, and non-alcoholic fatty liver.

However, the distinction between type 1 and 2 diabetes is becoming more difficult, with pancreatic autoimmunity present among those with typical type 2 features, and the absence of autoimmunity and the presence of obesity in type 1 diabetes.

The concept of ‘double diabetes’4 has been coined to capture this dilemma and it has implications for patient management, complications and outcomes.

In the management of type 2 diabetes mellitus, the severity of symptoms and signs at initial presentation determines the need for insulin during stabilisation. Thereafter, therapy includes dietary and lifestyle changes, exercise, weight management, and oral hypoglycaemic agents (metformin and sulphonylurea), with the need for insulin administration when these modalities fail to maintain glycaemic targets.

There is controversy as to when insulin is initiated in these patients and highlights again the multifactorial pathophysiology and ‘double diabetes’ phenomenon that makes individualised therapy necessary. Co-morbidities such as hypertension, dyslipidaemia, nephropathy – albuminuria, and retinopathy need screening at diagnosis and annually thereafter, for early detection and treatment of micro- and macrovascular complications. As diabetes in children and adolescents increases, the burden of ongoing care and complications will be borne by the adult services in the future and must be considered in resource allocation in South Africa.

Other types of diabetes include monogenic diabetes, with several genetic abnormalities identified with a strong family history, gestational diabetes during pregnancy, and diabetes secondary to other factors such as drugs, chemicals, infections and other diseases (cystic fibrosis, endocrinopathies, genetic syndromes and disorders of the exocrine pancreas). While insulin is the mainstay of therapy and is responsible for control and survival, other important facets of therapy cannot be ignored. These are similar to HIV/AIDS care with highly active antiretroviral therapy (HAART). A recent review by Westwood et al., of transitional care in long-term health conditions, while looking at a specific condition, makes reference to the latest understanding of care in these conditions.5 Innovation in insulin therapy has allowed flexibility and improved quality of life for many diabetic patients. These include the currently available human insulin, the variable onset and duration of insulin action, highlighted recently by the availability of insulin analogues both ultra-short-acting and long-acting preparations, the delivery systems for insulin, while still injectable, moving from syringes and vials to pen sets and insulin pumps, and now even the ‘bionic pancreas’ as described by Russell et al.6 Furthermore, patients on ‘intensive insulin therapy’ with multiple daily injections of four or more had better glycaemic control and long-term complications than ‘conventional’ twice-daily regimens with pre-mixed, bi-phasic insulin combinations.7

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Self-monitored blood glucose has also evolved with new technology from colour-coded glucostix to glucometers with downloadable memory and graphic data analysis, and now to continuous glucose monitoring sensors that can give you a more complete picture of glucose kinetics with more than 250 readings a day. This has helped improve understanding around several aspects, such as nocturnal hypoglycaemia, the ability to assess glucose responses, and specific diets, activities, and more.

Objective monitoring of glycaemic control with three-monthly HBA1c tests remains the standard of care. Comparisons between clinical symptoms and signs, self-monitored blood glucose readings, and HBA1c levels are an important aspect of ongoing, long-term care, especially during adolescence. There are also several newer oral hypoglycaemic agents on the market for adult care, with ISPAD guidelines suggesting the use of metformin and sulphonylureas.

This is best done by a paediatric endocrinologist/diabetiologist. A detailed discussion of these aspects of care is beyond the scope of this review, but we would like to focus on diet and psychosocial factors.

Dietetics and diabetes8 The involvement of a specialist paediatric dietician is important in the comprehensive management of diabetes in both childhood and adolescence. It is important that patients understand the relationship between the food they eat and the insulin they require, and for the MDT to understand the foods available to the patient. In South Africa, the presence of both ends of the economic spectrum means that MDTs have to be well prepared.

Prevention of obesity is a key strategy for optimal glycaemic control, especially in type 2 diabetes. Furthermore, body image issues among adolescents may play a large role in compliance, as insulin can increase weight, while hyperglycaemia can cause weight loss. While strict dietary control is desirable for optimal glycaemic control, this must be approached with care and respect for the adolescent patientâ&#x20AC;&#x2122;s needs, as disregarding them may lead to rebellion and poor compliance. Matching insulin to food intake may be taught as a strategy to overcome occasional dietary indiscretions. Health professionals should be aware of the possibility of eating disorders, however, this is rare in our setting.

Dietary recommendations need to be practical and achievable and based on cultural beliefs and family traditions. Dietary advice needs to be adapted to suit the economic availability of foods in the household and focus on healthy eating for all, not just the diabetic teen. Advice should include the amount, type and even distribution of carbohydrates as part of a healthy balanced diet. Excessive restriction of carbohydrates should be avoided. Insulin regimens can be adapted to suit the dietary patterns of the adolescent, which can often be erratic. Carbohydrate counting may be a complex concept for some patients, however, adolescents and caregivers, even with lower levels of education, can be taught the carbohydrate content of foods using exchanges and the skill of balancing carbohydrates throughout the day.

We have found that the majority of our diabetic patients have a predominantly starch-based diet (maize meal and samp), limited dietary diversity, and quantities vary with resources; adequate at the beginning of the month but less or non-existent towards the end of the month. In this situation, a fixed dose will result in erratic glucose values, while adjusting the dose according to the carbohydrates on the plate may produce better control.

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A large portion of our children rely on a school feeding-scheme meal, which is high in starch and fat and is often received at 10:00 rather than at lunch time. Health professionals need to be aware of this and not withhold this vital meal, but rather adjust the insulin regimen to allow for the meal. Active adolescents will need additional dietary advice to support their sporting aspirations, while maintaining blood glucose stability.

Child and adolescent diabetes: psychosocial factors Adolescence is generally considered a time of change, with often stressful adjustments for adolescents and their families in meeting new developmental demands, such as neurocognitive, social or physiological changes.9 It is well known that due to the physiological changes of puberty, and social and developmental adjustments, metabolic control is typically less effectively achieved in adolescence than in other phases of the life span.10 Repeated incidents of hypoglycaemia, especially with early-onset diabetes, is associated with significant cognitive impairments, which in turn affect school performance and diabetes self-management.11 Neuro-maturational impulsivity during adolescence is a particular challenge, especially given the normative social pressures for independence, risk-taking and self-assertion at this stage.12 Researchers have identified a range of cognitive and emotional factors affecting diabetes outcomes among adolescents. These include negative affective experiences, such as health anxiety and fears of complications, frustrations with the complexity of diabetes self-care, the difficult task of balancing necessary self-care behaviours with perceived independence, and peer acceptance.13 Studies show that although positive caregiver involvement is consistently associated with better outcomes, for the adolescent with diabetes there is a dilemma between the developmental needs, such as independence and peer identification, and the need for ongoing caregiver support. The kind of positive caregiver support required in adolescence also differs from the close, supervising presence of the caregiver with the child, to a collaborative, motivating involvement between caregiver and adolescent; additionally depending on cultural, contextual and social variations in parenting styles.14 From the age of 13 years onwards, individual self-management and adherence plays an increasingly important role in positive diabetes outcomes, with acquiring skills for active problem solving being valuable for adolescent diabetes self-management. As selfmanagement increases, the role of caregivers also shifts towards less direct supervision and support.15 Research into stress has identified the considerable demands placed on the adolescent and caregiver in coping with the multiple tasks required in diabetes self-management in addition to the burden of adaptation to chronic disease. Secondary negative associations with parenting stress, including lower family cohesion, higher psychological maladjustment, and lower rates of school completion are all multivariate contributors to negative diabetes outcomes.16 Levels of perceived stress among adolescents with diabetes are associated with lower regimen adherence, psychological distress and poor metabolic control, all of which highlight the importance of stress management skills as part of support programmes.17 Unified goal setting between adolescent, caregiver and the health provider team have been found to improve diabetes outcomes among adolescents with diabetes.18 Recent studies from developed world settings have explored the promising role of communication technology and the internet

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for supporting adolescents with diabetes through information and behavioural reinforcement.19 The potential of such interventions in resource- and technology-constrained contexts has not been investigated, given that access and availability of communication technology is not equitable across all contexts.

With much research on adolescent diabetes coming from the developed world, less research has been done around the specific challenges of adolescents with diabetes in developing world contexts.

Unique research from Ghana has revealed significant structural barriers facing adolescents with diabetes in this resource-constrained context. These included misdiagnosis or late diagnosis at primarycare level, stigmatising and unsupportive school environments, affordability and accessibility constraints, lack of diabetes-specific support systems and lack of accessible diabetes information.20 Again, from local research, common challenges identified by both caregivers and patients were negative emotional experiences, sustaining motivation for health compliance, and the physiological changes in adolescence. Caregivers included emotional challenges affecting the caregiver and practical issues of supervision, whereas the child/adolescent patients listed peer relations, school environments and family environments as significant psychosocial challenges in diabetes management.2 Along with the physiological changes of puberty, adolescents encounter a range of interpersonal adjustments and issues of sexuality within cultural and social contexts. These include negotiating love and friendships, variations in sexual activity, sexual preference and risks of unplanned pregnancy. Few studies have been done on sexuality and sex education for adolescents with diabetes, yet this is a crucial domain of adolescent development, as seen in recent research from Cuba.21 Defining diabetes outcomes is a difficult task, as objective measures of metabolic control may tell only some of the story.

Researchers on youth diabetes outcomes have defined diabetes outcomes as a multifaceted concept that can include measures of psychological well-being, mastery of developmental tasks, optimal metabolic control, and active participation in diabetes care. With this in mind, key interventional strategies should also include early detection and intervention for psychological distress, and support for transition from paediatric to adult care systems, a central challenge in late adolescence.22 Local research has suggested that optimal outcomes may be achieved by supporting caregiver and adolescent self-efficacy, a consistent and cohesive multidisciplinary treatment team with patient-centered collaboration, supporting caregiver and family functioning, supporting patient motivation, and appropriate facilitation of health information to enhance health literacy.2

References 1.

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2. Dhada B, Blackbeard D. Using intervention mapping to develop a child diabetes support intervention. Procedia Soc Behav Sci 2014; 113: 74–83.

3. Reddy Y, Ganie Y, Pillay K. Characteristics of children presenting with newly diagnosed type 1 diabetes. S Afr J CH 2013; 7(2): 46–48. DOI:10.7196/SAJCH.500 4. Libman IM, Becker DJ. Coexistence of type 1 and type 2 diabetes mellitus: double diabetes? Pediat Diabetes 2003: 4: 110–113.

5. Westwood A, Langerak N, Fieggen G. Review: Transition from child- to adultorientated care for children with long-term health conditions: A process, not an event. S Afr Med J 2014; 104( 4): 310–313.

6. Russell SJ, El-Khatib FH, Sinha M, Magyar KL, McKeon K, Goergen LG, et al.

Outpatient glycaemic control with a bionic pancreas in type 1 diabetes. N Engl J Med 19 June 2014. DOI: 10.1056/NEJMoa1314474.

7. Nathan DM, and the DCCT/EDIC Research Group. The Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Study at 30 years: Overview. Diabetes Care 2014; 37: 1 9–16; doi: 10. 2337/ dc13-2112 1935-5548.

8. Smart C, Aslander-van Vliet E, Waldron S, Swift P. Nutritional management.

Global IDF/ISPAD Guideline for Diabetes in Childhood and Adolescence 2011, ch 9: 66–69.

9. Pilgrim NA, Blum RW. Adolescent mental and physical health in the Englishspeaking Caribbean. Rev Panam Salud Publica 2012; 32(1): 62–69.

10. Moore SM, Hackworth NJ, Hamilton NJ, et al. Adolescents with type 1 diabetes: parental perceptions of child health and family functioning and their relationship to adolescent metabolic control. Health Qual Life Outcomes 2013; 11(1): e50.

11. Moosa FY, Segal D. Assessing maths literacy skills in type 1 diabetic children and their caregivers. J Endocrin Metab Dis South Afr 2011; 16(3): 117–160.

12. Cameron F. Teenagers with diabetes: management challenges. Austral Fam Physician 2006; 35(6): 385–390.

13. Herge WM, Streisand R, Chen R, et al. Family and youth factors associated with health beliefs and health outcomes in youth with type 1 diabetes. J Ped Psychol 2012; 37(9): 980–989.

14. Nordfeldt S, Angarne-Lindberg T, Nordwall M, et al. Parents of adolescents with type 1 diabetes – their views on information and communication needs and internet use: a qualitative study. PLoS One 2013; 8(4): e62096. doi:10.1371/ journal.pone.0062096.

15. Mulvaney SM, Rothman RL, Osborn CY, et al. Self-management problem solving for Adolescents with type 1 diabetes: intervention processes associated with an internet program. Patient Educ Couns 2011; 85(2): 140–142. doi:10.1016/j. pec.2010.09.018.

16. Maas-van Schaaijk NM, Roeleveld-Versteegh ABC, van Baar AL. The interrelationships among paternal and maternal parenting stress, metabolic control, and depressive symptoms in adolescents with type 1 diabetes mellitus. J Ped Psychol 2012; 38(1) 30–40.

17. Berlin KS, Rabideau EM, Hains AA. Empirically derived patterns of perceived stress among youth with type 1 diabetes and relationships to metabolic control. J Ped Psychol 2012; 37(9): 990–998.

18. Boot M, Volkening, LK, Butler DA, et al. The impact of blood glucose and HbA1c goals on glycaemic control in children and adolescents with type 1 diabetes.

Diabet Med 2013; 30(3): 333–337. doi:10.1111/dme.12083.

19. Hanberger L, Ludvigsson J, Nordfeldt S. Use of a web 2.0 portal to improve education and communication in young patients with families: randomized controlled trial. J Med Internet Res 2013; 15(8): e175.

20. Kratzer J, Structural barriers to coping with type 1 diabetes mellitus in Ghana: experiences of diabetic youth and their families. Ghana Med J 2012; 46(2): 39–45.

21. Granela K, Cardoso Y, Gutiérrez A, et al. Sex education for children and adolescents with type 1 diabetes in Camagüey Province, Cuba. MEDICC Rev 2013; 15(3): 34–37.

22. Northam EA, Werthier GA, Lin A, et al. Psychosocial well-being and functional outcomes in youth with type 1 diabetes 12 years after disease onset. Diabet Care 2010; 33: 1430–1437.

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A review of the literature on multidisciplinary interventions in cardiac rehabilitation Melisha Rabilal Introduction Cardiovascular disease (CVD) is a worldwide problem, with an increased prevalence in sub-Saharan Africa. Rheumatic heart disease, hypertension and cardiomyopathy are already prevalent, and coronary heart disease is assuming growing significance. It is vital that in developing countries, rehabilitative care be incorporated into the existing healthcare system.1 Cardiac rehabilitation is a complex intervention that requires the input of a multidisciplinary team of qualified and competent professionals to encompass and deliver the recommended core components. Cardiac rehabilitation can reduce morbidity and mortality rates for patients with many types of cardiac disease, yet is generally underutilised in South Africa.

