SAJDVD Volume 7, Issue 3 by Clinics Cardive Publishing

THE SOUTH AFRICAN JOURNAL OF

Diabetes Vascular Disease OBESITY

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Featured in this issue Diabetes and the eye P-values Diabetic retinopathy HbA1c in diagnosing diabetes Metabolic memory in type 1 diabetes Metabolic syndrome in non-diabetic hypertensive Nigerians Diabetes – a lifestyle Screening for retinopathy

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IN RESISTANC E INSUL

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DIABETES &

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Diabetes & vascular disease

R DISEA

THE SOUTH AFRICAN JOURNAL OF

HYPER INSULINAEMIA THROMBOSI S HYP

ERGLYCA

E MI A

VOLUME 7 NUMBER 3 • SEPTEMBER 2010 www.diabetesjournal.co.za

Corresponding Editor DR FA Mahomed Grey’s Hospital, Pietermaritzburg Consulting Editors PROF WF MOLLENTZE PROF J-C MBANYA PROF AJ BRINK National Editorial Board DR A AMOD Centre for Diabetes, Endocrinology and Metabolic Diseases, Life Healthcare, Chatsmed Gardens Hospital, Durban SR K BECKERT Diabetes Nurse, Paarl

CONTENTS

Editorials

Diabetes and the eye FA Mahomed

P-values: what are they? J Upton, E McCutcheon

PROF F BONNICI Emeritus Professor, Faculty of Health Sciences, University of Cape Town and President of Diabetes South Africa

Reviews

PROF R DELPORT Department of Family Medicine, University of Pretoria

What’s new in diabetic retinopathy?

DR L DISTILLER Director of the Centre of Diabetes and Endocrinology, Houghton, Johannesburg DR F MAHOMED Department of Endocrinology, Grey’s Hospital, Pietermaritzburg PROF CD POTGIETER Specialist Nephrologist, University of Pretoria and Jakaranda Hospital, Pretoria PROF K SLIWA Associate Professor of Medicine and Cardiology, Baragwanath Hospital, University of the Witwatersrand, Johannesburg PROF YK SEEDAT Emeritus Professor of Medicine and Honorary Research Associate, University of Natal, Durban International Editorial Board PROF IW CAMPBELL Physician, Victoria Hospital, Kircaldy, Scotland, UK PROF PJ GRANT Professor of Medicine and head of Academic Unit of Molecular Vascular Medicine, Faculty of Medicine and Health, University of Leeds; honorary consultant physician, United Leeds Teaching Hospitals NHS Trust, UK PROF J-C MBANYA Professor of Endocrinology, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Cameroon and President-Elect, International Diabetes Federation (2006−2009) PROF N POULTER Professor of Preventive Cardiovascular Medicine, Imperial College, School of Medicine, London, UK DR H PURCELL Senior Research Fellow in Cardiology, Royal Brompton National Heart and Lung Hospital, London, UK

L Visser

International expert committee recommends new role for HbA1c in diagnosing diabetes M Kirby

102

Metabolic memory in type 1 diabetes AD Wright

105

profile: Generic CMYK printer profile National Diabetes Information Service offersColor support Composite Default screen

B Young

Research Article

107

Metabolic syndrome among newly diagnosed non-diabetic hypertensive Nigerians: prevalence and clinical correlates

It's the shell that makes

AA Akintunde, OE Ayodele, PO Akinwusi, JO Peter, OG Opadijo

Diabetes Personality

111

Diabetes – a lifestyle, not a disease

safer.

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

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

Community Initiative

113

The ‘Changing Diabetes’ bus will now screen for retinopathy and diabetic foot syndrome

Diabetes Educator’s focus

114

South African approaches to structured education in type 1 diabetes Kamaretha Beckert

Patient Information Leaflet

117

Laser treatment for diabetic retinopathy L Visser

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

Hands On

119

Use of the retinal camera in diabetes eye care in South Africa G Ladner

ADA Watch

123

2010 update from Orlando, USA, 25–29 June 2010 J Aalbers, Dr F Mahomed, Prof WF Mollentze

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

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

Journal Update

127

Retinopathy focus J Aalbers

Drug Trends in Diabetes

131

Novo Nordisk update meeting at CDE

Aspirin in primary prevention: focus on people with diabetes

Erectile dysfunction and diabetes: a prelude to cardiovascular disease

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JL Aalbers

safer.

Front cover photographs from left to right: • Retinal cameras and their use in screening for retinopathy in diabetes (page 119). • Early detection of retinopathy depends on a regular eye examination (page 93). • Blood pressure monitoring is vital in diabetes.

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

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

EDITORIAL

Diabetes and the eye FA MAHOMED

iabetic retinopathy is an important microvascular complication of diabetes and remains one of the leading causes of blindness worldwide among adults.1 In relatively lowresource countries such as South Africa, it is important to establish a clear cost-effective strategy to tackle both preventative as well as curative aspects of the management of diabetic eye disease. Areas that are covered in this issue of the journal include the use of the retinal camera in screening, a national diabetes information service and structured education programmes. These are areas of growth that deserve our full attention and effort to assist with the improvement of our diabetes services. The retinal camera, although initially an expensive option, would allow a larger number of patients with diabetes to have access to good-quality screening. The cost per patient would be low. One could use technicians to operate the camera, and they could even do the screening by following standard charts. Ophthalmologists could oversee their work. The technology is mobile and could therefore provide a service in both rural and urban settings. While there are some retinal camera programmes operating in South Africa, it would be worthwhile having a national programme. Dr Ladner suggests starting with a pilot programme to consider the best way to roll out a national programme. A national diabetes information service is important. Knowing the number of patients with diabetes, whether it is type 1 or 2, their insulin usage, the burden of complications and geographical differences would allow for planning the diabetes services, namely the allocation of funds, staffing and resources. If we were to follow clinical outcomes and how they change over time, it would give us a measure of the quality of our care and whether we are making progress or not. Working with accurate data is important. The main challenges are upgrading computer infrastructure at all levels of healthcare, the costs involved, co-ordination of data gathering, statistical services and delivery of data to stakeholders for review and action. Structured education programmes would ensure us giving out a uniform message about diabetes. These may have to be adapted to local conditions depending on the predominant language of an area and the available resources. These programmes need to be part of a formal Department of Health diabetes strategy and

Correspondence to: FA Mahomed Grey’s Hospital, Pietermaritzburg Tel: +27 (0)33 897-3000 e-mail: Fazleh.Mahomed@kznhealth.gov.za S Afr J Diabetes Vasc Dis 2010; 7: 91

VOLUME 7 NUMBER 3 • SEPTEMBER 2010

FA Mahomed

must reach all levels of healthcare. There is considerable interest in receiving training in diabetes, especially among nursing staff. It is time we provided a comprehensive programme to meet this need. The use of HbA1c as a diagnostic test is discussed. This topic has been debated for some time and its feasibility in South Africa is still unclear. Some of the issues revolve around cost, access to the test in clinics, standardisation of the test and variability of the test between different population groups.2 We await a consensus statement from the Society of Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA). The Skinners in Pietermaritzburg are featured in the community personality section. We pay tribute to the countless dedicated people like them who face an uphill battle trying to provide support to the many patients with diabetes in South Africa. It is hoped that diabetes care and management of complications such as diabetic retinopathy will improve if we adopt a more structured approach to diabetes healthcare in South Africa.

References 1.

Abu El-Asrar AM, Al-Mezaine HS, Ola MS. Pathophysiology and management of diabetic retinopathy. Medscape CME. Released: 12/01/2009. http://cme. medscape.com/viewpublication/30067. Accessed 15/12/2009. Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-independent, black–white Differences in hemoglobin A1c levels: A cross-sectional analysis of 2 studies. Ann Intern Med 2010; 152: 770–777.

EDITORIAL

SA JOURNAL OF DIABETES & VASCULAR DISEASE

P-values: what are they? J Upton, E McCutcheon

-values are commonly included in the results sections of randomised controlled trials (RCTs), but what is a p-value and how should it be interpreted? The ‘p’ stands for ‘probability’; the chance of something happening. If there is a 0% chance of something occurring (i.e. it is impossible), then the p-value is 0. Similarly, if there is a 100% chance of something occurring (i.e. it is certain), then the p-value is 1. The p-value may fall anywhere between these two extremes. For example, there is a one-in-six chance that if you rolled a dice you would throw a 1. The p-value for this would be 0.1666 (i.e. 1 divided by 6). Further examples of p-values are given in Table 1. P-values are often included in the results sections of quantitative research papers to indicate whether a finding was likely to have occurred by chance. For example, Weekes, et al. (2009)1 conducted a randomised controlled trial2 to assess the impact of nutritional support on patient-centred outcomes in outpatients with COPD at risk of malnutrition. Patients were randomised to two groups. The treatment group received dietary counselling and advice on food fortification; the control group received a dietary advice leaflet. After six months the researchers compared outcomes between the two groups to see if there were any statistically significant differences between them, i.e. to see if nutritional support had made a greater impact on the outcome measures than the dietary leaflet. Two of the outcome measures included in the study were FEV1 and weight. The average difference in FEV1 between the two groups after six months was 0.03 litres; the average difference in weight between the two groups was 3.1 kg. The authors analysed the data to ascertain if these differences between the two groups were statistically significant. The p-value for weight was 0.02 and the p-value for FEV1 was 0.56. Researchers traditionally use a cut-off point of p = 0.05. If the p-value is 0.05 or higher the researcher is likely to conclude that there is no difference between the two groups. In the above study the p-value of 0.02 for weight was lower than this cut-off point.

Table 1. Examples of p-values

Certain

Chance of an event occurring

Percentage probability

p-value

100 times out of 100 (every time)

100%

1 (100/100)

56 times out of 100 (just over half of the time)

56%

0.56 (56/100)

25 times out of 100 (quarter of the time)

25%

0.25 (25/100)

5 times in 100

0.05 (5/100)

2 times in 100

0.02 (2/100)

0.01%

0.001 (0.1/100)

0 (0/100)

0.1 times in 100 Impossible 0 times in 100

The authors therefore concluded that nutritional support had a significant effect on body weight. There was a very small chance (2%) that there was really no difference in body weight between the two groups of patients but the authors were happy to accept this small chance. The p-value for FEV1 was 0.56. As this is higher than the 0.05 cut-off point the researchers concluded that ‘nutritional support had no significant effect on lung function’. The technical way of saying this is that they ‘failed to reject the null hypothesis’.3 The smallest p-value reported in scientific papers is ‘< 0.001’. In an RCT this indicates that there is a one-in-a-thousand chance that there is no difference between the treatment and control groups. It is not possible to have a p-value of zero in an RCT as there is always a small chance that the results would have been different if a different sample of participants had been included or the randomisation of participants to each of the study groups had been different.

References Jane Upton Research Project Manager, Education for Health

Ellen McCutcheon Research Assistant, Education for Health

S Afr J Diabetes Vasc Dis 2010; 7: 92

Weekes CE, Emery PW, Elia M. Dietary counselling and food fortification in stable COPD: a randomised trial. Thorax 2009 Apr; 64(4): 326–31. doi:10.1136/ thx.2008.097352. For further information about randomised controlled trials please see BJPCN Respiratory 2007; 1(3): 109; BJPCN Respiratory 2008; 2(2): 13. For further information about the null hypothesis please see BJPCN Respiratory 2008; 3(1): 17; BJPCN Respiratory 2008; 2(4): 15.

VOLUME 7 NUMBER 3 • SEPTEMBER 2010

SA JOURNAL OF DIABETES & VASCULAR DISEASE

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What’s new in diabetic retinopathy? Linda Visser Abstract

hat is new in diabetic retinopathy? In short – not that much! Most of what we know about diabetic retinopathy and the management of patients with diabetic retinopathy is based on extensive research and multicentre trials performed in the 1970s and 1980s, and laser treatment remains the gold standard. Newer treatments, such as intra-vitreal injections are mostly used as adjuncts to laser therapy. Indications for surgery (vitrectomy) have increased over the years as retinal imaging equipment, intraoperative instrumentation, viewing systems and surgical outcomes have improved. What is abundantly clear is that the ocular health of diabetic patients lies in the hands of the patient and his primary physician or endocrinologist. Good control of the diabetes, blood pressure and serum lipids as well as appropriate and timely referral for screening for diabetic retinopathy will go a long way to ensuring vision is maintained throughout life. Waiting for the patient to complain of visual problems before referring him for an eye examination could sentence him to a life of darkness.

Background Diabetes mellitus, a disease with significant morbidity and premature mortality, is affecting increasing numbers of people worldwide. In 2000, the WHO estimated there were 171 million people with diabetes worldwide, and this has been projected to increase to 366 million by 2030.1 There are no national prevalence statistics available for diabetes mellitus in South Africa, but it is estimated that 5.5% of the population over the age of 30 years have diabetes and 4.2% of all deaths in South Africa in 2000 were attributable to diabetes mellitus.2 An increase in the frequency of type 2 diabetes in the paediatric age group has been noted in several countries and has been associated with the increased frequency of childhood obesity.3 These trends predict an increase in the number of individuals with diabetes as well as associated increased costs for healthcare and the burden of disability, especially blindness, associated with diabetes and its complications. Diabetic retinopathy is a leading cause of new cases of legal blindness among working-age adults. The prevalence rate of retinopathy for adults aged 40 years and older in the United States is 3.4% and that for vision-threatening retinopathy is 0.75%.4 No equivalent statistics are available for South Africa. Correspondence to: Linda Visser Department of Ophthalmology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban Tel: +27 (0)31 260-4341 Fax: +27 (0)31 260-4221 e-mail: visser@ukzn.ac.za S Afr J Diabetes Vasc Dis 2010; 7: 93–98

VOLUME 7 NUMBER 3 • SEPTEMBER 2010

Linda Visser

Risk factors Duration of diabetes, severity of hyperglycaemia, presence of hypertension and raised serum lipid levels are all major risk factors associated with the development and progression of diabetic retinopathy. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) found that in type 1 diabetes, the prevalence of diabetic retinopathy varied from 17% in persons with diabetes for less than five years, to 97.5% in those with diabetes for 15 years or more. Proliferative diabetic retinopathy, the most vision-threatening form of the disease, was present in approximately 50% of type 1 patients with 20 years’ duration of the disease.5 In type 2 diabetes, 28.8% of persons with a known duration of diabetes of less than five years and 77.8% of those with diabetes for more than 15 years had retinopathy. The rate of proliferative diabetic retinopathy varied from 2% in patients who had had diabetes for less than five years to 15.5% of patients who had had diabetes for 15 years or more.6 Hyperglycaemia is the key alterable risk factor associated with the development of diabetic retinopathy. Support for this association is found in results of the Diabetes Control and Complications Trial (DCCT) for type 1 diabetics and the United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetics.7-9 Once retinopathy is present, duration of diabetes appears to be a less important factor than hyperglycaemia for progression from earlier to later stages of retinopathy. Intensive management of hypertension has been demonstrated to slow progression of retinopathy.9 Elevated serum lipid levels on the other hand speed up the process.10 As these factors are also associated with substantial cardiovascular morbidity and mortality and other complications associated with diabetes, it is reasonable to encourage patients with diabetes to be as compliant as possible with therapy for all medical aspects of their disease.

Natural history and clinical classification Without intervention, diabetic retinopathy will progress from minimal changes to more severe stages. It is important to recognise the stages in which treatment may be most beneficial. Decades

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

of clinical research have provided excellent data on the natural course of the disease and on treatment strategies that are highly effective in preventing the occurrence of severe vision loss. These studies include the following major clinical trials: DCCT, UKPDS, the Diabetic Retinopathy Study (DRS), the Early Treatment Diabetic Retinopathy Study (ETDRS) and the Diabetic Retinopathy Vitrectomy Study (DRVS). The earliest clinically apparent stage of retinopathy is called non-proliferative diabetic retinopathy (NPDR) and is characterised by retinal vascular abnormalities, including micro-aneurysms, intraretinal haemorrhages and cotton-wool spots (Table 1). Increased retinal vascular permeability that occurs at this or later stages of retinopathy may result in diabetic maculopathy, characterised by retinal thickening (oedema) and/or lipid deposits (hard exudates) in the macular region (central 5–6-mm diameter area of the posterior pole) (Table 2). Clinically significant macular oedema (CSME) is a term commonly used to describe retinal thickening and/or adjacent hard exudates that involve either the centre of the macula or threaten to spread into it (Figures 1 and 2). As diabetic retinopathy progresses, there is a gradual closure of retinal vessels, resulting in impaired perfusion and retinal ischaemia. Signs of increasing ischaemia include venous abnormalities (e.g. beading, loops), intra-retinal microvascular abnormalities (IRMA), and more severe and extensive retinal haemorrhages and exudation. When these signs progress beyond certain defined thresholds, severe NPDR is diagnosed (Table 1). The more advanced stage, proliferative diabetic retinopathy (PDR), is characterised by the onset of neovascularisation of the inner surface of the retina, induced by vascular endothelial growth factor (VEGF), a substance released by the ischaemic retina. New vessels at the optic disc (NVD) and new vessels elsewhere in the retina (NVE) are prone to bleed, resulting in vitreous haemorrhage. These new vessels may undergo fibrosis and contraction and may result in epi-retinal membrane formation, vitreo-retinal traction bands, retinal tears, and tractional or rhegmatogenous retinal detachments. Table 1. Classification of diabetic retinopathy by severity based on clinical findings. Disease severity level

Findings on dilated ophthalmoscopy

No apparent retinopathy

No abnormalities

Mild NPDR

Micro-aneurysms only

Moderate NPDR

More than just micro-aneurysms, but less than severe NPDR

Severe NPDR

PDR

Any of the following (4-2-1 rule) and no signs of proliferative retinopathy: • severe intra-retinal haemorrhages and microaneurysms in each of four quadrants • definite venous beading in two or more quadrants • moderate IRMA in one or more quadrants One or both of the following: neovascularisation vitreous or pre-retinal haemorrhage

IRMA = intraretinal microvascular abnormalities; NPDR = non-proliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy. Note: Any patient with two or more of the characteristics of severe NPDR is considered to have very severe NPDR.

When new vessels are accompanied by vitreous haemorrhage, or when new vessels at the optic disc occupy about one-quarter to one-third or more of the disc area, even in the absence of vitreous haemorrhage, PDR is deemed to be ‘high-risk’ (Figure 3). Neovascular glaucoma can result from new vessels growing on the iris (NVI) and anterior chamber angle structures.

Prevention and early detection A healthy lifestyle with exercise and weight control may decrease the risk of developing diabetes, but cannot completely prevent it. By contrast, the blinding complications of diabetes mellitus can be prevented or moderated in the majority of patients if their blood glucose control is tight (monitoring serum glycosylated haemoglobin levels), other risk factors such as hypertension and hyperlipidaemia are managed and they are referred to the ophthalmologist timeously (Table 3). Table 2. Classification of diabetic maculopathy. Disease severity level

Findings on dilated ophthalmoscopy

Diabetic macular oedema apparently absent

No apparent retinal thickening or hard exudates at posterior pole

Diabetic macular oedema apparently present

Some apparent retinal thickening or hard exudates at posterior pole

If diabetic macular oedema is present, it can be categorised as follows:* • mild

Retinal thickening or hard exudates in posterior pole but distant from centre of macula

• moderate

Retinal thickening or hard exudates in posterior pole approaching but not involving the centre of the macula

• severe

Retinal thickening or hard exudates in the posterior pole involving the centre of the macula

*Hard exudates are a sign of current or previous macular oedema. Diagnosing retinal thickening requires a three-dimensional assessment, best performed using slit-lamp biomicroscopy and/or stereoscopic fundus photography.

Table 3. Recommended intervals for eye examinations for patients with diabetes. Recommended time of first examination

Recommended follow-up*

Type 1

3–5 years after diagnosis

Yearly if no retinopathy or mild NPDR

Type 2

At time of diagnosis

Yearly if no retinopathy or mild NPDR

Prior to pregnancy type 1 or type 2**

Prior to conception and early in the first trimester

Every 3–12 months for mild or moderate NPDR. Every 1–3 months for severe NPDR or worse

Diabetes type

NPDR = non-proliferative diabetic retinopathy. *Abnormal findings may dictate more frequent follow-up examinations – see management section. **Women who develop gestational diabetes do not require an eye examination during pregnancy, because such individuals are not at increased risk for diabetic retinopathy during pregnancy.

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Early detection of retinopathy depends on educating patients with diabetes as well as their families and healthcare providers about the importance of regular eye examination even though the patient may be completely asymptomatic. Treatment can yield substantial cost savings compared with the costs for those disabled by vision loss. Analyses from the DRS, ETDRS and DRVS trials showed that the treatment for diabetic retinopathy may be 90% effective in preventing severe vision loss using current treatment strategies.11 Although effective treatment is available, their primary-care physicians for ophthalmic care refer far fewer patients with diabetes than would be expected. Even in a first-world environment such as the USA, it was found that less than 50% of diabetics underwent an annual eye examination.12 In South Africa, where the burden of

disease is very high and the numbers of ophthalmologists are low, it is likely that only 10% of patients receive eye examinations at the appropriate intervals. There are numerous screening programmes in existence

Figure 3. Proliferative diabetic retinopathy.

New vessels Pre-retinal haemorrhage Gliosis (fibrosis)

Figure 1. Moderate non-proliferative diabetic retinopathy with maculopathy.

