SAJDVD Volume 6, Issue 3

THE SOUTH AFRICAN JOURNAL OF

Diabetesvascular Disease

In association with the British Journal of Diabetes & Vascular Disease

Sept

20

09

Volu

me

6 N

um

ber

3

INSULIN RESISTANCE

OBESITY

HYPERTENSIONDYSLIPIDAEMIA

THROMBOSISATHEROSCLEROSIS

HYPERGLYCAEMIA

HYPERINSULINAEMIA

DIABETES &

VASCULAR DISEASE

Featured in this issue

Diabetes and the foot

Management of the diabetic foot

Insulin and malignancy

Beta-cell dysfunction in type 2 diabetes

Diabetic foot care in the community

GIVEAWAY

It's theshell that

makes

safer.

R

Hp

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

Safety-CoatedR

81mgThe ORIGINAL low dose aspirinfor optimum cardio-protection

INSULIN RESISTANCE

OBESITY

HYPERTENSIONDYSLIPIDAEMIA

THROMBOSISATHEROSCLEROSIS

HYPERGLYCAEMIA

HYPERINSULINAEMIA

DIABETES &

VASCULAR DISEASE

ISSN 1811-6515

THE SOUTH AFRICAN JOURNAL OF

Diabetes & vascular Diseasein association with the British Journal of Diabetes & Vascular Disease

CONTENTS Editorials

91 Diabetes and the foot: implications for South Africa

P Rheeder

93 Advances in the management of the diabetic foot

L Tudhope

95 A possible link between insulin glargine and malignancy: the facts

WF Mollentze

Review

100 GLP-1 and GLP-1-based therapies: addressing beta-cell dysfunction in type 2 diabetes

M Nauck

Hands On

108 Get your socks off: diabetic foot care in the community

B Karet

Patient Information Leaflet

111 Foot care for people with diabetes

Diabetes Personality

113 Dr Gabaza Ngobeni wins the Servier Award for Community Involvement

ADA Watch

116 Update from the American Diabetes Association, New Orleans, 2009

Corresponding EditorPROF WF MOLLENTZEHead of the Department of Internal Medicine, University of the Free State, Bloemfontein

Consulting EditorsPROF J-C MBANYAPROF AJ BRINK

National Editorial BoardDR A AMODCentre for Diabetes, Endocrinology and Metabolic Diseases, Life Health-care, Chatsmed Gardens Hospital, Durban

SR K BECKERTDiabetes Nurse, Paarl

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

PROF R DELPORTDepartment of Family Medicine,University of Pretoria

DR L DISTILLERDirector of the Centre of Diabetes and Endocrinology, Houghton, Johannesburg

DR F MOHAMEDDepartment of Endocrinology, Grey’s Hospital, Pietermaritzburg

PROF CD POTGIETERNephrologist, University of Pretoria and Jakaranda Hospital, Pretoria

PROF K SLIWAAssociate Professor of Medicine and Cardiology, Baragwanath Hospital, University of the Witwatersrand, Johannesburg

PROF YK SEEDATEmeritus Professor of Medicine and Honorary Research Associate, University of Natal, Durban

International Editorial BoardPROF IW CAMPBELLPhysician, Victoria Hospital, Kircaldy, Scotland, UK

PROF PJ GRANTProfessor of Medicine and head of Academic Unit of Molecular Vascular Medicine, Faculty of Medicine and Health, University of Leeds; honorary consultant physician, United Leeds Teaching Hospitals NHS Trust, UK

PROF J-C MBANYAProfessor of Endocrinology, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Cameroon and President-Elect, International Diabetes Federation (2006−2009)

PROF N POULTERProfessor of Preventive Cardiovascular Medicine, Imperial College, School of Medicine, London, UK

DR H PURCELLSenior Research Fellow in Cardiology, Royal Brompton National Heart and Lung Hospital, London, UK

VOLUME 6 NUMBER 3 • SEPTEMBER 2009www.diabetesjournal.co.za

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

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

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

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

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

All correspondence to be directed to:THE EDITORPO BOX 1013DURBANVILLE7551or [email protected]

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

The opinions, data and statements that appear in any articles pub-lished in this journal are those of the contributors. The publisher, edi-tors 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 inac-curate or misleading information.

Drug Trends in Diabetes

121 Lessons from the BEAUTIfUL trial

Importance of HbA1c assay in the diagnosis of diabetes mellitus

Generic drug companies need to build brands and consider clinical research

Primary prevention using losartan in type 1 diabetic patients significantly reduces retinopathy

127 Diabetes News

Front cover photographs from left to right:

This issue focuses on foot care – an often-neglected area of diabetes care. Contributions by South African and international experts provide valuable insights (page 108)Dr Gabaza Ngobeni won the national Servier Award for Community Involvement, which was presented at the CDE Meeting recently. She is seen here taking a patient’s blood pressure (page 113)Nutrition is a key aspect of diabetes care. Enter our book giveaway to win The Complete Nutritional Solution to Diabetes by Ria Catsicas (page 114)

It's theshell that

makes

safer.

Safety-CoatedR

81mgThe ORIGINAL low dose aspirinfor optimum cardio-protectionHp

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

55X78MM23 September 2008 10:04:25 AM

Color profile: Generic CMYK printer profileComposite Default screen

SA JOURNAL OF DIABETES & VASCULAR DISEASE EDITORIAL

VOLUME 6 NUMBER 3 • SEPTEMBER 2009 91

Diabetes and the foot: implications for South AfricaP RhEEdER

T he prevention of diabetic foot complications is recognised as critically important in the management of diabetes.

Global impact

This was reviewed by Andrew Bolton in the Lancet in 2005 (the year of the diabetic foot).1 he highlighted that the lifetime risk of a person with diabetes developing a foot ulcer could be as high as 25%,2 and it is believed that every 30 seconds a lower limb is lost somewhere in the world as a consequence of diabetes.3 Prevalence studies from Africa show varying frequencies of patients with foot ulcers but this can be as high as 13% (Cameroon).4

A study evaluating patients with new ulcers in Germany, India and Tanzania found that the patients were predominantly male and had type 2 diabetes. Importantly, the average diabetes duration until the onset of the initial foot lesion was 14 years in Germany and 12 years in India, but only five years in Tanzania. As expected, neuropathy was common in all three centres.

Peripheral vascular disease was a frequent risk factor in Germany (48%), while in Tanzania (12%) and India (13%) it was less common. Inadequate footwear was the most common cause of foot lesions in Germany (19%), whereas lack of footwear, irregular foot care and burns were the primary precipitating factors among patients in Tanzania and India.5

Recently a collaborative group reviewed the use of a clinical staging system to compare outcome of foot ulcer management across three continents. The SINBAD system (site, ischaemia, neuropathy, bacterial infection and depth) was used to classify patients with foot ulcers from Germany, Tanzania and Pakistan. Of interest was the fact that baseline factors contributing to outcome were different across the centres: ischaemia, ulcer area and ulcer depth contributed to outcome in the UK; ischaemia, area, depth and infection in Germany; depth, infection and neuropathy in Tanzania; and depth alone in Pakistan. The SINBAd score was associated with time to healing (with a step-up in days to healing found in those with scores of three and above (out of six).6

A collaborative group compared the incidence of

amputations between communities across the world. In their first report, this group described pronounced differences in amputation rates, with the highest in native Americans and the lowest in Madrid, Spain (43.9 vs 2.8 per 100 000 per year); diabetes was associated with 25 to 90% of all amputations.7

What data do we have from South Africa?

Very little research has been published regarding foot complications of diabetes in South Africa. In 1997, Levitt and colleagues did an audit of public-sector primary care in Cape Town. They used a stratified random sample of 300 patients attending the three largest ambulatory diabetes clinics in community healthcare centres. The prevalence of peripheral neuropathy was 27.6%, absent foot pulses 8.2% and amputations 1.4%. Strikingly, complications were not documented in the clinic records of the preceding year, with the exception of one patient with absent foot pulses and 12 patients with proteinuria.8

Since we were aware of the lack of complications screening in primary care, we also decided to assess this in a community academic hospital in Pretoria. Van Zyl and colleagues found the assessment of the foot for complications was done in 23 and 37% of patients in the two diabetes clinics evaluated. Importantly, the 23% increased to 89% after an educational intervention involving the clinic doctors in the intervention group, compared with from 37 to 49% in the control clinic (p = 0.04).9

Because the monofilament (used to detect peripheral neuropathy) is not freely available in South Africa, Rheeder and colleagues compared the detection of diabetic neuropathy using monofilament, cotton wool, pin-prick and vibration sense, and symptom evaluation in a community hospital diabetes clinic. We found there was very poor agreement between these different tests. The respective kappa values (kappa is a measure of agreement beyond that expected by chance) for the comparison between monofilament-defined neuropathy and cotton wool-, pin-prick- and symptom-defined neuropathy were 0.18, 0.21 and 0.06, respectively. The kappa value comparing monofilament- and tuning fork-defined neuropathy was 0.24. More abnormalities were detected using the monofilament compared with the other modalities.10 A kappa value of > 0.6 is regarded as good agreement.11

It had been suggested that calcification of the ankle arteries precludes assessment of peripheral arterial disease using the ankle-brachial index (ABI). We compared ankle- (AB) and toe- (TB) brachial indices in a convenience sample of 85 female patients with type 2 diabetes. The differences between the

Correspondence to: Prof P Rheederdivision of Clinical Epidemiology, Faculty of health Sciences, Steve Biko Academic hospital, PretoriaTel: +27 (0) 12 354-1488Fax: +27 (0) 12 [email protected]

S Afr J Diabetes Vasc Dis 2009; 6: 91–92.

EDITORIAL SA JOURNAL OF DIABETES & VASCULAR DISEASE

92 VOLUME 6 NUMBER 3 • SEPTEMBER 2009

two indices increased from 0.36 [95% confidence interval (CI): 0.32–0.41] to 0.58 (95% CI: 0.46–0.70), depending on whether ABI was less or greater than 1.3. The correlation coefficient for left versus right foot was 0.62 and 0.71 for ABI and TBI, respectively. The relationship between ABI and TBI was non-linear with a cut-off point close to 1.3, suggesting that as long as the ABI was below 1.3, it was as good a measure as the toe-brachial index.12

Since we had established a structured complication-assessment system in the Pretoria academic hospital diabetes clinics, we were interested to know whether patients with monofilament-detected neuropathy were better educated regarding their feet than those without neuropathy. We found that a composite foot-knowledge score was similar between the two groups but that those with feet at risk gave 20% more correct answers than those in the not-at-risk group with regard to the correct answer for the optimal frequency of foot inspection (daily) (p = 0.025).13

What about the outcome of vascular surgery in patients with diabetes? A retrospective review was conducted between January 1998 and december 2001. during this period, 65 patients underwent femoro-distal bypass at Groote Schuur hospital. Of these, 57 patients were analysed and eight patients were excluded from the study because of incomplete medical records. Twenty-eight patients (49%) were diabetic. An overall two-year mortality rate of 19.2% was recorded. In that unit, only two factors influenced the outcome of femoro-distal bypass; local sepsis in the foot and an increased early postoperative ankle-brachial index (p < 0.05). diabetes mellitus, gender, age and race had no influence on the outcome.14

Regarding transmetarsal amputations (TMAs), investigators from Cape Town carried out a retrospective study of 43 TMAs. Two groups were identified: group 1, TMAs performed in diabetic patients (27); group 2, TMAs done in non-diabetic patients (16). Peri-operative mortality rates were 7 and 4%, respectively. Overall, the healing rate was 67%: 62% (17/27) in group 1 and 75% (12/16) in group 2 (p > 0.05). The median times to healing were eight months in group 1 and seven months in group 2. Toe pressure and the presence of advanced tibioperoneal disease influenced the outcome of TMA in diabetic patients. There was no statistical difference in outcome in diabetic (group 1) versus non-diabetic (group 2) patients.15

The challenge for Africa and therefore South Africa

Bolton emphasises that sub-Saharan Africa contains 33 of the 50 poorest countries in the world, and this region will

experience the greatest rise in the prevalence of diabetes in the next 20 years.1,16

It is clear that every single practitioner and clinic managing patients with diabetes would need to ensure that they have adequate screening, education and management strategies in place to prevent the burden associated with diabetic foot disease.