Cardiac rehabilitation is cost effective, reduces mortality rates by 26% and improves quality of life for many. It can also help reduce unplanned admissions and yield significant savings.2-4 The beneficial effects of rehabilitation include a reduction in the rate of death from cardiovascular disease, improved exercise tolerance, fewer cardiac symptoms, improved serum lipid levels, decreased cigarette smoking, improvement in psychosocial well-being and increased likelihood of return to work.

The American Heart Association and American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) recognise that all cardiac rehabilitation/secondary prevention programmes should contain specific core components that aim to optimise cardiovascular risk reduction, foster healthy behaviours and compliance with these behaviours, reduce disability, and promote an active lifestyle for patients with cardiovascular disease.5 In 1994, the American Heart Association stated that cardiac rehabilitation programmes should consist of a multifaceted and multidisciplinary approach to overall cardiovascular risk reduction, and that programmes that comprise exercise training alone are not considered cardiac rehabilitation.

The staff of a cardiac rehabilitation programme usually include a medical doctor, physician, cardiologist trained in cardiac rehabilitation, physiotherapist, exercise physiologist/biokineticist, dietician, psychologist, and a cardiac-trained sister. Occupational therapists and social workers may also be involved in the programme. The importance of a mutlidisciplinary team approach to cardiac rehabilitation has been stressed by Kellerman.6

Correspondence to: Melisha Rabilal Physiotherapy Department, Grey’s Hospital, Pietermaritzburg e-mail: melisha.rabilal@gmail.com S Afr J Diabetes Vasc Dis 2014; 11: 111–114

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Physiotherapy management of patients with coronary artery disease: current practice in South Africa The Association of Chartered Physiotherapists in Cardiac Rehabilitation (ACPICR) and the British Association for Cardiac Rehabilitation (BACR) describe the phases of cardiac rehabilitation as follows: • Phase I: hospital in-patient period • Phase II : convalescent stage following discharge • Phase III: structured rehabilitation programme • Phase IV: long-term maintenance.

According to the ACPICR and BACR, physiotherapists play a role in the physical activity component of all phases of cardiac rehabilitation (many phase IV programmes however, are delivered by appropriately trained BACR exercise instructors).

Internationally, physiotherapists treat patients with coronary artery disease (CAD) in the acute stage following a coronary event and/or following coronary artery bypass (CABG) surgery. These patients are then subsequently followed up as out-patients during cardiac rehabilitation in order to improve function and quality of life and to delay the occurrence of subsequent coronary events.7-9 A study conducted recently in South Africa by Roos and van Aswegen10 aimed at establishing the number of physiotherapists working in the cardiopulmonary field of physiotherapy and involved in the care and rehabilitation of patients with CAD. The current physiotherapy interventions that are used in the management of patients with CAD were examined. The clinical settings (acute or out-patient care) in which patients with CAD regularly receive physiotherapy interventions was determined.

The study determined the frequency of physiotherapy interventions and follow up of patients with CAD. Also, explanations were presented as to the reasons for non-involvement of physiotherapists who work in a cardiopulmonary setting in rehabilitation of patients with CAD in certain instances.

An observational, cross-sectional study was conducted with questionnaires mailed to 50 regional and tertiary government institutions and 137 electronic questionnaires were circulated. A total of 187 questionnaires were sent out and 142 were returned (76%).

Results showed that 62% of the physiotherapists provided care to patients with CAD (50 government physiotherapists and 38 private practitioners). Of the 38% who did not treat patients with CAD, 38 were government physiotherapists and 16 private practitioners. Care was mostly provided in a hospital setting (81%) and out-patient phase III cardiac rehabilitation was lacking (11%).

In a study by Taylor et al.,11 a systematic review and meta-analysis of randomised, controlled trials was undertaken with reference to exercise-based rehabilitation for patients with coronary heart disease. The purpose was to review the effectiveness of exercisebased cardiac rehabilitation in patients with coronary heart disease.

Databases such as MEDLINE, EMBASE and the Cochrane Library were searched up to March 2003. Trials with six or more months

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of follow up were included if they assessed the effects of exercise training alone or in combination with psychological or educational interventions.

In the results, 48 trials were included, with a total of 8 940 patients. Compared with usual care, cardiac rehabilitation was associated with reduced all-cause mortality [odds ratio (OR): 0.80; 95% confidence interval (CI): 0.68–0.93] and cardiac mortality (OR: 0.74; 95% CI: 0.61–0.96); greater reductions in total cholesterol level [weighted mean difference: –0.37 mmol/l (– 14.3 mg/dl); 95% CI: –0.63 to –0.11 mmol/l (–24.3 to –4.2 mg/dl)]; triglyceride level [weighted mean difference: –0.23 mmol/dl (–20.4 mg/dl); 95% CI: –0.39 to –0.07 mmol/l (–34.5 to –6.2 mg/dl)], and systolic blood pressure (weighted mean difference: –3.2 mmHg; 95% CI: –5.4 to –0.9 mmHg); and lower rates of self-reported smoking (OR: 0.64; 95% CI: 0.50–0.83). There were no significant differences in the rates of non-fatal myocardial infarction and revascularisation, and changes in high- and low-density lipoprotein cholesterol levels and diastolic pressure.

Health-related quality of life improved to similar levels with cardiac rehabilitation and usual care. The effect of cardiac rehabilitation on total mortality was independent of diagnosis of coronary heart disease, type of cardiac rehabilitation, length of exercise intervention, length of follow up, and trial quality and publication date. The review by Taylor et al.11 confirmed the benefits of exercise-based cardiac rehabilitation within the context of today’s cardiovascular service provision.

In another study by Lawler et al.,12 a meta-analysis of randomised, controlled trials (RCTs) was undertaken to (1) estimate the effect of cardiac rehabililtation (CR) on cardiovascular outcomes, and (2) examine the effect of CR programme characteristics on the magnitude of CR benefits. The researchers systematically searched MEDLINE as well as relevant bibliographies to identify all Englishlanguage RCTs examining the effects of exercise-based CR among post-MI patients.

Data were aggregated using random-effects models. Stratified analyses were conducted to examine the impact of RCT-level characteristics on treatment benefits. Thirty-four RCTs were identified (n = 6.111).

Overall, patients randomised to exercise-based CR had a lower risk of re-infarction (OR: 0.53; 95% CI: 0.38–0.76), cardiac mortality (OR: 0.64; 95% CI: 0.46–0.88), and all-cause mortality (OR: 0.74; 95% CI: 0.58–0.95). In stratified analyses, treatment effects were consistent, regardless of study periods, duration of CR, or time beyond the active intervention. Exercise-based CR had favourable effects on cardiovascular risk factors, including smoking, blood pressure, body weight and lipid profile.

The study by Lawler et al.12 concluded that exercise-based cardiac rehabilitation is associated with reductions in mortality and re-infarction rate post MI. The researchers state that their secondary analyses suggest even shorter CR programmes may translate into improved long-term outcomes, although these results need to be confirmed in an RCT.

Nursing A study by Jiang in the West China School of Nursing, Sichuan University, indicates that a nurse-led cardiac rehabilitation programme improved health behaviours and cardiac physiological risk parameters.13 The aim of the study was to examine the effect of a cardiac rehabilitation programme on health behaviours and

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physiological risk parameters in patients with coronary heart disease in Chengdu, China.

Epidemiological studies indicate a dose-, level- and durationdependant relationship exists between cardiac behavioural and physiological risks and coronary heart disease incidence, as well as subsequent cardiac morbidity and mortality.

Cardiac risk-factor modification has become the primary goal of modern cardiac rehabilitation programmes. A randomised, controlled trial was conducted. Coronary heart disease patients (n = 167) who met the sampling criteria in two tertiary medical centres in Chengdu, south-west China were randomly assigned to either an intervention group (the cardiac rehabilitation programme) or control group (the routine care). The change of health behaviours (walking performance, step II diet adherence, medication adherence, smoking cessation) and physiological risk parameters (serum lipids, blood pressure, body weight) were assessed to evaluate the programme effect.

Patients in the intervention group demonstrated a significantly better performance in walking, step II diet adherence, and medication adherence; a significantly greater reduction in serum lipid levels including triglycerides, total cholesterol, and low-density lipoprotein cholesterol; and significantly better control of systolic and diastolic blood pressure at three months. The majority of these positive impacts was maintained at six months. The effect of the programme on smoking cessation, body weight, and serum highdensity lipoprotein levels was not confirmed.

The study concluded that a cardiac rehabilitation programme led by a nurse can significantly improve the health behaviours and cardiac physiological risk parameters in coronary heart disease patients. Nurses can fill significant treatment gaps in the risk-factor management of patients with coronary heart disease.

This study raises attention regarding the important role nurses can play in cardiac rehabilitation and the unique way for nurses to meet the rehabilitative care needs of coronary heart disease patients. Furthermore, the hospital–home bridging nature of the programme also created a model for interfacing acute care and community rehabilitative care.

Physician referral A study by Smith et al. at McMaster University, Canada, explains the role of automatic physician referral in predicting cardiac rehabilitation enrolment.14 Despite the established benefits of cardiac rehabilitation, evidence suggests referral to and subsequent enrolment in cardiac rehabilitation following a coronary event remains low (10–25%). The aim of this study was to identify predictors of attendance at cardiac rehabilitation intake and subsequent enrolment in rehabilitation after CABG surgery within the framework of an automatic referral system.

Researchers conducted a historical, prospective study of patients who underwent CABG surgery between 1 April 1996 and 31 March 2000 and lived within the geographic referral area of a multidisciplinary cardiac rehabilitation centre in southcentral Ontario, Canada. CABG surgery patients are automatically referred for cardiac rehabilitation at the time of hospital discharge.

Consecutive health records of eligible patients were reviewed for medical history, cardiac risk factor profiles, and evidence of cardiac rehabilitation intake attendance and enrolment.

A total of 3 536 patients met the eligibility criteria. Patients were predominantly male (79.1%), approximately 64 years of age,

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living with a spouse or a partner, English-speaking, retired and had multiple cardiac risk factors. Of the eligible patients, 2 121 (60%) attended the cardiac rehabilitation intake appointment. Of the patients who attended intake, 1 463 (69%) enrolled in at least one cardiac rehabilitation service, based on their risk-factor profile.

Selected cardiac rehabilitation services were exercise training (n = 1287; 88%), nutritional counselling (n = 571; 39.0%), nursing care (n = 546; 37.3%) and psychological intervention (n = 223; 15.2%).

The study concluded that an institutionalised, physician-endorsed system of automatic referral to cardiac rehabilitation resulted in higher rates of cardiac rehabilitation intake and enrolment following CABG surgery than previously reported and should be adopted for all cardiac populations.

Occupational therapy In an article relating to occupational therapy and cardiac rehabilitation, Torres asserted that occupational therapy in cardiac rehabilitation is aimed at enabling the patient to return to work.15 Ergonomics in relation to ‘dangerous tasks’ are taught to the patient so that work may be done without risk. This is necessary because there are differences between the work done in the effort tests and the work done in an occupation- or work-related setting.

Therefore cardiac rehabilitation provides an efficient share in coronary patient treatment and occupational therapy is a significant complementary procedure. This indicates that occupational therapists fulfil a role as part of the multidisciplinary team in a cardiac rehabilitation programme.

Dietetics A study by Holmes et al.16 was conducted in America to examine the effectiveness of the registered dietician and education and counselling on diet-related patient outcomes with general education provided by the cardiac rehabilitation staff. The study also evaluated the effectiveness of meat, eggs, dairy, fried foods, baked goods, convenience foods, table fats and snacks. The MEDFICTS dietary assessment questionnaire was used as an outcome measure in cardiac rehabilitation.

Observational study data from 426 cardiac rehabilitation patients discharged between January 1996 and February 2004 were examined. Groups were formed based on educational source: (1) registered dietician, and (2) general education from cardiac rehabilitation staff.

Baseline characteristics were compared between groups and pre/post diet-related outcomes (lipid levels, waist circumference, body mass index, MEDFICTS score) were compared within groups.

Controlling for baseline measures and lipid-lowering medication, associations were examined between (1) registered dietician education and diet-related outcomes, and (2) ending MEDFICTS score and diet-related outcomes.

Mean age was 62 ± 11 years, 30% of patients were female, and 28% were non-white. At baseline, the registered dietician group (n = 359) had more dyslipidaemia (88 vs 76%), more obesity (47 vs 27%), a larger waist (40 ± 6 vs 37 ± 5 inches), a higher body mass index (30 ± 6 vs 27 ± 5 kg/m2), a higher diet score (32 ± 28 vs 19 ± 19), and lower self-reported physical activity (7 ± 12 vs 13 ± 18 metabolic equivalent hours) (all p < 0.05) than the general education group (n = 67).

Registered dietician education was associated with improved

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levels of low-density lipoprotein (i = 0.13; p = 0.04) and triglycerides (i = 0.48; p = 0.01), and MEDFICTS score (i = 0.18; p = 0.01).

Improvements in MEDFICTS scores were correlated with improved total cholesterol and triglyceride levels, and waist measurements (all i = 0.19; p = 0.04).

The study concluded that dietary education by a registered dietician is associated with improved diet-related outcomes and that the MEDFICTS score is a suitable outcome measure in cardiac rehabilitation. This study affirms the role of the dietician as part of the multidisciplinary team in cardiac rehabilitation.

Psychology In a study by Yoshida in Sendai, Japan, physical and psychological improvements were reported after phase II cardiac rehabilitation in patients with myocardial infarction.17 A new four-week hospitalised phase II cardiac rehabilitation programme was designed.

Twenty-nine patients (27 males, 2 females) with acute myocardial infarction who enrolled in the programme were assessed. All patients enrolled in this study had received coronary interventions.

The rehabilitation consisted of exercise training, education and counselling. The physical and psychological status of the patients before and just after the programme and at a six-month follow up was evaluated.

The physical status was assessed by exercise tolerance measured by the peak oxygen consumption and anaerobic threshold, frequency of exercise, and serum concentrations of triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The psychological status was assessed by the Spielberger state-trait anxiety inventory questionnaire (STA) and the self-rating questionnaire for depression (SRQ-D). Thirty-four patients (27 men, 7 women) with MI who did not participate in the rehabilitation programme served as a control group.

After participation in the rehabilitation programme, exercise tolerance and serum lipid profiles of the patients were improved compared to six months after rehabilitation. The STA anxiety score was improved significantly and the SRQ-D depression score tended to be improved just after the rehabilitation programme. Regular physical activity was continued even six months after the completion of the programme.