Micro-aneurysms Hard exudates

Table 4. Management recommendations for patients with diabetes

Presence of CSME

Follow-up (months)

Pan-retinal laser

Focal and/ or grid laser*

1. Normal or minimal NPDR

2. Mild to moderate NPDR

No Yes

6–12 2–4

No No

No Usually**

3. Severe NPDR

No Yes

2–4 2–4

Sometimes+ Sometimes+

No Usually‡

4. Non-high-risk PDR

No Yes

2–4 2–4

Sometimes+ Sometimes+

No Usually**

5. High-risk PDR

No Yes

2–4 2–4

Usually Usually

No Usually‡

6. Inactive PDR

No Yes

6–12 2–4

No No

No Usually

Severity of retinopathy

Figure 2. Moderate non-proliferative diabetic retinopathy with massive macular exudation in a patient with hypertension and hyperlipidaemia.

Micro-aneurysms Hard exudates

VOLUME 7 NUMBER 3 • SEPTEMBER 2010

CSME = clinically significant macular oedema; NPDR = non-proliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy. *Adjunctive treatment, which may be used include intra-vitreal steroids or anti-vascular endothelial growth factor (VEGF) agents (off-label use). **Deferring treatment is an option when the centre of the macula is not involved, close-up follow-up is possible if the patient understands the risk. Treatment is more likely to stabilise vision, but treatment close to the fovea may result in damage to central vision and, with time, scars may expand and cause further deterioration of vision. + Benefit of early pan-retinal laser at severe NPDR or non-high-risk PDR stages is greater in patients with type 2 diabetes. Other factors such as poor compliance, impending cataract surgery or pregnancy and status of the fellow eye will help in determining the timing of the laser. ‡ Preferable to perform focal laser first, prior to pan-retinal laser to minimise pan-retinal laser-induced exacerbation of the macular oedema.

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Figure 4. OCT showing cystoid macular oedema.

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Figure 6. FFA showing capillary non-perfusion and leakage.

Capillary nonperfusion Leakage from NVE

Figure 5. OCT showing vitreo-macular traction

Figure 7. FFA showing leakage from new vessels elsewhere.

worldwide and the type of programme utilised will depend largely on the availability of personnel (trained ophthalmic nurses, general practitioners, endocrinologists, optometrists, technicians doing fundus photography). Single-field fundus photography is not a substitute for a comprehensive ophthalmic examination, but there is level I evidence that it can serve as a screening tool for diabetic retinopathy to identify patients with retinopathy for referral for ophthalmic evaluation and management. The advantages of single-field fundus photography interpreted by trained readers are: ease of use (only one photograph is required), convenience, and ability to detect retinopathy.13 Having said that, this technology is not considered a replacement for a comprehensive eye evaluation by an ophthalmologist, but in a resource-poor area, it can be of considerable assistance in sifting through a large number of patients to prioritise referrals to the ophthalmologist.

Ancillary tests Apart from colour fundus photography, other useful ancillary tests sometimes ordered by the ophthalmologist include: • optical coherence tomography (OCT). This is a new imaging technique using near-infrared frequency light to obtain an almost living histological picture of the retina, showing the vitreo-retinal interface, retina and sub-retinal space. It is extremely useful for exactly quantifying retinal thickness and diagnosing vitreo-macular traction, which is amenable to surgery (Figures 4 and 5). • fundus fluorescein angiography (FFA). This entails the intravenous administration of fluorescein dye, followed by

Leakage from NVE Microaneurysms

fundus photography through a special filter to identify areas of capillary non-perfusion, new vessels or sources of capillary leakage resulting in macular oedema (Figures 6–9).

Management Laser (photocoagulation) ‘surgery’ is still the gold-standard treatment for diabetic retinopathy. In general, it is advised for patients with high-risk PDR, CSME or neovascularisation of the anterior chamber angle (Table 4). Vitrectomy is also an important part of the treatment strategies for advanced diabetic retinopathy and has been shown to increase vision-related quality of life.14 Newer but generally temporary therapies include intra-vitreal injections of steroids (triamcinolone acetonide) or anti-VEGF

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Figure 8. FFA showing focal leakage amenable to focal laser.

Figure 9. FFA showing diffuse macular oedema amenable to grid laser.

Macular oedema Micro-aneurysms

Figure 10. Scatter laser scars

Right

drugs (bevacizumab, ranibizumab or pegaptanib) for their antipermeability and anti-angiogenic effects on decreasing macular oedema and neovascularisation. These drugs have a temporary effect though and repeated injections (with associated risks â&#x20AC;&#x201C; Table 5) are necessary. As an adjunct to laser or vitrectomy techniques, these drugs are showing excellent results.15 Laser techniques can be classified as pan-retinal, focal, or grid. Pan-retinal laser, also referred to as scatter laser, is used for the treatment of proliferative diabetic retinopathy and indirectly treats neovascularisation of the optic nerve, retinal surfaces, or in the anterior chamber angle by placing laser burns throughout the

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peripheral fundus. This ablation of the ischaemic peripheral retina leads to a decrease in the production of vascular endothelial growth factor (VEGF), which in turn leads to regression of the new vessels (Figure 10a, b). It may be done in more than one session. Focal and grid laser are used for the treatment of diabetic macular oedema. Focal laser applies light, small-sized burns to leaking micro-aneurysms in the macula, and grid laser applies a grid or pattern of burns (mimicking pan-retinal laser but using smaller burns) to the areas of macular oedema arising from diffuse capillary leakage. The goal of laser surgery is to reduce the risk of visual loss rather

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Table 5. Side effects and complications of treatment of diabetic retinopathy. Treatment

Side effect/complication

Focal/grid laser for DME

Initial decrease in central vision Paracentral scotomas if burns close to fovea Permanent central scotoma from inadvertent foveal burn

Pan-retinal laser for severe NPDR or PDR

Central vision loss from macular oedema Constriction of peripheral visual fields Poor dark adaptation Vitreous haemorrhage if new vessels present Loss of accommodation

Vitrectomy

Recurrent vitreous haemorrhage Retinal detachment Rubeosis iridis Severe visual loss Microbial endophthalmitis Cataract

Intra-vitreal injections

Cataract progression (especially steroid injections) Elevated intra-ocular pressure (more with steroids) Microbial endophthalmitis Transient sterile inflammatory reactions Possible systemic effect (NB anti-VEGFs)

DME = diabetic macular oedema; NPDR = non-proliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; VEGF = vascular endothelial growth factor.

than improve vision. Before doing the laser, the ophthalmologist should assess the presence and degree of the macular oedema (as pan-retinal laser may cause or increase macular oedema), discuss the side effects of treatment and risks of visual loss with the patient, and obtain informed consent (Table 5). Vitreous surgery is frequently indicated in patients with traction macular detachment (particularly of recent onset), combined traction–rhegmatogenous retinal detachment, and vitreous haemorrhage precluding pan-retinal laser. Patients with vitreous haemorrhage and rubeosis iridis should also be considered for prompt vitrectomy and intra-operative pan-retinal laser. Other drugs with anti-angiogenic activity that are currently being investigated are different inhibitors of VEGF, VEGF trap, protein kinase C inhibitors, and growth hormone antagonists. Routes of delivery such as oral, direct intra-vitreal injection, or intra-ocular implantation with slow release of the pharmacological agent are also being assessed.

Conclusions In this day and age, with all the available treatment options, blindness due to diabetic retinopathy should be decreasing. Instead, it is still on the increase. Why? There are probably a few reasons: • Diabetes itself is on the increase. • Patients are not compliant with treatment. • Primary-care physicians are not warning their patients often enough of the possible complications of diabetes should they not comply with treatment. • Patients are not screened or referred for screening for diabetic retinopathy until they have visual complaints, by which time it

is often too late. • Patients are terrified of the actual treatments (laser, intra-vitreal injections or surgery), having heard stories about patients losing vision after treatment, but not realising that this was often as a result of ‘too little too late’. Some visual loss may be inevitable, but the goal of treatment is preventing severe and debilitating loss of vision. What is the answer? Education, tight control of the diabetes, management of associated hypertension and hyperlipidaemia, timely referral for screening, increased screening potential utilising non-mydriatic fundus photography, prompt treatment with laser (with or without adjunctive intra-vitreal injections) when necessary, referral for surgery in amenable cases, and rehabilitation/support for those who still slip through the net despite all our best efforts.

Acknowledgements We thank the Department of Ophthalmology, University of KwaZulu-Natal, for the retinal photographs, fluorescein angiogram images and OCT images.

References 1.

3. 4. 5.

10.

11.

12. 13.

14.

15.

Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimate for the year 2000 and projections for 2030. Diabetes Care 2004; 27: 1047–1053. Bradshaw D, Norman R, Pieterse D, Levitt NS, South African Comparative Risk Assessment Collaborating Group. Estimating the burden of disease attributable to diabetes in South Africa in 2000. S Afr Med J 2007; 97(8 Pt 2): 700–706. Kaufman FR. Type 2 diabetes mellitus in children and youth: a new epidemic. J Pediatr Endocrinol Metab 2002; 15(Suppl 2): 737–744. Kempen JH, O’Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol 2004; 122: 552–563. Klein R, Klein BE, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1984; 102: 520–526. Klein R, Klein BE, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984; 102: 527–532. 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. The Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. J Am Med Assoc 2002; 287: 2563–2569. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 1998; 317: 703–713. Van Leiden HA, Dekker JM, Moll AC, et al. Blood pressure, lipids, and obesity are associated with retinopathy: The Hoorn Study. Diabetes Care 2002; 25: 1320– 1325. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology 1991; 98: 766–785. Brechner RJ, Cowie CC, Howie LJ, et al. Ophthalmic examinations among adults with diagnosed diabetes mellitus. J Am Med Assoc 1993; 270: 1714–1718. Williams GA, Scott IU, Haller JA, et al. Single-field fundus photography for diabetic retinopathy screening: a report by the American Academy of Ophthalmology. Ophthalmology 2004; 111: 1055–1062. Okamoto F, Okamoto Y, Fukuda S, et al. Vision-related quality of life and visual function following vitrectomy for proliferative diabetic retinopathy. Am J Ophthalmol 2008; 145: 1031–1036. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010; 117(6): 1059–1060.

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International expert committee recommends new role for HbA1c in diagnosing diabetes Michael Kirby Introduction

lycated haemoglobin – HbA1c, or A1c as it is now being called – should be used to diagnose diabetes, according to a recent recommendation from an international expert committee appointed by the American Diabetes Association, the International Diabetes Federation and the European Association for the Study of Diabetes. This review explores the basis for this recommendation, looking at why HbA1c would provide a more accurate measure for diagnosing diabetes than glucose tests and what the change would mean in clinical practice. The recommendation that HbA1c should replace glucose tolerance tests in the diagnosis of diabetes was made at the recent American Diabetes Association annual meeting and published in the July edition of Diabetes Care. Convened in 2008, the expert committee that wants to redefine the diagnosis of diabetes in nonpregnant individuals included members appointed by the American Diabetes Federation, the European Association for the Study of Diabetes and the International Diabetes Federation. Although it has not yet been finalised by the commissioning organisations, the high level nature of the committee suggests that their recommendation is likely to be adopted.

in type 1 and type 2 diabetes.4 Even mildly raised glycaemia can have damaging effects in the long term, so early diagnosis and treatment is important. Early diagnosis is also cost-effective because the presence of diabetic complications has been shown to increase NHS costs more than five-fold.5

The size of the problem

Barriers to the early detection of type 2 diabetes

Diabetes is a significant and increasing health problem that leads to serious complications and reduced quality of life, as well as increased healthcare costs. In 2008, the average UK prevalence of diabetes was estimated at 3.86% and the diagnosed population at 2.5 million people.1 With a growing aging population and increasing rates of obesity, diabetes prevalence in England is predicted to reach 5.05% by 2010.2 Diabetes accounts for around 5% of all NHS expenditure, with much spent on avoidable diabetic complications.3

A significant barrier to improving the early detection of type 2 diabetes has been inadequate screening using tests that are

Michael Kirby

Figure 1. Experts are recommending HbA1C for diagnosing diabetes.

The importance of early diagnosis Type 1 diabetes is often promptly and easily diagnosed on classical symptoms and acutely elevated blood glucose concentrations. Type 2 diabetes develops more gradually and typically involves a long asymptomatic period, which may result in a significant number of people with frank disease, or indicators of impaired glucose metabolism who are risk of developing type 2 diabetes (prediabetes), remaining undiagnosed. Hyperglycaemia has direct and indirect effects on the human vasculature, which are the main cause of morbidity and mortality Correspondance to: Michael Kirby Visiting Professor, Faculty of Health and Human Sciences, Centre for Research in Primary and Community Care (CRIPACC), and the Clinical Trials Coordinating Centre, University of Hertfordshire, Hatfield, UK. S Afr J Diabetes Vasc Dis 2010; 7: 99–101

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both time consuming and inconvenient to perform. Because type 2 diabetes is characterised by slowly rising glucose levels its diagnosis has traditionally required the measurement of specific blood glucose values in timed samples to differentiate it from the naturally variable glucose levels of non-diabetic individuals.6 Of the tests currently used to evaluate glycaemia and diagnose diabetes and pre-diabetes, the oral glucose tolerance test (OGTT) is considered the ‘gold standard’. However, the OGGT has several drawbacks: • Performing an OGTT is time consuming and costly • Patients have to fast for at least eight hours before having the test • Consuming the necessary glucose load on an empty stomach may make patients physically ill (i.e. faint, sweaty, nauseous). • The need for a confirmatory test on another day is often inconvenient and some patients may not return for the second test. The international expert committee’s recent investigations have shown that laboratory measurements of blood glucose may not be as accurate as we would hope, being flawed by the clinical instruments and methods used to measure it, errors in handling, length of storage, and even the nature of the molecule itself. Repeat test reproducibility can also be poor.6

Why HbA1c? The expert panel based their recommendation on the latest available evidence. They considered that a measure that captures chronic glucose exposure is more likely to be informative of the presence of diabetes than a single measure of glucose. HbA1c varies less than fasting plasma glucose values and the assay for HbA1c has technical advantages compared with the glucose assay. The test is also easier for patients who would no longer be required to perform a fasting or oral glucose tolerance test. Because diabetes is characterised by chronic hyperglycaemia sufficient to cause diabetes-specific complications, the expert committee rationalised that laboratory tests that measure longterm glycaemic exposure should be a better marker of the presence and severity of the disease than single measures of glucose concentration.6 HbA1c – which is glucose bound to a haemoglobin molecule – lasts for the lifespan of a red blood cell, so it reflects the blood glucose levels over the preceding 2–3 months.7 The Diabetes Control and Complications Trial (DCCT)8 and the UK Prospective Diabetes Study (UKPDS)9 have shown that in people with type 1 and type 2 diabetes, the risk of both microvascular and macrovascular complications increases with rising HbA1c levels.

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Retinopathy is a common microvascular complication of diabetes, which may start to develop as early as seven years before a diagnosis of diabetes is made.4 Observational studies examining the link between the measurement of long-term exposure to glycaemia with HbA1c and single or longitudinal measurement of blood glucose levels have consistently demonstrated a stronger correlation between retinopathy and HbA1c10–12 than between retinopathy and fasting glucose levels.13 The expert committee therefore suggests that because HbA1c measures longer-term exposure to raised glucose levels, it may be both a better biochemical marker of diabetes and a more accurate predictor of early diabetic complications, such as retinopathy, than single or episodic measurements of blood glucose levels.6 HbA1c also offers several other benefits over OGGT; it can be performed at any time, it involves one simple blood draw, and it is highly reproducible (see Table 1).

What is prompting the change? So why haven’t we been using HbA1c to diagnose diabetes and pre-diabetes previously? Well, doubts over a lack of assay standardisation have, until recently, largely precluded its general use. However, the expert committee’s recent examination of the laboratory measurements of both glucose and HbA1c indicates that improvements in instrumentation and standardisation have resulted in HbA1c assays being at least as accurate and precise as glucose assays. As opposed to glucose levels, HbA1c values also appear to vary less in an individual on a day-to-day basis, and between people generally. HbA1c values are also relatively stable after collection.6

International Expert Committee recommendations on the use of HbA1c for the diagnosis of diabetes Based on their research, the expert committee concluded that an HbA1c assay was superior to both fasting plasma glucose (FPG) and the OGTT for both the diagnosis of diabetes and the identification of those individuals at high risk of developing diabetes. They went on to define an HbA1c cut-off point of ≥ 6.5% for the diagnosis of diabetes, on the basis of it being at least as sensitive and specific in identifying the individuals at risk of the early microvascular changes most characteristic of diabetes.6 However, the committee points out there is no lower glycaemic threshold at which risk begins and the cut-off point it has suggested for diagnosis should not be used as an absolute dividing line between diabetes and normal glycaemia. Although committee members don’t define a specific cut-off point for a formal diagnosis

Key points: HbA1C in diagnosing diabetes

Table 1. Advantages of HbA1c over glucose measurement

• An expert committee is recommending that HbA1c should replace fasting glucose and oral glucose tolerance tests in the diagnosis of diabetes

•

• HbA1C provides a better indicator of overall glycaemic exposure and risk of complications • HbA1C varies less than fasting plasma glucose and is easier for patients because they don’t need to fast or consume glucose • The committee is recommending an HbA1C > 6.5% for the diagnosis of diabetes

100

• • • • • •

Standardised and aligned to DCCT (The Diabetes Control and Complications Trial)/UKPDS Samples don’t need to be fasting or timed Substantially less pre-analytic instability Substantially less biologic variability Relatively unaffected by acute fluctuations in glucose levels (caused by stress, illness etc.) Better indicator of overall glycaemic exposure and predictor of long-term complications Currently used to guide management and therapy.

(Adapted from The International Expert Committee’s Report, 20096)

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Table 2. Relationship between old and new HbA1C values DCCT-aligned HbA1C (%)

IFFC-aligned HbA1C (mmol/mol)

6.0

6.5

7.0

7.5

8.0

9.0

(Adapted from Diabetes UK. HbA1C Standardisation for Clinical Health Care Professionals7)

of pre-diabetes, they do recommend that prevention strategies are considered in people at highest risk of developing diabetes and its complications with an HbA1c between 6 and 6.5%, or an HbA1c below 6% in the presence of other diabetes risk factors such as high blood pressure, elevated levels of triglycerides, increased body mass index (BMI) and family history of diabetes.6 It is important to note that HbA1c is not infallible, and results may be unreliable in acute elevations of blood glucose and certain haematological situations, particularly where haemoglobin or red blood cell turnover is abnormal. HbA1c also increases with age. The expert committee therefore highlights the fact that the superiority of HbA1c testing does not invalidate FPG or the OGTT, which remain acceptable alternatives when required, and it recommends that whatever method is used, diagnosis should always be confirmed with a repeat test. Investigation of diabetes during pregnancy will continue to require glucose measurement.6

HbA1c standardisation in the UK is changing To achieve uniform international standardisation and allow global comparisons, the way HbA1c measurements are expressed in the UK is changing from a percentage to mmol/mol. HbA1c assays have traditionally been aligned to those used in the DCCT, where HbA1c is expressed as a percentage of the total haemoglobin concentration. To ease the transition, both units can be used until June 2011, but after that date HbA1c values will only be expressed as the International Federation of Clinical Chemistry and Laboratory Medicine’s (IFCC) reference method of mmol/mol of haemoglobin without glucose attached.7 This changes means that the current HbA1c targets of 6.5% and 7.5% equate to 48 mmol/mol and 59 mmol/mol, and the nondiabetic reference range of 4.0% to 6.0% equates to 20 mmol/ mol to 42 mmol/mol (see Table 2).7 To help facilitate the change,

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Diabetes UK has produced an easy-to-use online HbA1c converter, which is available at http://www.diabetes.org.uk/Professionals/ Information_resources/Changes-to-HbA1c-values/. While the International Expert Committee’s recommendation on the use of HbA1c for the diagnosis of diabetes has not yet been adopted by current guidelines, it represents best current evidence and so is a step in the right direction. Although patient education will always play a large part in improving the early diagnosis of type 2 diabetes, using a simpler and more convenient tests such as HbA1c will undoubtedly help, and better standardisation of HbA1c in the UK and globally will facilitate it further.

References 1.

4. 5.

10. 11.

12.

13.

Diabetes UK. Reports and statistics. Diabetes Prev 2008. Available at: http://www. diabetes.org.uk/Professionals/Publications-reports-and-resources/Reports-statistics-and-case-studies/Reports/Diabetes-prevalence-2008/ (Accessed 22/08/09). Yorkshire and Humber Observatory (YHPHO) Key Facts on Diabetes. March 2006. Available at: www.yhpho.org.uk/resource/item.aspx?RID=8872 <http://www. yhpho.org.uk/resource/item.aspx?RID=8872> (Accessed 22/08/09). Williams R, Gillams S, Murphy M et al.(2002) In: Yorkshire and Humber Observatory (YHPHO) Key Facts on Diabetes. March 2006. Available at: www.yhpho. org.uk/resource/item.aspx?RID=8872 <http://www.yhpho.org.uk/resource/item. aspx?RID=8872> (Accessed 22/08/09). Fowler M. Microvascular and Macrovascular Complications of Diabetes. Clin Diabetes 2008; 26: 77–82. doi:10.2337/diaclin.26.2.77 Alexander WD. In: Yorkshire and Humber Observatory (YHPHO) Key Facts on Diabetes. March 2006. Available at: www.yhpho.org.uk/resource/item. aspx?RID=8872 <http://www.yhpho.org.uk/resource/item.aspx?RID=8872> (Accessed 22/08/09). The International Expert Committee. International Expert Committee Report on the role of the A1c Assay in the Diagnosis of Diabetes. Diabetes Care 2009; 32(7): 1327–1334. Diabetes UK. HbA1c Standardisation for Clinical Health Care Professionals. Available at http://www.diabetes.org.uk/upload/Professionals/Key%20leaflets/ 53130HbA1cHCPleaflet.pdf (Accessed 26/06/09). DCCT Research Group. The association between glycaemic exposure and longterm diabetes complications in the Diabetes Control and Complications Trial. Diabetes 1995; 44: 968–83. doi:10.2337/diabetes.44.8.968. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes: prospective observational study (UKPDS 35) Br Med J 2000; 321: 405–12. Tapp RJ, Tikellis G, Wong TY, et al. Longitudinal association og glucose metabolism with retinopathy. Diabetes Care 2008; 31: 1349–54. Sabanayagam C, Liew G, Tapp RJ, et al. Relationship between glycated haemoglobin and microvascular complications: is there a natural cut-off point for the diagnosis of diabetes. Diabetologia 2009; 52(7): 1279–89. doi:10.1007/ s00125-009-1360-5. van Leiden HA, Dekker JM, Moll AC. Risk factors for incident retinopathy in a diabetic and nondiabetic population: the Hoorn study. Opthalmology 2003; 121: 245–51. Wong TY, Liew G, Tai ES, et al. Relation between fasting glucose and retinopathy for diagnosis of diabetes: three population based cross-sectional studies. Lancet 2008; 371: 736–43. doi:10.1016/S0140-6736(08)60343-8.