References1. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global

burden of diabetic foot disease. Lancet 2005; 366: 1719–1724.2. Singh N, Armstrong dG, Lipsky BA. Preventing foot ulcers in patients

with diabetes. J Am Med Assoc 2005; 293: 217–228.3. Time to Act: diabetes and foot care. Brussels: International Diabetes

Federation, 2005.4. Ndip EA, Tchakonte B, Mbanya JC. A study of the prevalence and

risk factors of foot problems in a population of diabetic patients in cameroon. Int J Low Extrem Wounds 2006; 5: 83–88.

5. Morbach S, Lutale JK, Viswanathan V, Möllenberg J, Ochs hR, Rajashekar S, et al. Regional differences in risk factors and clinical presentation of diabetic foot lesions. Diabet Med 2004; 21: 91–95.

6. Ince P, Abbas ZG, Lutale JK, Basit A, Ali SM, Chohan F, et al. Use of the SINBAD classification system and score in comparing outcome of foot ulcer management on three continents. Diabetes Care 2008; 31: 964–967.

7. LEA study group. Epidemiology of lower extremity amputations in centres in Europe, North America and East Asia. Br J Surg 2000; 87: 328–337.

8. Levitt NS, Bradshaw d, Zwarenstein MF, Bawa AA, Maphumolo S. Audit of public sector primary diabetes care in Cape Town, South Africa: high prevalence of complications, uncontrolled hyperglycaemia, and hypertension. Diabet Med 1997; 14: 1073–1077.

9. Van Zyl dG, Rheeder P. The efficacy of an intervention program aimed at diabetes care physicians regarding quality of diabetes care at a tertiary care hospital. S Afr Med J 2004; 94: 455–459.

10. Rheeder P, Van Wyk JT, hokken JWE, hueting. Monofilament assessment of neuropathy in a community diabetes clinic. S Afr Med J 2002; 92: 715–719.

11. Altman dG. Practical Statistics for Medical Research. London: Chapman and hall, 1991.

12. Rheeder P, Van Wyk J, Stolk R, Grobbee dE. Assessing peripheral arteries in South African black women with type 2 diabetes mellitus. S Afr Med J 2004; 94: 379–383.

13. Rheeder P, Venn M, de Korte E, Van Zyl d. Knowledge of foot-care in people with diabetes in a tertiary care setting. J Endocrinol Metab Diabetes S Afr 2008; 13: 105–108.

14. Mwipatayi BP, Jeffery PC, Motale P, Matley PJ, Immelman EJ, Kahn D, Welman CJ. Femoro-distal bypass surgery at Groote Schuur hospital – 4-year retrospective study. S Afr J Surg 2004; 42: 81–5.

15. Mwipatayi BP, Naidoo NG, Jeffery PC, Maraspini CD, Adams MZ, Cloete N. Transmetatarsal amputation: three-year experience at Groote Schuur hospital. Wld J Surg 2005; 29: 245–248.

16. Wild S, Roglic G, Green A, Sicree R, King h. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27: 1047–1053.



Advances in the management of the diabetic footL TUdhOPE

T he World health Organisation has predicted that there will be 380 million diagnosed diabetics worldwide by 2025. Africa will face the second highest increase in

prevalence of the disease; an expected increase of 160%, second only to that expected in the Middle East. This predicted increase equates to 760 million feet at risk of possible ulceration! It is crucial to note that not only those patients with longstanding diabetes but any person with newly diagnosed diabetes is at risk of developing foot complications, that is, a ‘diabetic foot’.1

Over the past decade, standards of care of the diabetic foot have improved dramatically. Recognition of the diabetic foot as a special clinical entity has led to a global awareness that the multidisciplinary approach is the most effective way to prevent amputation. The evidence continues to show that to achieve limb salvage rates of 95% or greater, no other more effective measure exists.2

The International Working Group on the Diabetic Foot (IWGdF) was established in 1996, and as a result of collaboration and communication between specialists in the field of diabetic foot salvage, the International Consensus on the Diabetic Foot3 and the Practical Guidelines on the Management and Prevention of the diabetic Foot were launched in 1999. A Cd-ROM with added supplements was introduced in 2003, and this is continuously updated with relevant consensus documents as more research is published on the diabetic foot. These clinical guidelines have been translated into 26 languages, and the IWGdF now has members in over 80 countries worldwide.3

Ultimately, the goal of any healthcare professional working with diabetic patients in both the public and private sector is to promote awareness of possible foot problems that may arise, and through patient education, improve outcomes. The implementation of foot-care protocols by a multidisciplinary team to prevent ulceration will reduce the amputation rate. The maths is simple: 85% of all amputations in diabetics are preceded by a foot ulcer; prevent ulceration, and amputation is avoided.4

Of course in every area of speciality of the multidisciplinary team there has been an avalanche of new products and technological innovations, some more tried and tested than

others. In the area of preventative medicine, control of risk factors over and above adherence to a low hbA1C level in type 2 diabetics, for instance, has proven to be more effective than serum glucose control alone. Cardiac risk-factor control with management of hypertension and low-density lipoprotein cholesterol levels, together with smoking cessation, weight loss and exercise, will decrease morbidity drastically. The availability of better oral anti-hyperglycaemics and bio-engineered insulins has also led to better disease control.

Diabetic neuropathy encompasses several neuropathic syndromes. At any time, nearly 30% of diabetics will be affected by distal symmetrical neuropathy. The EURODIAB prospective study showed that over a seven-year period, about 25% of type I diabetic patients developed neuropathy.5 Management of the diabetic patient with pain in the lower limb, after the exclusion of any ischaemic component, can pose a considerable challenge. Until recently, tricyclic drugs were the first-line treatment of choice in many countries: imipramine, 25–150 mg nocte or amitriptyline, 25–150 mg nocte.

Now there are a host of new and more expensive drugs available, such as the anti-epileptic Gabapentin, 300–3 600 mg per day, and Pregabalin, 150–600 mg per day. duloxetine, one of the newer agents, also has an antidepressant effect, and so can be used for its dual action.2

Acupuncture, an ancient therapy, has been revived as an alternative to drug therapy in the treatment of neuropathic pain. It has been shown to improve the debilitating symptoms of neuropathy in up to 77% of diabetics.6

Although most diabetic foot problems have a neuropathic aetiology, the fact that most do not go on to heal without complications is due to poor blood flow in nearly 85% of patients. The endovascular treatment of lower limb ischaemia in diabetics, be it from stenosis or occlusion of arteries, is definitely the first choice worldwide. The durability of open bypass surgery is not being challenged. Rather, the minimally invasive option of percutaneous balloon angioplasty (PTA), with or without stenting, addresses the problem of reperfusing the limb in order to heal a wound. Limb salvage rates, rather than patency rates of bypass/PTA and stenting become the issue.7

The technological advances in the field of peripheral arterial endovascular management now allow for PTA of long and short lesions from the iliac arteries down to the digital arteries of the foot. Dedicated low-profile systems and stents designed especially for the infra-popliteal region are reducing open-surgical interventions in every diabetic foot centre in the world. In fact, a 460% increase in endovascular procedures was reported over a 12-year period by Kudo et al.8 Further additions to the interventionalist’s armamentarium include

Correspondence to: Dr Lynne Tudhope Vascular surgeon and President of the diabetic Foot Working Group of South Africa, Montana hospital, PretoriaTel: +27 (0) 12 548-9499Fax: +27 (0) 12 548-4018e-mail: [email protected]




devices that core out plaque, those that lyse and suction thrombus out of the vessel lumen, and needle-piercing catheters that allow for easy re-entry into the calcified vessel lumen.

Control of infection is key to wound healing. Virtually all diabetic foot infections require antimicrobial therapy, but it is important to remember that wherever possible, treatment should be based on tissue culture. Antibiotic resistance is a worldwide problem and inaccurate empirical treatment regimes, especially in these immuno-compromised patients, should be avoided whenever possible. Methicillin-resistant Staphylococcus aureus (MRSA) is often the pathogen that delays wound healing or that suddenly causes deterioration of a wound that was progressing normally. The International Consensus on the Diabetic Foot3 and the Practical Guidelines on the Management and Prevention of the diabetic Foot contain up-to-date guidelines and should be consulted by any medical professional treating diabetic foot infections.

Wound-bed preparation with the removal of infected and necrotic tissue is essential in the management of all types of wounds, but nowhere is this more important than in the treatment of the diabetic foot. If surgical intervention is not an option, then alternative methods of debridement are now available. Sterile maggots were widely used in the early 1900s for debridement of necrotic tissue, but with the advent of antibiotic therapy, their popularity waned, until they re-emerged in 1995 as LarvE, distributed by ZooBiotic Ltd. Over 50 000 containers of maggots have been supplied to some 20 000 patients in the United Kingdom alone, and published data suggests that they are even effective against MRSA.6

The recognition of wound care as a speciality requiring extensive training and qualifications has been one of the most important advances in wound care. Wound-care products have also become extremely specific and abundant, and a thorough knowledge of these is only possible with experience and expertise.9 Living skin equivalents such as Apligraf and dermagraft, both bio-engineered from foetal foreskin, have proven in numerous studies to accelerate healing in chronic foot ulcers. Incidence of re-ulceration was also decreased when these products were applied.

The past decade has seen the production and use of several recombinant growth factors for the treatment of non-healing chronic wounds. The potential benefits of hormones and exogenous growth factors have led to the production of platelet-derived growth factors (PdGF) as an adjunct to skin grafting.

One of the most important advances in the closure of complicated wounds has been the development of negative-pressure wound therapy. This therapy involves the delivery of intermittent or continuous sub-atmospheric pressure through a specialised pump connected to a special foam dressing covered with an adhesive drape. Three negative-pressure systems are now available, and treatment with this therapy results in a higher proportion of wounds that heal, faster healing rates and potentially fewer amputations.9

Gene transfer and applications of progenitor cells are two

advanced technologies with great promise in wound healing. however, safety issues are still slowing the mass production of these two strategies.

Until recently, one of the most underestimated aspects of the care of the diabetic foot has been the area of foot biomechanics and offloading. Gait analysis of the diabetic patient has become a super-speciality of its own, because most foot injuries occur while the patient is walking. The measurement of plantar pressure via a matrix of transducers and computer-generated images has changed the way offloading in the diabetic foot is treated.

Therapeutic shoes and insoles that reduce friction and shear stress are also flooding the market, and the availability of style and comfort means that no person with diabetes should ever be wearing the ‘wrong shoe’. Of course, many cultures, and especially economically challenged societies often do not wear shoes at all, and so ongoing education and awareness remain a crucial part of any drive to promote advances in foot care worldwide.

The reduction and removal of weight bearing from the affected foot in the diabetic patient with a foot ulcer is the quickest way to close wounds on the foot. Total contact casting (TCC) is still the best way to ensure patient compliance in this regard, but less lifestyle limiting is the removable cast walker (RCW). TCC can also not be used in patients with septic wounds or in those with poor blood flow. The RCW, on the other hand, while reducing pressure as effectively as the TCC, can be easily removed for wound inspection and can be applied in the vasculopath as well.