The hospitalised phase II cardiac rehabilitation programme improved the management of cardiac risk factors and the psychological status in patients with MI. This comprehensive programme may contribute to the secondary prevention of MI as well as the recovery of physical and psychological activities.

Psychologists therefore form an integral component of the multidisciplinary cardiac rehabilitation team. The articles cited above describe the benefits of a multidiscipliary approach to a cardiac rehabilitation.

An article by Yohannes et al.18 describes the benefits following an investigation into the long-term benefits of a six-week comprehensive cardiac rehabilitation programme on physical activity, psychological well-being and quality of life in patients with coronary heart disease. The researchers asserted that CR in the short term improves exercise capacity and quality of life in patients with cardiac disease. However, the long-term benefits of CR were inconclusive.

A prospective CR programme with repeated-measures follow up over 12 months was the design. A six-week out-patient cardiac rehabilitation programme was conducted including 147 patients

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with coronary heart disease. Patients completed the Physical activity energy expenditure (seven-day recall activity), MacNew heart disease health-related quality of life (MacNew) and Hospital anxiety and depression scale (HADs) questionnaires at baseline, six weeks, six months and 12 months.

One hundred and five (71%) patients (76 male) with a mean age of 61.8 years (SD = 9.7) completed the four measurement points. Analysis of variance revealed that total energy expenditure [F (2.231) = 131, p < 0.001], HADs [F (2.237) = 19.3, p < 0.001], depression score [F (2.235) = 21.06, p < 0.001], anxiety score [F (2.237) = 17.02, p < 0.001) and MacNew [F (2.197) = 77.02, p < 0.001] were all statistically significant over time. Bonferroni pairwise follow up confirmed significant positive differences (p < 0.05) between baseline values and all subsequent measures over time. Depression was independently explained in 22% of the variance in quality of life at six or 12 months. The energy expenditure was significantly higher for men compared to women [F (1.103) = 31, p < 0.001].

The researchers concluded that a six-week cardiac rehabilitation programme is beneficial in improving quality of life, physical activity status, and anxiety and depression levels. These benefits were maintained at 12 months. Elevated levels of depression were associated with impaired quality of life.

Yohannes et al.18 assert that all relevant healthcare staff should be made aware of the benefits of cardiac rehabilitation and routinely refer and encourage patients with cardiac disease to attend a cardiac rehabilitation programme. The researchers indicate that depression and anxiety intervention strategies should be incorporated into cardiac rehabilitation programmes.

Conclusion The AHA/AACVPR statement presents specific information regarding evaluation, intervention and expected outcomes in each of the core components of cardiac rehabilitation/secondary prevention programmes. The outcomes of such programmes affirm a multidisciplinary approach.

Training of all healthcare workers involved with cardiac patients and the establishment of treatment protocols within a multidisciplinary framework is imperative for the development of integrated, holistic cardiac rehabilitation interventions in South Africa. Following multidisciplinary liaison, the establishment of cardiac rehabilitation protocols and the acquisition of human and equipment resources, the implementation of cardiac rehabilitation programmes would gain momentum.

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References 1. Mathes P. Cardiovascular Prevention and Rehabilitation. London: Springer, 2007.

2. Heran BS, et al. Exercise based cardiac rehabilitation for coronary heart disease.

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3. Lam G, et al. The effect of a comprehensive cardiac rehabilitation programme on 60-day hospital readmissions after an acute myocardial infarction. J Am Coll Cardiol 2011; 57: E597–E597.

4. Davies EJ, et al. Exercise based rehabilitation for heart failure. Cochrane Syst Rev 2010; 4. Art No CD 003331.tinyurl.com/exercise-CR. 5. Balady GJ, Williams MA, Ades PA, Bittner V, Comross P, Foofy JM, et al. Core components of cardiac rehabilitation/secondary prevention programmes – A scientific statement from the American Heart Association exercise, cardiac rehabilitation, and prevention committee, the Council on Clinical Cardiology; the councils on cardiovascular nursing, epidemiology and prevention, and nutrition, physical activity, and metabolism; and the American Association of Cardiovascular and Pulmonary Rehabilitation. Circulation 2007; 115: 2675–2682.

6. Kellerman JJ. Long-term comprehensive cardiac care – the perspectives and tasks of cardiac rehabilitation. Eur Heart J 1993; 14: 1441–1444.

7. Piotrowicz R, Wolszakiewicz J. Cardiac rehabilitation following myocardial infarction. Cardiol J 2008; 15: 481–487.

8. Martin AC. Current physiotherapy practice for post-operative cardiac patients. J Assoc Chart Physiother Resp Care 2007; 39: 27–312.

9. Tucker B, Jenkins S, Davies K, McGram R, Waddel J, King R, et al. The physiotherapy management of patients undergoing coronary artery surgery: A questionnaire survey. Australian J Physiother 1996; 42(2): 129–137.

10. Roos R, van Aswegen H. Physiotherapy management of patients with coronary artery disease: a report on current practice in South Africa. S Afr J Physiother 2011; 67(1) : 4–8.

11. Taylor RS, et al. Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med 2004; 116: 682–692.

12. Lawler PR, et al. Efficacy of exercise-based cardiac rehabilitation post-myocardial infarction: a systematic review and meta-analysis of randomized controlled trials.

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13. Jiang X, Sit JW, Wong TK. A nurse-led cardiac rehabilitation programme improves health behaviours and cardiac physiological risk parameters: evidence from Chengdu, China. J Clin Nurs 2007; 16(10): 1886–1897.

14. Smith KM, Harkness K, Arthur HM. Predicting cardiac rehabilitation enrolment: the role of automatic physician referral. Eur J Cardiovasc Prevent Rehab 2006; 13(1): 60–66.

15. Torres (Pastor) L, Sainz Hidalgo I, Guijarro Salcedo MC, Rena Sanchez M. Occupational therapy in cardiac rehabilitation. Revista Espanola de cardiologica, 1995; 48(Suppl 1): 28–32.

16. Holmes AL, Sanderson B, Maisiak R, Brown A, Bittner V. Dietician services are associated with improved patient outcomes and the MEDFICTS dietary assessment questionnaire is a suitable outcome measure in cardiac rehabilitation.

J Am Dietetic Assoc 2005; 105(10): 1533–1540.

17. Yoshida T, Kohzuki M, Yoshida K, Hiwatari M, Kamimoto M, Yamamoto C, et al.

Physical and psychological improvements after phase II cardiac rehabilitation in patients with myocardial infarction. Nurs Health Sci 1999; 1(3): 163–170.

18. Yohannes AM, et al. The long term benefits of cardiac rehabilitation on depression, anxiety, physical activity and quality of life. J Clin Nurs 2010; 19(19–20): 2806– 2813.

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The effects of medicinal plants on renal function and blood pressure in diabetes mellitus CT 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 wellestablished 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 diabetesassociated complications, with particular emphasis on kidney function and hypertension.

Keywords: diabetes mellitus, diabetic nephropathy, medicinal plants, hypertension Diabetes 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 Correspondence to: CT Musabayane Department of Human Physiology, Faculty of Medicine, University of KwaZulu-Natal, Durban e-mail: musabayanec@ukzn.ac.za Previously published in Cardiovasc J Afr 2012; 23(8): 462 S Afr J Diabetes Vasc Dis 2014; 11: 115–120

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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 socioeconomic 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 prevalent 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 streptozotocininduced (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

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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 disease Diabetic 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 sympatholytic 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 ACE inhibitors, angiotensin-1 receptor antagonists, or their combination.25,30,31 Although these treatments 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 disease Several 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

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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 endotheliumintact 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 mellitus Sustained 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 hyperactivation 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 antidiabetic from a herbal source,

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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 nephropathy Renal 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 nephropathy World 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 glucoselowering 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 strategy 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 disease Ethno-medicinal plants have traditionally been used for the treatment of diabetes and its complications. In fact, current preclinical and clinical studies have demonstrated that many have beneficial effects on some processes associated with reduced renal

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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.

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

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

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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 antidiabetic 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.

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

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

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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

improvement in renal function in experimental diabetes mellitus through inhibition of ET-1 and TGF-β1 and the endothelin-1 receptor A (ETRA).65

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) phenols ↑ insulin secretion ↑ GFR vasorelaxant, 67, 68 (Alliaceae) flavonoids ↑ hepatic glycogen ↓ hypolipidaemic Gongronema latifolium flavonoids ↑ hepatic glycogen anti-oxidant ↓ hypolipidaemic 69

saponins

polyphenols Foeniculum vulgare L phytoestrogens ↓ glucose absorption diuretic vasorelaxant 70 (Apiaceae) natriuretic Opuntia megacantha phenols, flavonoids ↓ glucose absorption ↑ GFR vasorelaxant 71, 72, 73

(quercetin) taxifolin Syzygium spp phenylpropanoids ↑ hepatic glycogen ↑ GFR vasorelaxant 63, 66, 74

flavonoids sesquiterpenes ↑ insulin secretion

oleanolic acid rhamnetin Sclerocarya birrea flavonoids, ↑ hepatic glucose ↑ GFR vasorelaxant 32, 75 [(A Rich) Hochst] alkaloids, triterpenoids, utilisation [Anacardiaceae] coumarins, ↑ insulin secretion

ascorbic acid Persea americana Mill tannins, saponins ↑ hepatic glycogen ↑ GFR vasorelaxant 32, 76, 77, 78 (Lauraceae) [Avocado] flavonoids, alkaloids ↑ insulin secretion bradycardia

glycosides ↓ hypolipidaemic Hypoxis hemerocallidea glycoside hypoxoside ↑ insulin secretion reno-toxic cardiodepressant 79, 80

β-sitosterol sterolins, ↓ GFR bradycardia

cytokinins Ficus thonningii (Blume) alkaloids anthraquinones ↑ hepatic glycogen ↑ GFR cardiodepressant 17, 81 [Morarceae] flavonoids saponins vasorelaxant

tannins bradycardia Olea europaea L, triterpenes, flavonoids, ↑ insulin secretion ↑ GFR cardiodepressant 36, 82, 83, 84 (Oleaceae) glycosides ↑ glucose utilisation antioxidant vasorelaxant

bradycardia Helichrysum ceres S polyphenols, tannins, unclear diuretic cardiodepressant 38, 39 Moore triterpenes natriuretic vasorelaxant [Asteraceae] saponins bradycardia

Ekebergia capensis saponins unclear unclear cardiodepressant 85 Sparrm alkaloids vasorelaxant (Meliaceae) flavonoids bradycardia

tannins

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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.

Conclusion We 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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50. Sheetz MJ, King GL. Molecular understanding of hyperglycaemia’s adverse effects for diabetes complications. J Am Med Assoc 2002; 288: 2579–2588.

51. Rahbar S, Figarola JL. Novel inhibitors of advanced glycation endproducts. Arch Biochem Biophys 2003; 419: 63–79.

52. Rahbar S, Yerneni KK, Scott S, Gonzales N, Lalezari I. Novel inhibitors of advanced glycation endproducts (part II). Mol Cell Biol Res Commun 2000; 3(6): 360–366.

53. Kim H, Kang KS, Yamabe N, Nagai R, Yokozawa, T. Protective effect of heatprocessed American ginseng against diabetic renal damage in rats. J Agric Food Chem 2007; 55: 8491–8497.

54. Kim JD, Kang SM, Park MY, Jung TY, Choi HY, Ku SW. Ameliorative anti-diabetic activity of Dangnyosoko, a Chinese herbal medicine in diabetic rats. Bioscience, Biotechnol Biochem 2007; 71(6): 1527–1534.

55. Kim SW, Jeon YS, Lee JU, Kang DG, Kook H, Ahn KY, et al. Diminished adenylate cyclase activity and aquaporin 2 expression in acute renal failure rats. Kidney Int 2000; 57(4): 1239–1417.

56. Wirasathiena L, Pengsuparpa T, Suttisria R, Uedab H, Moriyasub M, Kawanishib K. Inhibitors of aldose reductase and advanced glycation end-products formation from the leaves of Stelechocarpus cauliflorus R.E. Fr. Phytomedicine 2007; 14: 546–550.

57. Atlas of End-Stage Renal Disease in the United States. Excerpts from the United States Renal Data Systems 2002 annual report. Am J Kidney Dis 2003; 41(4): S7–254.

58. Mogensen CE, Christensen CK, Vittinghus E. The stages in diabetic renal disease.

With emphasis on the stage of incipient diabetic nephropathy. Diabetes 32 Suppl 1983; 2: 64–78.

59. Arije A, Kadiri S, Akinkugbe OO. The viability of hemodialysis as a treatment option for renal failure in a developing economy. Afr J Med Med Sci 2000; 29: 311–314.

60. Marles R, Farnsworth N. Plants as sources of antidiabetic agents. In: Wagner H, Farnsworth NR (eds). Economic and Medicinal Plant Research. UK: Academic Press Ltd, 1994; 6: 146–187.

61. Wang XM, Guan SH, Liu RX, Sun JH, Liang Y, Yang M, W et al. HPLC determination of four triterpenoids in rat urine after oral administration of total triterpenoids from Ganoderma lucidum . J Pharmaceut Biomed Anal 2007; 43: 1185–1190.

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62. Nakagawa T, Goto H, Hikiami H, Yokozawa T, Shibahara N, Shimada Y. Protective effects of keishibukuryogan on the kidney of spontaneously diabetic WBN/Kob rats J Ethnopharmacol 2007; 110: 311–317.

63. Mapanga RF, Tufts MA, Shode FO, Musabayane CT. Renal effects of plant-derived oleanolic acid in streptozotocin-induced diabetic rats. Renal Failure 2009; 31(6): 481–491.

64. Yokozawa T, Yamabe N, Kim HY, Kang KS, Hur JM, Park CH, Tanaka T. Protective effects of morroniside isolated from Corni Fructus against renal damage in streptozotocin-induced diabetic rats. Biol Pharm Bull 2008; 31: 1422–1428.

65. Rao NK, Nammi S. Antidiabetic and renoprotective effects of thechloroform extract of Terminalia chebula Retz. Seeds in streptozotocininduced diabetic rats.

BMC Complement Alternative Med 2006; 6: 17.

66. Musabayane C, Tufts MA, Mapanga RF. Synergistic antihyperglycemic effects between plant-derived oleanolic acid and insulin in streptozotocin- induced diabetic rats. Renal Failure 2010; 32: 832–839.

67. Al-Qattan K, Thomson M, Ali M. Garlic (Allium sativum) and ginger (Zingiber officinale) attenuate structural nephropathy progression in streptozotocininduced diabetic rats. Eur e-J Clin Nutr Metab 2008; 3: e62–e71.