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Metabolic memory in type 1 diabetes AlEx D WrIghT Abstract

etabolic memory and its possible mechanisms are reviewed. In clinical practice in type 1 diabetes the concept of metabolic memory has developed largely from the observations of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, which followed the Diabetes Control and Complications Trial (DCCT). In the former intensive treatment group, after 10 years follow up, when glycated haemoglobin levels had converged completely, there was less progression of retinopathy and lower rates of proliferative retinopathy. Diabetic nephropathy and neuropathy were similarly reduced. The combined DCCT and EDIC studies showed a reduction in the risk of any cardiovascular disease. Good early metabolic control affects outcome for at least 10 years and it is hoped this information can be translated into clinical practice to reduce significantly the burden of long-term complications. Keywords: DCCT, EDIC, glycaemic memory, legacy effect, longterm complications, metabolic memory

Introduction Memory is commonly perceived as a neurological phenomenon allowing mental or sensory information to be retained and reproduced. The word anamnesis is a good way to describe such recall and, for example, may be used to describe the account a patient gives of their medical history. A more general effect of neurological memory has been shown to occur in the delayed benefits of early education in under-privileged children.1 In other biological systems immunological memory has a different, but equally specific, meaning of a more rapid and enhanced immune response to the repeated exposure to a particular antigen. Immunological memory is thought to be based on long-lived memory in B and T lymphocytes. Does metabolic memory have an equally good definition and scientific basis? This review will explore the current use of this term as applied to patients with type 1 diabetes. One of the earlier uses of the term metabolic memory2 was not in diabetes but was concerned with control mechanisms and futile cycles. Examples given included the effect of diet altering metabolic patterns for several days and the effects of exercise on increasing high-density lipoprotein cholesterol and insulin receptor kinetics. More recently the broad category of metabolic memory has been used in diabetes to describe the delayed development Correspondence to: Dr Alex D Wright The Diabetes Centre, University Hospital, Selly Oak, Raddlebarn Road, Selly Oak, Birmingham, B29 6JD, UK. Tel: +44 (0)121 627 1627 Fax: 01922 656625 E-mail: a.wright@bmres.org.uk S Afr J Diabetes Vasc Dis 2010; 7: 102â&#x20AC;&#x201C;104

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Alex D Wright

Abbreviations and acronyms AGEs advanced glycation end-products DCCT

Diabetes Control and Complications Trial

EDIC

Epidemiology of Diabetes Interventions and Complications

HbA1C

glycated haemoglobin A1C

UKPDS

UK Prospective Diabetes Study

of a long-term complication associated with previous exposure to glucotoxicity, lipotoxicity and other metabolic disturbances. Other terms covering the same general area include metabolic imprint, legacy effects, glycaemic memory, hyperglycaemic memory and latent hyperglycaemic damage. Metabolic memory is an attractive, memorable alliteration, but the idea of enduring beneficial effects of good metabolic control early in the course of diabetes is difficult to define and for which it is difficult to establish basic mechanisms. It is better described as early or nascent pathology. Indeed the idea that poor foetal nutrition and nutrition in early life are associated with subsequent insulin resistance, metabolic syndrome and type 2 diabetes is a well established example of more long-term effects of nutrition/metabolism on development. Another example of longterm effects of asymptomatic tissue damage comes from studies of former smokers whose morbidity from pulmonary and vascular disease continues for many years after smoking has stopped.

Mechanisms of metabolic memory Memory probably results from tissue damage that is very slowly repaired or cannot be fully repaired. Two current hypotheses suggest that poor control of diabetes results in some irreversible mitochondrial or vascular change which then predisposes or progresses to overt long-term complications. To what extent the cause of the damage is glucotoxicity or lipotoxicity or a combination of these factors is unknown and no doubt these toxic effects are modified by other inherited or acquired metabolic processes. The well established time relationship of duration of diabetes and incidence of long-term complications is therefore shifted to the left by poor metabolic control. For most patients with type 1 diabetes HbA1c measurements are the only evidence available of their overall

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control as mitochondrial function or detailed vascular health are not easily or routinely assessed – and indeed, if irreversible, not particularly helpful for the individual. Perhaps carotid artery intimal thickness or vascular reactivity and resistance should be measured and followed to help identify good and poor risk patients. The accumulation of AGEs, which are formed during periods of hyperglycaemia and persist for many years, may be one of the important factors in metabolic memory. AGEs are a heterogenous group of chemical moieties occurring as a result of a nonenzymatic reaction of glucose with proteins, lipids and nucleic acids. The role of AGEs in the progression and complications of diabetes has been reviewed recently.3 AGEs act directly to induce cross-linking of long-lived proteins such as collagen to promote vascular stiffness, and, thus, alter vascular structure and function. AGEs can also interact with certain receptors, to induce intracellular signalling that leads to enhanced oxidative stress and elaboration of key proinflammatory and prosclerotic cytokines. AGE modification of mitochondrial proteins may be irreversible and may result in decline of mitochondrial function with excess formation of reactive species.4 Important support for the concept of the deleterious effects of the accumulation of AGEs (glycated collagen and carboxymethyllysine) has been obtained from skin biopsies in the DCCT and the EDIC study5 with the prediction of risk of progression of retinopathy and nephropathy even after adjustments for mean HbA1c. Indeed the predictive effect of HbA1c was abolished after adjustment for the two AGEs measured. Other theories on the mechanisms of metabolic memory have been reviewed recently6 and include the idea that overproduction of oxidative stress persists after normalisation of glucose levels,7 that there is long-lasting activation of epigenetic changes in the promoter of a key inflammatory marker by transient spikes of hyperglycaemia in mice8 and that insulin, not only suppressing glucotoxicity and lipotoxicity, has important anti-inflammatory effects.9

Clinical studies The importance of good glycaemic control in the early stages of diabetes with long-term benefits has been reviewed in this journal.10 Examples in type 2 diabetes include UKPDS,11 the Veterans Affair Diabetes Trial,12 and Steno-2 study.13 In the UKPDS the benefit of reduction in microvascular disease, largely laser therapy, seen in the sulphonylurea and insulin group, but not in the metformin group, was sustained in the 10-year post trial period despite rapid convergence of HbA1c. It is also possible that the period of exposure to hyperglycaemia before the diagnosis of type 2 diabetes may contribute to hyperglycaemic memory.14 Another important finding in type 2 diabetes in UKPDS was the absence of a significant legacy effect of blood pressure as the differences in end-points disappeared after about 2 years of the blood pressures coming together. In other words, blood pressure pathology is more related to current than to past levels of blood pressure whereas glycaemic pathology is more lasting. Equivalent data on the importance of good glycaemic control early in type 1 diabetes are limited and rely almost entirely on the DCCT and the EDIC study. However, astute observations were first made by diabetologists over 40 years ago15 though their data were limited by difficulties in documenting overall control of diabetes before the era of HbA1c measurements. Based on glycosuria percentage, the frequency of retinopathy in patients with initial

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good control and later poor control resembled that of patients with good control at all times (36– 38%) while in patients with initial poor control and later good control it resembled that in patients with poor control throughout (55–60%). good glycaemic control in the first five years of diabetes resulted in protection from proliferative retinopathy. One of the earlier, long-term, prospective studies using HbA1c16 in type 1 diabetes started in 1979 and the baseline HbA1c measured in 1980 onwards was one of the predictors for the future development of albuminuria (relative risk 1.18) in addition to blood pressure, height and being male.

Epidemiology of Diabetes Intervention and Complications study The first DCCT follow up showed that the risk of retinopathy remained significantly reduced in the intensive compared with the conventional treatment groups in the first four years after the end of the trial, despite similar HbA1c levels over this period.17 Perhaps more convincing are the results after 10 years EDIC follow-up in which the HbA1c levels had converged completely and the follow-up was longer. The former intensive treatment group still had lower rates of progression of retinopathy and proliferative retinopathy (Table 1) but the risk reductions at 10 years were attenuated compared with the first 4 years of follow up.18 Diabetic nephropathy was reported for the 8 years follow up and showed in the former intensively treated group a reduction of new microalbuminuria, a reduction in clinical albuminuria, and fewer cases of hypertension, and patients needing renal replacement therapy.19 Diabetic neuropathy was also reported at 8 years follow-up with a reduction in neuropathic symptoms and signs.20 During the 17 years of follow up in DCCT and EDIC, intensive therapy reduced the risk of any cardiovascular disease and the risk of non-fatal myocardial infraction, stroke or death from cardiovascular disease.21 A beneficial effect of former intensive diabetic control was noted

Table 1. Epidemiology of Diabetes Intervention and Complications (EDIC) study

Complication (years of follow-up)

% reduction in former intensive treatment group

Retinopathy (10 years EDIC) progression

proliferative

Nephropathy (8 years EDIC) new microalbuminuria

clinical albuminuria

Neuropathy (8 years EDIC) symptoms

signs

Cardiovascular disease (17 years DCCT + EDIC) any

non-fatal myocardial infarct, stroke or CVD death

CVD = cardiovascular disease; DCCT = Diabetes Control and Complications Trial

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Key messages • Good glycaemic control in the first six years of type 1 diabetes is highly beneficial in delaying long-term complications • Metabolic memory may contribute to the finding of long-term complications early or late in the course of the disease • Metabolic memory may contribute to the mildness/ severity of long-term complications • Metabolic memory should not be used as a reason for failing to improve diabetic control at any stage of the disease on coronary artery calcification at 7–9 years follow-up in the EDIC study22 and, after six years in the EDIC study, progression of carotid artery intima–media thickening was less in the former intensively treated group.23

Conclusions There are long-term consequences of glycaemic control early in the course of type 1 diabetes which show that good control protects against both microvascular and macrovascular complications occurring later. The effect is not necessarily a memory effect but rather a consequence or legacy of metabolic control in the early stages of type 1 diabetes. The mechanism of this legacy is probably irreversible, or very slowly reversible, vascular damage – similar to the legacy of smoking. The metabolic memory of glycaemic control in the early stages of type 1 diabetes causes a shift in the time relationship of duration of diabetes and incidence of long-term complications. Failure to maintain adequate control of diabetes in the first few years of type 1 diabetes cannot be excused by the knowledge that complications may take many years to develop.

7. 8.

9. 10. 11. 12. 13. 14.

15. 16.

17.

18.

19.

20.

21.

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Oden S, Schweinhart LJ, Weikart DP. Into Adulthood: a Study of the Effects of Head Start. ED444730. Ypsilanti: High/Scope Press, 2000. Cahill GF. Metabolic memory. N Engl J Med 1980; 302: 396–7. Goh SY, Cooper ME. Clinical review: the role of advanced glycation end products in progression and complications of diabetes. J Clin Endocrinol Metab 2008; 93: 1143–52. Rosca MG, Mustata TG, Kinter MT, et al. Glycation of mitochondrial proteins from

22.

23.

diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol 2005; 289: F420–30. Genuth S, Sun W, Cleary P, et al. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the Diabetes Control and Complications Trail and Epidmeiology of Diabetes Interventions and Complications participants with type 1 diabetes. Diabetes 2005; 54: 3103–11. Ceriello A, Ihnat MA, Thorpe JE. The ‘metaobolic memory’: is more than just tight glucose control necessary to prevent diabetic complications? J Clin Endocrinol Metab 2009; 94: 410–15. Ihnat MA, Thrope JE, Ceriello A. Hypothesis: the ‘metabolic memory’, the new challenge of diabetes. Diabet Med 2007; 24: 582–6. El-Osta A, Brasacchio D, Yao D, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 2008; 205: 2409–17. LeRoith D, Fonseca V, Vinik A. Metabolic memory in diabetes-focus on insulin. Diabetes Metab Res Rev 2005; 21: 85–90. Bailey CJ, Day C. Glycaemic memory. Br J Diabetes Vasc Dis 2008; 8:242–7. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577–89. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129–39. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348: 383–93. Khaw KT, Wareham N, Bingham S, et al. Association of haemoglobin A1c with cardiovascular disease and mortality in adults: the European Prospective Investigation into Cancer in Norfolk. Ann Intern Med 2004; 141: 413–20. Burditt AF, Caird FI, Draper GJ. The natural history of diabetic retinopathy. Quart J Med 1968; 37: 303–17. Hovind P, Tarnow L, Rossing P, et al. Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. Br Med J 2004; 328: 1105–08. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000; 342: 381–9. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus. Arch Ophthalmol 2008; 126: 1707–15. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy. J Am Med Assoc 2003; 290: 2159–67. Martin Cl, Waberski B, Albers J, et al. Neuropathy among the Diabetes Control and Complications Trial cohort 8 years after trial completion. Diabetes Care 2006; 29: 340–4. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643–53. Cleary PA, Orchard TJ, Genuth S, et al. The effect of intensive glycemic treatment on coronary artery calcification in type 1 diabetic participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC) study. Diabetes 2006; 55: 3556–65. Nathan DM, Lachin J, Cleary P, et al. Intensive diabetes therapy and carotid intimamedia thiskness in type 1 diabetes mellitus. N Engl J Med 2003; 348: 2294–303.

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REVIEW

National Diabetes Information Service offers support Bob Young Introduction

he National Diabetes Information Service (NDIS)1 has been established to support everyone involved in diabetes care. Led by the NHS Information Centre for Health and Social Care, its initial aim is to maximise the value that can be yielded from existing data sources about diabetes. In the longer term, it will also support the generation of useful new data about diabetes. Its intention is to bring these data sources together in such a way as to deliver benefit. A fundamental objective is to minimise the need to collect additional data separately. Instead, the aim will always be to utilise, where it is available, information that is routinely recorded in everyday clinical practice. NDIS believes that if the burden of data collection can be minimised and the reports made relevant to all stakeholders, a valuable new dimension can be added to the delivery of diabetes care and the experience of diabetes care. Very importantly, NDIS aims to create products that are of value to everyone. There will be reports for people with diabetes, primary care providers of diabetes care and diabetes specialists, commissioners of diabetes care, regulators of diabetes care and health policy makers.

Partners in NDIS NDIS was launched at the end of November 2008 at the inaugural meeting of the partnership board. Its composition reflects the numerous existing sources of data about diabetes and the breadth of key stakeholders who need to use information about diabetes. The partnership board is chaired by the National Clinical Director for Diabetes, Rowan Hillson. The Department of Health Policy Team and NHS Diabetes are both represented. The NHS Information Centre, which is responsible for such important sources of data as the National Diabetes Audit2, Quality and Outcomes Framework data, and Healthcare Population Deprivation data, is a key member. The Yorkshire and Humber Public Health Observatory3 has, for some years, had a pivotal role in the provision of information about diabetes care to the NHS. Diabetes E is an electronic service self-assessment tool that is being used by more than 70% of local health economies to help them work towards comprehensive delivery of the Diabetes National Service Framework. It is another key data partner in NDIS. Diabetes UK,4 as well as being an advocate for people with diabetes and providing an important representation on the partnership board of people with diabetes is also, via its regular Primary Care Trust (PCT) progress surveys, an important source of information and another data contributor to NDIS. The National Diabetic Retinopathy Screening Programme is also a partner. Other Correspondence to: Bob Young Clinical Lead for the National Diabetes Information Service at the NHS Information Centre for Health and Social Care, 1 Trevelyan Square, Boar Lane, Leeds, LS1 6AE, UK. S Afr J Diabetes Vasc Dis 2010; 7: 105–106

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stakeholders represented include the Royal Colleges of General Practitioners, physicians and nurses, Association of British Clinical Diabetologists (ABCD), dietitians and podiatrists. The partnership board is responsible for setting the agenda and monitoring progress, and for ensuring that all the stakeholders are fully able to participate. This board is backed up by an expert reference group drawn from clinical, information and managerial experts in diabetes across the country. The Expert Reference Group comprises consultant diabetologists, general practitioners, diabetes specialist nurses, diabetes specialist dietitians, diabetes specialist podiatrists, NHS Diabetes Regional Programme managers, commissioners, and informaticians. NDIS operates mostly by commissioning tasks from others using joint funding from NHS Diabetes5 and the NHS Information Centre. There are presently two part-time personnel coordinating the work of NDIS: Margaret Baldock, the programme manager, and Bob Young, the clinical lead.

NDIS projects already underway For local diabetes network management and commissioners Diabetes is a classic long-term condition that needs to be managed across all the traditional NHS care boundaries. Groups trying to provide integrated care in a local health economy and commissioners of diabetes care have long required overview information to support their endeavours. The diabetes commissioning toolkit developed by NHS Diabetes (formerly National Diabetes Support Team – NDST) includes a very comprehensive framework for this. By bringing together information from the National Diabetes Audit, Yorkshire and Humber Public Health Observatory (YHPHO), the Quality and Outcomes Framework (QOF), health episode statistics, Diabetes E, Diabetes UK, and the Healthcare Commission, a comprehensive report that covers all of the Diabetes Commissioning Toolkit framework can be produced using existing data. It is hoped that this will become a service by the middle of 2009. The web interface will not only allow local health economies to review their own reports, but will also allow them to compare themselves with similar health economies throughout England.

Diabetes patient experience project Diabetes is not just about the clinical outcomes of care but it is also about the experience of care. Good quality care optimises both. A project is underway to develop easy-to-use methods to enable people to express their views on the diabetes care they are receiving that could be replicated in any health economy.

For specialist care providers Diabetes inpatient care has belatedly been recognised as requiring targeted additional input. Information to support this will be provided by NDIS reports that illustrate the number of people admitted to hospital who have diabetes, the reasons for their admission, the length of stay as compared to similar patients

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For specialist providers of diabetes care Systems are being developed to provide ongoing, continuous, prospective quality audits of foot care services, diabetes pregnancy services, children and young people’s services and insulin pump services.

For regulators of diabetes care NDIS will create reports that summarise compliance with NICE guidelines, the Diabetes National Service Framework, CEMACH reports on diabetic pregnancy and other quality standards.

For policy makers without diabetes, readmission and mortality rates for people with diabetes compared with those who do not have diabetes. This project will involve linking hospital episode statistics and National Diabetes Audit information.

New work streams For people with diabetes

Those responsible for developing policy in Strategic Health Authorities and the Department of Health will have easy access to accurate aggregated figures about diabetes incidence, prevalence, distribution, morbidity, service utilisation, service quality and associated costs.

Summing up

Two products are planned for people with diabetes. The first will give them the opportunity to compare their own personal treatment experiences and outcomes with similar people who have diabetes throughout England – a sort of ‘personal diabetes benchmarking tool’. They will also be able to get information about the performance of the services they use in comparison to similar services throughout England.

In conclusion, the National Diabetes Information Service is a pragmatic development that recognises that there are already a lot of data in the NHS about diabetes available to be harvested and repackaged. NDIS will try to ensure that this process results in products that become essential supports for the delivery of reliable and quality-assured services to people with diabetes throughout England.

For primary care providers of diabetes services

References

NDIS will enable general practices to compare themselves with other practices and to obtain integrated information about how patients attending their practice have fared when attending specialist services or during admission to hospital.

1. 2. 3. 4. 5.

NDIS website: www.ic.nhs.uk/dpep National Diabetes Audit: www.ic.nhs.uk/diabetesauditreports Yorkshire and Humber Public Health Observatory: www.yhpho.org.uk Diabetes UK: www.diabetes.org.uk NHS Diabetes: www.diabetes.nhs.uk

Book giveaway Congratulations to Sharon Boks and Dr B Seetharam who have won the June book giveaway: Eating for Sustained Energy 4 by Gabi Steenkamp and Liesbet Delport.