The incidence of Charcot foot in diabetes is reported to be around 0.1 to 0.5%. Traditionally, Charcot foot has been described as either a traumatic or neurovascular disease, depending on whether you adhere to the German or French interpretation. The most recent theory proposed in the research of endocrinologist William Jeffcoate from Nottingham is that the aetiology has an inflammatory origin.(ref) For this reason, the temperature measured on the foot becomes an indicator of possible pathology and pending acute Charcot/ inflammation. Infrared skin thermometers created especially for use on the foot allow for daily self-assessment by the patient; ‘a glucometer for the foot’. A 2ºC increase in temperature on the affected foot alerts the patient to seek help immediately at the multidisciplinary clinic.

All the abovementioned innovations and resurrections cannot substitute for good clinical judgment and examination. In spite of new therapies and multidisciplinary, specialised treatment, there is the very necessary factor of patient compliance. Before exorbitant expenditure occurs, it is the responsibility of every member of the multidisciplinary team to ensure that the patient is a willing player. If this is not the case, then amputation may be a better option in some patients. Fortunately, the majority of patients who are positively reinforced by their care giver/specialist team go on to wound healing and limb salvage.10

continued on page 106.



A possible link between insulin glargine and malignancy: the factsWF MOLLENTZE

O n 26 June 2009 Diabetologia, official mouthpiece of the European Association for the Study of diabetes (EASd), sounded the alarm in a press

release regarding a possible association between the use of insulin glargine and an increased risk for the development of certain malignancies compared to human insulin and other insulin analogs.1 The evidence for such an increased risk is based on a single study recently conducted in Germany and available on the Diabetologia website.2 Before making the results of the German study known, the editor of Diabetologia sensibly commissioned three additional studies in an effort to reach more clarity on the issue. These studies were done in Sweden,3 the UK4 and Scotland.5

The German study followed an earlier retrospective UK study, which showed an increased risk for colorectal cancer in patients with type 2 diabetes receiving chronic insulin treatment.6 In the latter study by Yang et al, no distinction was made between the different types of insulin or the effect of insulin dose. The hazard ratio (hR) of colorectal cancer associated with ≥ one year of insulin use was 2.1 (95% CI: 1.2–3.4). The odds ratio of developing colorectal cancer increased by 21% for each incremental year of therapy. This increase in risk is comparable to that of patients with familial colorectal cancer. Since there is no alternative to insulin therapy in patients with type 2 diabetes and failing beta-cell function, the recommendation from Yang et al was to assess the cost-effectiveness of a more stringent colorectal cancer-screening programme among patients with type 2 diabetes receiving insulin.

The German study1 reported by hemkens et al was a retrospective cohort study of 127 031 patients without any known malignancy who exclusively received human insulin or only one type of insulin analogue for the first time.The type of insulin analogue was restricted to the short-acting analogues insulin aspart or lispro and the long-acting analogue, glargine. The mean follow-up time was 1.63 years

and the period of interest was between 1 January 2001 and 30 June 2005. during this period, malignant neoplasms were observed in 5 009 patients.

A positive association between cancer incidence and insulin dose was found for all insulin types. A dose-dependent increase in cancer risk was found for insulin glargine compared to human insulin in contrast with insulin aspart or lispro.The hR was 1.09 (95% CI: 1.00–1.19) for a daily dose of 10 IU, 1.19 (95% CI: 1.10–1.30) for a daily dose of 30 IU, and 1.31 (95% CI: 1.20–1.42) for a daily dose of 50 IU. The number needed to harm was 100 patients treated for a period of 18 months.7 The authors admitted to the ‘relatively fragile nature’ of their data, and underscored the fact that their study results could not prove causality between glargine use and the increased risk of cancer. hemkens et al concluded that this issue should be investigated in a properly designed prospective study.

In the first of the three commissioned studies, Jonasson et al3 performed a retrospective study of 114 841 individuals in Sweden who received a prescription for insulin over a two-year period. They found that women who used insulin glargine as monotherapy had a relative risk (RR) of breast cancer of 1.97 (CI 95% CI: 1.29–3.00), compared to women who used an insulin other than insulin glargine, after adjusting for known confounders. The authors attributed this increase in risk of breast cancer to ‘random fluctuation’ and concluded that no definite conclusions regarding a possible causal relationship between insulin glargine use and the occurrence of malignancies could be drawn from the results of this study.

In the second of the commissioned studies, Currie et al4 performed a retrospective analysis of 62 809 patients with type 2 diabetes treated with four different regimens since 2000: metformin monotherapy, sulfonylurea monotherapy, sulphonylurea plus metformin, and insulin-based therapy. This study showed that metformin carried the lowest risk of cancer compared to no therapy (but failed to reach statistical significance to reduce cancer). Of these, 2 106 patients progressed to develop a solid tumour during the study period (an annual incidence of 1.1%).

Compared to meformin, the adjusted hR for metformin plus sulphonylurea was 1.08 (95% CI: 0.96–1.21), while the hR for sulphonylurea monotherapy was 1.36 (95 CI: 1.19–1.54), and that for insulin-based regimens was 1.42 (95% CI: 1.27–1.60). Insulin therapy compared to metformin increased the risk of colorectal cancer (hR 1.69, 95% CI: 1.23–2.33) and

Correspondence to: Prof WF MollentzeCorresponding Editor: SA Journal of Diabetes and Vascular Diseasedepartment of Internal Medicine, University of the Free State, BloemfonteinTel: +27 (0) 51 405-3154Fax: +27 (0) 51 444-3138e-mail: [email protected]




pancreatic cancer (hR 4.63, 95% CI: 2.64–8.10) but did not increase the risk of breast or prostate cancer. The results for sulphonylureas were similar to those for insulin. In this study, the use of insulin analogues (including glargine) compared to human insulin was not associated with increased risk of cancer.

In the third commissioned study,5 also retrospective, a two-pronged approach was used to investigate the effect of insulin use on the incidence of cancer. In the first approach, a fixed cohort of 36 254 people with diabetes (19 899 definite type 2 patients) was identified in Scotland. They had received any type of insulin during the four-month period July to October 2003. This cohort was followed up until 31 december 2005. A total of 715 incident cancers occurred in this cohort (1.97%, 0.95 events per 100 person-years at risk).

After adjusting for age and gender, those patients who used non-glargine plus glargine insulin compared to those using non-glargine insulin alone had a lower rate of cancer but the difference was not significant. however, those using insulin glargine alone had a higher rate of cancer compared to those patients who used non-glargine insulin. This difference was only of borderline statistical significance and only so for breast cancer. The authors attributed this slight increase in risk for breast cancer associated with insulin glargine to allocation bias.

In the second approach, a group of patients (n = 12 852) with definite type 2 diabetes and who received insulin for the first time between January 2002 and 31 december 2005 were investigated. A total of 378 cancers occurred in this group. Overall, the incidence of cancer was no different between the insulin glargine users (regardless of what other type of insulin they used) compared to the users of non-glargine insulin alone. Likewise, the incidence rate of cancer in the glargine-only users was not higher than in users of non-glargine insulin alone. In this cohort, the incidence of breast cancer was not increased in the glargine users compared to the non-glargine users.

The analysis summarising exposure across the entire follow up showed that there was a significantly lower rate of total cancers (hR 0.66, 95% CI: 0.57–0.76) in those receiving any insulin glargine (regardless of what other insulin they used), compared to the non-glargine insulin users. This hR was even lower in subjects who had had an exposure of at least two years. For breast cancer there was a slight but non-significant increase in incidence in glargine-only users compared to non-glargine insulin users. In this study, the insulin glargine-only users at baseline differed substantially as a group from those using non-glargine plus glargine insulin or those using non-glargine insulin alone. The authors concluded that in spite of shortcomings in their study, the results were reassuring that use of insulin glargine was not associated with an increased incidence of cancer. Although their data do not provide complete reassurance, they do not point to unequivocal evidence of harm either.

Summary of findings and recommendations (adapted from EASD8):

• The German study found that a patient on insulin glargine was more likely to be diagnosed with cancer than a patient on the same dose of human insulin. This difference was equivalent to one extra case of cancer for every 100 patients taking glargine insulin for one year.

• The Swedish study found no increase in risk of cancer in patients taking glargine along with other types of rapid-acting insulin. Women on glargine alone were twice as likely to be diagnosed with breast cancer. This risk was equivalent to one new case of breast cancer for every 1 000 women treated for one year.

• The UK study found no increase in risk of any cancer including breast cancer between the four insulin regimens studied. Patients on metformin tablets were less likely to be diagnosed with cancer than patients on other forms of treatment. This was also seen when metformin was taken with other tablets or with insulin.

• The Scottish study found a slightly reduced risk of cancer in those patients (who were younger and included patients with type 1 diabetes) who took glargine insulin along with other insulins, compared to those who took only human insulin. The patients who took glargine only (who were older) were more likely to have any form of cancer including breast cancer, although the risk was statistically not significant.

• The researchers involved in all four studies agreed that these findings were not conclusive since the studies were observational and not clinical trials. The possibility that differences between groups of people were responsible for the different rates of cancer cannot be excluded. Further studies are needed before a final conclusion can be reached.

• Insulin glargine is widely used and was found to be helpful on an individual basis, although clinical trials did not show that it provided better overall glucose control than human insulin in patients with type 2 diabetes. however, some patients with troublesome hypoglycaemia may find it beneficial.

• The EASd does not recommend that patients should stop taking insulin glargine on the basis of evidence presented in these trials. Patients do, however, have the option of using long-acting human insulin or a mixture of short- and long-acting human insulin twice a day instead of the once-daily analogue. Especially patients who already have cancer or women with a family history of breast cancer may wish to consider this option.

The American Association of Clinical Endocrinologists (AACE) takes a slightly different view from the EASD.9 This organisation, representing mainly practicing clinicians, agrees that the evidence presented in the four studies is not sufficient to warrant any firm conclusions. The findings were not consistent and were even contradictory in some respects,



the patient populations were not always comparable, and the duration of observation was short. The AACE does not recommend that the use of any insulin should be changed but supports the view that further research is warranted to establish the safety and efficacy of all diabetes therapies. Meanwhile, individual patient concerns should be discussed with their doctors.

The American Diabetes Association (ADA) was even more cryptic in its comments.10 The ADA simply states that if patients taking insulin glargine consider switching to another form of insulin, these studies make it unclear whether one type of insulin increases the risk of cancer more than other types of insulin. The ADA also recommends that concerned patients should not stop taking their insulin on the basis of these studies but should talk to their doctors.

The EASd, the AACE and the AdA do not suggest the introduction of any cancer screening programme in patients with type 2 diabetes who were exposed to insulin or any form of diabetes therapy over a long period. It is however clear that the relationship between type 2 diabetes, including its therapy, and the risk of cancer, warrants further research. Meanwhile, it may be prudent to emphasise that patients with type 2 diabetes are not only at risk of macro- or microvascular disease but that they have a similar or even increased risk of certain cancers compared with to the non-

diabetic population. Patients with type 2 diabetes should at least be offered the standard screening guidelines for commonly occurring cancers.11 Any remaining concerns individual patients may have regarding the continued used of insulin glargine should be discussed with their doctors.