68. Eidi A, Eidi M, Esmaeili E. Antidiabetic effect of garlic (Allium sativum L.) in normal and streptozotocin-induced diabetic rats. Phytomedicine 2005; 13: 624–629.

69. Ugochukwu NH, Cobourne MK. Modification of renal oxidative stress and lipid peroxidation in streptozotocin-induced diabetic rats treated with extracts from Gongronema latifolium leaves. Clin Chim Acta 2003; 336: 73–81.

70. El-Hilaly J, Hmammouchib M, Lyoussi B. Ethnobotanical studies and economic evaluation of medicinal plants in Taounate province (Northern Morocco). J Ethnopharmacol 2003; 86: 149–158 71. Tabassum M, Mumtaz M, Haleem MA. Electrolyte content of serum, erythrocyte, kidney and heart tissue in salt induced hypertensive rats. Life Sci 1996; 59: 731– 747.

72. Bwititi P, Musabayane CT, Nhachi CFB. Effects of Opuntia megacantha on blood glucose and kidney function in streptozotocin diabetic rats. J Ethnopharmacol 2000; 69(3): 247–252.

73. Bwititi PT, Machakaire T, Nhachi CB, Musabayane CT. Effects of Opuntia megacantha leaves extract on renal electrolyte and fluid handling in streptozotocin (STZ)-diabetic rats. Renal Failure 2001; 23: 149–158.

74. Prince PS, Menon VP, Pari L. Hypoglycaemic activity of Syzigium cumini seeds: effect on lipid peroxidation in alloxandiabetic rats. J Ethnopharmacol 1998; 61: l–7.

75. Braca A, Politi M, Sanogo R, Sanou H, Morelli I, Pizza CN. Chemical composition and antioxidant activity of phenolic compounds from wild and cultivated Sclerocarya birrea(Anacardiaceae) leaves. J Agric Food Chem 2003; 51(23): 6689–6695.

76. Afzal M, Khan NA, Ghufran A, Iqbal A, Inamuddin M. Diuretic and nephroprotective effect of Jawarish Zarooni Sada – a polyherbal unani formulation. J Ethnopharmacol 2004; 91(2–3): 219–223.

77. Yasir M, Das S, Kharya MD. The phytochemical and pharmacological profile of Persea americana Mill. Phcog Rev 2010; 4: 77–84.

78. Owolabi MA, Coker HAB, Jaja SI. Bioactivity of the phytoconstituents of the leaves of Persea americana. Journal of Medicinal Plants Research 2010; 4(12): 1130–1135.

79. Musabayane CT, Xozwa K, Ojewole JAO. Effects of 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.

80. Ojewole JAO. Antinociceptive, anti-inflammatory and antidiabetic properties of Hypoxis hemerocallidea Fisch. & C.A. Mey. (Hypoxidaceae) corm [African Potato] aqueous extract in mice and rats. J Ethnopharmacol 2006; 103(1): 126–134.

81. Usman H, Abdulrahman F, Usman A. Qualitative phytochemical screening and in vitro antimicrobial effects of methanol stem bark extract of Ficus thonningii (Moraceae). Afr J Tradit Complement Altern Med 2009; 6(3): 289–295.

82. Benavente-Garcia O, Castillo J, Lorente J, Ortuno A, Del Rio JA. Antioxidant activity of phenolics extracted from Olea europaea L. leaves Food Chem 2000; 68: 457–462.

83. Bennani-Kabchi N, Fdhil H, Cherrah Y, El Bouayadi F, Kehel L, Marquie G. 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.

84. Al-Azzawie HF, Alhamdani MS. Hypoglycemic and antioxidant effect of oleuropein in alloxan-diabetic rabbits Life Sci 2006; 78: 1371–1377.

85. Fitzpatrick DF, Hirschfield SL, Ricci T, Jantzen P, Coffey RG. Endothelium-dependent vasorelaxation caused by various plant extracts. J Cardiovas Pharmacol 1995; 26: 90–95.

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The ADVANCE cardiovascular risk model and current strategies for cardiovascular disease risk evaluation in people with diabetes Andre Pascal Kengne Abstract Purpose: To critically examine existing approaches to cardiovascular disease (CVD) risk evaluation in people with diabetes, and discuss the use of accurate and validated absolute CVD risk tools as an appropriate basis for CVD prevention in people with diabetes.

Methods: This was a narrative review using evidence from the ADVANCE study and all relevant publications identified via PubMed MEDLINE. Results: There is sufficient evidence that diabetes does not confer a CVD risk equivalent to that in non-diabetic people with existing CVD in all circumstances. In people with diabetes, CVD risk follows a gradient. Reliably capturing this gradient depends on an adequate combination of several risk factors. Many global CVD risk tools applicable to people with diabetes have been developed. Those derived from older cohorts are less accurate in contemporary populations and many newer tools have not been tested. The ADVANCE risk engine, recently developed from the large multinational ADVANCE study, showed acceptable performance on the ADVANCE population and largely outperformed the popular Framingham risk equation when tested on the multinational DIAB-HYCAR cohort of people with type 2 diabetes.

Conclusions: The high-risk status conferred by diabetes does not preclude estimation of absolute CVD risk using tools such as the ADVANCE risk engine and its use as the basis for initiating and intensifying CVD preventative measures.

Adopting such an accurate and validated tool will likely improve prescriptions and outcomes of diabetes care.

Keywords: diabetes mellitus, cardiovascular disease, risk evaluation, ADVANCE, absolute risk Cardiovascular disease (CVD), the leading global killer, is multifactorial by nature. No single risk factor taken alone is able to distinguish people who will go on to develop a cardiovascular event from those who will not. This consideration forms the basis of the contemporary multifactorial approaches to CVD risk evaluation and reduction.

A key aim of CVD risk evaluation is to identify those in the population who’s health outcomes can be modified by performing more medical tests, starting treatments to reduce the level of Correspondence to: Andre Pascal Kengne South African Medical Research Council, Tygerberg, Cape Town, South Africa e-mail: andre.kengne@mrc.ac.za Previously published in Cardiovasc J Afr 2013; 24(9): 351 S Afr J Diabetes Vasc Dis 2014; 11: 121–125

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risk factors or increasing the doses of prescribed riskreducing therapies.1,2 Estimated risks are also used to educate patients about their chances of experiencing a cardiovascular event within a given time period (for example, five or 10 years).

Equipped with this knowledge, patients are more likely to be motivated to adopt healthy lifestyle measures and/or to observe prescribed risk-modifying treatments. These patients are also more likely to regularly report back to their healthcare provider for monitoring and adaptation of treatments, to lower and maintain their risk factors at optimal levels.

Concerning CVD in people with diabetes, healthcare providers who see these patients on a routine basis are interested in gauging the chances of their patients developing any major CVD event over a reasonable period of time (often five to 10 years), and not just specific components such as stroke or myocardial infarction. These busy healthcare providers are also interested in assessing the CVD risk of their patients using accurate and validated global CVD riskevaluation tools.3-5 In the general population, efforts to develop reliable tools for evaluating CVD risk based on a combination of several risk factors have paralleled efforts to improve our understanding of the determinants of CVD and more efficient ways to control them.6 These efforts were initially led by the Framingham investigators, and more recently by investigators from other parts of the world.6,7 The first attempts to develop such tools from the Framingham study date back to the year 1967.8 These first tools, however, did not account for diabetes status or for any other indicator of chronic hyperglycaemia.

Although many subsequent Framingham tools took diabetes status into consideration, the uptake of the Framingham tools in people with diabetes around the world has remained very limited, resulting in the adoption of multivariable CVD tools in people with diabetes to lag behind the general population. One reason was the lack of trust among researchers on the validity of the Framingham tools in people with diabetes, due to the relatively small number of people with diabetes in the Framingham cohort, and the noninclusion of other indicators of exposure to chronic hyperglycaemia in the Framingham tools.9 Another major reason was the publication in the late 1990s of a study from Finland suggesting that people with diabetes but no history of cardiovascular disease had a future risk of CVD similar to the risk of non-diabetic people who have survived a CVD event in the past.10 This study inspired the concept of diabetes as a ‘CVD risk equivalent’, based on which people with diabetes should be treated with cardiovascular risk-reducing therapies such as statins or aspirin, without taking into consideration their absolute CVD risk levels.

However, the concept of diabetes as a CVD risk equivalent has been losing ground in recent years, with the accumulating evidence challenging its validity in all circumstances,11 and supporting the

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importance of absolute risk estimation in people with diabetes as the appropriate basis for CVD risk-factor modification. Such an approach is further supported by the gradual shift in the management of diabetes mellitus from a glucocentric focus to an intensive multifactorial strategy targeting reduction in the risk of both macro- and microvascular complications of diabetes.12,13 The growing recognition of the importance of global CVD risk in people with diabetes has generated interest among researchers to develop tools with improved performance to estimate absolute risk in people with diabetes, or to establish the validity of the existing ones and refine their performance.7 The following development is a discussion on the rationale and strategies for global CVD risk estimation in people with diabetes, with emphasis on the specificities and limitations of these strategies. The discussion is largely inspired by new knowledge gained from CVD risk modelling in the ADVANCE study.3,14

Overview of global cardiovascular risk assessment Global cardiovascular risk assessment is based on the combination of predictive information from several cardiovascular risk factors using mathematical equations (also called models). In those models, the coefficient of each included risk factor indicates its relative contribution to the overall (global) CVD risk.2,15 A model can be used to estimate the risk that a disease is present (diagnostic model) or to estimate the risk that a particular disease or health event will occur within a given time period (prognostic models). The focus of the current article is on prognostic models.

Once developed, a cardiovascular risk model normally requires a validation in both the sample population that was used to develop the model (internal validation) and in independent populations (external validation). Validation consists of testing whether the prognostic model accurately estimates the risk of future events in one or several populations.2,15 The performance of absolute cardiovascular risk models in validation studies is commonly assessed in terms of discrimination, calibration and, more recently, reclassification.2,15 Discrimination is the ability of the model to distinguish people who go on to develop a cardiovascular event and those who remain event free.2,15 For example, for two individuals with diabetes with one developing a cardiovascular event after 10 years of follow up and the other remaining CVD free within that same time period, a discriminating model will systematically assign, at the start of the follow up, a higher absolute risk to the first subject compared to the second.

Discrimination is commonly assessed using the C-statistic, which ranges from 0.5 (lack of discrimination) to 1.0 (perfect discrimination).1,2,15 In general, a C-statistic of 0.7 or greater is considered acceptable.

Calibration describes the agreement between estimated and observed risks. It is assessed by comparing absolute risk estimates from the model with the actual event rates in the test population.1,2,15 For illustration, a 10-year estimated absolute risk of CVD of 20% for a patient indicates that, in a given group of patients with similar characteristics, 20% will experience a cardiovascular event within a 10-year period of follow up. The most commonly reported measure of calibration is the Hosmer-Lemeshow statistic.

Estimates of calibration are sensitive to differences in background levels of risk across populations. For example, if a given CVD risk model is developed in a high-risk population but tested in a lowrisk population, the estimated absolute risks will be unreliably

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high. Recalibration of the risk model by adjusting the baseline risk estimates to fit the target population may help correcting the overor underestimation of risk.1,15

Global cardiovascular risk estimation in people with diabetes Global CVD risk has been estimated in people with diabetes using essentially three main approaches.16 In the ‘CVD riskequivalent’ approach described above, the presence of diabetes mellitus is considered to confer a 10-year absolute CVD risk of 20% or more, which is approximately the 10-year CVD event rate observed in non-diabetic individuals with a prior history of CVD. Such an approach appears to be counter-intuitive as the CVD risk is not uniformly distributed among people with diabetes. This is further supported by many studies showing multivariable risk estimation to be significantly better than classification of diabetes as a cardiovascular risk equivalent.17,18 In the second approach, also termed ‘step approach’, unifying CVD risk-estimation models are developed for both people with diabetes and those without the condition. This approach assumes that major risk factors for CVD are related to future occurrence of CVD in a similar way, regardless of the status for diabetes mellitus.

Stated otherwise, everything else being equal, an individual with diabetes will always have a higher risk of CVD (by a constant amount) than the non-diabetic subject with the same level of other risk factors (e.g. blood pressure or lipid levels). This has been the basis for models such as the popular Framingham cardiovascular absolute-risk models.16 In the last approach, also known as the ‘interaction approach’, CVD risk models are constructed separately for people with and without diabetes. This approach suggests that risk factors are related to future CVD risk in different ways in people with and without diabetes. This approach in people with diabetes was initially used by the UKPDS investigators.9,19 Available studies largely suggest that classical cardiovascular risk factors (including smoking, blood pressure and lipid variables) and even some novel risk factors,16,20-23 affect the risk of CVD in similar ways in people with and without diabetes with no evidence of interaction.

Some risk factors or characteristics are likely to be more frequent in people with diabetes and may justify separate cardiovascular risk models for people with diabetes. These diabetes-specific characteristics include prescriptions of cardiovascular risk-reducing therapies, which may differ in people with and without diabetes.

Additional specific factors are haemoglobin A1c (HbA1c) levels, urinary albumin excretion rate and markers of microvascular complications of diabetes in general (especially retinopathy). These have been demonstrated to be associated with CVD risk and can contribute useful information to predictions.24-29

Performance of popular CVD risk models and the ADVANCE study At the time the ADVANCE study was conducted, CVD riskprediction models in the general population were dominated by models developed from the Framingham Heart study, which for many could also be used in people with diabetes.7 CVD risk models specific to people with diabetes were also available, particularly those from the UKPDS study.7 However, the clinical utility and comparative performance of these popular CVD risk models in contemporary populations with diabetes in diverse settings were still to be established.

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Therefore, one of the major initial steps was to conduct extensive validation studies of the Framingham and UKPDS CVD risk models, using the unique features of the ADVANCE cohort.3 These validation studies revealed that, in the cohort of ADVANCE participants who had no known history of CVD at their enrolment in the trial, the four-year absolute risk of cardiovascular events and components was largely overestimated by the Framingham– Anderson,30 Framingham–D’Agostino31 and UKPDS risk models.9,19 This overestimation was also observed in men and women, Caucasians and non-Caucasians, and the double-placebo cohort (i.e. those assigned to the placebo group in the blood pressurelowering arm and the standard-care group of the blood glucose control arm).3 Discrimination of the Framingham and UKPDS risk models in predicting CVD events in ADVANCE was poor for stroke, and modest to acceptable for coronary heart disease and total CVD. Recalibration substantially attenuated the magnitude of risk overestimation by the Framingham and UKPDS risk models in ADVANCE. Discrimination was unaffected as expected, indicating the need for new CVD risk models with improved predictive accuracy for people with diabetes, particularly those who are receiving many contemporary cardiovascular riskreducing therapies.