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RESEARCH ARTICLE

Metabolic syndrome among newly diagnosed non-diabetic hypertensive Nigerians: prevalence and clinical correlates AA Akintunde, OE Ayodele, PO Akinwusi, JO Peter, OG Opadijo Abstract

ackground: Hypertension is the most common cardiovascular risk factor worldwide. Clustering of cardiovascular risk factors has been noted to increase the risk of developing type 2 diabetes mellitus and cardiovascular diseases. Reports of the metabolic syndrome among African hypertensive subjects are scarce. Methods: One hundred and forty newly diagnosed hypertensive subjects and 70 apparently healthy controls were recruited consecutively for this study. Demographic and clinical parameters were assessed using a pre-tested data-collection form. Fasting blood sugar and fasting serum lipid level were determined. The metabolic syndrome was defined according to NCEP ATP III criteria. Statistical analyses were performed using SPSS 16.0. Intergroup comparisons were done using the t-test and chi square as appropriate. Results: Hypertensive and control subjects were similar in age (55.14 ± 10.83 vs 54.67 ± 10.89 years, p = 0.8) and gender distribution [female 75 (53.6%) vs male 37 (52.9%), p = 0.3]. The metabolic syndrome was diagnosed in 44 (31.4%) of the hypertensive subjects and 11 (15.7%) of the controls. Systolic blood pressure, body mass index and prevalence of left ventricular hypertrophy were higher among subjects with the metabolic syndrome than those without it. Prevalence of the metabolic syndrome increased with age and was more common among female subjects. Conclusion: This study showed that the prevalence of the metabolic syndrome was high among newly diagnosed hypertensive subjects in Osogbo, Nigeria. It was however lower than that described among many Caucasian populations. The presence of the metabolic syndrome in Nigerian hypertensive subjects is closely related to and influenced by demographic and clinical factors. Keywords: metabolic syndrome, prevalence hypertension, Nigeria, diabetes, impaired glucose tolerance Systemic hypertension affects about one billion people and accounts for about 7.1 million deaths per year worldwide.1 It is the commonest non-communicable disease in Nigeria with prevalence Correspondence to: Adeseye A Akintunde Department of Medicine, Cardiology Unit, Eberhard Karls’ University, Tübingen, Germany Tel: +49 15227790146 e-mail: iakintunde2@yahoo.com AA Akintunde, OE Ayodele, PO Akinwusi, JO Peter, OG Opadijo Department of Internal Medicine, Division of Cardiology, Ladoke Akintola University of Technology Teaching Hospital, Osogbo, Nigeria S Afr J Diabetes Vasc Dis 2010; 7: 107–110

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rates ranging from seven to 20%, according to published studies.2-4 Hypertension is commonly associated with many other cardiovascular risk factors such as obesity, dyslipidaemia, impaired glucose tolerance (or hyperglycaemia) and hyperuricaemia.5-9 The metabolic syndrome (MS) is defined as a clustering of components that reflects the expanding waistlines of the world. Although there are different criteria for the definition of the MS as recommended by the various working groups, the core components of the syndrome, which include increased waist circumference, impaired glucose tolerance, dyslipidaemia and hypertension, are commonly required by the various groups for diagnosis.10 The prevalence of the metabolic syndrome varies in different populations and is influenced by race, gender, differing socioeconomic status, work-related activities and cultural views on body fat.10 Reported prevalence rates in different countries vary between two and 66.9%.10 Reports also showed that the prevalence of the MS is increasing to epidemic proportions, not only in the USA and other developed countries but also in developing nations.10 The clustering of cardiovascular risk factors is associated with increased risk of the development of cardiovascular diseases (CVD), such as coronary heart disease (CHD) and stroke, as well as an increase in all-cause mortality. The metabolic syndrome has been shown to predict the development of diabetes. Various studies have demonstrated that the presence of multiple risk factors confers greater risk than a single factor.11-16 In the Kuopio Ischaemic Heart Disease Risk Factor study, Finnish men without CVD were followed up for approximately 11 years, and those with the MS were three to four times more likely to die of CHD, 2.6 to three times more likely to die of CVD and twice as likely to die from all causes.12 The age-adjusted relative risks for CVD and CHD in men with the MS were 2.88 and 2.54, respectively, and 2.55 and 1.54 in women, respectively, using the Framingham data base.13 Information on the prevalence of the metabolic syndrome among Nigerian hypertensive subjects is scarce.

Methods The metabolic syndrome was defined in this study as the presence in patients of three or more of five cardiovascular risk factors, according to the National Cholesterol Education Programme Adult Treatment Panel III criteria. These include fasting plasma glucose > 6.1 mmol/l, fasting plasma triglycerides > 150 mg/dl (1.7 mmol/l), fasting plasma high-density lipoprotein cholesterol (HDLC) levels for men < 1.04 mmol/l, fasting plasma HDL-C levels for women < 1.29 mmol/l, blood pressure ≥ 130/85 mmHg and waist circumference for men > 102 cm and for women > 88 cm.17 This was a cross sectional study and 140 newly diagnosed, non-diabetic, hypertensive subjects and 70 normotensive controls were recruited consecutively from the cardiology clinic of LAUTECH Teaching Hospital, Osogbo, Nigeria. Control subjects were patients’ relatives and hospital staff who voluntarily gave their consent to participate in the study.

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Hypertensive subjects and controls were well matched in age and gender distribution. Hypertension was diagnosed as systolic blood pressure of ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg taken twice after at least five minutes of rest at the clinic, according to standardised criteria. Subjects with mild hypertension were asked to return after two weeks for confirmation. Those with moderate and severe hypertension (JNC 7 stage 2) were recruited for the study immediately. Patients with chronic kidney disease, known diabetics, those with clinical evidence suggestive of coronary heart disease and pregnant patients were excluded from the study. Clinical and demographic data were taken using a structured data form. Laboratory analyses performed included fasting plasma glucose, urinalysis, ultrasound, fasting serum plasma lipids, electrolytes, urea and creatinine. All subjects had 12-lead resting electrocardiography. Patients and controls were recruited after an informed consent. Ethical approval was obtained for the study from the Ethics Board of LAUTECH Teaching Hospital, Osogbo, Nigeria. Statistical analyses were performed using the Statistical Package for Social Sciences 16.0. Quantitative variables were summarised as means ± standard deviation while qualitative data were summarised using proportions and percentages. Intergroup comparison was done using the t-test and chi square as appropriate; p < 0.05 was taken as statistically significant.

Results One hundred and forty hypertensive subjects and 70 controls were recruited for this study. The mean age of the patients and the controls was 55.14 ± 10.83 years (range 23–82) and 54.67 ± 10.89 years (range 35–75), respectively. There was no statistically significant difference between the mean ages of the subjects and Table 1. Clinical and demographic parameters of study participants

Parameters

Hypertensive subjects (n = 140)

Control subjects (n = 70)

Age (years)

55.14 ± 10.83

54.67 ± 10.89

> 0.05

75 (53.6)

37 (52.9)

> 0.05

Male

92.5 ± 13.4

84.0 ± 7.3

< 0.005*

Female

94.3 ± 11.5

84.6 ± 10.7

100.15 ± 11.63

92.79 ± 9.92

Family history of diabetes mellitus

0.94 ± 0.082

Mean WHR

0.91 ± 0.054

The frequency of occurrence of the metabolic syndrome in this study was 31.4% in the hypertensive subjects, compared to 15.7% in the control group. A similar report by Okpechi et al.18 among

Table 2. Biochemical parameters of the study population

Parameter

Hypertensive subjects (n = 140)

Mean sodium (mmol/l)

Control subjects (n = 70)

p-value

135.9 ± 4.7

133.7 ± 2.4

Mean potassium (mmol/l)

3.8 ± 0.5

3.1 ± 0.4

< 0.05*

< 0.005*

Mean urea (mmol/l)

5.8 ± 2.2

3.2 ± 1.7

> 0.05

Mean creatinine (μmol/l)

84.2 ± 12.6

68.4 ± 10.8

> 0.05

Mean FBS (mmol/l)

5.6 ± 1.9

4.0 ± 1.3

Mean WC (cm)

Mean HC (cm)

Discussion

p-value

Gender Female (%)

controls (p > 0.05). The demographic and clinical parameters of the study participants are shown in Table 1. When compared with control subjects, the hypertensive subjects had a higher mean systolic blood pressure (147.18 ± 26.47 vs 115.06 ± 13.11 mmHg, p < 0.005), diastolic blood pressure (89.25 ± 17.04 vs 70.96 ± 9.67 mmHg, p < 0.005), pulse pressure (57.93 ± 24.38 vs 44.75 ± 10.25 mmHg) and fasting plasma glucose (5.6 ± 1.9 vs 4.0 ± 1.3 mmol/l, p < 0.005) although the mean fasting plasma glucose levels were both within normal limits. Also, the waist circumference of the hypertensive subjects was significantly higher than the controls (93.89 ± 11.96 vs 83.82 ± 9.0 cm, p < 0.05). Table 2 shows the biochemical profile of the study population. The hypertensive subjects had significantly higher mean fasting plasma glucose levels (5.6 ± 1.9 vs 4.0 ± 1.3 mmol/l, p < 0.05). The lipid profile analysis of the study population is shown in Table 2. Hypertensive subjects had a significantly lower HDL-C compared to control subjects (1.06 ± 0.36 vs 1.29 ± 0.46 mmol/l, p < 0.05). Although mean total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglyceride levels were higher among hypertensive subjects than controls, they were not statistically significant. Hypertensive subjects with the metabolic syndrome were older and were more likely to be female than those without the MS. They also had a higher body mass index, systolic blood pressure, fasting plasma glucose level and increased prevalence of left ventricular hypertrophy, as shown in Table 3. Table 4 shows that hypertension combined with obesity and low HDL-C was the commonest pattern of combination of cardiovascular risk factors among hypertensive subjects, followed by a combination of hypertension, obesity and impaired glucose tolerance.

> 0.05

< 0.005*

Mean BMI (kg/m )

26.89 ± 5.31

23.86 ± 3.46

> 0.05

Mean LDL-C (mmol/l)

2.49 ± 1.41

2.35 ± 0.63

> 0.05

Mean SBP (mmHg)

147.18 ± 26.47

115.06 ± 13.11

< 0.005*

Mean HDL-C (mmol/l)

1.06 ± 0.36

1.29 ± 0.46

< 0.05*

Mean DBP (mmHg)

89.25 ± 17.04

70.96 ± 9.67

< 0.005*

Mean TG (mmol/l)

1.33 ± 0.59

1.18 ± 0.41

> 0.05

Mean PP (mmHg)

57.93 ± 24.38

44.75 ± 10.25

< 0.005*

Mean TC (mmol/l)

4.84 ± 1.69

4.23 ± 1.29

> 0.05

WHR: waist–hip ratio, BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, PP: pulse pressure, HC: hip circumference. * Statistically significant.

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FBS: fasting blood sugar; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; TG: triglycerides; TC: total cholesterol. * Statistically significant.

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RESEARCH ARTICLE

black hypertensives in South Africa documented a frequency of occurrence of 33.5%. Therefore, about a third of newly diagnosed subjects with hypertension already have at least two other major cardiovascular risk factors, and are already at increased risk of developing cardiovascular events. It is also more likely that other cardiovascular risk factors might appear in these patients over time.6,10 Therefore, newly diagnosed subjects with hypertension should be adequately screened for other cardiovascular risk factors so as to reduce the burden of cardiovascular disease in the population. The prevalence of the metabolic syndrome among hypertensive subjects was however lower than that reported among Caucasians. A report from Spain shows that 52% of a hypertensive cohort fulfilled the NCEP ATP III criteria for diagnosing the metabolic syndrome.19 Some authors have linked race with the frequency of occurence of the metabolic syndrome and suggested that African blacks are at a lower risk than whites and Indians.20 It has been suggested that black Africans have lower serum levels of lipoproteins and apolipoproteins than their Caucasian counterparts.21 Blacks have also been reported to have a lower blood level of total cholesterol when compared to whites, and a comparably higher value of HDL cholesterol, especially among females. This was suggested to be due to the dietary pattern in blacks, which is particularly low in dietary fat, especially among Nigerians.21 This and a possible genetic difference may be responsible for the difference in frequency of occurence of cardiovascular risk factor clustering among black and Caucasian subjects.10,22 Hypertension has been closely associated with many other cardiovascular risk factors. This clustering of risk factors increases the risk of cardiovascular events for these groups of patients.22-24 The suggested reason for the increased cardiovascular risk factors among hypertensive subjects is the similar pathogenetic pathways underlying the clustered risk factors.25,26 These include insulin resistance, hyperinsulinaemia, inflammation and the hyperadrenergic state. Hypertensive subjects with the metabolic syndrome were significantly older than their counterparts without the MS. There were more female than male hypertensives with the metabolic

syndrome. Several studies have documented increased prevalence with increased age and the female gender.27-31 However reports are not consistent, as other reviews have found marginal increases in prevalence among males.27 This gender-related difference may be due to differing work-related activities, and cultural views on body fat and work-related activities. The apparent increasing prevalence of the metabolic syndrome may be real, since many of the components increase in prevalence with age. Hypertensives with the metabolic syndrome seem to be those with a greater degree of target-organ damage, as indicated by increased prevalence of left ventricular hypertrophy and cardiomegaly. Left ventricular hypertrophy is an important pointer to cardiovascular risk and morbidity. Apart from this, hypertensive subjects with the metabolic syndrome also had a higher QTc, body mass index and systolic blood pressure than those without the metabolic syndrome. QTc prolongation is a non-invasive marker for the development of arrhythmias and sudden cardiac death. The combination of hypertension, obesity and low HDL-C was the commonest pattern among hypertensive subjects with the metabolic syndrome, followed by the combination of hypertension, obesity and impaired fasting plasma glucose. Hypertensives with the metabolic syndrome had higher fasting plasma glucose levels than those without the metabolic syndrome. Impaired fasting plasma glucose has been associated with an increased likelihood of developing diabetes mellitus. These groups of hypertensive subjects therefore require intensive cardiovascular evaluation and care to reverse the increased tendency for the development of diabetes and cardiovascular diseases. As Africa undergoes an epidemiological transition, the inevitable increase in prevalence of the metabolic syndrome would have important implications with respect to the potential rise in the incidence of ischaemic heart disease and diabetes. Available evidence suggests that the prevalence of cardiovascular disease among Nigerians is increasing.32-34 Therefore it is important to identify high-risk individuals for target therapy to reduce the overall prevalence of cardiovascular disease.

Conclusion This study showed that the prevalence of the metabolic syndrome among newly diagnosed hypertensive Nigerian subjects was high

Table 3. Clinical characteristics of hypertensive subjects with and without the metabolic syndrome Table 4. Pattern of combination of risk factors among subjects with the metabolic syndrome

Parameter

Hypertensives with MS (n = 44)

Hypertensives without MS (n = 96)

p-value

Age (years)

57.22 ± 9.65

53.52 ± 10.58

< 0.05*

38 (27.1%)

39 (27.9%)

< 0.05*

Mean BMI (kg/m )

30.15 ± 5.27

24.14 ± 4.10

< 0.005*

Mean SBP (mmHg)

141.36 ± 23.66

130.16 ± 29.50

< 0.05*

Mean DBP (mmHg)

86.17 ± 18.19

80.97 ± 17.54

> 0.05

Hypertensives with LVH

39 (70.9%)

56 (65.9%)

< 0.05*

Mean QTc (msec)

0.42 ± 0.03

0.41 ± 0.03

< 0.05*

4.7 ± 1.6

5.6 ± 1.2

< 0.05*

Gender 2

FBS (mmol/l)

BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, LVH: left ventricular hypertrophy. *Statistically significant.

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Combination of risk factors

Number (%)

Hypertension + obesity + low HDL

29 (20.7)

Hypertension + obesity + IFG

5 (3.6)

Hypertension + obesity + hypertriglyceridaemia

3 (2.1)

Hypertension + low HDL + hypertriglyceridaemia

2 (1.4)

Hypertension + low HDL + IFG

2 (1.4)

Hypertension + hypertriglyceridaemia + IFG

1 (0.7)

Hypertension + hypertriglyceridaemia + IFG

1 (0.7)

Hypertension + obesity + low HDL + hypertriglyceridaemia + IFG

1 (0.7)

HDL: high-density lipoprotein, IFG: impaired fasting glucose.

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and was influenced by demographic and clinical factors such as age, gender, systolic blood pressure and body mass index. These observations also raise major clinical and public health concerns, including an inevitable increase in the prevalence of cardiovascular diseases due to the increasing frequency of hypertension and other cardiovascular risk factors in the population. The cost of the management of cardiovascular disease is enormous, therefore there is a serious economic burden imposed, especially on developing countries. As urbanisation and westernisation increase, the clustering of cardiovascular risk factors is likely to be more common due to the expected increase in the prevalence of high blood pressure. The potential economic impact will be huge. Therefore lifestyle modification measures need to be reinforced, as they have the potential to reduce cardiovascular disease arising from the epidemic of obesity and the metabolic syndrome.

References 1.

2. 3. 4.

5. 6. 7. 8.

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12.

13.

14.

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World Health Report 2002. Reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization, 2002. Available at: http: //www.who.int / whr 2002. Accessed on May 2, 2005. Akinkugbe OO. The Nigerian hypertension programme. J Human Hypertens 1996; 10(Suppl 1): S43–S46. Cooper R, Rotimi C, Ataman S, et al. The prevalence of hypertension in seven populations of West African origin. Am J Publ Hlth 1997; 87: 160–168. Kadiri S, Walker O, Salako BL, Akinkugbe O. Blood pressure, hypertension and correlates in urbanized workers in Ibadan, Nigeria: a revisit. J Hum Hypertens 1999; 13: 23–27. Nilsson S. Research contributions of Eskil Kylin. Sven Med Tidskr 2001; 5: 15–28. Avogaro P, Crepald G, Enzi G, et al. Association of hyperlipidaemia, diabetes mellitus and obesity. Acta Diabetol Lat 1967; 4: 36–41. Reaven G. Banting lecture 1988: Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1600. Isezuo SA, Badung SL, Omotoso AB. Comparative analyses of lipid profiles among patients with type 2 diabetes mellitus, hypertension and concurrent type 2 diabetes and hypertension. A view of metabolic syndrome. J Nat Med Ass 2003; 95: 328–334. Obasohan AO, Ajuyah CO. How common is heart failure due to hypertension alone in hospitalized Nigerians? J Hum Hypertens 1996; 10: 810–804. Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev 2008; 29: 777–822. Jeppesen J, Hansen TW, Ibsen H, Torp-Pedersen C, Madsbad S. Insulin resistance, the metabolic syndrome, and the risk of incident cardiovascular disease: a population-based study. J Am Coll Cardiol 2007; 49: 2112–2119. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. J Am Med Assoc 2002; 288: 2709–2716. Wilson PW, D’Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005; 112: 3066–3072. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality

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associated with the metabolic syndrome. Diabetes Care 2001; 24: 683–689. 15. McNeil AM, Rosamond WD, Girman CJ, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care 2005; 28: 385–390. 16. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review. J Am Coll Cardiol 2007; 49: 403–414. 17. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the NCEP expert panel on detection and treatment of high blood cholesterol in adults. (Adult Treatment Panel III). J Am Med Assoc 2001; 285: 2486–2497. 18. Okpechi IG, Pascoe MD, Swanepoel CR, et al. Microalbuminuria and the metabolic syndrome in non diabetic Black Africans. Diab Vasc Dis Res 2007; 4(4): 365–367. 19. Barrios V, Escobar C, Calderon A, et al. Prevalence of the metabolic syndrome in patients with hypertension treated in general practice in Spain: An assessment of blood pressure and low density lipoprotein cholesterol control and accuracy of diagnosis. J Cardiomet Syndr 2007; 2(1): 9–15. 20. Prussian KH, Barksdale-Brown DJ, Dieckmann J. Racial and Ethnic differences in the presentation of metabolic syndrome. J Nurse Pract 2007; 3(4): 229–239. 21. Kesteloot H, Oviasu VO, Obasohan AO, et al. Serum lipid and apolipoprotein levels in a Nigerian population sample. Atherosclerosis 1989; 78(1): 33–38. 22. Wilson PW, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 1837–1847. 23. Scuteri A, Najar SS, Muller DC, et al. Metabolic syndrome amplifies the ageassociated increases in vascular thickness and stiffness. J Am Coll Cardiol 2004; 43: 1388–1395. 24. Marroquin DC, Laksmen D, Lakka T, et al. The metabolic syndrome and total cardiovascular disease mortality in middle aged men. J Am Med Assoc 2002; 288: 2709–2716. 25. Hu G, Qiao Q, Tuomilehto J, et al. For the DECODE study group. Prevalence of metabolic syndrome and its relation to all cause morbidity and cardiovascular mortality in non-diabetic European men and women. Arch Int Med 2004; 164: 1066–1076. 26. Isezuo SA. Systemic hypertension in Blacks: An overview of current concepts of pathogenesis and management. Nig Postgrad Med J 2003; 10(3): 144–153. 27. DeFronzo RA, Ferrannini E. Insulin resistance: A multifaceted syndrome for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173–194. 28. Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev 2008; 29: 7Jeppesen J, Hansen TW, Ibsen H, Torp-Pedersen C, Madsbad S. Insulin resistance, the metabolic syndrome, and the risk of incident cardiovascular disease: a population-based study. J Am Coll Cardiol 2007; 49: 2112–2119. 29. Tonstad S, Sandvik E, Laren PG, Thelle D. Gender differences in the prevalences and determinants of the metabolic syndrome in screened subjects at risk for coronary heart disease. Metab Syndr Relat Disord 2007; 5(2): 174–182. 30. Njeleka MA, Mpembeni R, Muhihi A, et al. Gender related differences in the prevalence of cardiovascular disease risk factors and their correlates in Urban Tanzania. BMC Cardiovasc Disord 2009; 17(9): 30. 31. Ayodele OE, Alebiosu CO, Salako BL, Awoden OG Adigun AD. Target organ damage and associated clinical conditions among Nigerians with treated hypertension. Cardiovasc J South Afr 2005; 16(2): 89–93. 32. Alebiosu CO, Odusan BO. Metabolic syndrome in subjects with metabolic syndrome. J Natl Med Asso 2004; 96: 817–821. 33. Yusuf S, Reddy S, Dompao S, et al. Global burden of cardiovascular disease: Part I: General considerations, the epidemiologic transition, risk factor and impact of urbanization. Circulation 2001; 104: 2746–2753.