References1. http://www.diabetologia-journal.org/cancer.html#press. Accessed on 2

July 2009.2. http://www.diabetologia-journal.org/cancer_files/081131hemkenscorr

ectedproofs.pdf. Accessed 2 July 2009.3. http://www.diabetologia-journal.org/cancer_files/090776Jonassonacce

ptedpaper.pdf. Accessed on 2 July 2009.4. http://webcast.easd.org/press/glargine/download/090740Currie

2ndproofs.pdf. Accessed 2 July 2009.5. http://webcast.easd.org/press/glargine/download/090818Colhounacce

ptedpaperadjusted.pdf. Accessed on 2 July 2009. 6. Yang YX, hennessy S, Lewis Jd. Insulin therapy and colorectal cancer

risk among type 2 diabetes mellitus patients. Gastroenterology 2004; 127: 1044–50.

7. http://www.diabetologia-journal.org/cancer_files/Patientsummary-hemkens.pdf. Accessed 2 July 2009.

8. http://www.diabetologia-journal.org/cancer_files/patientinfo.pdf. Accessed 2 July 2009.

9. http://www.aace.com/newsroom/alerts/index.php.10. ht tp : / /profess iona l .d iabetes .org/News_disp lay .aspx?TYP=

9&CId=71434. Accessed 3 July 2009.11. http://www.cansa.org.za/cgi-bin/giga.cgi?c=1056.

Comment from Prof François BonniciA time for transparency, accessible information and wise

recommendations, including a heightened awareness of the present ravages of long-term, uncontrolled hyperglycaemia, the potentially protective role of metformin, the often-forgotten value on cancer risk reduction of lifestyle measures, healthy diet, exercise and smoking cessation.

A time for prudence for individuals with type 2 diabetes on high insulin doses, those with increased cancer risk or with recent cancer diagnoses, who may wish to discuss with their doctors safe and effective alternative therapies.

There are legitimate causes for concern regarding increased cancer risk in people with type 2 diabetes. The analysis of the available studies is however controversial, the questions at issue are not yet resolved, but the implications are serious. Reassuringly, no such associations have ever been shown in younger type 1 diabetes patients who most benefit from insulin analogue therapy.

Prof François Bonnici

Editorial Board memberEmeritus Professor, Faculty of health Sciences, University of Cape Town

Reference1. Smith U, Gale EAM. does diabetes therapy influence the risk of cancer?

Diabetologia 2009. dOI 10.1007/500125-009-1441-5.

The recent news alerting the diabetes world to safety concerns regarding primarily insulin glargine, in fact bring to the fore a wider debate, that of increased risk of cancer in patients with type 2 diabetes, and the treatment of diabetes with other insulins and insulin secretagogues. Indeed, there are putative mechanistic explanations of this risk, through high insulin levels and associated changes in the IGF-1 axis accelerating the progression of existing cancer.

how should we react to such disturbing news? The findings of all the quoted studies have to be interpreted with caution. We need an honest, sensible, but prudent response, as reasoned as the one expressed by Smith and Gale and the various international diabetes organisations. Cause for concern, not panic.1

We would not wish to see a mass withdrawal of effective therapy, an indiscriminate switch to other insulin products, and unwarranted alarm in an already vulnerable population. There is no evidence that insulin, however formulated, directly causes cancer, but pre-clinical and epidemiological indications exist to suggest that high concentrations of insulin, both endogenous and exogenous, may promote its development.

A time for questions then, to futher elucidate aspects of association, causation and effect of confounding factors, through prospective clinical studies on patients with type 2 diabetes and all its forms of therapy.



Reply from Dr Navin Singhproduct. We are committed to patient health and safety and treat these matters with the highest degree of importance. Sanofi-aventis will continue to vigorously monitor the safety of Lantus® in close collaboration with regulatory authorities, including the Medicines Control Council, and with clinicians and scientific experts.

Should you require further information, please contact the sanofi-aventis medical advisor or medical director on 011 256-3700.

Dr Navin Singh

Medical Director Sanofi-aventis

References 1. hemkens LG, et al. Risk of malignancies in patients with diabetes treated

with human insulin or insulin analogues: a cohort study. Diabetologia 2009; dOI 10.1007/s00125-009-1418-4. Accessed 30/06/2009 at URL: http://webcast.easd.org/press/glargine/download/081131hemkenscorrectedproofs.pdf.

2. Jonasson JM, et al. Insulin glargine use and short-term incidence of malignancies – a population-based follow-up study in Sweden. Diabetologia 2009. Accessed 30/06/2009 at URL: http://webcast.easd.org/press/glargine/download/090776Jonassonacceptedpaper.pdf.

3. SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: A study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009. Accessed 30/06/2009 at URL: http://webcast.easd.org/press/glargine/download/090818Colhounacceptedpaper.pdf.

4. Currie CJ, et al. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009. dOI 10.1007/s00125-009-1440-6. Accessed 30/06/2009 at URL: http://webcast.easd.org/press/glargine/download/090740Currie2ndproofs.pdf.

5. Sanofi-aventis. data on file. 6. Rosenstock J, Fonseca V, McGill JB, et al. Similar progression of diabetic

retinopathy with insulin glargine and neutral protamine hagedorn (NPh) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study. Diabetologia 2009. dOI 10.1007/s00125-009-1415-7.

7. Rosenstock J, et al. Similar progression of diabetic retinopathy with insulin glargine and neutral protamine hagedorn (NPh) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study. Diabetologia 2009. dOI: 10.1007/s00125-009-1415-7. Accessed 29/06/2009 at URL: http://webcast.easd.org/press/glargine/download/081539Rosenstock.pdf.

Four registry analyses were published on the website of Diabetologia, the journal of the European Association for the Study of diabetes (EASd) on 26 June 2009, discussing a hypothetical link between treatment with insulin glargine and cancer.1-4

All four studies are retrospective observational registries from different populations (Germany, Sweden, Scotland, UK). A possible dose-response association between insulin glargine and cancer was observed in the German study but not in the Swedish, Scottish, or UK studies. A possible association between insulin glargine and breast cancer risk was found in the Swedish study but not consistently in the others.

Common limitations and weaknesses of observational studies can be identified in all of these registries. Overall, results from the four studies were inconsistent. No definitive conclusion can be drawn regarding a possible causal relationship between insulin glargine use and the occurrence of malignancies.

Clinical studies do not indicate an association between insulin glargine and cancer. This includes data from clinical studies covering over 70 000 patients. In controlled trials in 10 465 people with type 1 or type 2 diabetes, there was no difference in the incidence of malignancies in patients treated with insulin glargine versus comparators, including NPh insulin.5

In a five-year controlled clinical trial in 1 017 patients with type 2 diabetes, the overall rate of malignancies was similar in the insulin glargine and NPh groups [insulin glargine 23 patients (4.5%), NPh 32 (6.4%)]. The number of patients with breast cancer was also similar (insulin glargine, three; NPh, five). This report is now published in Diabetologia.6,7

Since insulin glargine was first launched, its global exposure is estimated to be 24 million patient-years. From post-marketing safety data of the cases of malignancy that have been reported, there is no specific pattern with regard to cell type-specific malignancy and no trends or risk factors have been identified. Based on this analysis, the post-marketing cases of malignancy reported to the company do not indicate a newly identified risk for insulin glargine users.

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References: 1. Klein O. et al. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profi les but less variability than insulin glargine in type 2 diabetes. Diabetes, Obesity and Metabolism. 2007;9:290-299. 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. Clinical Therapeutics. 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.

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REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE


GLP-1 and GLP-1-based therapies: addressing beta-cell dysfunction in type 2 diabetesMIChAEL NAUCK

Abstract

A lthough insulin resistance and impaired beta-cell function typically coexist in type 2 diabetes, recent evidence points to a decline in beta-cell

function and mass as the key elements in the development of overt hyperglycaemia and progression of the disease. However, most of the current therapies for the treatment of type 2 diabetes aim to ameliorate hyperglycaemia through mechanisms of action that do not affect the beta-cell directly. By contrast, the incretin hormone glucagon-like peptide-1 (GLP-1) and GLP-1-based therapies act directly on the beta-cell by stimulating insulin secretion in a glucose-dependent manner, and in in vitro and animal studies by promoting beta-cell proliferation and inhibiting apoptosis.

This review aims to identify the factors behind beta-cell dysfunction, outline the limitations of the most commonly used type 2 diabetes therapies and explain how GLP-1-based therapies can overcome these limitations.

Introduction

In healthy individuals, plasma glucose concentration remains within narrow limits (4–7 mM) due to a tight balance between glucose absorption from the intestine, production by the liver and uptake and metabolism by muscle and adipose tissue. Although many hormones and metabolites are involved directly or indirectly in the regulation of these processes, insulin plays a key role in maintaining glucose homeostasis by increasing glucose uptake in peripheral tissues and inhibiting hepatic glucose production.1

In type 2 diabetes, insulin-mediated regulation of glucose homeostasis is compromised due to a decrease in insulin action (mediated via insulin resistance, associated generally with obesity) and dysregulated insulin secretion due to impaired beta-cell function. however, most obese individuals who are insulin resistant do not develop overt type 2 diabetes because their pancreatic beta-cells are able to compensate by

hypersecreting insulin to meet increasing needs.2 In addition, data from the United Kingdom Prospective diabetes Study (UKPdS) show that beta-cell function, which is already reduced by approximately 50% at diagnosis, deteriorates over time regardless of treatment (diet and exercise, sulphonylurea or metformin), whereas insulin sensitivity remains relatively unchanged.3 Taken together, these findings suggest that, although insulin resistance and impaired beta-cell function are, in most cases, key co-existing elements in the pathophysiology of type 2 diabetes, a decline in beta-cell function may be the key factor in the development of overt hyperglycaemia and subsequent disease progression.

The aim of this review is to identify the factors behind beta-cell dysfunction, outline the limitations of commonly used antihyperglycaemic agents in addressing the decline in beta-cell function and explain how the recently developed glucagon-like peptide-1 (GLP-1)-based therapies can overcome these limitations.

Beta-cell dysfunction

The typical biphasic insulin secretion pattern seen in healthy individuals in response to an intravenous glucose bolus is characterised by a rapid phase lasting for five to 10 minutes, followed by a prolonged phase lasting for the duration of the stimulus. In patients with type 2 diabetes, beta-cell dysfunction is characterised by the lack of a first-phase insulin response, a blunted and delayed second-phase insulin response,4,5 abnormalities in insulin pulsatility,6,7 and an increased proinsulin-to-insulin ratio.8-10

Defects in insulin biosynthesis and secretion are behind the observed deficiencies in beta-cell function.11 For instance, defects in proinsulin-to-insulin processing,12 decreases in the amount of mature insulin granules and insulin stores,13 and decreases in glucose sensitivity13 and in the responsiveness to other stumuli (e.g. incretin hormones)14 may render beta-cells unable to rapidly change the rate of insulin secretion according to needs, resulting in relative insulin deficiency. In addition, changes in beta-cell mass also play a role in beta-cell dysfunction (figure 1).15

In pathological studies, beta-cell mass has been shown to be reduced by up to 65% in individuals with type 2 diabetes,16,17 due to a decrease in the number of beta-cells rather than the volume of individual cells.17 These reductions in beta-cell mass are driven by increases in beta-cell apoptosis, whereas new islet formation and beta-cell replication are normal and, therefore do not compensate for increased cell

Correspondence to: Michael Nauckdiabeteszentrum, Kirchberg, Bad Lauterberg im harz, GermanyTel: +49 (0) 5524-81218Fax: +49 (0) 5524-81398e-mail: [email protected]


SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW


loss.17 Therapies for the treatment of type 2 diabetes should therefore improve beta-cell function and halt the loss of beta-cell mass, as these are key aspects responsible for the natural progression of the disease.