Development of the ADVANCE cardiovascular risk model In developing a new model for risk prediction, it is critical to account for the limitations of existing ones in order to improve performance.

The inclusion in ADVANCE of participants from many countries provided the opportunity to account for the substantial variation in the care of diabetes and CVD around the world. Available models so far had been derived from homogenous populations.

The ADVANCE model targets total CVD and therefore captures the interrelation between components of CVD such as CHD or stroke, unlike many existing models that have focused specifically on these components.

The complexity of the relationship between chronic hyperglycaemia and cardiovascular risk has been less fully addressed in existing models. Some improvement was achieved in the ADVANCE model through integration of risk factors to capture both the exposure to chronic hyperglycaemia prior to and after the clinical diagnosis of diabetes. Statistical method is an important component of model development. Trusted statistical methods were used to select the potential risk factors and test their suitability for inclusion in the ADVANCE risk model.14 Risk factors considered for inclusion in the ADVANCE model were: age at clinical diagnosis of diabetes, duration of diagnosed diabetes, gender, blood pressure (BP) indices [systolic BP, diastolic BP, mean arterial (MAP) and pulse (PP) pressures], lipid variables [total, high-density lipoprotein (HDL) and non-HDL cholesterol, ratio of total:HDL cholesterol and triglycerides], body mass index (BMI), waist circumference, waist-to-hip ratio, BP-lowering medication (i.e. treated hypertension), statin use, current smoking, retinopathy, atrial fibrillation (past or present), urinary albumin:creatinine ratio (ACR), serum creatinine (Scr), HbA1c and fasting blood glucose levels, and randomised treatments (BP lowering and glucose control regimens).

Ten of these candidate risk factors were included in the final ADVANCE risk model. Age at diabetes diagnosis and known duration of diabetes were preferred to age at baseline to improve

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the applicability of the ADVANCE risk model to other populations.

The beta coefficients and accompanying standard error for risk factors in the ADVANCE risk model are shown in Table 1.14

Performance of the ADVANCE risk model The applicability of the ADVANCE risk model14 was tested on the same population used to develop the model (i.e. internal validation) and on an independent external sample for which the DIABHYCAR cohort32 was used. In both internal and external validations, the discrimination of the ADVANCE model was acceptable. In comparison with existing total CVD models, the ADVANCE model largely outperformed the Framingham–Anderson and Framingham D’Agostino models. The calibration of the ADVANCE model was excellent in internal validation and good in external validation, with only a modest risk underestimation. This is likely explained by the difference in the levels of preventive therapies between ADVANCE and DIABHYCAR population.

Interestingly, the agreement between predictions by the ADVANCE models and the observed CVD events was consistent across different cut-off points or predicted risk for CVD. For comparison, the two Framingham equations overestimated the risk of CVD in the DIAB-HYCAR cohort by 65% (Anderson equation) and 99% (D’Agostino equation). Using a cut-off point for fouryear predicted risk of ≥ 8% (which is approximately equivalent to a 10-year predicted risk of 20% and above), the ADVANCE model Table 1. BETA coefficients (95% confidence interval) and standard errors for predictors in the advance CVD prediction model14

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would reliably identify 22% of the ADVANCE participants and 39% of the DIAB-HYCAR participants in whom 48% and 66% of CVD events, respectively, occurred during follow up. Further intensifying treatment in such groups on top of any baseline therapy could achieve significant gain in terms of CVD risk reduction.

Dissemination of the ADVANCE risk model To facilitate the uptake of the ADVANCE model in clinical practice, a hand-held calculator and a risk-scoring chart (Fig. 1) have been developed.14 Other tools from this model, including an online calculator, are available on the website of the model to improve its uptake.33 Extensive validations have been conducted to assure that these tools provide estimates similar to those from the full ADVANCE risk equation.

Performance of existing global risk tools for cardiovascular risk estimation in diabetics Two systematic reviews have examined the performance of CVD risk-evaluation models applicable to people with diabetes.7,34 The

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most recent and comprehensive review identified 45 CVD risk models applicable to people with diabetes.7 Of these, 12 were specifically developed for people with type 2 diabetes (including the ADVANCE model) and 33 were developed in the general population, accounting for diabetes as a risk factor. These models vary greatly in their quality and the methodology used to develop them.

Only about a third of the existing CVD risk tools applicable to people with diabetes have been externally validated in a population with diabetes. The discriminative ability of both diabetes-specific CVD prediction models and general population prediction models that use diabetes status as a predictor was generally acceptable to good (i.e. C-statistic ≥ 0.70). The discrimination of prediction models designed for the general population was moderate (C-statistic: 0.59–0.80) and their calibration generally poor.

The most commonly validated models were the general population-based Framingham cardiovascular risk equations and the diabetes-specific UKPDS risk engines. The Framingham prediction models also showed a low-to-acceptable discrimination and a poor calibration. Although the discriminative power of

As an illustration of the use of the risk-scoring chart, a male subject, diagnosed with diabetes three years previously at the age of 50 years, who has a pulse pressure of 50 mmHg and is currently treated for hypertension, also has retinopathy, atrial fibrillation and microalbuminuria, an HbA1c level of 7% and a nonHDL cholesterol level of 3.3 mmol/l, will receive a total score of 13 points: 0 for gender, 3 for age at diagnosis, 1 for known duration, 1 for pulse pressure, 1 for treated hypertension, 1 for retinopathy, 2 for atrial fibrillation, 2 for microabuminuria, and 1 for HbA1c and non-HDL cholesterol level each. A score of 13 points is equivalent to a four-year estimated risk of 6.2%, which is similar to the risk estimated for the same patient using the full equation.

Fig. 1. Major cardiovascular disease points and four-year predicted risk by the ADVANCE model equation.14

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UKPDS engines was acceptable, it had a poor calibration and a tendency toward systematic overestimation of risk, particularly in recent cohorts. The models with best external validity were more contemporary but these had been validated in other patient populations only once.7

Conclusion The quest for the appropriate approaches to assess cardiovascular risk and thus prevent vascular complications in individuals with diabetes is a continuing pursuit. Diabetes mellitus is not a cardiovascular risk equivalent in all circumstances. The CVD risk is not uniformly distributed in individuals with diabetes, but rather follows a gradient. Adequately capturing this gradient depends on the combination of individual risk factors.

Global risk assessment appears to be the way forward for managing CVD risk among people with diabetes. Both the ADVANCE and subsequent studies have provided evidence that existing popular models derived from older cohorts were less accurate for cardiovascular risk evaluation in contemporary population with diabetes.7 The recognition of this non-optimal performance and other limitations of existing models have stimulated efforts to develop new cardiovascular risk models (including the ADVANCE model14) with improved predictive accuracy for people with diabetes.

The ADVANCE model continues to enjoy the unique property that it was developed from a contemporary multinational cohort of people with diabetes, and has been successfully validated in another recent multinational cohort of individuals with diabetes. Inclusion of participants from developing countries in the ADVANCE cohort highlights the potential of the ADVANCE risk model for assisting cardiovascular risk-stratification efforts in many settings around the world.

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18. Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors. Arch Intern Med 2011; 171: 404–410. 171/5/404 [pii] 10.1001/ archinternmed.2011.2.

19. Kothari V, Stevens RJ, Adler AI, Stratton IM, Manley SE, Neil HA, et al. UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk engine. Stroke 2002; 33: 1776–1781.

20. Asia Pacific Cohort Studies Collaboration. Systolic blood pressure, diabetes and the risk of cardiovascular diseases in the Asia–Pacific region. J Hypertens 2007; 25: 1205–1213.

21. Asia Pacific Cohort Studies Collaboration. Cholesterol, diabetes and major cardiovascular diseases in the Asia–Pacific region. Diabetologia 2007; 50: 2289– 2297.

22. Asia Pacific Cohort Studies Collaboration. Smoking, diabetes and cardiovascular diseases in men in the Asia–Pacific Region. J Diabetes 2009; 1: 173–181.

23. Kengne AP, Batty GD, Hamer M, Stamatakis E, Czernichow S. Association of C-reactive protein with cardiovascular disease mortality according to diabetes status: pooled analyses of 25,979 participants from four U.K. prospective cohort studies. Diabetes Care 2012; 35: 396–403. 10.2337/dc11-1588.

24. Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999; 22: 233–240.

25. Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, Golden SH. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004; 141: 421–431.

26. Miettinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Retinopathy predicts coronary heart disease events in NIDDM patients. Diabetes Care 1996; 19: 1445–1448.

27. Van Hecke MV, Dekker JM, Stehouwer CD, Polak BC, Fuller JH, Sjolie AK, et al. Diabetic retinopathy is associated with mortality and cardiovascular disease incidence: the EURODIAB prospective complications study. Diabetes Care 2005; 28: 1383–1389.

28. Targher G, Bertolini L, Tessari R, Zenari L, Arcaro G. Retinopathy predicts future cardiovascular events among type 2 diabetic patients: The Valpolicella Heart Diabetes Study. Diabetes Care 2006; 29: 1178.

29. Juutilainen A, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women. Diabetes Care 2007; 30: 292–299.

30. Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardiovascular disease risk profiles. Am Heart J 1991; 121: 293–28.

31. D’Agostino RB, Sr., Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, Kannel WB. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008; 117: 743–753.

32. Marre M, Lievre M, Chatellier G, Mann JF, Passa P, Menard J. Effects of low-dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). Br Med J 2004; 328: 495.

33. The ADVANCE Collaborative Group. ADVANCE Risk Engine. Available at http:// www.advanceriskengine.com/index.html. Accessed on 04.06.2012 34. Chamnan P, Simmons RK, Sharp SJ, Griffin SJ, Wareham NJ. Cardiovascular risk assessment scores for people with diabetes: a systematic review. Diabetologia 2009; 52: 2001–2014.

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Prevalence and determinants of electrocardiographic abnormalities in sub-Saharan African individuals with type 2 diabetes ANASTASE DZUDIE, SIMEON-PIERRE CHOUKEM, ABDOUL KADIR ADAM, ANDRE PASCAL KENGNE, PATRICIA GOUKING, MESMIN DEHAYEM, FÉLICITÉ KAMDEM, MARIE SOLANGE DOUALLA, HENRY ACHU JOKO, MARIELLE EPACKA EWANE LOBE, YVES MONKAM MBOUENDE, HENRY LUMA, JEAN CLAUDE MBANYA, SAMUEL KINGUE Abstract Aim: This study assessed the prevalence and determinants of electrocardiographic abnormalities in a group of type 2 diabetes patients recruited from two referral centres in Cameroon.

Methods: A total of 420 patients (49% men) receiving chronic diabetes care at the Douala General and Yaoundé Central hospitals were included. Electrocardiographic abnormalities were investigated, identified and related to potential determinants, with logistic regressions.

Results: The mean age and median duration of diagnosis were 56.7 years and four years, respectively. The main electrocardiographic aberrations (prevalence %) were: T-wave abnormalities (20.9%), Cornell product left ventricular Correspondence to: Anastase Dzudzie Department of Internal Medicine, Buea Faculty of Health Sciences, and Department of Internal Medicine, Douala General Hospital, Cameroon e-mail: aitdzudie@yahoo.com Department of Internal Medicine, Buea Faculty of Health Sciences, Cameroon Simeon-Pierre Choukem Félicité Kamden Solange Doualla Henry Achu Joko Marielle Epacka Ewane Lobe Yves Monkam Mbouende Henry Luma Université des Montagnes, Bangangte, Cameroon Abdoul Kadir Adam Department of Medicine, University of Cape Town and Medical Research Council, Cape Town, South Africa Pascal Kengne Diabetes and Endocrine Service, Yaoundé Central Hospital and Faculty of Medicine, Cameroon Patricia Gouking Mesmin Dehayem Jean Claude Mbanya Department of Internal Medicine, Yaoundé Faculty of Medicine, Cameroon Solange Doualla Henry Luma Jean Claude Mbanya Samuel Kingue Previously published in Cardiovasc J Afr 2012; 23(10): 533 S Afr J Diabetes Vasc Dis 2014; 11: 126–130

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hypertrophy (16.4%), arrhythmia (16.2%), ischaemic heart disease (13.6%), conduction defects (11.9%), QTc prolongation (10.2%) and ectopic beats (4.8%). Blood pressure variables were consistently associated with all electrocardiographic abnormalities. Diabetes-specific factors were associated with some abnormalities only.

Conclusions: Electrocardiographic aberrations in this population were dominated by repolarisation, conduction defects and left ventricular hypertrophy, and were more related to blood pressure than diabetes-specific factors.

Keywords: diabetes mellitus, sub-Saharan Africa, Cameroon, ECG, cardiovascular disease A major threat to the health of diabetes subjects is cardiovascular disease (CVD), which currently accounts for about threequarters of all deaths in diabetes patients in major populations and settings.1 Attempts to maintain cardiovascular health in diabetics include: (1) routine prescription of medications with proven beneficial effects on cardiovascular health, such as statins and aspirin; (2) investigation and treatment of individuals with abnormal levels of modifiable risk factors; (3) monitoring of individuals for infra-clinical changes, which are indicators of future high risk for cardiovascular events, or those with lessadvanced stages of diabetes, whose course could be modified through early intervention.2 The electrocardiogram (ECG) is widely used for monitoring.3 ECG changes appear early in the course of diabetes, and usually include alterations such as sinus tachycardia, QTc prolongation, QT dispersion, changes in heart rate variability, ST–T changes, and left ventricular hypertrophy. These changes and others, detected with the use of a resting ECG, often together with an exercise ECG, are used to detect silent ischaemia, assess prognosis and predict future risk. Because the ECG is a non-invasive and relatively easy test to perform, it is used in the series of investigations conducted as part of the annual clinical evaluation of people with diabetes around the world.3 The use of this modality however varies substantially, guided essentially by the availability of ECG machines and the cost of such investigations. As a result, the regional office of the International Diabetes Federation (IDF) for Africa recommends ECG monitoring in diabetes only at the secondary or tertiary level of the healthcare system where facilities for performing an ECG are more readily available.4 Therefore in sub-Saharan Africa, the majority of patients with diabetes who receive care in primary healthcare facilities do not have

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routine ECG screening. Failure to perform regular ECGs means that opportunities to improve cardiovascular health in this population are being missed. Furthermore, our knowledge of the major ECG abnormalities and their determinants in this environment remains very limited.

In this study we assessed the distribution of ECG aberrations and investigated their potential determinants in a group of individuals with type 2 diabetes who were receiving chronic care in two referral hospitals in the two largest cities of Cameroon, Central Africa.