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Diabetes Personality DIABETES – A LIFESTYLE, NOT A DISEASE S Afr J Diabetes Vasc Dis 2010; 7: 111–112

iv Skinner and his wife, Ruby, are two of the lynchpins of the Pietermaritzburg branch of Diabetes SA, along with their colleagues, Felicity Giles and Sheila Pillay. They give their services free of charge and are well known in the community for their commitment to diabetes education and support. Local general practitioners have been known to refer patients to them, advising, ‘They know more about diabetes than I do’. ‘We probably do’, says Ruby. ‘I am a type 1 diabetic who has lived with the condition for 49 years and I’ve been on insulin all that time. I can therefore bring first-hand insight into my counselling and guidance that most doctors can’t. For example, I can guide patients in respect of dealing with the need to inject themselves.’ Viv describes their operation as a support group with three main areas of focus. The first is the ongoing support of existing diabetics. To this end, three counsellors, trained at the Centre for Diabetes and Endocrinology in Johannesburg, are available for consultation three days a week. ‘We also work to make this expensive condition cheaper’, says Viv, ‘selling a range of testing equipment, recipe books and A happy group of children attending a children’s camp for diabetic-friendly products diabetic children, which is held annually.

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at reasonable prices’. Ruby adds that they aim to ensure that the diabetics they work with lead as normal a life as possible. The second focus area targets Pietermaritzburg’s undiagnosed diabetics. To this end, the three counsellors go out ‘along the highways and byways’ as Viv puts it, setting up tables and undertaking random screening at shopping centres, for example. ‘We have identified quite a few undiagnosed diabetics this way’, he says. They have also partnered with large firms in the area such as Hulamin and Illovo Sugar. ‘We have attended wellness days and tested entire staff complements, thus raising awareness and “spreading the gospel”, as it were.’ The third priority is children, whose needs are different from those of adult diabetics. Every year Felicity Giles and her husband are instrumental in arranging camps for juvenile diabetics, usually at a wilderness area. ‘These camps give them the opportunity to mix with other diabetic children, which allows them to realise that they are not alone, as diabetic children can feel very isolated when constantly surrounded by “normal” siblings and classmates. We help them come to terms with the fact that diabetes will require a lifetime of accommodations, but that there is “life after all” following a diagnosis. It is very rewarding to see diabetic children gain control and excel, both at sport and academically, often as a direct consequence of the healthy diet and disciplined behaviour the condition requires. One might almost be tempted to say that for some children it can be good to be a diabetic’, comments Viv. When it comes to challenges, the branch faces many of the same issues that confront other diabetes educators, notably the anger and denial that follow diagnosis, along with what Ruby describes as the perception that diabetes is a ‘death sentence’ and

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patients’ belief that their lives might just as well be over. Viv feels strongly that nothing could be further from the truth, and even takes issue with labelling diabetes a ‘disease’. ‘It’s really just a different lifestyle and as long as you make the necessary changes, it is possible to live a completely normal life.’ Ruby adds that the biggest challenge is that people don’t know how to eat correctly and this is where Diabetes SA plays a key role, facilitating quality-of-life improvements through diet and lifestyle measures. ‘Just recently, we had someone walk in who had just received the diagnosis, was very stressed and had no idea of what to expect in the future. In the course of a long counselling session, we were able to help him plan his future eating patterns with a view to ensuring that he could still live “normally”.’ Another concern for the branch is Diabetes SA’s lack of human resources in Pietermaritzburg. The Skinners are trying to recruit more volunteers to assist in their work. ‘We are not getting any younger’, says Ruby.

Members of the team caring for a patient at a medical camp.

Patients on a supermarket tour, where a dietician teaches diabetics how to eat correctly by learning to read food labels properly.

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‘Unfortunately, it’s very hard to find people who are prepared to work for nothing.’ The branch has high praise for the medical community and the wonderful co-operation received. Diabetes SA holds a monthly meeting that is always well supported. On each occasion a specialist gives a talk on a specific aspect of the condition. ‘Most recently, a clinical psychologist talked about the emotional impact of a diabetes diagnosis’, says Ruby. ‘We’ve also had talks by eye specialists, endocrinologists and dieticians, among others.’ Meetings are also held in the predominantly Indian area of Northdale, where diabetes is very prevalent. Summing up, Viv feels that their primary function is to reassure. ‘A diagnosis of diabetes is not the end of the line. With the correct guidance, these individuals can live long, productive and high-quality lives’, he concludes. ‘It is our job to ensure that they know and believe this!’

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Community Initiative

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The ‘Changing Diabetes’ bus will now screen for retinopathy and diabetic foot syndrome S Afr J Diabetes Vasc Dis 2010; 7: 113

fter three successful years of raising diabetes awareness among the general population and healthcare professionals alike, the Novo Nordisk’s ‘Changing Diabetes’ bus is expanding its services to include screening for complications of diabetes such as retinopathy and diabetic foot syndrome. These new services on board will facilitate the early diagnosis of these common complications, with a view to optimising current therapy and thus improving outcomes. Eric Reurts, Novo Nordisk general manager for the southern African region, explains further. ‘To date the bus has travelled all over southern Africa and has evaluated more than 32 000 individuals, all of whom have had their risk factors for diabetes assessed, for example, weight and blood pressure. Our finding that many of the people we saw required further investigation confirmed what we already knew – that diabetes is underdiagnosed and often misdiagnosed. We wanted to make a difference in respect of raising the profile of this condition, while at the same time making government aware that this region has healthcare priorities other than HIV/AIDS, which is where much of government’s attention is focused. If everyone who has diabetes were diagnosed, the number of patients with the condition would probably be higher than that of HIV sufferers.’ Foot amputations are common among diabetics, and add greatly to the costs associated with the disease, hence Novo Nordisk’s upgrading of the bus’s functions to include diabetic foot assessment. ‘We have all the necessary testing equipment on board to assess nerve conduction to the feet’, says Reurts. He also has high praise for the Podiatry Association of South Africa’s support in this regard.

Retinopathy is another common complication of diabetes and Novo Nordisk recently partnered with the University of Pretoria to help address this. ‘The project is being piloted over a six-month period that commenced on 28 June 2010. The bus now visits all the diabetic clinics that feed into Pretoria Academic Hospital. We do a full screen for complications on all patients, including a retinal examination. Staff from Pretoria Academic Hospital undertake this, using the fundus camera that we purchased recently and installed on the bus.’ ‘We also have the facility to undertake laser treatment on those patients who require it’, Reurts continued. ‘The camera screens patients on four days of the week and the pictures are then analysed at the University of Pretoria’s ophthalmology department. Thereafter, patients requiring treatment are invited back to the bus to have their eyes lasered. Based on an earlier initiative undertaken in a rural population with fundus cameras donated by the World Diabetes Federation, we’re anticipating a referral rate of around 30%.’ Reurts pointed out that while Novo Nordisk provides the infrastructure, the multidisciplinary staff on board the bus (e.g. endocrinologists, podiatrists, diabetes nurse educators) are all being provided by the University of Pretoria. The intention is that they will also transfer their skills to clinic staff. ‘Six months after completion of the project, we will assess its impact’, Reurts concluded. ‘We hope ultimately to roll it out to other provinces. Once again, we’ll provide, in the form of the bus, the environment in which treatment can be optimised, while the provincial health departments provide the staff complement required.’

The fully fledged laboratory has a dedicated team supporting this massive education effort.

A new full retinopathy service and laser treatment is offered from the bus.

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Diabetes Educator’s Focus SOUTH AFRICAN APPROACHES TO STRUCTURED EDUCATION IN TYPE 1 DIABETES Correspondence to: Kamaretha Beckert Centre for Diabetes and Endocrinology, Paarl, Western Cape Cell: 082 438 2747 e-mail: diabetes@telkomsa.net Laurie van der Merwe Centre for Diabetes and Endocrinology, Richards Bay, KwaZulu-Natal Cell: 078 802 7505

e as specialised diabetes nurse educators encounter many obstacles when educating patients on effective management of their condition. Often people with diabetes are confused as a result of unstructured or incomplete education on their condition and therefore cannot maintain optimal health and a good quality of life. There may be underlying emotional or stress-related issues that should be addressed before patients can become self-motivated with regard to managing their disease. Much needs to be done in South Africa to improve education and care of people with diabetes.

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Diabetes is an important cause of morbidity and mortality in Africa and prevention and control programmes are needed to stem the rising epidemic of diabetes and its complications.1 In Asia and Africa, the incidence of diabetes has risen at an extreme rate and the total number of people with diabetes was expected to have reached 221 million by 2010. According to the International Diabetes Federation (IDF), the estimated number of people with diabetes in South Africa is around 840 000. The World Health Organisation (WHO) and International Diabetes Federation (IDF) predicts that in South Africa, the numbers will increase to more than 1.3 million in the next 25 years. Although all groups are affected, those most at risk are the black community, who are undergoing rapid changes in lifestyle and culture, and people of Indian descent, who have a gene pool that makes them unusually susceptible to diabetes.2 The incidence of type 1 diabetes is rapidly increasing in children and adolescents in many countries and the global prevalence of type 1 diabetes in the child population from birth to 14 years of age is assessed to be 479 600.3 The first long-term outcome study of type 1 diabetes in sub-Saharan Africa, done in Soweto and published in 2005, indicates that although the mortality rate was substantial, it was similar to equivalent studies in the United States of Afro-Americans with type 1 diabetes. The outlook for individuals with type 1 diabetes in Africa therefore remains poor,4 as ‘efforts to prevent this disease and its complications

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in Africa are impeded by inadequate healthcare infrastructure, inadequate supply of medications, absence of educational programs, and lack of available healthcare facilities and providers’.5 Limitations of current treatment programmes About 47 million people live in South Africa. Approximately 80% of these receive government-sponsored medical care and 20% receive medical care in the private sector, paid for by either themselves or medical insurance schemes. The costs of diabetes management are considerable, both for the person with the condition and the healthcare provider.2 In a review of public-sector primary care of diabetics in Cape Town,6 it was found that care was inadequate, and simple but appropriate protocols and education were needed to improve the care and health outcomes of these patients. A study of the diabetic population in the public health sector in rural KwaZulu-Natal found that only 15.7% had acceptable glycaemic control. In fact the average HbA1c was 11.3% despite having good rates of attendance at the health clinic and compliance with medication. Again the care and control of diabetes was found to be sub-optimal and the suggestion was made that additional training for nursing staff and education for patients is needed.7,8 In the private healthcare sector, individuals with diabetes may be referred to a dietician or diabetes nurse educator following diagnosis and may receive basic

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education in hospital on the use of a glucometer and self injecting, but few receive any follow up or ongoing life skills training in diabetes management. In general, medical aids will only cover the costs of one annual visit to a dietician and there is no specific allocation for diabetes education. Certain medical aids are affiliated to the Centre for Diabetes and Endocrinology (CDE), which is the only doctor-based managed healthcare programme in South Africa. It is considered the premier diabetes programme in the country, giving comprehensive diabetes treatment and management programmes and providing one-on-one and group education.9 Alternative approaches to intensive insulin therapy in type 1 diabetes The DCCT/EDIC10 showed that the intensive insulin therapy approach, using either multiple daily injections or insulin pump therapy, is the best treatment for individuals with type 1 diabetes regardless of age.11 It provides greater glycaemic control and reduces the risk of complications. The Global Partnership for Effective Diabetes Management recommends: ‘It is important that patients adjust their insulin doses appropriately in response to factors such as carbohydrate intake, lifestyle, exercise and inter-current illness to minimise the risk of hypo- or hyperglycaemia. As described above, insulin pumps may allow greater flexibility of dosing, but as all patients will not have access to pump therapy, alternative strategies are needed and education is required for all patients. Modification of insulin dosages based on diet and exercise can be challenging for patients and should be considered an essential part of patient education.’11 Despite randomised trials12 showing insulin pump therapy (CSII) provides some advantages over multiple daily injections in type 1 diabetes for both children and adults, multiple daily injections are the most commonly prescribed insulin regimen for type 1 diabetics in South Africa. Although insulin pump therapy is becoming more common, it remains expensive and costs are only covered by a few medical aids. A new equation has been derived at the North-West University, Pretoria to estimate bolus insulin need,12 and should be able to estimate insulin dosage requirements for bolus insulin in a patient with type 1 diabetes more accurately than with carbohydrate counting. Further investigations are continuing. This would be an asset for both multiple daily injections and pump therapy. Effectiveness of structured training in intensive insulin therapy in type 1 diabetes There is much evidence to show the effectiveness of structured education. In a Portuguese review of 40 articles published between 2000 and 2007,10 focusing on diabetes educational programmes designed for children, young adults and their families and regular pump users, they assessed recommendations and standards of intervention, and methods of education in self-management. They found that education in self-management improved glycaemic control whether given on an individual or

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group basis, and the longer the education the more effective it was. According to The Global Partnership for Effective Diabetes Management, structured educational programmes have been demonstrated to have substantial benefits in terms of outcomes. These programmes demonstrate that appropriate education can improve glycaemic control while giving the individual more flexibility in terms of diet, rather than having to adhere to rigid calorie control and fixed insulin doses. Other important considerations include the use of carbohydrate counting, a common meal-planning method used by patients, which must of course be adapted to local diet and lifestyle. Appropriate adjustment of insulin doses surrounding exercise is also important. In addition, many patients may not know the effect of factors such as exercise or alcohol on glucose levels and the need for appropriate adjustment of insulin therapy, highlighting the importance of education on this subject.11 For example, the Dose Adjustment For Normal Eating (DAFNE) programme14 has been shown to improve glycaemic control, with a reduction in severe hypoglycaemic episodes and an improved quality of life. This UK-based14,15 programme has shown similar results in Australia.14 In the Dusseldorf Diabetes Treatment and Teaching programme (DTTP), which involves a five-day in-patient course for individuals with type 1 diabetes, HbA1c levels fell significantly from 8.1 to 7.3% over the subsequent year, as did the number of severe hypoglycaemic episodes. The CASCADE trial16 is currently assessing long-term effectiveness of structured, intensive education programmes for self-management of diabetes and their cost effectiveness. The XPERT programme17 is a six-week structured patient education programme that has also shown improved diabetes control and more confidence in the self-management of diabetes. An American trial18 also showed that structured diabetes education was more effective in improving metabolic control in type 1 diabetic adolescents. Current status of structured training programmes for type 1 diabetes in South Africa South Africa has no structured education programme for either public or private healthcare settings. One of the problems in South African is that many people live in rural areas so any health education system for people with diabetes needs to be effective in the primary-care clinics, where resources are poor. Even those attending a tertiary-care hospital have problems with poverty, transport and distances to be travelled. A monthly endocrinology clinic visit can mean a round trip of six hours or more in transit. Most education if any, at primary-clinic level is done by nurses who have had no specialised education in diabetes, and is very generalised and outdated – certainly not suitable for type 1 diabetics. At specialised units in tertiary hospitals, type 1 diabetics are more likely to receive some one-on-one or group education, but the effectiveness is varied. Most structured training programmes are three to five days in duration.

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Diabetes Educator’s Focus Table 1. Guidelines for patient education Understanding diabetes • Causes of diabetes • Symptoms of diabetes • Different types of diabetes Health management • Diet and nutrition therapy: understanding food and its role in blood glucose regulation –– Carbohydrate counting –– Role of fat and protein –– Meal planning • Regulation of blood glucose levels • How to use alcohol appropriately • Different sweeteners: pro’s and con’s • Essential supplements • Special occasions • Exercise principle and guidelines • Managing weight Diabetes treatment • Goals for diabetes management • Blood glucose monitoring • Different types of blood glucose-lowering medication • Correct use and timing of medication • Self management skills, e.g. how to correct low and high blood glucose levels • Complications.

Many South Africans with diabetes would need to stay in a boarding facility or be admitted to hospital for that time. Conclusions Structured training programmes have been proven to be effective in allowing persons with type 1 diabetes to better manage their condition. In the private healthcare system, a structured education model such as DAFNE could be very effective in South Africa. The first training course has recently been held at the CDE in Johannesburg. However, for the majority of type 1 diabetics, this will not be a viable proposition. A standardised education model specifically designed for the African situation should be the goal but it would also need recognised diabetes educator training to ensure that nurses implementing this education are adequately trained. In a study done in primary-care clinics in rural South Africa,19 it was shown that when diagnostic and treatment protocols were designed to be nurse led and implemented, the majority of patients with chronic conditions showed an improvement in clinical condition and an improved adherence to treatment. Without adequate knowledge and skills, the person with type 1 diabetes is unable to manage his/her condition effectively and the ideal would be a structured training programme suitable for South African cultures, foods and lifestyles, to be delivered by trained diabetes educators, for rural clinics and specialised hospital settings, and for private and public healthcare facilities. This is unfortunately a tall order.

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References 1. Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabetes Med 1997; 14(Suppl 5): S1–85. 2. World Diabetes Foundation presentation at the International Management meeting in Novo Nordisk. Rome, 2010. 3. Author? IDF Diabetes Atlas. Diabetes in the Young: a Global Perspective. Publisher, city and date? 4. Gill GV, Huddle KR, Monkoe G. Long-term (20 years) outcome and mortality of type 1 diabetic patients in Soweto, South Africa. Diabetes Med 2005; 22(12): 1642–1646. 5. Motala AA. Diabetes trends in Africa. Diabetes Metab Res Rev 2002; 18(Suppl 3): S14–20. 6. Rotchford AP, Rotchford KM. Diabetes in rural South Africa – an assessment of care and complications. S Afr Med J 2002; 92(7): 536–541. 7. Van de Sande M, Dippenaar H, Rutten GE. The relationship between patient education and glycaemic control in a South African township. Prim Care Diabetes 2008; 2(2): 105. 8. http://www.cdecentr.co.za 9. DCCT⁄EDIC Research Group. Modern-day clinical course of type1 diabetes mellitus after 30 years’ duration: the Diabetes Control and Complications Trial⁄Epidemiology of Diabetes Interventions and Complications and Pittsburgh Epidemiology of Diabetes Complications experience (1983-2005). Arch Intern Med 2009; 169: 1307–1316. 10. Leite SA Zanim LM, Granzotto PC, Heupa S, Lamounier RN. Educational program to type 1 diabetes mellitus patients: basic topics. Arq Bras Endocrinol Metabol 2008; 52(2): 233–242 11. Aschner P, Horton E, Leiter LA, Munro N, Skyler JS. Practical steps to improving the management of type 1 diabetes: recommendations from the Global Partnership for Effective Diabetes Management. Int J Clin Pract 2010; 64(3): 305–315. 12. Cummins E. Clinical effectiveness and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes: systematic review and economic evaluation. Health Technol Assess 2010; 14(11): iii–iv, xi–xvi, 1–181. 13. Mathews EH, Pelzer R. A new model to estimate bolus insulin need. Diabetes Technol Ther 2009; 11(12): 813–817. 14. McIntyre HD, Knight BA, Harvey DM, Noud MN, Hagger VL, Gilshenan KS. Dose adjustment for normal eating (DAFNE) – an audit of outcomes in Australia. Med J Aust 2010; 192(11): 637–640. 15. Dinneen SF, Irish DAFNE study group. The Irish DAFNE study protocol: a cluster randomised trial of group versus individual follow-up after structured education for type 1 diabetes. Trials 2009; 10: 88. 16. Christie D, Strange V, Allen E, Oliver S, Wong IC, Smith F, et al. Maximising engagement, motivation and long term change in a structured intensive education programme in diabetes for children, young people and their families: Child and Adolescent Structured Competencies Approach to Diabetes Education (CASCADE). BMC Pediatr 2009; 9: 57. 17. Deakin T, Whitham C. Structured patient education: the X-PERT Programme. Br J Commun Nurs 2009; 14(9): 398–404. 18. Wang YC, Stewart SM, et al. A randomized controlled trial comparing motivational interviewing in education to structured diabetes education in teens with type 1 diabetes. Diabetes Care 2010; 33(8): 1741–1743. E-pub May 2010. 19. Coleman R, Gill G, Wilkinson D. Noncommunicable disease management in resource-poor settings: a primary care model from rural South Africa. Bull Wld Hlth Org 1998; 76(6): 633–640.

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Patient information leaflet

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Keep and Copy Series LASER TREATMENT FOR DIABETIC RETINOPATHY S Afr J Diabetes Vasc Dis 2010; 7: 117â&#x20AC;&#x201C;118

Linda Visser Department of Ophthalmology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal Tel: +27 (0)31 260-4341 e-mail: visser@ukzn.ac.za

WHAT IS LASER? Laser is the acronym for Light Amplification by Stimulated Emission of Radiation. The laser machine generates a powerful light beam consisting of a single wavelength of light.