Limitations of current therapies

Results from homeostatic model assessment of beta-cell function (hOMA-B), which is used to yield an estimate of beta-cell function from fasting plasma insulin and glucose concentrations,18,19 have shown that established type 2 diabetes therapies such as metformin, sulphonylureas (SUs) and thiazolidinediones (TZds) given as initial treatment to patients recently diagnosed with type 2 diabetes improve beta-cell function during the first year of treatment. Thereafter, levels of beta-cell function decline progressively.3,20,21 Glycaemic control, as assessed by hbA1c level, parallels changes in beta-cell function, decreasing in the first year of therapy and then increasing progressively over the duration of the studies (up to six years).20,21 A similar pattern in hbA1c levels was observed in patients treated with insulin. however, beta-cell function in these patients could not be assessed, as the administration of exogenous insulin is a confounding factor.3

Although there were differences in the velocity of progression (slowest with rosiglitazone, fastest with glibenclamide21) none of metformin, SU, TZd or insulin monotherapy can halt the progressive deterioration of metabolic control completely. Furthermore, most of these therapies are associated with undesirable side effects that have a negative impact on the successful management of type 2 diabetes. hypoglycaemia, for instance, is a common side effect with insulin and sulphonylureas22 and has a negative

effect on treatment adherence23 and glycaemic control.24 More recently, severe hypoglycaemia has been linked with an increased risk of dementia in type 2 diabetic patients over 65 years of age.25 Similarly, weight gain is a common side effect with insulin, SU and TZd treatment, which also has a negative impact on adherence26 and is associated with a worsening cardiovascular (CV) risk profile.27

To halt or reverse disease progression, an ideal treatment for type 2 diabetes should achieve restoration of beta-cell function and mass without undesirable side effects such as hypoglycaemia or weight gain. In addition, because the risk of CV disease is increased at least two- to threefold in patients with type 2 diabetes compared with healthy counterparts,28,29 any pharmacological therapy should, ideally, lead to improvement in CV risk.

GLP-1 and its potential for treating type 2 diabetes

The phenomenon by which orally administered glucose elicits a much larger increase in plasma insulin levels when compared with the same glucose challenge given intravenously30 is known as the incretin effect,31 and is mediated by two hormones secreted by the intestine after nutrient ingestion: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).32 In type 2 diabetes, the incretin effect is reduced due to a severe impairment in the insulinotropic action of GIP and a slight reduction in the secretion of GLP-1.33,34 Although reduced slightly compared to healthy subjects,14 the insulinotropic action of GLP-1 is relatively well preserved in patients with type 2 diabetes33 and provides the basis for using GLP-1 as ‘replacement therapy’ to restore, at least partially, incretin activity.

Figure 1. Factors involved in the regulation of beta-cell function and beta-cell mass.



GLP-1 acts on the beta-cell by stimulating insulin secretion glucose dependently and by replenishing insulin stores via stimulation of proinsulin gene expression.35 In addition, in in vitro and animal studies, GLP-1 promotes differentiation of endocrine precursor cells into mature beta-cells, stimulates replication of pancreatic beta-cells as well as new islet formation after partial pancreatectomy, and inhibits apoptosis,36 all of which may lead to expansion of beta-cell mass through overall increases in beta-cell numbers.37 Other GLP-1 actions not related directly to the beta-cell include glucose-dependent suppression of glucagon secretion,33 slowing of gastric emptying38 and reduction of appetite.39 Moreover, GLP-1 has been shown to have a beneficial effect on the endothelium and the myocardium.40,41 Therefore, intravenous infusion with GLP-1 has been shown to have a direct beneficial effect on endothelium-dependent vasodilation40 and to improve regional and global left ventricular function after acute myocardial infarction.41

Most of these effects have been demonstrated in humans. Exceptions are the GLP-1 effects on beta-cell growth, neogenesis and apoptosis – leading to expansion of beta-cell mass – which, in humans, cannot be measured in vivo with current methods.36 however, native GLP-1 is degraded rapidly by the ubiquitous enzyme dipeptidyl-peptidase-4 (dPP-4). As a result, the plasma half-life (t1

2) of intravenously administered

GLP-1 is only one to two minutes,32 which greatly limits its potential as a therapeutic agent. To overcome this limitation, analogues with extended half-lives and dPP-4 inhibitors must be developed.32

GLP-1-based therapies

Currently, two GLP-1 analogues are approved for the treatment of type 2 diabetes: exenatide and liraglutide. These compounds are structurally quite different. Exenatide is derived from a peptide found in Helodermus suspectum – a lizard commonly known as the Gila monster – which shares approximately 50% of its amino acid sequence with the native GLP-1 molecule. By contrast, liraglutide is obtained by slightly modifying the structure of native GLP-1 through a single amino acid substitution and the addition of an acyl side change. Therefore, liraglutide shares 97% of its amino acid sequence with native GLP-1.32

These differences in structure decrease, directly or indirectly, the susceptibility of these molecules to degradation by dPP-4, thus prolonging their plasma half-lives42,43 and making them suitable for once- (liraglutide) or twice-daily (exenatide) subcutaneous administration. Because of the differences in structure, exenatide is often referred to as a GLP-1 mimetic, whereas liraglutide is referred to as a GLP-1 analogue.

Three dPP-4 inhibitors are approved for the treatment of type 2 diabetes: sitagliptin, vildagliptin and saxagliptin. These agents act by reducing serum dPP-4 activity by more than 80%, with some inhibition maintained for 24 hours with once-daily treatment,44 thereby increasing the levels of endogenously secreted GLP-1.

Effect of GLP-1-based therapies on the beta-cell

A variety of studies have measured the effect of GLP-1 analogues and dPP-4 inhibitors on several indicators of beta-cell function, such as the proinsulin-to-insulin ratio (a low value indicating the release of mature insulin from granules fully processed before secretion) and the hOMA-B index (a measure of insulin secretion relative to the ambient glucose concentration in the fasting state) in patients with type 2 diabetes (figure 2).45-53

Results from clinical studies with GLP-1 analogues. In a combined analysis of three 26-week trials, which were carried out as part of the Liraglutide Effect and Action in diabetes (LEAd) phase 3 development programme, treatment with liraglutide 1.8 mg once daily in combination with oral antidiabetes (OAd) agents (glimepiride, metformin or a combination of glimepiride plus metformin) resulted in a 28–34% increase in hOMA-B versus active comparator.54 The same analysis demonstrated that the proinsulin-to-insulin ratio decreased significantly from baseline compared with combinations of glimepiride, metformin, glimepiride and metformin, and metformin and rosiglitazone.54

however, in a 52-week trial (also part of the LEAd programme) that compared liraglutide with glimepiride, both as monotherapy, in patients recently diagnosed with type 2 diabetes, between-treatment differences in hOMA-B and proinsulin-to-insulin ratio were not significant at the end of the study.55 Nevertheless, given that glimepiride acts by stimulating insulin secretion directly from the beta-cell and is known to improve beta-cell function during the first year of treatment, these findings are not surprising.3,7

After 16 weeks, treatment with exenatide 10 µg twice daily added to a thiazolidinedione, with or without metformin, resulted in significant improvements in hOMA-B compared with placebo (19 vs –6%, respectively; p < 0.005).51 After 30 weeks, treatment with exenatide 10 µg twice daily, added to metformin or sulphonylurea, resulted in significant decreases from baseline in proinsulin-to-insulin ratio compared with placebo.48,49

Results from clinical studies with DPP-4 inhibitors. After 54 weeks, treatment with sitagliptin, given as monotherapy (100 mg once daily), resulted in an increase in hOMA-B from a baseline of 18.1%, whereas sitagliptin (50 mg twice daily) treatment, added to metformin (500 mg or 1 000 mg twice daily), resulted in hOMA-B increases from baseline of 34.7 and 41.9%, respectively. In this study, a decrease from baseline in proinsulin-to-insulin ratio was also observed in all treatment arms.52

A pooled analysis of data from randomised, placebo-controlled trials demonstrated that, after 24 weeks, treatment with vildagliptin (100 mg once daily) given as monotherapy increased hOMA-B significantly from baseline by 11.5% (p < 0.05) and decreased proinsulin-to-insulin ratios from baseline.53 Similarly, treatment with saxagliptin monotherapy



(2.5–40 mg once daily) resulted in increases in hOMA-B from a baseline of 16.9 to 24.7% after 12 weeks, whereas a 100-mg dose once daily increased hOMA-B from baseline by 13.8% after six weeks.56

The same effects on beta-cell differentiation, neogenesis, apoptosis and mass observed with GLP-1 have been demonstrated with GLP-1 analogues and dPP-4 inhibitors.57-61

GLP-1 receptor agonists. Liraglutide and exenatide have been shown to promote beta-cell neogenesis and to inhibit beta-cell apoptosis in in vitro and animal models of diabetes.57–60

DPP-4 inhibitors. In rodent models of diabetes, the dPP-4 inhibitor isoleucyl thiazolidide has been shown to significantly increase the number of beta-cells and islet neogenesis,61 whereas a sitagliptin analogue has been shown to significantly increase beta-cell mass.62

Although the potential for beta-cell proliferation in adult humans has long been questioned, thereby raising the

issue of whether similar effects would also be detectable in adults with diabetes, evidence from recent studies in human pancreatic tissue suggests that beta-cell replication is indeed ongoing in humans until late in life, and that under certain circumstances it can even be enhanced.63,64 These studies raise hopes that GLP-1-based treatment regimens may also lead to some restoration of beta-cell mass in humans and, unlike other therapies, potentially halt the progression of the disease. however, because pancreatic islet turnover in humans is slow (2.5–5 years65), a time span of several years would be expected for beta-cell replenishment with GLP-1-based therapies, which should ideally be started early in the course of the disease.

In summary, these findings suggest that GLP-1-based therapies may halt or reverse the progressive loss of beta-cell function observed in type 2 diabetes by addressing all the components behind beta-cell dysfunction: insulin deficiency, beta-cell secretory defects and reduced beta-cell mass.

Figure 2. Changes from baseline in homeostatic model assessment of beta-cell function (hOMA-B), proinsulin-to-insulin ratio, hbA1c and body weight with liraglutide, exenatide, sitagliptin and vildagliptin. *Only patients previously drug-naïve were included in the study.



Effect of GLP-1-based therapies on glycaemic control and CV risk factors

Glycaemic control. The improvements in beta-cell function reported in this review were accompanied by improvements in glycaemic control, as assessed by hbA1c levels, which decreased by 0.7 to 1.8% from baseline (figure 2). The incidence of hypoglycaemia with GLP-1-based therapies was low. Major hypoglycaemia was therefore rare (≤ 2.2%) and occurred only with liraglutide and exenatide in combination with sulphonylurea. The incidence of minor hypoglycaemia was also low with exenatide, liraglutide and sitagliptin, either as monotherapy or combined with metformin or a thiazolidinedione (≤ 10.7%), but was slightly higher with exenatide or liraglutide in combination with a sulphonylurea (≤ 28.0%).45-49,51-53,56

CV risk factors. Improvements in glycaemic control were achieved with significant decreases in weight from baseline in the case of exenatide and liraglutide (up to 2.8 kg).45-49,51 When combined with metformin (2 000 mg once daily), sitagliptin treatment also resulted in significant weight loss from baseline (1.7 kg).52 Treatment with sitagliptin, vildagliptin and saxagliptin as monotherapy was weight neutral, with no significant changes from baseline observed (–1.3 to 0.6 kg) (figure 2).52,53,56

Liraglutide treatment (1.8 mg once daily) as monotherapy or in combination with either glimepiride, metformin or glimepiride plus metformin resulted in reductions in systolic blood pressure from baseline of 2 to 4 mmhg.44–47 Improvements from baseline in other CV risk factors, such as total cholesterol (TC), low-density lipoprotein cholesterol (LdL-C), triglycerides (TGs) and free fatty acids (FFAs), as well as in biomarkers of CV risk, such as brain natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hsCRP), also occurred.66

Although changes in systolic blood pressure and CV risk factors with exenatide were not reported in the studies discussed previously in this review, patients who completed open-label extensions of various exenatide trials for a total exposure of 3.5 years also experienced reductions from baseline in systolic blood pressure (SBP) (3.5 mmhg) and other CV risk factors (TC, LdL-C, hdL-G and TGs).67 The effects of dPP-4 inhibitors on SBP and CV risk factors are unclear.68

In summary, these findings demonstrate that GLP-1-based therapies can overcome many of the limitations of other antihyperglycaemic agents, as they can lower hbA1c effectively with concomitant weight loss or no weight gain and with a low risk of hypoglycaemia. Additionally, the GLP-1 analogues liraglutide and exenatide appear to have a beneficial effect on SBP and CV risk factors.