Methods The out-patient sections of the Yaoundé Central Hospital’s diabetes and endocrine service, and the Douala General Hospital’s (DGH) internal medicine service and sub-specialties served as settings for recruitment of participants for this study. The Yaoundé Central Hospital (YCH) has been described in detail elsewhere.5,6 The DGH internal medicine and sub-specialities service has an individualised, dedicated endocrine section, which is the main referral centre for endocrine diseases and diabetes in Douala, the second major city of Cameroon (approximately 2.5 million people). Patients with diabetes and its complications, residing in Douala and surrounding regions were the most likely to receive care in our clinic during the study period.

Overall, the healthcare system in Cameroon is organised into primary, secondary and tertiary levels. Care at the primary level is provided by nurses and general practitioners and is essentially geared towards acute conditions. Secondary-level facilities provide access to some form of specialist care. Tertiary-level facilities (including YCH and DGH) serve as a referral hospital for primaryand secondary-level health facilities, and for routine consultations and follow up, as in our study.

From January 2010, the Yaoundé health service has had three endocrinologists and the Douala health service two. Patients with diabetes who received chronic care in the two study clinics were required to have an annual evaluation as part of their routine care.

In addition to a clinical consultation, this evaluation included: (1) an assessment of diabetes control (fasting glucose and haemoglobin A1c levels); (2) an assessment of chronic complications (eyes: fundoscopy, kidney function: albuminuria, serum urea and creatinine levels); (3) a cardiovascular work up including an assessment of lipid profiles (total cholesterol, high-density lipoprotein cholesterol and triglycerides) and a resting ECG. Participants in this study were recruited from patients presenting for these annual evaluations. The study was approved by the administrative authorities of the two health facilities, and ethical clearance was obtained from the Cameroon National Ethics Committee.

Four hundred and twenty individuals with type 2 diabetes receiving chronic care in the two study facilities were consecutively enrolled over a two-year period from January 2008 to January 2010. Only the patients’ first consultation during this period was considered, and no other exclusion criteria were applied. The type of diabetes was based on the diagnosis of the attending physician.

In addition, patients had to be at least 30 years of age at the time of their first diagnosis of diabetes.

Blood pressure (mmHg) was measured on the right arm with the participant in a seated position, after 10 minutes’ rest, with an Omron® MX2 basic electronic device (Omron Healthcare Co, Ltd, Kyoto, Japan) with the appropriate cuff size. The average of two

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measurements recorded five minutes apart was used in this study.

Body weight (kg) was measured in light clothing, using a SECA® scale, and height (m) was measured with a standard stadiometer.

The body mass index (BMI) for each patient was calculated as weight/height2 (kg/m2). The waist circumference (cm) was measured with a tape measure on the horizontal plane midway between the lowest rib margin and upper edge of the iliac crest.

A 12-lead resting ECG was done on all subjects using the Cardi Max Fx-7302®. All ECG tracings were centrally interpreted by the same investigator who is a cardiologist (AD) and did not know the subjects’ backgrounds. Significant ECG findings such as ST-segment elevation or depression, T-wave aberrations (inversion or tall T wave), bundle branch block, left ventricular hypertrophy (LVH), right and left atrial enlargement, arrhythmias and other changes were noted.

LVH was defined according to three different criteria: • Cornell voltage-duration product [(RaVL + SV3) × QRS complex duration] > 2.623 mm × ms in men and > 1.558.7 mm × ms in women,7 • Cornell voltage (SV3 + RaVL > 24 mm in women and 28 mm in men) • Sokolov-Lyon index (SV1 + RV5/6 > 35 mm).

Compared with echocardiography, the cut-off values for the Cornell voltage duration product gave the best sensitivity with a specificity of 95%.7 ECG measurements were done with a ruler on the resting ECG tracings, and were expressed as the average of three determinations on consecutive QRS complexes. R-wave amplitude in aVL and S-wave depth in V3 were measured as the distance (mm) from the isoelectric line of their zenith and nadir, respectively. QRS duration was measured from the beginning to the end of the QRS complex.

QTc prolongation was defined as a QTc > 460 ms in both men and women.

A diagnosis of ischaemic heart disease was made based on the American Heart Association criteria. These criteria include ECG features of significant ST-segment depression, defined as an ST-segment depression > 1 mm in more than one lead, and T-wave inversion. Myocardial infarction was defined as an ST-segment elevation (convex upwards) > 0.08 s, associated with T-wave inversion in multiple leads, and reciprocal ST-segment depression in opposite leads.

Statistical analysis Data were analysed using SPSS® version 17 for Windows (SPSS, Chicago, IL). Differences in means and proportions for participants’ characteristics were assessed using analysis of variance and χ2 tests as applicable, and the influence of likely confounders was adjusted for with logistic regressions models. A probability of p < 0.05 was set as the threshold of statistical significance.

Results Of the 420 patients recruited, 207 (49%) were men and 250 (56%) were from the Yaoundé centre. The mean age was 56.7 years and the median duration of diagnosed diabetes was four years (IQR 25th to 75th percentiles: 1–9).

As expected, anthropometric characteristics were different between men and women. Diabetes control was also poorer in men than in women (all p < 0.04), otherwise men were similar to women with regard to many other characteristics, including history

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of diabetes, treatment and complications, and cardiovascular risk profile (Table 1).

With few exceptions, participants’ characteristics were mostly similar across the participating centres. The few exceptions related to hip circumference (p < 0.001), diastolic blood pressure (p < 0.001), haemoglobin A1c level (p < 0.001), creatinine clearance rate (p = 0.04), the use of ACE inhibitors (p = 0.01) and the presence of neuropathy (p = 0.008).

The distribution of ECG abnormalities was: T-wave aberrations (20.9%), left ventricular hypertrophy according to the Cornell product criteria (16.4%), arrhythmia (16.2%), ischaemic heart disease (13.6%), conduction defects (11.9%), QTc prolongation (10.2%) and ectopic beats (4.8%). Unlike T-wave aberrations and left ventricular hypertrophy, the prevalence of major aberrations was similar in men and women (Table 2). The distribution of subtypes of arrhythmia, conduction defects and T-wave aberrations is shown in Fig. 1.

Table 1. Profile of the 420 men and women with type 2 diabetes Variables Number (%) Age (years) Median (range) known duration of diabetes (years) Parental history of diabetes Smoking Body mass index (kg/m2) Waist circumference (cm) Hip circumference (cm) Waist-to-hip ratio

Men n (%)

Women n (%)

p

207 (49) 213 (51) 55.9 (9.83) 57.5 (9.96) 0.09 4 (0–9) 4 (1–8) 0.71 103 (49.7) 110 (51.6) 27 (13.1) 5 (2.3) 27.2 (4) 29.7 (6) 95.3 (10.8) 94.9 (12.92) 98.5 (10) 103.7 (12.9) 0.96 (0.08) 0.91 (0.11)

Total n (%) 56.7 (9.92) 4 (1–9) 213 (50.7)

0.69 32 (7.6) < 0.001 28.5 (5.2) < 0.001 95.1 (11.9) 0.71 101.2 (11.8) < 0.001 0.94 (0.10) < 0.001 142.2 (25.3)

Hypertension and treatments Systolic blood pressure 142.8 (23.6) 1 41.6 (26.91) 0.61 85.1 (13.2) (mmHg) Diastolic blood pressure 85.6 (12.2) 84.5 (14.15) 0.37 57.1 (18.2) (mmHg) Pulse pressure (mmHg) 57.2 (16.8) 57.1 (19.49) 0.95 211 (50.2) Hypertension 97 (46.8) 114 (53.5%) 0.17 186 (44.3) Any blood pressurelowering 83 (40.1) 103 (48.4) 0.09 139 (33.1) medication ACE inhibitors 70 (33.8) 69 (32.4) 0.84 5 (1.2) ARA II antagonists 2 (1) 3 (1.4) 0.99 118 (28.1) Diuretics 54 (26.1) 64 (30) 0.37 69 (16.4) Calcium channel blockers 33 (15.9) 36 (16.9) 0.79 30 (7.1) Beta-blockers 7 (3.4) 23 (10.8) 0.004 185 (49) Lipid profile and lipid-modifying therapies Total cholesterol (mg/dl) 187 (49) 184 (51) 0.57 47 (18) HDL cholesterol (mg/dl) 47 (19) 48 (18) 0.52 101 (67–141) Median (range) triglycerides 99 (64–142) 1 02 (68–140) 0.62 35 (13.2) (mg/dl) Lipid modifying therapies 19 (9.2) 16 (7.5) 0.58 1 (0.2) History of cardiovascular disease Coronary heart disease 0 (0.0) 1 (0.5%) Cerebrovascular diseases 6 (2.9) 9 (4.2%) Lower limb occlusive 3 (1.4) 3 (1.4%) vascular disease Median (range) creatinine 91 (70–113) 88(63–108) clearance (ml/min/1.73 m2)

0.32 15 (3.6) 0.46 6 (1.4) 0.97 89 (67–111) 0.23

273 (66)

0.58 0.69 0.19 0.34 0.04

185 (44) 9 (2.1) 68 (16.2) 177 (81) 8.2 (2.3)

Diabetes treatment and control Metformin 133 (64.7) 143 (67%) Suphonamide 93 (45) 92 (43%) Acarbose 2 (0.9) 7 (3.3%) Insulin 37 (17.9) 31 (14.5%) Fasting capillary glucose 185 (85) 169 (77) (mg/dl) Haemoglobin A1c (%) 8.5 (2.3) 7.9 (2.2)

0.03

Microvascular complications Any diabetic retinopathy 38 (18.3%) 28 (13.1) Any diabetic nephropathy 30 (14.5%) 37 (17.4) Any diabetic neuropathy 52 (25.1%) 42 (19.7)

0.14 0.42 0.18

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66 (15.7) 67 (15.9) 94 (22.4)

Fig. 1. Rhythm, conduction and T-wave changes in 420 men and women with type 2 diabetes.

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Table 2. ECG changes in 420 men and women with type 2 diabetes

Variables Number (%) Arrhythmia Conduction changes Ectopic beats T-waves changes QTc prolongation Ischaemic heart disease

Men n (%) 207 (49) 31 (15) 28 (13.5) 10 (4.8) 53 (25.6) 18 (8.7) 34 (16.4)

Women n (%) p 213 (51) 37 (17.4) 0.51 22 (10.3) 0.37 10 (4.7) 0.99 35 (16.4) 0.02 25 (11.7) 0.34 23 (10.8) 0.12

Left ventricular hypertrophy by diagnostic criteria Cornell product 14 (6.7) 55 (25,8) < 0.001 Sokolov index 17 (8.2) 7 (3.3) 0.03 Cornell index 12 (5.8) 5 (2.3) 0.09

Total n (%) 420 68 (16.2) 50 (11.9) 20 (4.8) 88 (20.9) 43 (10.2) 57 (13.6)

69 (16.4) 24 (5.7) 17 (4.1)

The distribution of subtypes of conduction defects was significantly different in men and women (p = 0.03). Significant predictors of ECG abnormalities are shown in Table 3. Age variables (age at diabetes diagnosis and duration of diagnosed diabetes), and blood pressure variables were the common significant predictors of ECG abnormalities.

The presence of diabetic nephropathy was significantly associated with T-wave aberrations [OR: 0.45 (95% CI: 0.24–0.83)] and ischaemic heart disease [OR: 0.47 (0.23–0.95)]; otherwise, diabetes medications and markers of disease control were not associated with the outcomes. Waist circumference was associated with a 3% (95% CI: 1–6%) higher risk of QTc prolongation, otherwise no other marker of adiposity was associated with the outcomes.

Similarly, none of the lipid variables was significantly associated with ECG abnormalities.

Discussion This study revealed the high prevalence of ECG aberrations in this population of individuals with a short duration of clinically overt type 2 diabetes. While some of these aberrations were benign, others were potential indicators of the presence of serious conditions such as ischaemic heart disease, or were associated with increased future

risk of fatal and non-fatal cardiovascular events. The minimal use of preventive treatment for cardiovascular disease in this population highlights the scope for improving cardiovascular health in people with type 2 diabetes in this region.

Some aspects of ECG abnormalities in people with diabetes, such as those relating to LVH,8 ischaemic heart disease9 or QTc prolongation10 have been investigated in a few studies on diabetics in Africa. To the best of our knowledge, however, there is no recent study that has investigated the full spectrum of resting ECG aberrations and potential determinants in people with diabetes in this part of the world.

In accordance with a previous study in Tanzania,8 we found a 16% prevalence of LVH in our study. Interestingly, blood pressure variables were also the main determinants of LVH, with approximately similar range of effects.8 That more than one in 10 participants in the current study had ECG aberrations suggestive of ischaemic heart disease has relevance in sub-Saharan Africa where cardiovascular diseases are not considered a major priority health issue in people with diabetes.11 In a previous study in the same region, using both resting and exercise ECGs, a prevalence of 7.5% for cardiac ischaemia was found; although this was based on a small sample size.12 Even after accounting for the uncertainties around the estimates from this and other studies in sub-Saharan Africa,9 our findings support a growing prevalence of ECG-diagnosed ischaemic heart disease in diabetes patients in our region over time. This prevalence was similar to that found in stroke survivors in Africa,13 and therefore provides more evidence in support of the high cardiovascular risk of diabetes patients in this part of the world.