WHAT IS DIABETIC RETINOPATHY? Over time, high blood glucose will cause damage to retinal blood vessels, leading to diabetic retinopathy. The damaged blood vessels might leak onto the macula at the centre of the retina (often referred to as diabetic maculopathy or diabetic macular oedema/swelling) or, because of the damage to the blood vessels, they eventually close off completely, leading to ischaemia (death) of the peripheral retina. This ischaemic retina then produces a substance called vascular endothelial growth factor (VEGF), which stimulates the growth of abnormal new vessels on the surface of the retina (referred to as proliferative diabetic retinopathy). These vessels often bleed or are accompanied by scar tissue, which contracts over time and pulls the retina off (tractional retinal detachment). HOW DOES LASER WORK IN DIABETIC RETINOPATHY? When a laser is aimed at the eye, there are three types of tissue reactions that can be seen depending on the wavelength of the laser light used: photocoagulation (burns), photodisruption (small explosion), or photoablation (precise removal of tissue). Many people are familiar with the excimer laser, which utilises light of 193 nm and causes ablation of the surface of the cornea, thereby changing the

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refraction of the eye and allowing patients to see without spectacles. This is however not the same laser used for the treatment of diabetic retinopathy. In the case of diabetic retinopathy we need to use a laser with a wavelength of 532 nm to photocoagulate (burn) the retina. Retinal phototcoagulation is usually of three types: Panretinal (scatter) laser photocoagulation A large number of laser burns (up to 3 000) are made to the peripheral retina to destroy the ischaemic areas of retina thereby decreasing the production of vascular endothelial growth factors and ultimately leading to regression of the abnormal new vessels on the surface of the retina. Focal laser photocoagulation The laser beam is directed at specific leaking blood vessels (micro-aneurysms) in a small area at the centre of the retina (macula) to seal off the leak. The burns are usually few, small and of low power. Grid laser photocoagulation The laser treatment is done for diffuse leakage in the macular region. The beam is not aimed at specific blood vessels, but rather is put down in a grid pattern around the central point (fovea) at the back of the eye, always remaining about 1 mm away from the fovea. WHY SHOULD I HAVE LASER TREATMENT? Laser treatment is done to reduce the risk of vision loss caused by diabetic retinopathy. It is most often used to stabilise vision and prevent future loss rather than improve vision loss that has already occurred.

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Focal laser for focal maculopathy may sometimes restore some lost vision. WHAT TO EXPECT DURING TREATMENT Your treatment will be performed in a specially equipped laser room. Your pupils will be dilated in order for your doctor to see your retina well. Topical local anaesthetic drops will be instilled into your eye. In the majority of patients this is enough anaesthesia, but a small percentage of patients, who have a lower pain threshold, may need a regional local anaesthetic injection for scatter laser treatment. The laser can be performed in one of two ways: • Most commonly you will be seated at a slit lamp and a contact lens will be placed on the cornea (front of the eye). This keeps the eye open and stabilises the eye and also helps to focus the laser beam on the retina. • Sometimes your doctor might prefer to have you lie down on a bed and use an indirect ophthalmoscope (attached to the doctor’s head) to deliver the laser beam. This method is useful when the doctor’s view of the retina is slightly obscured by cataract or blood, but is a more difficult technique to master. It can only be used for scatter laser and not for focal or grid laser. Focal or grid laser is usually done in one sitting, but scatter laser might be accomplished over a few sessions. WHAT TO EXPECT AFTER TREATMENT The vision will be blurred immediately after the treatment, but should recover to the pre-treatment level over time. You should plan to have someone drive you home and you should relax for the rest of the day. Remember to bring a pair of dark glasses, as your pupils will remain

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dilated for a few hours making your eyes very sensitive to light. Most patients resume normal activities within a day or two. Regular follow-up visits are required. HOW WELL DOES IT WORK? Laser is unlikely to restore vision already lost, but when performed in a timely manner: • focal laser, targeting specific blood vessels, is effective in reducing the risk of vision loss in people with macular oedema • scatter laser, treating the peripheral ischaemic retina, reduces the risk for severe vision loss by 50 to 60% over six years in people with high risk of vision loss. Studies suggest that up to 90% of cases of legal blindness caused by proliferative retinopathy could be prevented by prompt scatter laser. WHAT ARE THE RISKS? Laser burns and destroys part of the retina and can result in some permanent vision loss, which is unavoidable. Panretinal/scatter treatment may cause mild loss of central vision (due to increased macular oedema), reduced night vision, reduced peripheral vision and decreased ability to focus. This is mild compared to the vision loss that may be caused by untreated retinopathy. Rare complications of laser treatment, which may cause severe loss of vision, include: • bleeding in the eye/vitreous haemorrhage (as part of scar formation) • tractional retinal detachment (as part of scar formation) • accidental laser burn of the fovea (centre of the macula). WHAT IF I DECIDE NOT TO HAVE THE TREATMENT? Untreated retinopathy invariably leads to severe loss of vision.

VOLUME 7 NUMBER 3 • SEPTEMBER 2010

Keep and Copy Series

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Hands On USE OF THE RETINAL CAMERA IN DIABETES EYE CARE IN SOUTH AFRICA

Grant Ladner Moorfields Eye Hospital, London, UK Tel: +44 (0)20 725 33411 e-mail: grant.ladner@moorfields.nhs.uk

his article outlines the rationale for a screening programme for diabetic retinopathy. This includes an understanding of the pathogenesis of the disease and the need for early intervention to prevent blindness. It explains the requirements for such a screening programme to function properly, including the need to train staff, use the correct equipment and have an appropriate follow-up and referral protocol and quality control. The main purpose of the article is to advocate for a pilot project so that the resources are in place when a comprehensive programme is instituted. Such a programme will require the commitment of the medical profession, government and civil society in order to function properly. S Afr J Diabetes Vasc Dis 2010; 7: 119–121

The incidence of type 2 diabetes is increasing worldwide.¹ The most significant increase will be in the developing world.2 One study found the incidence of the metabolic syndrome in Mexico to be 40 and 60% in men and women, respectively.3 The metabolic syndrome predisposes people to diabetes. Diabetes is one of the most common causes of irreversible blindness in the elderly and the leading cause of visual impairment in those in the adult working age group in England and Wales.4 The magnitude of the disease and the efficacy of early treatment warrant the implementation of a screening programme. Such a programme would require the combined efforts and co-ordination of medical practitioners, government and civil society. A useful tool in such a screening programme, which would identify those needing referral, diagnosis and management, is the non-mydriatic retinal camera. The pathogenesis, pathology and treatment of diabetic retinopathy The purpose of retinal photography is to screen those with diabetic retinopathy who need referral for possible treatment. The Early Treatment of Diabetic Retinopathy study (ETDRS) provides the guidelines for when to treat retinal damage caused by diabetes. This study classified patients into the following groups: no retinopathy, non-proliferative diabetic retinopathy and proliferative retinopathy.5 Maculopathy is classified into two groups: patients

VOLUME 7 NUMBER 3 • SEPTEMBER 2010

with and without clinically significant macular oedema.5 Clinically significant macular oedema and proliferative diabetic retinopathy can result in significant and profound visual loss, respectively. Retinal disease in diabetes is multi-factorial and poorly understood. There are multiple mechanisms, including the release of vascular endothelial growth factors (VEGFs), abnormal platelet function, increased blood viscosity, and dysfunction of pericytes in the small blood vessel walls. These factors result in the leakage of retinal vessels, infarcts, the formation of abnormal new vessels and fibrovascular membranes. The formation of new vessels signals the presence of proliferative retinopathy. The treatment of diabetic retinopathy has been assessed in various trials. The Diabetic Retinopathy study found that the use of pan-retinal photocoagulation significantly decreased the progression to loss of vision in those with proliferative retinopathy including high-risk characteristics (HRC).6-10 The ETDRS found that early treatment of proliferative retinopathy prevented the progression to HRCs, and that 50% of patients with severe non-proliferative diabetic retinopathy progressed to proliferative retinopathy within one year. However the recommendations of this study were to await the onset of HRC before starting treatment.11 There is now a trend to treat those with diabetic retinopathy at a less advanced stage, particularly in our setting in South Africa, as there is often poor disease education and difficulty with follow up.

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Hands On Various studies have investigated the relationship between diabetic retinopathy and glucose control in diabetics. These include the Diabetes Control and Complications study and the UKPDS.12,13 Both these studies demonstrated that initially, when tight blood sugar control was instituted, the proliferation worsened, but after one year the outcome was better in those with tight control. There is inevitably a group of patients that will continue to worsen. This is referred to as retinopathic momentum. Starting a screening programme for diabetic retinopathy The non-mydriatic camera The advantage of this camera is that there is no waiting time for the test and the patient is able to drive immediately afterwards. The risks of dilatation are small but significant. There are numerous studies comparing the efficacy of identifying diabetic retinopathy (DR) using photography through a dilated pupil, indirect fundoscopy through a dilated pupil and photography through an undilated pupil. These studies indicate that photography through the undilated pupil is comparable as a screening tool.14-16 These studies, however, used cameras that are no longer manufactured and the results may have compared even more favourably if current technology had been used. In one of the studies, no patients were missed who needed urgent referral for laser or surgery for treating proliferative DR. In the absence of macular exudates or haemorrhages, macular oedema may be difficult to identify but in the above study no patients were missed due to concurrent retinopathy needing referral.15 The camera should be used in a dark room to optimise the natural dilatation of the pupil but with adequate lighting to ensure quick thoroughfare of the patients. Patients should ideally be in the dark room or a darkened waiting area for at least a minute prior to the testing. The minimal pupil size is between 3.2 and 3.8 mm and this allows one to take 45-degree photographs of the retina. Some models have an internal fixation device, which enables one to make a collage of the retina extending further into the periphery. Any dense opacities of the media in front of the retina would preclude the use of the camera. The most common of these is cataract but may include corneal opacities and vitreous haemorrhage. It may not be possible to take photographs in those with pinpoint pupils. In one large study it was not possible to take images due to small pupils and media opacities in 7% of patients.14 If the photographer is also trained as a reader/screener these problems may be identified at the time of imaging. Modern cameras are digital, which allows one to view images in real time. The images can be viewed, repeated if improvement in image quality is possible, and read at the screening centre, or stored and sent to a distant reading centre on an appropriate storage device or via the Internet. There are commercially available packages to send many images in a

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compressed format. These one can buy with the camera. In California there is a non-propriety-based Internet system called EYEPACS, which allows for the distant reading of photographs.16 There are also various commercially available proprietary-based systems. These systems have security measures to allow controlled access and patient privacy. Photographers and readers The staff that are trained for these tasks should preferably not be medically qualified. Screening programmes would create a new career direction for interested people. A programme would have to be created to train and certify the personnel. For example, in the USA the EYEPACS system requires photographers to take 10 photographs of readable quality in order to be certified. They also offer a training programme where photographs are sent in and suggestions are made to improve the quality. For each patient screened as part of EYEPACS, four photographs are required. One photograph is an external image to verify the size of the pupil, the presence of cataract and corneal clarity. The other three photographs are retinal and include one centred on the disc, a second including the macula and disc, and the third includes the macula and the temporal retina. One proposed model is that the photographers be trained to also read the images. The alternative would be for eye specialists to perform the screening. One would have to set up local guidelines for referral and follow up. The grading of diabetic retinopathy for a screening programme could be devised as part of a pilot project so that the most pragmatic system is adopted. This would have to take into consideration the limited human resources and other constraints in South Africa. The grading for a screening programme would differ considerably from the ETDRS grading since the photographs would be different and it would be a screening test. A screening programme would employ a considerable number of people if it were decided to train personnel for this task. In the south-west region of the UK a screening programme was proposed which would serve a population of 4.9 million people. This programme would employ 21 photographers/screeners if their only tasks were to take photographs and screen patients.17 If their work included education, the number of staff would increase to 30 people. A follow-up and referral pattern A question that could only be answered by a pilot project is whether the ophthalmology services in a specific region would be able to manage the increased workload. For example, in the region of South Africa where I lived, there is a large Indian population. Among the Indian people in this region, the prevalence of diabetes is 15%. This percentage is much higher than the prevalence quoted from the literature for developed nations. The majority of patients would be referred for cataracts and retinopathy.

VOLUME 7 NUMBER 3 â&#x20AC;˘ SEPTEMBER 2010

Hands On One would have to divide the referrals into urgent and routine. Screening follow-up protocols would also need to be devised. A contact system would be different for those from an urban and rural background due to communication difficulties in rural areas. In parts of the UK, patients are posted annual invitations for their diabetic screening; the so-called ‘call and recall’ system. In South Africa some form of electronic message may be more appropriate, such as SMS or e-mail. Photography and screening centre Studies indicate that the most appropriate place to have such a centre would be adjacent to the primary-care physician’s rooms or clinic. Screening is least threatening if it forms part of the routine diabetic check up. Compliance is optimal in this setting.18,19 Essential for the service to function properly is the appropriate back-up service of the camera. It would need to be replaced temporarily at short notice if there was camera failure. This would have to be part of the sales agreement with the provider. Quality assurance Essential to any screening programme is quality control and audit. One needs to identify the pick-up rate of the programme and monitor the pho-

SA JOURNAL OF DIABETES & VASCULAR DISEASE

tography and reading. The referral and follow-up pattern needs to identify deficiencies so that these can be addressed. Conclusion In order to ensure better management of diabetic retinopathy, there is a need for a screening programme in KwaZulu-Natal and other parts of South Africa where this service does not exist. Many patients who present to ophthalmology departments with inoperable disease would not have reached this advanced stage if they had been identified earlier. DR screening is an essential part of a comprehensive management plan for diabetic patients. In order to plan correctly, a pilot project would be the ideal starting point. A customised system could then be created that would manage the ever-increasing burden of disease in our unique setting. Key points • The magnitude of the disease and the efficacy of early treatment warrant the implementation of a screening programme. • Studies indicate that a photograph through the undilated pupil is comparable as a screening tool for diabetic retinopathy. continued on page 129 …

Tel: (012) 370-4175/ 3383/ 3951; 0861 3876 8324 / 0861 EUROTECH Solly Moosa – 076 454 0930 Ahmed – 082 414 1472 e-mail: sales@eurotechoptical.com www.eurotechoptical.com

More than 20 years service to South African and African markets Eurotech Optical, established in South Africa in 1989, has grown to be a serious contender within the optical industry Eurotech supplies the Kowa non-myd 7 (12 megapixel) and the Kowa non-myd 7 WX (3-D) fundus cameras at affordable prices. Kowa Instruments have been active in the opthalmological market for more than 100 years, supplying a global market. Eurotech also supplies the Kowa VK2 digital opthalmic imaging system, which expands imaging management systems in opthalmological practices and is capable of integrating images from three cameras at once.

Non-myd 7 WX

Non-myd 7

Does anterior and posterior photography The world’s first and only 3-D non-mydriatic fundus camera – take one image with the first shot and display two different images at two different angles three dimensionally Nine-point internal fixation lights enables nine different angles to be taken with mosaic (montage) feature – automatic mosaic merge feature with automatic image rotation and alignment The only non-mydriatic fundus camera with disk-damage likelihood scale-depth distribution for the graphical display or the cross section of an arbitrary position Two angles: 20 and 45 degrees New embossing feature Numerical display of optic disc parameters Polar coordinates display of the depth distribution permits visual display of the thin part of the rim VOLUME 7 NUMBER 3 • SEPTEMBER 2010 Contour line depth distribution of cup and disc profiles Follow up of graphical display of cup/disc Award-leading camera system from NIKON Cup/disk measurement by angle or points

Does anterior and posterior photography Free mosaic (montage) software included Three-point internal fixation to use with the montage software Nine-point fixation target (optional) to use with the montage software New embossing feature Two angles: 20 and 45 degrees Stereo photography available Cup/disk measurement by angle or points Award-leading camera system from NIKON

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ADA WATCH

ADA WATCH SUMMARIES

2010 UPDATE FROM ORLANDO, USA American Diabetes Association Contributors: J Aalbers, Dr F Mahomed, Prof WF Mollentze

Clinical trial updates ACCORD retinopathy study shows intensive glycaemic control, and combination dyslipidaemia therapy with fenofibrate reduces retinopathy progression A study group of the ACCORD study has shown that targeting glycaemic control at the 6% HbA1c level and lipid therapy with fenofibrate instead of placebo significantly reduced the rate of progression of diabetic retinopathy.1 Intensive blood pressure control did not reduce progression. The ACCORD study was an independent study sponsored by the National Heart, Lung and Blood Institute and companies did not participate in the study design or conduct, data accrual or analysis, or manuscript preparation, providing only the study drugs. The more than 10 000 ACCORD patients with type 2 diabetes and HbA1c higher than 7.5% were randomly assigned to either the intensive glycaemic-control arm or standard control. Of these participants, 5 518 with dyslipidaemia were also randomly assigned in a two-by-two factorial design to receive simvastatin and fenofi-

Table. 1. Progression to retinopathy and moderate vision loss Progression of retinopathy Treatment

(%)

Moderate vision loss

(%)

Glycaemic therapy Intensive

104/1429

(7.3) 266/1629 (16.3)

Standard

149/1427 (10.4) 273/1634 (16.7)

Dyslipidaemia With fenofibrate

52/806

(6.5) 145/908 (16)

With placebo

80/787

(10.2) 136/893 (15.2)

Intensive

67/647

(10.4) 145/749 (19.4)

Standard

54/616

Antihypertensive (8.8)

113/13 (15.8)

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25–29 June 2010

brate or placebo. The remaining 4 733 participants were randomly assigned to either the intensive blood-pressure control (< 120 mmHg systolic blood pressure) or standard therapy (< 140 mmHg). In this ACCORD eye study, participants with retinopathy at baseline were excluded; those included were comprehensively evaluated at baseline and at year four of the study. Progression of diabetic retinopathy was defined as at least three steps on the EDTRS severity scale or development of retinopathy requiring photocoagulation therapy or vitrectomy. Results of the progression to retinopathy and moderate vision loss are summarised in Table 1. The early stoppage of the intensive

glycaemic-control arm due to an increased rate of death from any cause after a mean of 3.5 years has influenced the retinopathy results in this arm, potentially underestimating the retinopathy benefits of good glycaemic control. The beneficial effect of fenofibrate therapy on the progression of diabetic retinopathy at four years (6.3 vs 10.2% on placebo) provides further support to the findings of the FIELD study, which also showed visual benefits with fenofibrate. 1.

The ACCORD stu3dy group and ACCORD Eye study group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 10.1056/NEJM oa1001288. Pub 29/6/2010.

TABLE OF CONTENTS Clinical trial updates ACCORD retinopathy study shows intensive glycaemic control, and combination dyslipidaemia therapy with fenofibrate reduces retinopathy progression ��123 Optimising glucose control in ICU patients reduces costs (TRIUMPH three-year results) ��124 VADT study: further analysis of results shows intensive glycaemic control offered some renal protection to patients with more advanced microvascular disease ��124 VADT trial: intensive glycaemic control did not prevent progression of calcified atherosclerosis in patients with longstanding type 2 diabetes ��124 Once-weekly exenatide injection improves blood sugar control more than daily oral sitagliptin or pioglitazone and induces more weight loss (DURATION-2 study) ��124 Pathogenesis of type 2 diabetes Intramyocellular lipid accumulation does not occur in pre-diabetes, but only after manifestation of hyperglycaemia ��124 Insulin resistance study (IRAS) shows problems for HBA1c levels as diagnostic tool ��124 New metabolic syndrome definition and value of waist circumference evaluated in type 2 diabetes ��125 Diabetes therapy Metformin protects against antidepressant diabetes risk? ��125

Once-daily liraglutide lowers systolic blood pressure (SBP) in treated and untreated hypertensive patients ��125 Dietary omega-3 polyunsaturated fatty acid (fish oil capsules) reduced atherosclerosis progression in type 2 diabetes ��125 Costs of continuing sulphonylureas with insulin therapy in type 2 diabetes: more hypoglycaemia and weight gain but less insulin needed ��125 Reducing complications of diabetes Infliximab treatment improves visual acuity in diabetic macular oedema that does not respond to laser photocoagulation ��126 Point-of-care testing of diabetic keto-acidosis avoids unnecessary DKA work-ups in hyperglycaemic patients presenting at emergency departments ��126 Rotating glucometer usage after achieving glucose control in the first patient improves HBA1c levels in resource-constrained settings in Kenya ��126 Poor glycaemic control slows wound healing ��126 Encouraging and educating physicians can result in earlier insulin prescription with enhanced HBA1c control ��126 Cardiovascular outcomes trial initiated for liraglutide ��126

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Optimising glucose control in ICU patients reduces costs (TRIUMPH three-year results) Targeting lower glucose levels (9.18 mg/dl, AACE guideline) in ICU patients has been shown to reduce length of stay (LOS) and ICU costs ($8 000) in the extended threeyear period of the TRIUMPH study involving more than 11 000 patients. The use of intensive insulin therapy (IIT) also reduced complications and improved outcomes. The benefit of IIT was confirmed in this study, which compared intervention ICUs to control ICUs, which did not apply the intensive insulin therapy protocol. Source: Presidents Poster, 0433-PP. Sadhu AR, Ang AC, Ingram-Drake LA, et al. Length of stay – cost-savings of intensive insulin therapy in ICU patients – 3-year results of the TaRgeted InsUlin therapy to iMProve Hospital outcomes (TRIUMPH) program.

VADT study: further analysis of results shows intensive glycaemic control offered some renal protection to patients with more advanced microvascular disease The Veterans Affairs Diabetes Trial (VADT) in type 2 diabetes, although not able to show reduced cardiovascular events compared to average control in this further analysis of renal outcomes, provided data not yet published on the microvascular protection achieved by intensive control (INT). In the VADT trial, the average age of patients was 60 years, duration of diabetes was 11 years, with HbA1c levels of 9.4% at the outset of the study. With regard to renal function, patients were excluded if the serum creatinine was above 1.6 mg/dl. Renal progression was evaluated in terms of worsening urine albumin:creatinine ratio (ACR) and sustained worsening of estimated glomerular filtration rate (eGFR). It was found that INT did not independently attenuate ACR or eGFR progression but did retard ACR progression by 72% in those who had photocoagulation, and by 95% in those requiring cataract surgery. The beneficial effect of INT was also more evident in patients with a BMI ≥ 34 kg/m2. In conclusion, INT had no independent beneficial renal effect but afforded some protection in those with more advanced microvascular disease, lower baseline BP or higher baseline BMI. Source: Presidents Poster 0412-PP. Agrawal L, Azad N, Emanuele N, et al. Renal outcomes in Veterans Affairs Diabetes Trial.