Adverse events associated with GLP-1-based therapies

GLP-1 analogues. The only side effects consistently observed in clinical trials with GLP-1 analogues were of a

gastrointestinal nature. Among these, the most common was nausea, which was probably related to the effect of GLP-1 analogues on gastric emptying. Overall, up to 30% of liraglutide-treated patients and 51% of exenatide-treated patients experienced nausea in clinical trials, with a higher incidence over the first four to eight weeks of treatment and a marked decline thereafter.48-50,69 Therefore, although relatively frequent, nausea is transient and can be minimised with gradual dose escalation at treatment initiation.48-50,69-71

DPP-4 inhibitors. The only safety issue associated with dPP-4 inhibitors is an increased risk of nasopharyngitis and urinary tract infections relative to active comparators.68

Conclusion

A decline in beta-cell function and mass may be the key factor in the development of type 2 diabetes. Most therapies for the treatment of this condition aim at reducing hyperglycaemia, the main symptom of the disease, through mechanisms of action that do not have a direct effect on the beta-cell; therefore, in this respect, failing to address the key underlying factor in the pathophysiology of the disease. By contrast, the incretin hormone GLP-1 and GLP-1-based therapies act directly on the beta-cell, stimulating insulin secretion in a glucose-dependent manner and possibly increasing beta-cell mass by stimulating neogenesis and inhibiting apoptosis. This is reflected in improvements in beta-cell function, as measured by hOMA-B and proinsulin-to-insulin ratio, although long-term studies are necessary to confirm these findings. Moreover, GLP-1 and GLP-1-based therapies have important biological effects on the digestive, nervous and vascular systems that may be responsible for additional benefits in terms of weight management and CV risk factors.

The author is grateful for the writing assistance provided by Angela Pozo Ramajo from Watermeadow Medical (supported by Novo Nordisk A/S).

Key messages

• A decline in beta-cell function and beta-cell mass are key elements in the development and progression of type 2 diabetes.

• Most type 2 diabetes therapies do not have a direct effect on the beta-cell.

• GLP-1 and GLP-1-based therapies act directly on the beta-cell, stimulating insulin secretion in a glucose-dependent manner and possibly increasing beta-cell mass by stimulating neogenesis and inhibiting apoptosis (demonstrated in animal models).

• GLP-1-based therapies improve beta-cell function, as measured by hOMA-B indices and proinsulin-to-insulin ratios.



References1. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and

lipid metabolism. Nature 2002; 414: 799–806.2. Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes:

defining their role in the development of insulin resistance and β-cell dysfunction. Eur J Clin Invest 2002; 32: 14–23.

3. UK Prospective diabetes Study (UKPdS) Group. UK Prospective diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes 1995; 44: 1249–1258.

4. Pfeifer MA, haiter JB, Porte d. Insulin secretion in diabetes mellitus. Am J Med 1976; 60: 80–88.

5. Porte d. Beta-cells in type II diabetes mellitus. Diabetes 1991; 40: 166–180.

6. Ward WK, LaCava EC, Paquette TL, Beard JC, Wallum BJ, Porte d. disproportionate elevation of immune-reactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia 1987; 30: 698–702.

7. Kahn SE, halban PA. Release of incompletely processed proinsulin is the cause of the disproportionate proinsulinemia of NIDDM. Diabetes 1997; 46: 1725–1732.

8. Pørksen N. Early changes in beta-cell function and insulin pulsatility as predictors for type 2 diabetes. Diabetes Nutr Metab 2002; 15: 9–14.

9. Polonsky KS, Given Bd, hirsch LJ, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med 1988; 318: 1231–1239.

10. de Koning EJP, Bonner-Weir S, Rabelink TJ. Preservation of β-cell function by targeting β-cell mass. Trends Pharmacol Sci 2008; 29: 218–227.

11. donath MY, halban PA. decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications. Diabetologia 2004; 47: 581–589.

12. Porte d Jr, Kahn SE. hyperproinsulinemia and amyloid in NIddM – clues to etiology of islet b-cell dysfunction? Diabetes 1998; 38: 1333–1336.

13. Marchetti P, del Guerra S, Marselli L, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 2004; 89: 5535–5541.

14. Kjems LL, holst JJ, Vølund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003; 52: 380–386.

15. Tibaldi J. Preserving insulin secretion in type 2 diabetes mellitus. Exp Rev Endocrinol Metab 2008; 3: 147–159.

16. Clark A, Wells CA, Buley Id, et al. Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res 1988; 9: 151–159.

17. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza A, Butler PC. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102–110.

18. Matthews dR, hosker JP, Rudenski AS, Naylor BA, Treacher dF, Turner RC. homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

19. Wallace TM, Levy Jd, Matthews dR. Use and abuse of hOMA modelling. Diabetes Care 2004; 27: 1487–1495.

20. UK Prospective diabetes Study (UKPdS) Group. Effective of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPdS 34). Lancet 1998; 352: 854–865.

21. Kahn SE, haffner SM, heise MA, et al. for the AdOPT study group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427–2443.

22. UK Prospective diabetes Study (UKPdS) Group. Intensive blood-glucose controlled with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPdS 33). Lancet 1998; 352: 837–853.

23. Meece J. dispelling myths and removing barriers about insulin in type 2 diabetes. Diabetes Educ 2006; 32: 9S–18S.

24. ho MP, Rumsfeld JS, Masoudi FA, et al. Effect of medication non-adherence on hospitalization and mortality among patients with diabetes mellitus. Arch Int Med 2006; 166: 1836–1841.

25. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Selby JV. hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. J Am Med Assoc 2009; 301: 1565–1572.

26. Korytkowski M. When oral agents fail: practical barriers to starting insulin. Int J Obesity 2002; 26(Suppl 3): S18–S24.

27. Purnell JQ, hokanson JE, Marcovina SM, et al. Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. J Am Med Assoc 1998; 280: 140–146.

28. Kannel WB, McGee dL. diabetes and cardiovascular risk factors: the Framingham study. Circulation 1979; 59: 8–13.

29. haffner SM, Lehto S, Rönnema T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 23: 229–234.

30. Elrick h, Stimmler L, hlad CJ, Arai Y. plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 1964; 24: 1076–1082.

31. Creutzfeldt W. The incretin concept today. Diabetologia 1979; 16: 75–85.

32. drucker dJ, Nauck MA. The incretin system: glucagons-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696–1705.

33. Nauck MA, heimeaat MM, Ørskov C, holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 (7-36 amide) but not of synthetic human gastric inhibitory polypeptide in patients with type 2 diabetes mellitus. J Clin Invest 1993; 91: 301–307.

34. Vilsbøll T, Krarup T, deacon CF, Madsbad S, holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001; 50: 609–613.

35. drucker dJ. The biology of incretin hormones. Cell Metab 2006; 3: 153–165.

36. Nauck MA, Meier JJ. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regul Pept 2005; 128: 135–148.

37. Brubaker PL, drucker dJ. Minireview: glucagon-like peptides regulate cell proliferation an apoptosis in the pancreas, gut and central nervous system. Endocrinology 2004; 145: 2653–2659.

38. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, holst JJ. Truncated GLP-1 (proglucagon 78–107 amide) inhibits gastric and pancreatic function in man. Dig Dis Sci 1993; 38: 665–673.

39. Flint A, Raben A, Astrup A, holst JJ. Glucagon-like peptide-1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998; 101: 515–520.

40. Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ. Beneficial effect of GLP-1 on endothelial function in humans: dampening by glyburide but no glimepiride. Am J Physiol Endocrinol Metab 2007; 293: E1289–E1295.

41. Nikolaidis LA, Mankad S, Sokos GG, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004; 109: 962–965.

42. Kolterman OG, Kim dd, Shen L, et al. Pharmacokinetics, pharmaco-dynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm 2005; 62: 173–181.

43. Elbrønd B, Jakobsen G, Larsen S, et al. Pharmacokinetics, pharmaco-dynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagons-like peptide 1 derivative, in healthy male subjects. Diabetes Care 2002; 25: 1398–1404.

44. Ahren B, Landin-Olsson M, Jansson PA, Svensson M, holmes d, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004; 89: 2078–2084.

45. Marre M, Shaw J, Brandle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 produces greater



improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAd-1 SU). Diabetic Med 2009; 26: 268–278.

46. Nauck MA, Frid A, hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes. Diabetes Care 2009; 32: 84–90.

47. Russell-Jones d, Vaag A, Schmitz O, et al. Significantly better glycemic control and weight reduction with liraglutide, a once-daily human GLP-1 analog, compared with insulin glargine: all as add-on to metformin and a sulfonylurea in type 2 diabetes. diabetologia 2009; doi: 10.1007/s00125-009-1472-y.

48. deFronzo RA, Ratner RE, han J, Kim dd, Fineman MS, Baron Ad. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092–1100.

49. Buse JB, henry RR, han J, Kim dd, Fineman MS, Baron Ad for the exenatide-113 clinical study group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 2628–2635.

50. Kendall dM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and sulfonylurea. Diabetes Care 2005; 28: 1083–1091.

51. Zinman B, hoogwerf BG, duran Garcia S, et al. The effect of adding exenatide to a thiazolidinediones in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2007; 146: 477–485.

52. Williams-herman d, Johnson J, Teng R, et al. Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study. Curr Med Res Opin 2009; 25: 569–583.

53. Pratley RE, Schweizer A, Rosenstock J, et al. Robust improvements in fasting and prandial measures of β-cell function with vildagliptin in drug-naive patients: analysis of pooled vildagliptin monotherapy database. Diabetes Obes Metab 2008; 10: 931–938

54. Matthews dR, Marre M, Le-Thi Td, et al. Liraglutide, a human GLP-1 analogue significantly improves beta cell function in subjects with type 2 didabetes. Diabetes 2008: 57: A150–A151.

55. Garber A, henry R, Ratner R, et al. for the LEAD-3 (Mono) study group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAd-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009; 373: 483–471.

56. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab 2008; 10: 376–386.

57. Bregenholt S, Møldrup A, Blume N, et al. The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits beta-cell apoptosis in vitro. Biochem Biophys Res Commun 2005; 330: 577–584.

58. Sturis J, Gotfredsen CF, Rømer J, et al. GLP-1 derivative liraglutide in rats with beta-cell deficiencies: influence of metabolic state on beta-cell mass dynamics. Br J Pharmacol 2003; 140: 123–132.

59. Li Y, Cao X, Li LX, Brubaker PL, Edlund h, drucker dJ. Beta-cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1. Diabetes 2005; 54: 482–491.