It is possible that the prevalence of ECG-diagnosed cardiac ischaemia was inflated in our study for at least two reasons: (1) in the absence of a correlation between ECG aberrations and clinical features, some of the observed ST-segment and T-wave changes could have been variants of normal ECGs, as previously described in blacks;14 (2) some of the repolarisation changes could have been secondary to hypertension, which is very common in diabetes patients in this region.5 In a cohort of black and white subjects with no known

Table 3. Odds ratio and 95% confidence intervals for predictors of ECG changes Variables Age at diabetes diagnosis (years) Duration of diagnosed diabetes (years) Gender (men vs women) Recruitment centre (Yaoundé vs Douala) Presence/history of nephropathy Metformin use Suphonylurea use Insulin use Waist circumference (cm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse pressure (mmHg) Heart rate (beats/min) Total cholesterol (mg/dl) HDL cholesterol (mg/dl)

Arrhythmia Conduction T-wave changes Long QTc IHD LVH Ectopic beat 1.02 (0.99–1.04) 1.06 (1.02–1.09) *1.02 (0.99–1.04) 1.02 (0.99–1.06) 1.00 (0.97–1.03) 1.05 (1.02–1.08)* 1.06 (1.01–1.12)* 1.02 (0.97–1.06) 1.01 (0.96–1.07) 1.04 (1.00–1.08)* 1.08 (1.03–1.13)* 1.02 (0.98–1.07) 1.05 (1.00–1.10)* 1.04 (0.97–1.12) 1.16 (0.69–1.96) 0.66 (0.36–1.22) 0.55 (0.34–0.89)* 1.40 (0.73–2.68) 0.62 (0.35–1.09) 4.86 (2.54–9.25)* 0.84 (0.34–2.12) 0.89 (0.52–1.53) 0.69 (0.34–1.38) 1.06 (0.61–1.84) 0.87 (0.51–1.47) 0.60 (0.31–1.18) 0.98 (0.96–1.00) 1.00 (0.99–1.01) 1.00 (0.98–1.02) 1.01 (0.99–1.02) 1.01 (0.99–1.03) 0.60 (0.35–1.04) 0.66 (0.15–2.82)

0.89 (0.48–1.66) 0.76 (0.33–1.73) 0.87 (0.46–1.67) 0.90 (0.49–1.65) 3.26 (0.96–11.09) 1.01 (0.98–1.03) 1.01 (1.00–1.03)* 1.01 (0.99–1.04) 1.02 (1.00–1.04)* 0.98 (0.96–1.01) 1.15 (0.63–2.10) 1.39 (0.29–6.51)

1.78 (1.10–2.87) 0.45 (0.24–0.83)* 1.04 (0.63–1.73) 0.71 (0.44–1.15) 1.06 (0.54–2.09) 0.98 (0.96–1.00) 1.01 (1.00–1.02)* 1.01 (0.99–1.03) 1.02 (1.00–1.03) 0.98 (0.96–1.00)* 1.55 (0.96–2.52) 2.23 (0.63–7.98)

1.05 (0.55–2.02) 1.28 (0.73–2.26) 3.79 (2.13–6.75)* 0.53 (0.25–1.15) 0.47 (0.23–0.95)* 0.66 (0.31–1.40) 1.86 (0.97–3.55) 0.85 (0.46–1.56)0.89 (0.48–1.64) 1.47 (0.76–2.86) 0.58 (0.33–1.02) 1.23 (0.69–1.20) 0.51 (0.26–1.11) 1.11 (0.50–2.47) 0.93 (0.40–2.17) 1.03 (1.01–1.06)* 1.00 (0.97–1.02) 1.02 (1.00–1.04) 1.02 (1.01–1.03)* 1.01 (0.99–1.02) 1.02 (1.01–1.03) 1.05 (1.02–1.07)* 1.01 (0.99–1.03) 1.01 (0.99–1.04) 1.02 (1.00–1.03) 1.01 (0.99–1.03) 1.03 (1.01–1.05)* 1.05 (1.03–1.08)* 0.99 (0.97–1.01) 0.99 (0.97–1.01) 1.22 (0.64–2.36) 1.27 (0.72–2.24) 1.24 (0.71–2.16) 1.03 (0.17–6.01) 3.82 (0.92–15.96) 1.13 (0.24–2.39)

2.36 (0.93–5.95) 0.52 (0.17–1.66) 0.47 (0.15–1.46) 0.62 (0.25–1.57) 1.44 (0.31–6.75) 1.01 (0.97–1.04) 1.01 (0.99–1.02) 1.01 (0.98–1.05) 1.00 (0.98–1.03) 1.03 (0.97–1.04) 1.19 (0.48–2.97) 1.97 (0.19–19.98)

*p < 0.05; IHD, ischaemic heart disease; LVH, left ventricular hypertrophy; all models are adjusted for gender, age and diabetes diagnosis, known duration of diabetes and study centre

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cardiovascular disease who were participants of the Health, Aging, and Body Composition study (Health ABC study), the presence of major or minor ECG aberrations at baseline was associated with coronary heart disease risk during follow up, independent of classical cardiovascular risk factors.15 The findings of the Health ABC study suggest that the presence of ECG aberrations, including those used to diagnose cardiac ischaemia in our study, should be given consideration as they may indicate an adverse underlying cardiovascular risk profile.

Approximately 13% of participants in this study were on a statin, preventive treatment widely recommended for routine use in people with diabetes. No correlation was found between statin use and ECG-diagnosed ischaemic heart disease. This suggests that the use of statins in this population could be almost doubled by using ECG criteria to diagnose for ischaemic heart disease. It was shown in a recent study that the use of recommended preventive therapies for cardiovascular disease risk reduction, based on global risk evaluation, was limited in Africa in people with diabetes and those without.16 Our study had some limitations. In the absence of follow up, we were unable to establish any causal relationship between identified predictors of cardiovascular risk and ECG aberrations. This was a hospital-based study and therefore included participants who may not have been typical of those in the community where the majority of type 2 diabetes persons remain undiagnosed.17 While this could have affected the prevalence of ECG changes found in our study, it was less likely to have affected the direction of associations described, and therefore would not have invalidated the major findings from this study.

That ECGs were interpreted by an investigator who was unaware of the clinical background of the patients, which could have affected the prevalence of some of the outcomes. Indeed, using such an approach resulted at best in a description of significant changes, with no assumption about possible correlations between coincident aberrations in the same patient.

Our study had some major advantages, including the considerable sample size, which gave us reasonable statistical power to reliably investigate the parameters. We were also able to investigate the full spectrum of resting ECG aberrations, which no previous study has achieved in Africa. The extensive data collection of both clinical and biological profiles enabled a wide range of predictors to be investigated for their possible link with prevalent ECG aberrations.

Conclusion ECG aberrations are frequent in people with diabetes in sub-Saharan Africa. While some may be benign, others are indicators of serious

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underlying conditions or high future risk for cardiovascular disease.

These aberrations have the potential to improve cardiovascular disease risk stratification and the implementation of preventative strategies in people with diabetes in sub-Saharan Africa.

The growing prevalence of serious ECG aberrations over time suggests the need for strategies to monitor such changes and their determinants, so as to refine the cardiovascular preventative strategies in sub-Saharan Africa. Elsewhere, dedicated diabetes registries have successfully served these functions.

References 1. International Diabetes Federation. Diabetes Atlas. 4th edn. Brussels: IDF, 2009.

2. International Task Force for Prevention of Coronary Heart Disease, International Atherosclerosis Society. Pocket Guide to Prevention of Coronary Heart Disease.

Munster: Born Bruckmeier Verlag GmbH, 2003.

3. International Diabetes Federation. Global Guidelines for Type 2 Diabetes. Brussels: International Diabetes Federation, 2005.

4. IDF Africa Region Task Force on Type 2 Diabetes Clinical Practice Guidelines. Type 2 clinical practice guidelines for sub-Saharan Africa: IDF Afro Region, 2006.

5. Choukem SP, Kengne AP, Dehayem YM, Simo NL, Mbanya JC. Hypertension in people with diabetes in sub-Saharan Africa: revealing the hidden face of the iceberg. Diabetes Res Clin Pract 2007; 77: 293–299.

6. Kengne AP, Djouogo CF, Dehayem MY, Fezeu L, Sobngwi E, Lekoubou A, et al.

Admission trends over 8 years for diabetic foot ulceration in a specialized diabetes unit in Cameroon. Int J Low Extrem Wounds 2009; 8: 180–186.

7. Norman JE, Jr., Levy D. Improved electrocardiographic detection of echocardiographic left ventricular hypertrophy: results of a correlated data base approach. J Am Coll Cardiol 1995; 26: 1022–1029.

8. Lutale JJ, Thordarson H, Gulam-Abbas Z, Vetvik K, Gerdts E. Prevalence and covariates of electrocardiographic left ventricular hypertrophy in diabetic patients in Tanzania. Cardiovasc J Afr 2008; 19: 8–14.

9. Lester FT, Keen H. Macrovascular disease in middle-aged diabetic patients in Addis Ababa, Ethiopia. Diabetologia 1988; 31: 361–367.

10. Odusan O, Familoni OB, Raimi TH. Correlates of cardiac autonomic neuropathy in Nigerian patients with type 2 diabetes mellitus. Afr J Med Med Sci 2008; 37: 315–-320.

11. Kengne AP, Amoah AG, Mbanya JC. Cardiovascular complications of diabetes mellitus in sub-Saharan Africa. Circulation 2005; 112: 3592–3601.

12. Mbanya JC, Sobngwi E, Mbanya DS, Ngu KB. Left ventricular mass and systolic function in African diabetic patients: association with microalbuminuria. Diabetes Metab 2001; 27: 378–382.

13. Joubert J, McLean CA, Reid CM, Davel D, Pilloy W, Delport R, et al. Ischemic heart disease in black South African stroke patients. Stroke 2000; 31: 1294–1298.

14. Brink AJ. The normal electrocardiogram in the adult South African Bantu. S Afr J Lab Clin Med 1956; 2: 97–123.

15. Auer R, Bauer DC, Marques-Vidal P, Butler J, Min LJ, Cornuz J, et al. Association of major and minor ECG abnormalities with coronary heart disease events. J Am Med Assoc 2012; 307: 1497–1505.

16. Kengne AP, Njamnshi AK, Mbanya JC. Cardiovascular risk reduction in diabetes in sub-Saharan Africa: What should the priorities be in the absence of global risk evaluation tools? Clin Med: Cardiol 2008; 2: 25–31.

17. Mbanya JC, Kengne AP, Assah F. Diabetes care in Africa. Lancet 2006; 368: 1628– 1629.

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Diabetes Personality Making a difference, one patient at a time S Afr J Diabetes Vasc Dis 2014; 11: 131–132

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r Hester Davel, a diabetes nurse educator at the Centre for Diabetes and Endocrinology (CDE) in Houghton, Johannesburg, has been involved in diabetes education for 18 years. Her interest in chronic disease, and diabetes in particular, began when she was working in a medical ward and encountered a young boy with type 1 diabetes.

‘The other staff made sure he didn’t have access to sweets. At night, however, he used to steal sweets from other patients while they were asleep, and the next day his diabetes would be uncontrolled.

When I asked him why he did it, his answer was that because his own sweets were always taken away, “Nobody gives me a choice”.’

Hester has a particular interest in type 1 diabetes patients, especially children, and much of her work has focused on them. ‘They tend to feel that no one understands them. Often they feel deprived of things, like sweets, that other children take for granted. This makes them naturally rebellious.’ She recalls being something of a rebel herself as a child and is therefore able to relate.

Type 1 diabetes is hard work and as that boy said, these young people are not given any choice in the matter. It requires a demanding regimen of constant testing and injecting, and patients don’t have the option to say, ‘I don’t want this!’ Hester feels that her job as an educator is to walk the diabetes road beside her patients, not ahead of them or behind them. ‘It’s important to listen to them and hear what they want me to hear. I need to understand them in order to help them live well with diabetes. It’s not about me being prescriptive and dictating what I think is good for them, without regard for their feelings.’

So she works with patients to set goals that are their own, rather than hers, and then facilitates their making the difference in their lives that they want for themselves. This is what she means by walking beside them. ‘If you walk ahead of your patient, it means you’re more interested in yourself than him/ her and more focused on what you think they need to know and do. When you walk behind the patient, it means you’re not engaged enough and while you might listen to them, you don’t interact actively enough to help them effect the changes they might need to make.’

Along with paediatric endocrinologist, Dr David Segal, Hester was the driving force behind the establishment of regular camps for young diabetes patients. The first one took place in 2005. ‘I felt like I was fulfilling my purpose on earth, because I had always wanted to create a space for children with diabetes where they could play, laugh, sing, paint and just have fun and be creative; a place where they would not feel deprived in any way, and where they would experience unconditional love and a sense of complete safety.’ While not in the form of camps, she is also currently focusing on creating an environment of safety and understanding for those living with diabetes, family members, siblings and caretakers from all walks of life.

Hester considers it a gift to be a diabetes nurse educator and often uses the ‘starfish’ fable to explain this. ‘A little boy, who was walking along the shore, picking up beached starfishes and throwing them back in the sea, was stopped by a man who asked him why he was doing this as he couldn’t save them all. The boy replied as he flung yet another starfish back into the water, “I’ve made a

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difference for that one!” And that’s what drives me, making a difference one patient at a time.’

‘It’s important to see each patient as an individual and not only the diabetes’, she says. ‘This requires genuine interest in who they are, the whole person, and to help them see the light within.’ She knows she’s succeeding when a patient smiles when she enters a room or unexpectedly gives her a hug.

There is an emotional component to diabetes that Hester thinks is often under-recognised. Diabetes patients and their families face many challenges – there are lots of ups and downs and a lot of pain. These emotional aspects can sometimes seem overwhelming.

Hester understands this at a deeply personal level. Several years ago she took Gareth in, a teenager with type 1 diabetes, becoming, as she puts it, an ‘instant mom’. ‘So I live with the reality every day myself. I

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see his fears of hypoglycaemic episodes and of long-term complications – and have experienced first-hand the challenges of dealing with medical schemes to ensure that my “pot of gold at the end of the rainbow” gets the best treatment possible. Today he is an awesome, responsible young man who shares our vision of creating a better place for those living with diabetes. He sees his diabetes as a gift rather than a disadvantage.’

Concluding, she underscores that it’s a great honour to work at the CDE with a team of colleagues she considers mentors. ‘I learn more and more from them every day. And despite the challenges, I can honestly say that there has never been a day when I’ve hated my job. I’ve never been bored. I love what I do!’

P Wagenaar

A single injection of FGF1 arrests type 2 diabetes in mice

I

n mice with diet-induced diabetes, the equivalent of type 2 diabetes in humans, a single injection of the protein FGF1 was enough to restore blood glucose levels to a healthy range for more than two days. The discovery by Salk scientists, published recently in the journal Nature, could lead to a new generation of safer, more effective diabetes drugs.

The team found that sustained treatment with the protein doesn’t merely keep blood glucose under control, it also reverses insulin insensitivity, the underlying physiological cause of diabetes. Equally exciting is that it doesn’t result in the side effects common to most current diabetes treatments.

‘Controlling glucose is a dominant problem in our society’, says Ronald M Evans, director of Salk’s Gene Expression Laboratory and corresponding author of the article. ‘And FGF1 offers a new method to control glucose in a powerful and unexpected way.’

Diabetes drugs currently on the market aim to boost insulin levels and reverse insulin resistance by changing expression levels of genes to lower glucose levels in the blood. But many of these drugs, which increase the body’s production of insulin, can cause glucose levels to dip too low and lead to life-threatening hypoglycaemia, as well as other side effects.

In 2012, Evans and his colleagues discovered that FGF1, a long-ignored growth factor, has a hidden function: it helps the body respond to insulin. Unexpectedly, mice lacking FGF1 quickly develop diabetes when placed on a high-fat diet, which suggests that FGF1 plays a key role in managing blood glucose levels. This led the researchers to wonder whether providing extra FGF1 to diabetic mice could affect symptoms of the disease.

Evans’ team injected doses of FGF1 into obese mice with diabetes to assess the protein’s potential impact on metabolism.

The researchers were stunned by what happened: they found that with a single dose, blood glucose levels quickly returned to normal.