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VADT trial: intensive glycaemic control did not prevent progression of calcified atherosclerosis in patients with long-standing type 2 diabetes The VADT trial was able to show reduced cardiovascular events in participants with low levels of calcified coronary atherosclerosis at baseline. This newly presented study evaluated 197 patients with calcified atherosclerosis at baseline, as measured by CT scan and after 4.6 years in both the intensive glycaemic-control arm and the normal control group. These scans showed no treatment benefit of intensive versus standard therapy with regard to either pre-existing coronary artery calcium (CAC) or abdominal aortic artery calcium (AAC). Source: Presidents Poster 0405-PP. Saremi A, Anderson RJ, Duckworth WC, et al. Intensive glucose lowering therapy and progression of coronary (CAC) and abdominal aortic artery calcium (AAC) in the Veterans Affairs Diabetes Trial (VADT).

Once-weekly exenatide injection improves blood sugar control more than daily oral sitagliptin or pioglitazone and induces more weight loss (DURATION-2 study) A convenient, once-weekly injection of exenatide in patients with type 2 diabetes was more effective at improving blood sugar control and inducing weight loss than were either daily oral sitagliptin or pioglitazone. In this 26-week, randomised trial, the patients included all had type 2 diabetes and had been treated with metformin. The mean baseline glycosylated haemoglobin (HbA1c) concentration in the cohort was 8.5%, the mean fasting plasma glucose was 9.1 mmol/l, and the mean body weight was 88.0 kg. The study included patients from the USA, India and Mexico. Patients were randomly assigned to exenatide 2 mg injected once weekly plus daily oral placebo (170 patients); daily oral sitagliptin 100 mg plus placebo injected once weekly (172); or daily oral pioglitazone plus placebo injected once weekly (172). All patients continued their metformin treatment throughout the study. Four hundred and ninety-one patients received at least one dose of the study drug and were included in the final analysis (160 exenetide, 166 sitagliptin, 165 pioglitazone). Treatment with exenatide reduced HbA1c by 1.5%, compared with 0.9% in

the sitagliptin group and 1.2% in the pioglitazone group. Patients in the exenatide group lost on average 2.3 kg, compared with a mean weight loss of 0.8 kg in the sitagliptin group and a mean weight gain of 2.8 kg in the pioglitazone group. No major episodes of hypoglycaemia (abnormally low blood sugar) occurred in any group. The most frequent adverse events with exenatide and sitagliptin were nausea (24 and 10%, respectively) and diarrhoea (18 and 0%, respectively); while upper respiratory tract infection (10%) and peripheral oedema (fluid retention/swelling in the legs) (18%) were the most frequent events with pioglitazone. Source: Oral presentation, ADA

Pathogenesis of type 2 diabetes Intramyocellular lipid accumulation does not occur in pre-diabetes, but only after manifestation of hyperglycaemia Using prior gestational diabetes (GDM) as a model to study early changes in the development of type 2 diabetes, the researchers used magnetic resonance imaging (MRI) and MR spectroscopy to measure left ventricular function and myocardial lipid accumulation in the cardiac septum of women with prior GDM with normal glucose tolerance, in women with prior DGM and type 2 diabetes, and controls without GDM and with normal glucose tolerance. There was no difference in left ventricular function between the groups except for stroke volume, which was decreased in women with type 2 diabetes. Also, these women showed increased intramyocellular lipid content compared to the women with GDM and normal glucose tolerance and decreased levels of high-density lipids, which were inversely related to the intramyocellular lipid content. Source: Abstract ADA, 0014-OR. Winhofer Y, Krissak M, Anderwald C, et al. Cardiac function and lipid metabolism in women with prior gestational diabetes.

Insulin resistance study (IRAS) shows problems for HBA1c levels as diagnostic tool The IRAS study of some 417 patients at risk of developing diabetes has shown that the 6.5 and 5.7% HbA1c thresholds have

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a low sensitivity of detecting the onset of both diabetes and pre-diabetes, as defined by previous definitions of diabetes, using fasting glucose values (≥ 11.1 mmol/l), impaired glucose tolerance (IGT) (2-h glucose: 7.8–11.0 mmol/l) and impaired fasting glucose (IFG) (fasting glucose: 5.6–6.9 mmol/l). The sensitivity and specificity of HbA1c ≥ 6.5% for detecting incident diabetes was 22 and 99.5%, respectively. The low sensitivity of these HbA1c cut-off points could jeopardise the timely implementation of protective lifestyle and pharmacological interventions. Source: Presidents Poster, 0424-PP. Haffer SM, Wagenknecht LE, Hanley AJ, et al. HbA1c and fasting and 2-h glucose concentrations for detecting worsening of glucose tolerance status in individuals with normal glucose tolerance at baseline: the Insulin Resistance Atherosclerosis Study.

New metabolic syndrome definition and value of waist circumference evaluated in type 2 diabetes The recent consensus definition of the metabolic syndrome allows for both the IDF and NCEP ATP III cut-off points for the diagnosis of a large waist in Caucasians. Its value in predicting type 2 diabetes has not yet been assessed. This prospective study assessed and followed up for eight years, more than 500 non-diabetic Caucasians undergoing coronary angiography for evaluation of stable CAD. At baseline, 50% of the patients met the novel consensus metabolic syndrome definition but the predictability of this definition was enhanced when the NCEP ATP III waist circumference cut-off values of more than 102 cm for men and more than 88 cm in women were used. The eight-year incidence of type 2 diabetes was 32% in patients defined according to these criteria, compared to 15% using the smaller waist circumference measure. Source: Abstract 0381-OR. Saely CH, Vonbank A, Rein P, et al. Prediction of type 2 diabetes with the novel metabolic syndrome consensus definition: The importance of waist circumference.

ADA WATCH

diabetes in the 10 years of the extended Diabetes Prevention Programme Outcomes Study (DPPOS) in those patients not receiving metformin. There was no association between antidepressant medication usage and diabetes risk in patients receiving metformin. This ADA-sponsored research confirms the strong positive and statistically significant association between continuous antidepressant medication use and increased diabetes risk found in the three-year follow-up period of the DPP in those patients on the placebo and intensive lifestyle arm. The researchers noted that this association was still significant when controlled for depression symptom level. While acknowledging that this finding does not allow the interpretation of a protective effect of metformin, it does alert clinicians to the higher diabetes risk facing patients who are being treated also for long-term depression. Source: Presidents Poster. Abstract No 0479-PP. Rubin RR, Marrero DG, Yong MA, et al. Antidepressant medication use and risk of developing diabetes during the Diabetes Prevention Program and the Diabetes Prevention Programme Outcomes study.

Once-daily liraglutide lowers systolic blood pressure (SBP) in treated and untreated hypertensive patients A meta-analysis of six randomised, controlled trials (n = 3 967) has shown that the reduction in SBP with liraglutide was independent of concomitant antihypertensive treatment (AH), and that this reduction was additive to concomitant antihypertensive therapy. The evaluation was done using an ANCOVA model, which included randomised treatment effect, use of AH therapy at 26 weeks and interaction with liraglutide/placebo at 26 weeks.

Table. 1. Change in SBP from baseline to week 26 (mmHg)

Diabetes therapy Patient group

Difference between liraglutide Liragutide and 1.8 mg Placebo placebo

Metformin protects against antidepressant diabetes risk?

Overall

–2.55

0.19

–2.37

Continuous use of antidepressant medication increased the risk of developing

AH treat at week 26

–2.03

0.76

–2.79

No AH treat

–3.07

–1.13

–1.95

VOLUME 7 NUMBER 3 • SEPTEMBER 2010

Source: Abstract 0296-OR. Fonseca V, Plutzky J, Montanya E, et al. Liraglutide, a once-daily human GLP-1 analog, lowers systolic blood pressure (SBP) independently or concomitant antihypertensive treatment.

Dietary omega-3 polyunsaturated fatty acid (fish oil capsules) reduced atherosclerosis progression in type 2 diabetes This one-year study of 300 patients with type 2 diabetes showed that carotid intima–media thickness did not progress in patients receiving fish oil capsules, compared to patients following the diet recommended by ESC/EASD. The dosage of omega-3 was 1 g EPA, 1 g DHA and 0.1 g alpha-tocopherol acetate. Interestingly, total cholesterol, HDL cholesterol and triglyceride levels improved in those patients on the fish oil capsules. Source: Abstract 0193-OR. Dragomir AD, Radulian G, Rosu E, et al. One-year administration of dietary omega-3 polyunsaturated fatty acid decreases oxidative stress and atheroscerlosis progression in type 2 diabetes.

Costs of continuing sulphonylureas with insulin therapy in type 2 diabetes: more hypoglycaemia and weight gain but less insulin needed There is no consensus on whether insulin secretagogues should be maintained when analogue insulin therapy is added to the type 2 diabetes regimen, while metformin is continued. This multinational study of almost 1 000 insulin-naïve patients tracked diabetes control when basal insulin (glargine once daily or detemir twice daily) was added and sulphonylureas and glinides were retained/ stopped. Glucose control was not statistically significantly different but patients who continued with sulphonylureas had more hypoglycaemia (40 vs 24.5%) and gained significantly more weight (1.5 vs 0.4 kg). End-of study daily insulin doses were however significantly lower in patients continuing secretagogues than in those stopping these agents (0.6 vs 0.8 units/kg/day). Source: Abstract 0037-OR. Swinnen SG, Dain MP, Mauricio D, et al. Continuation versus discontinuation of insulin sceretagogues when initiating insulin in type 2 diabetes.

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Reducing complications of diabetes Infliximab treatment improves visual acuity in diabetic macular oedema that does not respond to laser photocoagulation This small phase III study suggested that larger and long-term trials should be undertaken to assess the efficacy of the systemic or intravitreal anti-TNF monoclonal antibody, infliximab, to improve the vision of patients with diabetic macular oedema refractory to laser therapy. This single-centre, double-blind, randomised, placebo-controlled, crossover study in 11 patients showed that intravenous infliximab (5 mg/kg) at weeks zero, two, six and 14, followed by placebo to 32 weeks, improved visual acuity by 24% compared to placebo-treated eyes. Source: Presidents Poster 0416-PP. Tentolouris IV, Grigcropoulos V, Emfietzoglou I, et al. Infliximab for diabetic macular edema refractory to laser photocoagulation.

Point-of-care testing of diabetic keto-acidosis avoids unnecessary DKA work-ups in hyperglycaemic patients presenting at emergency departments The poor specificity of urine dipstick tests for diabetic ketones resulted in a high falsepositive rate with increased hospital costs. This study used the point-of-care (POC) capillary beta-hydroxybutyrate test (the Precision Xtra meter, Abbott Laboratories) to obviate these additional costs. Five hundred hyperglycaemic patients admitted to the emergency department were enrolled in the study and 53 met all ADA criteria for DKA. The urine dipstick had a sensitivity of 98%, but a specificity of 40%, whereas use of the Precision Xtra meter had an equal sensitivity but a specificity of 80%, thereby significantly reducing unnecessary DKA work-ups in hyperglycaemic patients. Source: Presidents Poster 0386-PP. Arora S, Peters AL, Long T, et al. Utilising point-of-care testing to identifiy

diabetic ketoacidosis at emergency department triage: beta hydroxybutyrate vs urine dip.

Rotating glucometer usage after achieving glucose control in the first patient improves HBA1c levels in resource-constrained settings in Kenya A home glucose-monitoring programme for Kenyan patients with an HbA1c above 10% and a cell phone has shown a mean drop in HbA1c of 3% in a remotely managed cost-effective process of diabetes care. Patients are given a glucometer and provided with glucose testing strips. They are called weekly by community workers, who record their results and relay the information to clinicians, who then adjust the insulin dose based on a standardised protocol. Once a patient achieves good control, he/she returns the glucometer, which is then given to another patient. The researchers plan to extend this model to rural areas of Kenya. Source: Presidents Poster, Abstract No 0432-PP. Ouma MN and Pastakia SK. A comprehensive collaborative enhanced diabetes care program in the rural resource constrained setting of Eldoret (western) Kenya.

Poor glycaemic control slows wound healing This evaluation of raw data from several multi-centre, randomised, FDA-approved clinical trials among similar populations incorporated 411 diabetic patients with neuropathic foot ulcerations and evaluated the clinical and laboratory data during a 12-week period of wound healing. The relationship between HbA1c and successful wound healing over 12 weeks of standardised treatment was then evaluated. After adjusting for covariates (duration of diabetes, age, gender, race, etc), the evaluation showed that the odds of healing decreased by 15% for every 1% increase in HbA1c during the preceding 12 weeks of wound care. Source: Abstract 0189-OR. Cook EA, Cook JJ, Henao M, et al. The importance of sustained glycaemic control during wound healing.

Encouraging and educating physicians can result in earlier insulin prescription with enhanced HBA1c control Using the updated ADA/EASD consensus statement, which includes earlier use of insulin in patients not achieving HbA1c goals on metformin and lifestyle, this certified diabetes educator (CDE) programme increased insulin use rates from 25 to 39%. Patient HbA1c values improved with the proportion of diabetics with HbA1c > 8.5% dropping from 36 to 24%. The intervention was not too labour intensive, and was conducted over six months and included three main components: office-based education, print and monthly e-mail reminders. Source: Abstract 0108-OR. Endsley S, Leal S, Choi J, Martinez AN. An office-based physician education program to enhance the earlier initiation of insulin: An evaluation of an academic detailing intervention in the US.

Cardiovascular outcomes trial initiated for liraglutide Novo Nordisk announced at the ADA meeting details of the company’s cardiovascular outcomes trial for liraglutide, which is set to start in the autumn of 2010. The LEADER™ trial (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results) aims to assess and confirm the cardiovascular safety of the company’s new once-daily human GLP-1 analogue and potentially show its ability to improve cardiovascular outcomes. The trial also satisfies the new FDA guideline for type 2 diabetes treatments. The protocol has been designed in close collaboration with an international expert steering committee as well as US and EU regulatory authorities, and with assistance from the Population Health Research Institute (PHRI) at McMaster University, Canada. Furthermore, an independent data-monitoring committee will monitor progress of the trial and ensure that it meets the highest standards of ethics and patient safety.

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

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ABSTRACTS

Journal update: Retinopathy focus Sustained reductions in retinopathy are determined by early optimal glucose control – the DCCT/EDIC study at 10 years (adolescents and adults) Further analyses of the EDIC retinopathy data at 10 years have shown that prior early glycaemic control without hypoglycaemia is critical for reducing progression of retinopathy in type 1 diabetic patients. This study compared the 10-year progression of retinopathy in the DCCT/EDIC study in 156 adolescents and 1 211 adults for whom retinopathy data was available. While the number of adolescents in the trial was small and their HbA1c levels were generally higher than that of the adults over the period of the study, the legacy effect of intensive glucose control was not retained in this group of patients at 10 years, compared to the adults. This was seen in the three-step progression of retinopathy from the DCCT close at year four of 7.9% prevalence, to the 10-year EDIC prevalence of 40% in both the conventionally treated and intensively treated adolescents. This was in contrast to the intensively treated adults who at 10 years still had lower levels of retinopathy (22%) than the conventionally treated adults (40%). Source: White NH, Sun W, Cleary PA, Tamboriane WV, Danis RP, Hainsworth DP, Davis MD, for the DCCT-EDIC Research Group. Effect of prior intensive therapy in type 1 diabetes on 10-year progression of retinopathy in the DCCT/EDIC: comparison of adults and adolescents. Diabetes 2010; 20: 1244–1253.

Saving vision – a successful behavioural intervention for inner-city adult diabetics A telephonic contact programme to educate patients about diabetes and related eye health helped motivate participants to have a dilated fundus examination, achieving a 74% increased rate of screening in this ethnically diverse urban population in New York. This programme was driven by certified diabetes nurse educators in New York and was conducted in both English and Spanish. Interestingly, the ethnic match between nurse and patient was not a significant factor in achieving a successful outcome, namely a fundus examination.

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Not a great deal of contact time was spent on building rapport, but rather focused on patient education about the need for eye care and the importance of screening and early treatment of such problems. The intervention was not overly intensive (seven calls over a six-month period) but did include problem solving, such as where to have the eye examination, costs and insurance costs coverage. Source: Jones HL, Walker EA, Schechter CB, Blanco E. A successful behavioural intervention to increase the rate of screening for diabetic retinopathy for innercity adults. Diabetes Ed 2010; 201036(1): 118–126. Doi:10.1177/0145721709356116

Early retinal alterations may be useful markers of diabetic microvascular complications in young type 1 diabetics Variations in retinal microvascular geometric characteristics in young type 1 diabetics are associated with factors such as longer duration of diabetes, higher blood pressure, HbA1c and cholesterol levels. This Australian study is the first to show specific retinal microvascular changes in diabetic patients without retinopathy as a predictor of future microvascular complications. The longer duration of diabetes was associated with a larger arteriolar branching angle and increasing deviation from normal patterns. This is interesting, as an optimal branching angle is associated with greater efficiency in blood flow, with lower energy demand. This efficiency is reduced when the branching angle becomes too large. Of interest is that female diabetics have a larger arteriolar branching angle than men, perhaps a reason for the observation that females have a greater risk for diabetic microvascular complications than their male counterparts. Arterial tortuosity was associated with raised HbA1c levels of above 8.5%, indicative of a threshold effect with regard to this microvascular injury. Increasing width of the arteriole was associated with raised systolic blood pressure and this may have been due to impaired autoregulation of the small blood vessels. Higher cholesterol levels were associated with changes in length-to-diameter ratio and deviation in venular optimality suggests that lipid levels may also have an influence

on the microvasculature in young type 1 diabetic patients. The strength of this study is that it included a large cohort (944 patients) with a high participation rate of more than 80%. Also all measurements were quantified measurements of retinal microvasculature using computer programs as opposed to observational studies. This study of early vascular changes before retinopathy developed in young diabetics, highlights the importance of managing blood pressure, lipids and glucose levels in younger type 1 diabetics. Source: Sasongko MB, Wang JJ, Donaghue KC, Cheung N, Benitez-Agurre P, Jenkins A, et al. Alterations in retinal microvascular geometry in young type 1 diabetes. Diabetes Care 2010; 33(6): 1331–1336.

Long-term risk of retinopathy – highest in younger age at onset (5–14 years) in type 1 diabetes While type 1 diabetic patients diagnosed at the youngest age (0–4 years) enjoy the longest mean duration of retinopathy-free diabetes, this earlier advantage is lost and after 30 years, this group has a similar risk to the older age-of-onset group of 5–15 years. This study from the Finnish Diabetic Nephropathy study included more than 1 000 consecutively recruited patients with diabetes, defined as insulin treatment within one year, age of onset before 40 years and C-peptide levels less than 0.3 mmol/l. Retinopathy was defined based on ophthalmic records and/or fundus photographs. The lower incidence of proliferative retinopathy in the age-at-onset group of 15–40 years compared to the younger group could be explained by higher β-cell function, as indicated by higher C-peptide concentrations. It is important for clinicians to note the loss of the initial advantage of the younger patients with regard to proliferative retinopathy and to ensure that these patients undergo regular eye examinations using fundus photography as the preferred screening method. Source: Hietala K, Harjutsalo V, Forsblom C, Summanen P, Groop PH on behalf of the FinnDiane study group. Age at onset and the risk of proliferative retinopathy in type 1 diabetes. Diabetes Care 2010; 33(6): 1315–1319.

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Mild progression of retinopathy occurs during pregnancy in type 2 diabetic women

Blockade of the renin–angiotensin system slows retinopathy progression in type 1 diabetes

Lower dose of bevacizumab (avastin) effective as pre-operative adjunct therapy

This study of more than 100 pregnant women with type 2 diabetes showed that progression of diabetic retinopathy was associated with a longer duration of diabetes and insulin treatment prior to pregnancy. Fundus photography was performed at about 10 weeks of pregnancy, and in the third trimester at about 28 weeks (range 27–37). Diabetic retinopathy was present in 14% of women in early pregnancy and one in seven progressed during the pregnancy. Only one had sight-threatening diabetic retinopathy following poor compliance with treatment for glycaemic control and hypertension management. The strength of the study is that the population was an unselected cohort. Clinicians should be aware of the need to screen for retinopathy and warn their patients that poor compliance could compromise their vision.

A multi-centre, double-blind, controlled trial of normotensive type 1 diabetic patients with normo-albuminuria has shown that blockade of the renin–angiotensin system using either losartan (100 mg daily) or enalapril (20 mg daily) slowed the progression of retinopathy but not nephropathy. This study was investigator-initiated in the USA and recruited 285 type 1 diabetic patients of 18 years and older who were normotensive (< 135/85 mmHg). They were followed for five years. Primary endpoint was a change in the fraction of glomerular volume occupied by the mesangium in kidney biopsy specimens. The retinopathy endpoint was progression on a retinopathy severity scale of two steps or more. Compared to placebo, the odds of retinopathy progression were reduced by 65% with enalapril and by 70% with losartan, independent of changes in blood pressure. The beneficial effects of early use of renin–angiotensin blockers may represent direct effects on the eye, independent of the effects of systemic blood pressure.

A lower dose (0.16 mg) of bevacizumab was as effective as the standard dose (1.25 mg) in reducing vitreous vascular endothelial growth factor (VEGF) concentration and intra-operative bleeding during vitrectomy. This clinical study of 52 patients who were given varied doses of bevacizumab or placebo, three days before vitrectomy for proliferative diabetic retinopathy, showed that the intravitreal bevacizumab reduced the number of intra-operative coagulation spots, compared to placebo. The lower dose of bevacizumab may help to avoid ocular complications such as retinal detachment.