60. Xu G, Kaneto h, Lopez-Avalos Md, Weir GC, Bonner-Weir S. GLP-1/exendin-4 facilitates beta-cell neogenesis in rat and human pancreatic ducts. Diabetes Res Clin Pract 2006; 73: 107–110.

61. Pospisilik JA, Martin J, doty T, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates β-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 2003; 52: 741–750.

62. Mu J, Woods J, Zhou YP, et al. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes 2006; 55: 1695–1704.

63. Meier JJ, Butler AE, Galasso R, Rizza RA, Butler PC. Increased islet beta cell replication adjacent to intrapancreatic gastrinomas in humans. Diabetologia 2006; 49: 2689–2696.

64. Meier JJ, Lin JC, Butler AE, Galasso R, Martinez DS, Butler PC. Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia 2006; 49: 1838–1844.

65. Butler PC, Ritzel RA, Butler AE, Rizza RA. Islet turnover in lean and obese humans. Diabetes 2004; S1: 1479-P.

66. Plutzky J, Garber A, Falahati A, Toft Ad, Poulter NR. Meta-analysis demonstrates that liraglutide, a once-daily human GLP-1 analogue, significantly reduces lipids and other markers of cardiovarcular risk in T2d. Diabetologia 2009; 52(Suppl 1): A762-P.

67. Klonoff dC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 2008; 24: 275–286.

68. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. J Am Med Assoc 2007; 298: 194–206.

69. Madsbad S. Liraglutide Effect and Action in diabetes (LEAdTM) trial. Exp Rev 2009; 4: 119–129.

70. Fineman MS, Shen LZ, Taylor K, et al. Effectiveness of progressive dose-escalation of exenatide (exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes. Diabetes Metab Res Rev 2004; 20: 411–417.

71. Irie S, Matsumura Y, Zdravkovic M, et al. Tolerability, pharmacokinetics and pharmacodynamics of the once-daily human GLP-1 analog liraglutide in Japanese healthy subjects: a randomized, double-blind, placebo-controlled dose-escalation study. Int J Clin Pharmacol Ther 2008; 46: 273–279.

continued from page 94.

References1. ‘Facts & Figures: did You Know’. International diabetes Federation.

Available at http://www.idf.org2. Boulton AJM. The pathway to ulceration: aetiopathogenesis. In: Boulton

AJM, Cavanagh PR, Rayman G, eds. The Foot in Diabetes, 4th edn. hoboken NJ: Wiley & Sons, 2006: 51–67.

3. International Working Group on the Diabetic Foot. International Consensus on the diabetic Foot. Maastricht, 1999.

4. Levin ME, O’Neil LW, Bowker Jh, Pfeifer MA, eds. The Diabetic Foot, 7th edn. Philadelphia: Mosby Elsevier, 2008.

5. Kempler P, Tesfaye S, et al; EURODIAB IDDM. Complications Study Group. Autonomic neuropathy is associated with increased cardiovascular risk

factors: the EURODIAB IDDM Complications Study. Diabetic Med 2002; 19(11): 900–909.

6. Edmonds ME, Foster AVM, Sanders LJ. A Practical Manual of Diabetic Foot Care. Massachusetts: Blackwell, 2004.

7. Palumbo PJ, Melton LJI. Peripheral vascular disease and diabetes. In: National diabetes data Group, eds. Diabetes In America, 2nd edn. (NIh publ. no 495-1468). Washington, dC: US Government, 1995: 401–408.

8. Kudo T, Chandra FA, Kwan Wh, haas BT, Ahn SS. J Vasc Surg 2006; 44(2): 304–312.

9. Armstrong d, Lavery L; diabetic Foot Study Consortium. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomized controlled trial. Lancet 2005; 366(9498): 1704–1710.

10. Lancet 2005; 366(9498): 1673–1750.

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Hands on

GET YOUR SOCKS OFF: DIABETICFOOT CARE IN THE COMMUNITY

All of us delivering care to people with diabetes know that it’s increasingly common,affecting two million people in the UK, according to figures for 2007. It is alsoexpensive, taking up about 10% of NHS costs and 5% of social costs. We also knowit’s the commonest cause of non-traumatic lower limb amputations and that’s just one

of the reasons that we spend so much time in clinics optimising care and detectingcomplications. But how well do we understand the impact of foot disease and how organisedare we in assessing and treating it?

26

Brian Karet GPwSI Diabetes in Bradford

�…the good news is that there is some evidence that structured,multidisciplinary care combined with patient education improves

outcomes for diabetes patients with foot problems�

One in four patients with diabetes has

detectable diabetic neuropathy at any time, and

about 2% have a foot ulcer. Someone with

diabetes is 13 times more likely to have a lower

limb amputation than someone who is not

diabetic. It’s hardly surprising that quality of life

is reduced after an amputation, but patients

with foot ulcers also rate their quality of life as

being significantly lower than patients whose

ulcers have healed.

Peripheral vascular disease (PVD) is

implicated in more than half of diabetic foot

problems, and a recent study in London

showed that more than half of people with

symptomatic PVD were dead within five years,

with diabetic patients doing particularly badly.

So, there’s plenty of bad news, but the good

news is that there is some evidence that

structured, multidisciplinary care combined with

patient education improves outcomes for

diabetes patients with foot problems. What

should a community-based diabetes foot care

service look like? The components are spelt

out in the recent NICE publication,

Commissioning a foot care service for peoplewith diabetes (see Table 1), and include

regular review and risk factor assessment

and reduction.

Brian KaretGPwSI Diabetes in Bradford


Hands on




26













ulcers have healed.

















and reduction.

GET YOUR SOCKS OFF: DIABETIC FOOT CARE IN THE COMMUNITY

SA JOURNAL OF DIABETES & VASCULAR DISEASEHands on




26













ulcers have healed.

















and reduction.

Hands on




26













ulcers have healed.

















and reduction.


SA JOURNAL OF DIABETES & VASCULAR DISEASE

Hands on

Testing for neuropathy to reduce the risk of ulcers

is easy. All you need is a 10 g monofilament and a

128 Hz tuning fork. The monofilament is applied, as

shown in Figures 1a and b. Ask the patient to close

their eyes and say when they feel the touch.

The tuning fork should be made to vibrate by

gently squeezing and releasing the prongs and

placing over the patient’s ankle bone. It’s a good

idea to try it out on the elbow first so the patient

knows what it feels like. Again, ask the patient to

say if they can feel it, and don’t forget to record the

results, preferably on a diabetes template.

The less well-recognised motor neuropathy leads

to a high arched, clawed foot (see Figure 2).

Recognition of autonomic neuropathy is equally

important, with reduced sweating, dilated veins

and oedema being the commonest signs. The skin

of the foot feels noticeably dry and warm on

examination.

PERIPHERAL VASCULAR DISEASEPVD is the commonest cause of amputation in

people with diabetes, and 70% of people having

amputations for PVD are dead within three years. It

can occur at any age and rapidly deteriorate, but it

is relatively easy to assess by feeling foot pulses

and using a Doppler assessment.

Feeling for foot pulses takes just a bit of practice.

Only two arteries in each foot need assessing:

the posterior tibial artery is felt just behind the

medial malleolus (inside ankle prominence)

the dorsalis pedis artery is felt on the dorsal

surface (top) of the foot, between the first and

second long bones.

You can practise on your own feet, but when testing a

patient don’t get your pulsations mixed up with theirs!

As with neuropathy testing, pulses should be recorded

as being present or absent. If you can confidently feel

either pulse, it’s very unlikely there is significant PVD.

If you’re not sure, or the patient’s foot is

oedematous, then arrange for a Doppler

assessment. If you can’t feel the foot pulses, then

it’s important to check for pulses higher up the leg.

The popliteal pulse is felt behind the knee, with the

knee joint slightly bent. The femoral pulse is felt in

the groin, half way between the outer part of the hip

joint and the midline. If no pulses are felt, an urgent

vascular surgical appointment should be made or

referral to your local rapid access foot clinic.

EXAMINING THE SKIN AND NAILSCareful examination of the feet and giving simple

advice can prevent a lot of potentially serious foot

problems. Dry skin should be treated with regular

applications of an emollient cream and signs of

cracking and fissuring, particularly around the edges

of the heels, should be noted and a podiatry referral

made. Fissures can ulcerate and become necrotic,

particularly when significant ischaemia is present.

As long as all these components are in place,

then the placement and organisation of services can

be left to local diabetes planners. However, there

are some factors that are key to success. It’s almost

impossible to have regular reviews without effective

call and recall systems and, in turn, this implies

integrated information technology (IT) systems,

without which comprehensive audit cannot be

undertaken.

Training and education of healthcare

professionals are crucial, and everyone involved in

delivering diabetes care should know how to do a

basic foot examination, including three core

activities:

Inspection

Monofilament sensation testing

Palpation of pulses.

Much of the prevention of chronic foot conditions is

based on the recognition and early treatment of foot

problems, so let’s look in a bit more detail at the

important aspects of looking after our patients’ feet.

PERIPHERAL NEUROPATHYThis is the commonest complication affecting

people with diabetes and it becomes more common

the longer someone has had diabetes. Neuropathy

can be sensory, motor or autonomic, and more than

one type may often occur together.

Patients with sensory neuropathy complain of

numbness, pins and needles, or coldness in their

feet. Objectively, they have impaired responses to

light touch (with a wisp of cotton wool), vibration

(with a 128 Hz tuning fork), temperature (with cold

and warm tubes of water) and pain (with neurotips).

This leads to injuries and ulcers going unnoticed,

and almost two-thirds of people with foot ulcers

have some degree of neuropathy.

Regular review

Risk factor assessment and reduction

Risk factor education

Foot risk stratification

Direct access to foot clinics for at-risk patients

Specialist skin and nail care

Specialist footwear advice

Specialist wound care and ulcer treatment.

Table 1: Components of an effectivefoot care service

Figure 2: Motor neuropathy

Place the monofilament on the skin and push so as to bend the filament. Repeat as shown on soles of both feet.

Figure 1: Testing for neuropathy

a b


� NICE. Commissioning a foot care service for people with diabetes.

http://www.nice.org.uk/usingguidance/commissioningguides/footcare/

commissioningafootcareserviceforpeoplewithdiabetes/commissioning_a_

foot_care_service_for_people_with_diabetes.jsp

� Turning the Corner: Improving diabetes services. DoH London. 2006

http://www.dh.gov.uk/PublicationsAndStatistics/Publications/Publications

PolicyAndGuidance/PublicationsPolicyAndGuidanceArticle/fs/en?CONTENT_ ID=4136141&chk=uS4XxF

References

� Bird CE, Criqui MH, Fronek A et al. Quantitative and qualitative progression of peripheral arterial disease by non-

invasive testing. Vascular Med 1999; 4: 15-21.

� Melville A, Richardson R, McIntosh A et al. Complications of diabetes: screening for retinopathy and management of

foot ulcers. Quality in Health Care 2000; 9: 137-41.

� Missouris CG, Kalaitzidis RG, Kerry SM, Capuccio FP. Predictors of mortality in patients with peripheral vascular

disease. A prospective follow-up study. Br J Diabetes Vasc Dis 2004; 4: 196-200.

� Morris AD, McAlpine R, Steinke D et al. Diabetes and lower-limb amputations in the community. A retrospective

cohort study. Diabetes Care 1998; 21: 738-743.

� Ramsey SD, Newton K, Blough D et al. Incidence, outcomes, and cost of foot ulcers in patients with diabetes.

Diabetes Care 1999; 22: 382-387.