‘Many previous studies that had injected FGF1 showed no effect on healthy mice’, says Michael Downes, a senior staff

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scientist and co-corresponding author of the study. ‘However, when we injected it into a diabetic mouse, we saw a dramatic improvement in glucose levels.’

Importantly, FGF1, even at high doses, did not cause glucose to drop to dangerously low levels, a risk factor associated with many glucose-lowering agents. Instead, the injections restored the body’s own ability to regulate insulin and blood sugar naturally, keeping glucose levels within a safe range and effectively reversing the core symptoms of diabetes.

‘With FGF1, we really haven’t seen hypoglycaemia or other common side effects’, says Salk postdoctoral research fellow Jae Myoung Suh, a member of Evans’ laboratory. ‘It may be that FGF1 leads to a more “normal” type of response compared to other drugs because it metabolises quickly in the body and targets certain cell types.’

The mechanism of FGF1 still isn’t fully understood; neither is the mechanism of insulin resistance, but Evans’ group discovered that the protein’s ability to stimulate growth is independent of its effect on glucose, bringing the protein a step closer to therapeutic use.

‘There are many questions that emerge from this work and the avenues for investigating FGF1 in diabetes and metabolism are now wide open’, Evans says. Identifying the signalling pathways and receptors that FGF1 interacts with is one of the first issues he would like to address. He is also planning human trials of FGF1 with collaborators, but it will take time to finetune the protein into a therapeutic drug.

‘We want to move this to people by developing a new generation of FGF1 variants that solely affect glucose and not cell growth’, he says. ‘If we can find the perfect variation, I think we will have found a new, very effective tool for glucose control.’

Source: http://medicalxpress.com/news/2014-07-diabetes-tracks-mice-side-effects. html

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Patient information leaflet

Ottilia Brown Clinical Psychology Department, Grey’s Hospital, Pietermaritzburg e-mail: Ottilia.Brown@kznhealth.gov.za

S Afr J Diabetes Vasc Dis 2014; 11: 133–136

Keep and Copy Series PSYCHOLOGICAL CONSIDERATIONS IN THE MANAGEMENT OF DIABETES Diabetes is a complex non-communicable disease requiring lifelong management and personal responsibility of the patient for every aspect of treatment. Inadequate metabolic control in diabetic patients is well documented. This article focuses on psychology and diabetes in terms of examining the role of psychology in management of the illness throughout its course, and the negative influence of psychological presentations on diabetes management. The article also highlights the prevalence of these presentations and emphasises the importance of identifying and treating these conditions, as this can significantly improve adherence and glycaemic control. In closing, some thoughts on the way forward are discussed.

S

outh Africa faces a quadruple burden of diseases consisting of HIV and AIDS, other communicable diseases, non-communicable diseases, and violence and injuries. The consequence of this is high levels of mortality.1 Non-communicable diseases (NCDs) are the leading cause of mortality globally, causing more deaths than all other causes combined. �������������������������������������� The Negotiated Service Delivery Agreement signed between the Minister of Health and the President identified four strategic outputs for national health, namely increasing life expectancy, decreasing maternal and child mortality, combating HIV and AIDS and decreasing the burden of diseases from tuberculosis, and strengthening health system effectiveness.2 Reducing mortality from NCDs is critical to increasing life expectancy. Diabetes is classified as a non-communicable chronic disease.

According to the World Health Organisation (WHO),3 36 million people died globally from NCDs in 2008, with 3% of these deaths being attributed to diabetes. Premature deaths from NCDs are particularly high in poorer countries with around 80% of such deaths occurring in low- and middle-income countries. Globally, deaths due to NCDs are projected to increase by 17% over the next 10 years, but the

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greatest increase (24%) is expected in the African region. By 2030 it is estimated that NCDs will contribute to 75% of global deaths.4 Accurate reporting on NCDs in South Africa is affected by inadequate surveillance and research and hence there is a lack of recent data on the prevalence of diabetes in South Africa.5 According to the WHO,6 NCDs accounted for 29% of deaths in South Africa in 2008, with 3% of these deaths being attributed to diabetes. Statistics South Africa attributed 40% of deaths to NCDs in 2008, with 2% being attributed to diabetes. While this prevalence may seem small in relation to other NCDs, cardiovascular morbidity and mortality related to diabetes is well documented,7 meaning that diabetes contributes to high NCD mortality in other ways.

Diabetes is a complex disease requiring multiple treatment modalities, the bulk of which are reliant on the patient taking primary responsibility for the day-to-day management of the illness. Diabetes has been recognised as one of the most emotionally and behaviourally challenging and demanding chronic illnesses.8 Both type 1 and type 2 diabetes require treatment regimens that are complex, including medication, self-monitoring and lifestyle

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management (diet, exercise, coordination of food intake and exercise to prevent hypoglycaemia).9 Adherence to these complex regimens is paramount to delaying and/or preventing the onset of serious diabetes complications, such as retinopathy, neuropathy and nephropathy.10 Research indicates that psychological factors such as depression, anxiety, diabetes-specific distress, fear of hypoglycaemia, and eatingdisordered behaviours play a significant role in adherence to diabetes regimens.11,12 In addition to adherence outcomes, research also indicates that psychological factors can increase the risks of poor glycaemic control and diabetic keto-acidosis (DKA).13 The psychological aspects of diabetes are overwhelming and should be considered and included in the treatment of diabetes in order to ensure the effective management of the illness.14 DISEASE COURSE AND THE ROLE OF PSYCHOLOGY The primary reasons for psychological referral of diabetic patients are poor adherence to treatment regimen, poor adjustment to illness, stress exacerbating medical symptoms and/or self-care, psychiatric presentations, and cognitive problems.15 The mental health of the diabetic patient is an important consideration as the patient requires considerable motivation and ego strength to comply with the self-care demands of the illness.8 Psychology has a significant role to play throughout the course of the disease.

At diagnosis, patients are suddenly expected to make significant lifestyle changes and integrate complex treatment regimens into their lives.

Individuals diagnosed with type 2 diabetes are faced with challenges pertaining to the fact that their nutrition and exercise habits are already deeply entrenched.9 Patients inevitably respond differently to the diagnostic news, some may experience shock which may cause emotional distress while others may respond indifferently or with relief as the reason for symptom presentation can now be explained.8 Following diagnosis, depending on the type of diabetes and stage at diagnosis, a treatment regimen is prescribed. While adherence can significantly delay the onset of diabetes-related complications, it does not always translate into immediate good results, and positive feedback may not be possible in the short term, causing the patient to have to persist for long periods of time before benefitting from regimen adherence. This delay in results, despite considerable efforts, may be frustrating and even demotivating for patients. Patients can therefore benefit from learning active, problem-focused, and pro-active coping behaviours, which can be applied across settings and over a long period of time.8 Patients can further benefit from psychological interventions that identify barriers to adherence,16 and use this information to develop new healthy behaviours, enhance existing healthy behaviours, and eliminate unhealthy behaviours as they relate to improved glycaemic control.17

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PSYCHOLOGICAL PRESENTATIONS AND DIABETES MANAGEMENT Depression Depression is twice as common in diabetic patients as the general population.18,19 It has been associated with hyperglycaemia for type 1 and type 2 diabetes.20 This co-morbidity is often under-diagnosed and undertreated in more than a quarter of the diabetic population.19,21 The clinical relevance of this under-treatment is significant as depression has been associated with decreased metabolic control,19 poor adherence to treatment regimens,22 diminished quality of life,19 and early mortality.23 Poor glycaemic control can also exacerbate depression and diminish response to anti-depressant therapy.19 In addition, the combination of depression and diabetes has been shown to increase the risk of developing diabetes complications such as cardiovascular disease.24 Anxiety It has been reported that the prevalence of anxiety in diabetic patients is 30 to 40%.25 Anxiety has been related to poor glycaemic control, poorer quality of life,25,26 and decreased self-care behaviours.27 A number of explanations exist for this link. It has been postulated that sympathetic nervous system responses to hyperglycaemia can produce anxiety symptoms. Further, endocrine abnormalities resulting from diabetes may be aggravated by normal physiological stress responses. Lastly, anxiety may be a response to the complexity of the illness and the associated treatment regimen, which may negatively affect coping ability.15 Regardless, the negative effect of anxiety on adherence and quality of life makes this condition clinically relevant in the effective management of diabetes.

Eating-disordered behaviour Eating disorders and eating-disordered behaviour are a major concern in managing diabetes.28 Eating problems that may be considered mild in non-diabetic patients can have significant clinical consequences for diabetic patients.29 In particular, insulin restriction to lose weight in type 1 diabetes patients increases risk for potentially life-threatening complications of diabetes, including higher HbA1c readings, more frequent DKA episodes, higher risk for developing infections, more frequent use of medical services, and increased risk of mortality.29,30 Insulin restriction has also been related to earlier onset of diabetes-related complications, retinopathy and neuropathy.31 Disordered eating behaviour is often well hidden and therefore diabetes healthcare providers have to ask pertinent questions to uncover this behaviour.28 Stress The link between psychological stress and poor diabetes control is well known.32 Stressful life events have been found to be concomitant with an increased risk of the development of type 1 diabetes in children,33,34 as

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PATIENT INFORMATION LEAFLET

well as type 2 diabetes in predisposed individuals.32 Psychological distress and poor glycaemic control have been linked in patients with established type 1 and type 2 diabetes.32,35 Stress elicits the release of counter-regulatory hormones, such as adrenaline and cortisol, which in turn results in energy mobilisation, often resulting in elevated glucose levels. In addition, stress can disrupt diabetes control by negatively affecting indispensable self-care behaviours.36 Fortunately stress-management techniques can play a significant role in long-term glycaemic control.32 Diabetic patients can therefore benefit greatly from stress-management training.37

screening and appropriate referral becomes essential. The psychological problems of depression, anxiety, eating-disordered behaviour and eating disorders discussed in this article require comprehensive psychotherapeutic and psychopharmacological intervention. Screening for cognitive decline and involving the family in diabetes management is essential to ensure glycaemic control despite cognitive deficits. Addressing these psychological presentations and recognising the role of psychology in diabetes management can significantly improve glycaemic control and delay and/or prevent diabetes complications.

Cognitive impairment Diabetes is associated with a greater rate of decline in cognitive function and a greater risk of cognitive decline.38,39 Findings with regard to the contribution of co-morbid depression and diabetes to the development of cognitive impairment have been mixed. While one study showed no significant relationship between depression and dementia,39 another study with a cohort of 3 837 diabetic patients found that patients with major depression and diabetes had an increased risk of the development of dementia compared to those with diabetes alone.40 With regard to the aetiology of diabetes, cognitive deficits have been associated with chronic hyperglycaemia and frequent, severe hypoglycaemic episodes.41 Cognitive deficits and decline will have a direct effect on the patient’s ability to self-care. Family involvement becomes a crucial part of diabetes care at this point. Screening and early detection are essential to ensure that adherence is not adversely affected.

References

THE WAY FORWARD The clinical significance of identifying and appropriately treating psychological problems in diabetic patients is well documented. Psychosocial adaptation is an important treatment outcome as it positively influences quality of life and treatment efficacy.8 Given the adverse effect of the presence of psychological conditions on diabetes management, a comprehensive approach to managing diabetes is required.

A multidisciplinary team comprising relevant medical and allied health professionals would be ideal in order to tackle the physical and psychological complexities of diabetes.42 In addition, a patient-centred collaborative treatment approach that engages with and empowers the patient to actively participate in his/her consultations and treatment and encourages open communication between patient and provider is highly recommended as a means of enlisting adherence.8 This open collaborative communication should include discussions about barriers to adherence, emotional responses to diabetes and psychological factors that affect adherence and coping. Various authors have made a case for empowering patients, simply because every aspect of diabetes management is dependent on the patient choosing to adhere.11,43 In cases where a multidisciplinary approach is not possible, effective

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18. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of co-morbid depression in adults with diabetes: a meta-analysis. Diabetes Care 2001; 24: 1069–1078. Available from: http://care.diabetesjournals.org/content/24/6/1069. full.pdf+html.

19. Lustman PJ, Clouse RE. Depression in diabetic patients: the relationship between mood and glycemic control. J Diabetes Complicat 2005; 19(2): 113–122. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15745842.

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39. Bruce DG, Davis WA, Casey GP, Starkstein SE, Clarnett RM, Foster JK, et al.

Predictors of cognitive impairment and dementia in older people with diabetes.

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Comorbid depression is associated with an increased risk of dementia diagnosis in patients with diabetes: a prospective cohort study. J Gen Intern Med 2010; 25: 423–429. Available from: http://europepmc.org/articles/PMC2855007.

41. Fontbonne A, Berr C, Ducimetière P, Alpérovitch A. changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects. Diabetes Care 2001; 24(2): 366–370. Available from: http://care.diabetesjournals.org/ content/24/2/366.full.pdf+html.

42. Bayless M, Martin C. The team approach to intensive diabetes management.

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Glucose ‘control switch’ in the brain key to both types of diabetes

R

esearchers at Yale School of Medicine have pinpointed a mechanism in part of the brain that is key to sensing glucose levels in the blood, linking it to both type 1 and type 2 diabetes.

The findings were published in the July 28 issue of Proceedings of the National Academies of Sciences. ’We’ve discovered that the prolyl endopeptidase enzyme, located in a part of the hypothalamus known as the ventromedial nucleus, sets a series of steps in motion that control glucose levels in the blood’, said lead author Sabrina Diano, professor in the Departments of Obstetrics, Gynecology and Reproductive Sciences, Comparative Medicine, and Neurobiology at Yale School of Medicine. ‘Our findings could eventually lead to new treatments for diabetes.’

The ventromedial nucleus contains cells that are glucose sensors. To understand the role of prolyl endopeptidase in this part of the brain, the team used mice that were genetically engineered with low levels of this enzyme. They found that in the absence of this enzyme, mice had high levels of glucose in the blood and became diabetic.

136

Diano and her team discovered that this enzyme is important because it makes the neurons in this part of the brain sensitive to glucose. The neurons sense the increase in glucose levels and then tell the pancreas to release insulin, thus preventing diabetes.

‘Because of the low levels of endopeptidase, the neurons were no longer sensitive to increased glucose levels and could not control the release of insulin from the pancreas, and the mice developed diabetes’, said Diano, who is also a member of the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism.

Diano said the next step in this research is to identify the targets of this enzyme by understanding how the enzyme makes the neurons sense changes in glucose levels. ‘If we succeed in doing this, we could be able to regulate the secretion of insulin, and be able to prevent and treat type 2 diabetes’, she said.

Source: http://medicalxpress.com/news/2014-07-glucose-brain-key-diabetes.html

VOLUME 11 NUMBER 3 • SEPTEMBER 2014

Lipanthyl + Statin Better Outcome

THE MISSING PIECE IN LIPID MANAGEMENT 1

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