Source: Rasmussen KL, Laugesen CS, Ringholm L, Vestgaard M, Damm P, Matheisen ER. Progression of diabetic retinopathy during pregnancy in women with type 2 diabetes. Diabetologia 2010; 53: 1076–1083. DOI: 10.1007/s00125 010-1697-9.

Increased risk of severe retinopathy in type 2 diabetics with sub-clinical hypothyroidism This study of the relationship between subclinical hypothyroidism and diabetic retinopathy in a large cohort of type 2 diabetic patients in China has highlighted the statistically significantly increased risk of retinopathy in patients with this endocrine disorder. Sub-clinical hypothyroidism was defined as normal free FT3 and FT4 levels but with increased TSH. These patients were matched to 200 randomly selected euthyroid type 2 diabetic patients. After adjustment for potential variables (age, duration of diabetes, HbA1c levels, BMI, blood pressure and blood lipid levels), subclinical hypothyroidism was associated with diabetic retinopathy (odds ratio: 2.02). This study emphasises that sub-clinical hypothyroidism is complicated by endothelial dysfunction and raised high-sensitivity C-reactive protein levels, which are likely to be responsible for the increase in retinopathy. Source: Yang JK, Li YB, Liu W, Siu J. An association between subclinical hypothyroidism and sightthreatening diabetic retinopathy in type 2 diabetic patients. Diabetes Care 2010; 33(5): 1018–1020.

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Source: Mauer M, Zinman B, Gardiner R, Suissa S, Sinaido A, Strand T, Drummond K, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Eng J Med 209; 361: 40–51.

Experimental studies on low-dose erythropoietin shows beneficial vascular retinal changes The use of epoetin delta, as administered to diabetic Wistar rats, showed that this agent reduced oxidative and nitrosative stress in the retinal, kidney and heart tissues of the experimental animals. The dose of erythropoietin was chosen at a lower level and did not alter haematological variables. Epoetin delta reduced retinal angio-poietin 2 expression and pericyte loss in the retina. These studies of the experimental use of sub-erythropoietic doses show promise and should be extended in other experimental studies of larger animals. Source: Wang Q, Pfister F, Dorn-Beineke A, von Hagen F, Lin J, Feng Y, Hammes HP. Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina. Diabetologia 2010; 53: 1227–1238.

Source: Hattori T, Shimada H, Nakashizuka H, Mizutani Y, Mori R, Yuzawa M. Dose of intravitreal bevacizumab (avastin) used as preoperative adjunct therapy for proliferative diabetic retinopathy. Retina 2010; 30: 761– 764.

Useful summary of standards of medical care in diabetes Diabetes Care has published a useful executive summary of current recommendations concerning type 2 diabetes from diagnosis to monitoring and risk-factor management. The summary of retinopathy screening and treatment in diabetic patients is pertinent to clinical care and is provided below with the level of evidence indicated in parenthesis. Screening • Adults and children aged 10 years or older with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within five years of the onset of diabetes (B). • Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist shortly after the diagnosis of diabetes (B). • An ophthalmologist or optometrist for type 1 and type 2 diabetic patients should repeat subsequent examinations annually. Less-frequent examinations (every two to three years) may be considered following one or more normal eye examinations. Examinations will be required more frequently if retinopathy is progressing (B). • High-quality fundus photographs can detect most clinically significant diabetic retinopathy. A trained eyecare provider

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should perform interpretation of the images. While retinal photography may serve as a screening tool for retinopathy, it is not a substitute for a comprehensive eye examination, which should be performed at least initially and at intervals thereafter as recommended by an eyecare professional (E). • Women with pre-existing diabetes who are planning pregnancy or who have become pregnant should have a comprehensive eye examination and should be counselled on the risk of development and/or progression of diabetic retinopathy. The eye examination should occur in

DRUG TRENDS

the first trimester, with close follow up throughout pregnancy and for one year postpartum (B). Treatment • Promptly refer patients with any level of macular oedema, severe non-proliferative diabetic retinopathy (NPDR), or any proliferative diabetic retinopathy (PDR) to an ophthalmologist who is knowledgeable and experienced in the management and treatment of diabetic retinopathy (A). • Laser photocoagulation therapy is indicated to reduce the risk of vision loss in patients with high-risk PDR, clinically

significant macular oedema, and in some cases of severe NPDR (A). • The presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection, as this therapy does not increase the risk of retinal haemorrhage (A). Source: Executive summary: Standards of medical care in diabetes – 2010. Diabetes Care 2010; 33: S4–9

Compiled by J Aalbers, Special Assignments Editor

… continued from page 121

References 1. World Health Organisation. The World Health Report 2002. htpp://www.who.int. 2. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 1998; 21: 1414–1431. 3. The prevalence of the metabolic syndrome did not increase in Mexico City between 1990–1992 and 1997–1999 despite more central obesity. Diabetes Care 2005; 28: 2480–2485. 4. Office of Population Censuses and Surveys. Causes of blindness and partial sight in England and Wales 1990–1991. London: HMSO, 1995. 5. Grading diabetic retinopathy from stereoscopic colour fundus photographs – An extension of the Airlie House classification. ETDRS report number 10. Ophthalmology 1991; 98(Suppl): 786–806. 6. Four risk factors for severe visual loss in diabetic retinopathy. The third report from the Diabetic Retinopathy Study. The Diabetic Retinopathy Study Research Group. Arch Ophthalmol 1979; 97(4): 654–655. 7. Preliminary report on effects of photocoagulation therapy. The Diabetic Retinopathy Study Research Group. Am J Ophthalmol 1976; 81(4 Group): 383–396. 8. Photocoagulation treatment of proliferative diabetic retinopathy. The second report of the Diabetic Retinopathy Study Research Group. The Diabetic Retinopathy Study Research. Ophthalmology 1978; 85(1): 82–106. 9. Indication for photocoagulation treatment of diabetic retinopathy. The Diabetic Retinopathy Study Research. Int Ophthalmol Clin 1987; 27(4): 239–253. 10. Group photocoagualation treatment of proliferative diabetic retinopathy: clinical application of Diabetic Retinopathy Study (DRS) findings. The Diabetic Retinopathy Study Research. DRS report number 8. Ophthalmology 1981; 88(7): 583–600.

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11. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study research group. Ophthalmology 1991; 98(5 Suppl): 766–785. 12. Diabetes Control and Complications Trial research group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependant diabetes mellitus. N Engl J Med 1993; 329(14): 977–986. 13. UK Prospective Diabetes Study (UKPDS) group. Intensive blood glucose control with sulphonylureas and insulin compared with conventional treatment and the risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352(9131): 837–853. 14. Sui SC, Ko TC Wong KW, Chan WN. Effectiveness of non-mydriatic retinal photography and direct ophthalmoscopy in detecting diabetic retinopathy. Hong Kong Med J 1998; 4(4): 367–370. 15. Lin DY, Blumenkranz MS, Brothers RJ, Grosvenor DM. The sensitivity and specificity of single-field nonmydriatic monochromatic digital fundus photography with remote image interpretation for diabetic retinopathy screening: a comparison with ophthalmoscopy and standardized mydriatic colour photography. Am J Ophthalmol 2002; 134(2): 204–213 16. Cuadros J, Bresnick G. Eyepacs: An adaptable telemedicine system for diabetic retinopathy screening. J Diabetes Sci Technol 2009; 3(3): 509–516. 17. Freudenstein U, Verne J. A national screening programme for diabetic retinopathy. Needs to learn the lessons of existing screening programmes. Br Med J 2001; 323(7303): 4–5. 18. Mukamel DB, Bresnick GH, Wang Q, Dickey CF. Barriers to compliance with screening guidelines for diabetic retinopathy. Ophthalmic Epidemiol 1999; 6(1): 61–72. 19. Moss SE, Klein R, Klein BE. Factors associated with having eye examinations in persons with diabetes. Arch Fam Med 1995; 4(6): 529–534.

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No other basal insulin can offer you more References 1. Blonde L et al. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets – the TITRATE™ study. Diabet. Obes. and Metab. 2009;11:623–631. 2. Philis-Tsimikas A et al. Comparison of Once-Daily Insulin Detemir with NPH Insulin Added to a Regimen of Oral Antidiabetic Drugs in Poorly Controlled Type 2 Diabetes. Clin Ther 2006;28(10):1569–1581. 3. Rosenstock J et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008;51:408–416. 4. Hermansen K et al. A 26-Week, Randomized, Parallel, Treat-to-Target Trial Comparing Insulin Detemir With NPH Insulin as Add-On Therapy to Oral Glucose-Lowering Drugs in Insulin-Naïve People with Type 2 Diabetes. Diabetes Care 2006;29(6):1269–1274. 5. Klein O et al. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabet. Obes. and Metab. 2007;9:290–299. 6. World IMS Data, September 2009. Proprietary Name: Levemir®. Scheduling Status: S3 Composition: Insulin detemir 100 units /ml. Indication: Treatment of insulin requiring patients with diabetes mellitus. Registration Number: 38/21.1/0084. For full prescribing information refer to package insert approved by the medicines regulatory authority. Novo Nordisk (Pty) Ltd. Reg No. 1959/000833/07. PO Box 783155, Sandton 2146. Tel: (011) 202 0500 Fax: (011) 807 7989 www.novonordisk.co.za NN/DUO3817/02/2010ver1

SA JOURNAL OF DIABETES & VASCULAR DISEASE

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Drug Trends

Novo Nordisk update meeting at CDE The weight of diabetes: South African opinion leaders set a new clinical framework Looking at weight gain and how to get patients to lose weight in a NEW context was the theme of the Novo Nordisk/Life Scan-sponsored forum at the CDE meeting in Johannesburg last month.

New perspectives • Type 1 and type 2 diabetes are the same disorder of insulin resistance, set against a different genetic background. • Being overweight accelerates the tempo of β-cell loss, so the phenotype of type 1 and type 2 diabetics converges over time. • Post-prandial dysglycaemia upregulates the β-cell, driving it to failure. • Doctors have an ethical responsibility to tell their patients that type 2 diabetes is a potentially curable disease. Intensive lifestyle change and bariatric surgery can achieve a more than 80% cure rate. • Sibutramine is still an effective weight-loss drug when used in appropriate patients, essentially those without cardiovascular disease. • ‘Testing’ is the secret to diabetes care in both type 1 and type 2 diabetes. The clinician must educate the patient to understand the individual disease pattern (three days of six tests daily from breakfast to bed), and then address the pattern with the patient to set suitable parameters of glucose control. • Modern man’s limbic system of emotional attachment to attractive, flavourful food overrides the satiety centre. • Health professionals should lead by example and there should be weight audits of both patients and staff in diabetes practices.

The weight of the world Prof P Joshi, Diabetes Care Centre, Pretoria Weight loss is vital to reducing diabetic morbidity and deaths. In diabetic patients, a decrease in weight of 5 kg or more reduces the risk of death by 50%; just as an increase in weight (6–7 kg) increases the risk of death by 50%.1 Health professionals must lead by example, particularly in Africa where obesity is driving the diabetic explosion. In fact, worldwide, death from diabetes in 2007 has equalled the HIVrelated death of 2002 when antiretrovirals were not readily available in developing countries. Prof Joshi appealed to CDE units to introduce a weight audit in their practices – for

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both patients and staff. ‘We need to be advocates of social change in South Africa with regard to our food and lifestyle choices’, Prof Joshi concluded.

Weight gain in the younger population

Understanding the mechanisms of weight gain

Dr Segal sketched the neuro-economics of food intake, particularly for children where food procurement requires no energy expenditure – a walk to the fridge or the school tuckshop! Children are consuming huge amounts of fructose, which is increasingly being used as a natural sweetener in a syrup format. ‘Excess fructose goes directly to fat’, he noted. Ascribing the worldwide increase in type 1 and type 2 diabetes primarily to weight gain, which correlates with the risk of developing pancreatic islet cell auto-immunity in children with a first-degree relative with type 1 diabetes,5 Dr Segal urged South African practitioners to place more emphasis on the need for weight loss in younger diabetic patients.

Dr Fraser Pirie, University of KwaZulu-Natal The reasons for developing obesity are complex and interrelated: • a vulnerable genetic profile and environmental influences of lifestyle and nutrition • control by the ‘upper-order’ hypothalamus, cortex and limbic system • the presence of gastrointestinal tract microbes and peptides • nutrition in early life • factors/hormones that regulate appetite and are anorexigenic. Dr Pirie predicts that there will be a flood of new data on the genetic front with regard to obesity in the next decade, which will continue to influence clinical practice. A recent review is of considerable value in understanding this arena.2 In the interim, clinicians must recognise the therapeutic aspects of weight gain in type 2 diabetes and seek to use agents with the least weight gain (Table 1). Dr Pirie pointed out that metformin does limit weight gain when patients are put on insulin; 50% of weight gain occurs in the first three months of insulin therapy, thereafter it slows. Insulin detemir causes less weight gain due to its lipophylic nature, slow release, less hypoglycaemia and central anorexigenic effect.3 In the LOOK AHEAD long-term study of type 2 diabetic patients, increased physical activity showed the strongest correlation with weight loss,4 while orlistat contributed little to weight loss.

Dr Dave Segal, paediatric endocrinologist, University of the Witwatersrand

Type 2 diabetes is a potentially curable disease Dr Greg Hough, specialist endocrinologist, East London

Weight loss

Weight neutral Weight gain

Dr Hough pointed out that type 2 diabetes can be cured by sufficient weight loss and bariatric (gastric bypass) surgery, which results in a 80 to 87% cure rate. ‘The risks of bariatric surgery are the normal risks of surgery, with very few additional risks following treatment, although patients are advised to adopt a moderate-fat diet to avoid the risk of gallstones.’ Pointing out that exercise is vital to the maintenance of weight loss, Dr Hough cited the SCOUT study of sibutramine, which showed that it is still an effective drug and one of the few to induce significant weight loss when used in appropriate patients. ‘Clearly sibutramine should be avoided in patients with cardiovascular disease and in those on MAOI, erythromycin and ketoconazole, which interfere with the P450 system. Exenatide use results in a bit more impressive weight loss with patients losing on average 4.5 kg over an 18-month period.’

Pramlintide

Metformin

J Aalbers, Special Assignments Editor

Table 1. Effect of therapy for type 2 diabetes on weight

GLP-1 agonist Acarbose DPP4-inhibitors

Sulphonylureas (least with gliclazide MR) Glinides TZD (thiazolidinediones) Insulins

1. Daniels SR. Future Child 2006; 16(1): 47–67. 2. Fawcett KA, Barroso I. Trends Genet 2010; 26(6): 266–274. 3. Hallischmid M, et al. Diabetes 2010; 59(4): 1101–1107. 4. Wadden T, et al. Obesity 2009; 17(4): 713–722. 5. Couper JJ, et al. Diabetes Care 2009; 32(1): 94–99.

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Aspirin in primary prevention: focus on people with diabetes

n expert consensus view on the use of aspirin in patients with diabetes has just been published and provides an excellent overview of aspirin trials in diabetic patients.1 Reviewing all the evidence of aspirin in primary prevention, the consensus statement by the American Diabetes Association, the American Heart Association and the American College of Cardiology Foundation concludes that aspirin has a significant effect on reducing cardiovascular events (RRR of about 10%) and that the extent of reduction is dependent on the underlying cardiovascular risk. While consensus statements in general risk introducing compromise, the recommendations of these societies are clear. They point out that further evidence from ongoing trials such as ACCEPT D (Aspirin and simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes) and ASCEND (A Study of Cardiovascular Events iN Diabetes) may alter the consensus view. Their recommendations are: • Use low-dose (75–162 mg/day) aspirin for prevention in adults with diabetes and no previous history of vascular disease who are at increased risk for cardiovascular disease (CVD) (10-year risk of CVD events over 10%) and who are not at increased risk for bleeding (based on a history of previous gastrointestinal bleeding or peptic ulcer disease or concurrent use of other medications that increase bleeding risk, such as NSAIDS or warfarin). Those adults with diabetes at increased risk for CVD

include most men over the age of 50 and women over 60 years who have one or more of the following additional major risk factors: smoking, hypertension, dyslipidaemia, family history of premature CVD and albuminuria (ACCF/AHA class IIa, level of evidence: B) (ADA level of evidence: C). • Aspirin should not be used for CVD prevention in adults with diabetes at low CVD risk (men under 50 years of age and women under 60 with no major additional CVD risk factors; 10-year CVD risk under 5%) as the potential adverse effects from bleeding offset the potential benefits (ACCF/AHA class III, level of evidence: C) (ADA level of evidence: C). • Low-dose (75–162 mg/day) aspirin use for prevention might be considered for those with diabetes at intermediate CVD risk (younger patients with one or more risk factors, or older patients with no risk factors, or patients with 10-year CVD risk of 5–10%) until further research is available (ACCF/AHA class IIb, level of evidence: C) (ADA level of evidence: E). Importantly, the statement points out that cardiovascular risk must be accurately defined and also that blood pressure and lipid management, and smoking cessation strategies should be introduced first. This will reduce cardiovascular risk and also the number of patients with diabetes requiring aspirin therapy. The recommendation notes that not all diabetes patients have high cardiovascular risk, as was proposed in earlier guidelines, such as the NCEP, 2001.2

Preventing cardiovascular events and stroke Interestingly, the US Preventative Services Task Force (USPSTF) recommendations on the benefits and harm of aspirin for primary prevention of vascular disease, including cardiovascular and cerebrovascular disease, also noted that aspirin should be used cautiously in women (whether diabetic or not) under the age of 60 years at low risk (under 5%) as primary prevention.3 The ADA/AHA/ACC consensus recommendations regard the balance of benefit and risk for aspirin usage in diabetic men at low cardiovascular risk (less than 5%) as being reached at a younger age of 50 years, compared to the USPSTF calculation of reaching a balanced benefit–risk for cardio- and cerebrovascular events for men under the age of 60 years at 4 to 5% cardiovascular risk. J Aalbers, Special Assignments Editor 1.

Pignone M, Alberts MJ, Colwell JA, Cushman M, Inzucchi SE, Mukherjee D, et al. J Am Coll Cardiol 2010; 55(25). Published online. Doi:10.1016/j. jacc.2010.04.003. Expert panel on detection, evaluation and treatment of high blood cholesterol in adults. J Am Med Assoc 2001; 285: 2486–2497. US Prevention Services Task Force. A Intern Med 2009; 150(6): 396–413.

Erectile dysfunction and diabetes: a prelude to cardiovascular disease

rectile dysfunction (ED) occurs in 80% of diabetic men over 60 years of age, due to both endothelial and neurological abnormalities. Early and vigorous glucose control may prevent erectile dysfunction. In addition, early statin use and the use of phosphodiesterase type 5 (PDE5) inhibitors may help to preserve the endothelial function in diabetic men, according to a recent expert committee review of the worldwide literature concerning erectile dysfunction, coronary artery disease and diabetes.1,2 The presence of erectile dysfunction in younger diabetic men may point to increased risk of coronary artery disease (CAD) and therefore should be treated, while also aggressively lowering other risk factors such as alcohol, smoking, inactivity and overweight. In a study of 2 306 diabetic men in China with no clinical evidence of CAD (27% suffered from ED at baseline), over a median course of four years, ED was an independent predictor of CAD with a hazard ratio (HR) of 1.58 after adjustment for confounding factors.3 In a second European study evaluating erectile dysfunction as a predictor of major cardiovascular

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events, the researchers also investigated which other factors predicted cardiovascular events and mortality. A group of 291 diabetic men with silent CAD detected angiographically were followed up for a period of four years. The presence of erectile dysfunction, as expected, was significantly related to an increased risk of major cardiovascular events. Of more interest was that in men with both CAD and ED, statin and PDE5 use was associated with a lower risk of major events. Statin use significantly reduced risk, while use of PDE5 inhibitors approached significance (HR 0.68; 95% CI: 1.46–1.01; p = 0.056). In choosing which PDE5 inhibitor to use in diabetic patients, vardenafil has been shown to achieve a significantly higher success rate in diabetic men than its competitors.1 Sildenafil and tadalafil have shown an average success rate in diabetic patients of 60 to 64% compared to placebo, whereas vardenafil has shown that erectile function improved in 72% of diabetic patients compared to placebo. Vardenafil has a shorter half-life than sildenafil, which has a peak effect from one to 12 hours. Vardenafil’s shorter half-life has advantages in the

therapeutic treatment of erectile dysfunction, but has less value as a once-a-day preventative treatment for endothelial dysfunction. It is normally administered in 5-, 10- and 20-mg doses with a recommended starting dose of 10 mg. Adverse effects are generally mild; there is no impairment of exercise ability in patients with stable CAD who have been carefully assessed. None of the PDE5 inhibitors have been shown to increase myocardial infarction rates. In addition, PDE5 inhibitors provide benefit in treating pulmonary hypertension and have shown some encouraging results in heart failure, which may contribute to their wider use in these patient groups.

J Aalbers, Special Assignments Editor 1.

Gazzaruso C, Solerte SB, Pujia A, Coppola A, Vezzoli M, Salvucci F, et al. J Am Coll Cardiol 2008; 51: 2040–2044. Jackson G, Montorsi P, Adams MA, Anis T, El-Sakka A, Miner M, et al. J Sex Med 2010; 7: 1608–1626. DOI:10.1111/j.1743-6109.2010.01779.x. Ma RC, So WY, Yang X, Yu LW, Kong AP, Ko GT, et al. J Am Coll Cardiol 2008; 51: 2045–2050.

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