� Ragnarson-Tennvall G, Apelqvist J. Health-related quality of life in patients with diabetes mellitus and foot ulcers.

Journal of Diabetes and its Complications 2000; 14: 235-241.

� Walters DP, Gatling W, Mullee MA, Hill RD. The distribution and severity of diabetic foot disease: a community study

with comparison to a non-diabetic group. Diabetic Med 1992; 9: 354–58.

� Young MJ, Boulton AJM, MacLeod AF et al. A multicentre study of the prevalence of diabetic peripheral neuropathy

in the United Kingdom hospital clinic population. Diabetologia 1993; 36: 150-54.

Hands on

The development of calluses on the soles of

the feet is of concern. Small thin areas of callus

can be treated with urea-based creams, but

thicker areas need treating by a podiatrist. The

presence of blood under a callus is very

suggestive of ulceration and needs urgent referral.

This can look like dark red jelly under the skin.

Nails can become overgrown and thickened

and can cause ulceration in the presence of

neuropathy and badly fitting shoes. Fungal

infections can occur between the toes and need

treating as they can cause cracking and act as

sites of bacterial entry. Any infection of the foot is

serious and can spread very quickly. Because of

impaired circulation, the normal signs of warmth

and redness may be diminished and the

response to systemic antibiotics slowed. If you

are in any doubt, it’s always better to refer to a

rapid access foot clinic.

Any skin ulceration needs rapid attention and

should never be left. Specialist advice should be

sought as soon as possible.

CHARCOT FOOTThis is, fortunately, a rare but very serious

complication of the foot in people with diabetes.

It presents as a sudden event with a sometimes

painful, usually red, warm and swollen foot,

where the medial arch has recently collapsed.

One way to assess the degree of deformity is to

compare the affected foot with the other one.

It’s a rapidly progressive degenerative arthritis

caused by loss of sensation within the foot and is

always an emergency. Patients should be told not

to weight bear on the affected foot until they

have been assessed.

IN CONCLUSIONHealthcare professionals working in the

community have a great opportunity to reduce

the morbidity, and costs, of diabetic foot

problems. We are already doing much in terms of

reducing risk factors such as hyperglycaemia,

hypertension and hyperlipidaemia, prescribing

aspirin and promoting smoking cessation. We

need to use the podiatry, vascular and wound

care expertise in our multidisciplinary teams, and

establish clear pathways in order to make sure

all patients with diabetes receive regular foot

care and those at high risk are referred.









References










Diabetes Care 1999; 22: 382-387.







Hands on


































have been assessed.




















References










Diabetes Care 1999; 22: 382-387.







Hands on


































have been assessed.













"

Keep and Copy Series



Patientinformationleaflet

If you have diabetes it is essential that you look after your feet, so that

they can look after you. However, it does not mean that you are doomed

to suffer serious complications such as loss of sensation, poor circula-

tion, infection, ulcers, gangrene and finally, amputation. Fortunately, most

of the conditions that affect your feet can be prevented by being well

informed about the status of your feet, doing your best to control your

blood sugar and taking some daily precautions to reduce this risk.

Most people with diabetes know they may suffer foot complications

but often don’t know why. The best way to prevent complications is to

understand your diabetes. For example, the comment that type 2 diabe-

tes is less severe than type 1 is not true, diabetes is diabetes and it can

affect your feet.

If the circulation to the limbs and extremities is poor, it reduces your

body’s ability to quickly heal even the smallest cut or abrasion. Due to this

delay, a simple scratch can become infected and possibly develop into an

ulcer. Another effect of poor circulation is reduced blood flow to your calf

muscles, which causes pain in the legs when walking.

HOW DO I KNOW MY CIRCULATION IS POOR?Symptoms such as cold feet, pale or bluish skin on your toes or the sides

of your feet, calf cramps when you walk, painful legs in bed, relieved by

hanging your feet out of bed, frequent small sores or abrasions at the tips

of your toes and ulcers under the nails or around the heels.

A gradual loss of sensation is a common result of diabetes. This is often

unnoticed until a painless injury occurs. This neuropathy, as it is called,

produces strange sensations such as walking on cotton wool, feeling as

if you have socks on when you are barefoot, feeling as if you have water

running down your legs, numbness, pins and needles, burning and even

the failure to feel sharp objects or heat and cold.

HOW DO I KNOW I HAVE NEUROPATHY?Symptoms such as burning feet, pins and needles, numbness, painful

feet or no pain, dry, cracked skin and changes in the shape of your foot.

HOW DO I KNOW I HAVE A FOOT INFECTION?Symptoms such as swelling and redness in the foot or leg, raised blood

sugar and possibly feeling unwell, pus or discharge from a part of the

foot, sores or cracks in the skin, especially the heels, and discolouration

and swelling under a callus.

HOW CAN I TRY AND PREVENT FOOT COMPLICATIONS?You need to know your level of risk. Is it low or high? Do you already have

complications of an ulcer, infection, gangrene or a previous amputation?

Find out your level of risk by having an annual foot examination by a

trained healthcare professional – preferably a podiatrist. This examination

checks your circulation, nerves, skin, bones and joints, and your footwear.

It usually takes about 30 minutes and will include some foot health advice

specifically for you, based on the examination.

WHAT ELSE CAN I DO?Establish a good foot hygiene routine by inspecting your feet every day.

Look for changes in colour (red, blue or white), blisters, abrasions, corns

and calluses, and damaged nails. Remember to look between the toes for

soft white skin or cracks, which could be a fungal infection.

Basic foot care means daily washing with mild soap, drying carefully,

especially between the toes, followed by the application of a cream to

moisturise the skin. Use a pumice stone to reduce calluses, but do it

gently. Cut your toenails to follow the line of your toes and finish off with

a sandpaper nail file.

Properly fitting footwear should not press or cut into your feet or cause

blisters. You need a protective sole and a low (not flat) heel to protect your

feet. Old, worn shoes should be thrown away and don’t spend all day in

your slippers. There are fashionable shoes available with better fit.

Regular exercise helps to control both your weight and blood sugar, so

try to walk for 30 minutes every day, or break it up into shorter blocks of

time. Do some bending and flexing between the adverts on TV!

Please don’t smoke. Did you know that after every cigarette, your blood

vessels go into spasm for six hours, so smoking keeps them in a constant

state of spasm and reduces blood flow to your feet.

Finally, control your blood sugar. Not only does this prevent foot compli-

cations but it also helps to heal any damage more quickly.Andrew Clarke ([email protected])

S Afr J Diabetes Vasc Dis 2009; 6: 111.

FOOT CARE FOR PEOPLE WITH DIABETES



DR GABAzA NGOBENI WINS THE SERvIER AWARD FOR COMMUNITY INvOLvEMENT

T he Servier Award for Community Involvement

was presented at the 11th Centre for Diabetes

and Endocrinology (CDE) Postgraduate Forum in

Diabetes Management, held in Johannesburg in Au-

gust. It comprises an unconditional educational grant

to the value of R10 000 and is presented to the CDE

centre that exhibits the highest degree of commitment

to the community it serves.

The winner was Soweto-based general practitioner,

Dr Gabaza Ngobeni, who has done sterling work in

her community over the past few years. The Journal

of Diabetes and Vascular Disease profiled Dr Ngobeni

and her initiatives in the November/December 2008

issue.

On setting up practice in Diepkloof, Soweto, she

became aware within a short time of a notably high

incidence of diabetes among her patients. Having edu-

cated herself as a doctor, she then turned her attention

to educating her patients and enhancing her commu-

nity’s knowledge and awareness of the condition.

To this end she initiated an ongoing series of work-

shops that were open to all. She hosted the first work-

shop at her practice, the Dr Gabaza Healing Centre, in

August 2006 and in the ensuing three years has held

similar workshops on a regular basis, sometimes sev-

eral per month, to an ever-growing number of attend-

ees. She has seen the positive effects they have had,

as patients became not only more aware of their dis-

ease, but also more compliant with their treatment.

She was absolutely delighted to receive the Servier

Award for Community Involvement. ‘It means so much

to have my work recognised like this, and I feel as

though I’ve just been given new strength to do more

and expand my programmes even further. Having

achieved so much in respect of education and aware-

ness, my next priority will be to enhance clinical skills

in my community so that my patients can access the

best and most up-to-date treatment. Now that we

have the awareness, we really need the clinical skills

to go with it.’

Since the Journal last spoke to her, Dr Ngobeni has

expanded her workshop programme, most notably over

the last six months, introducing workshops focused

solely on insulin therapy and how to administer the

injections. With sponsors’ support, she has also been

able to hand out free glucometers to patients who at-



Dr Gabaza NgobeniDr Gabaza Healing CentreDiepkloof, Soweto

Dr Gabaza Ngobeni receiving her award, with Gaynor Ireland (left) and Judith Herald (right) from Servier.



tend her workshops. ‘Now, thanks to the Servier Award, I can plough even

more back into the community and grow my work still further.’

Dr Ngobeni is passionate about patient education, believing that an

aware patient is an empowered patient. ‘Education is critical to managing

a chronic illness such as diabetes, which is very different from something

simple like the ’flu. Patients need to know why it is so important to have

their blood pressure, blood glucose levels and urine checked regularly,

and the messages need to be imparted clearly and effectively.’

She has greater plans in mind, hoping to extend her workshop pro-

grammes to other areas of Soweto and even beyond, as well as broaden-

ing the focus beyond diabetes to other chronic diseases. ‘In future I’d like

to be able to do road shows along the lines of what Novonordisk does with

its diabetes bus. People attending the road shows would be able to ac-

cess information leaflets, attend talks and have their blood glucose levels

tested. It would be more encouraging too, if other general practitioners

were to initiate programmes similar to mine, in other areas. We would then

be able to link up and work together. I’m really hoping that what I have

achieved with my workshops so far will indeed encourage other health

professionals to do the same in their practices.’

The Complete Nutritional Solution to Diabetes: Ria Catsicas

R ia Catsicas RD (SA) is a registered clinical dietician

who has been in private prac-tice for 20 years. She gradu-ated with a BSc (hons) (cum laude) in Dietetics from the North West University and subsequently completed a BA (Psychology) from UNISA. She is currently studying a Master’s degree in Nutrition with a spe-cial focus on diabetes.

Ria has been involved in the nutritional aspects of diabetes since she was asked by Diabe-tes South Africa to establish a support group for parents of children with type 1 diabe-tes. She is registered with the health Professions Council of South Africa and is a member of the Association of Dietetics of South Africa.

The Complete Nutritional Solution to Diabetes is the first book of its kind that examines the relationship between nutri-tion and diabetes. It gives the reader a comprehensive under-standing of how and why nutrition helps with glycae-

mic control in the short term, and the complications of poor glycaemic control in the long term.

Good nutrition is a criti-cal element to achieving opti-mal blood glucose levels. The Complete Nutritional Solution to Diabetes guides the reader from diagnosis of diabetes, through the fundamental prin-ciples of good nutrition, to the importance of regular physical activity.

Chapters are dedicated to the subject of carbohydrates (the importance of glycaemic load), the role of fats and pro-tein, and how to incorporate whole grains, sugar and sweet-eners into our diets. Ria has also incorporated a chapter on the special needs of children and adolescents with diabetes.

A unique feature of the book is the meal plans pro-vided, based on three levels of intake. These meal plans are complemented with 44 recipes that are suitable for the entire family, ranging from breakfasts

to desserts.This book is a must read for

anyone with type 1 or 2 dia-betes and even for those who are pre-diabetic. We are what we eat; and the reader will be empowered to make the right nutritional choices.

The book is available from bookstores nationwide, the South African Diabetes Asso-ciation and from the following websites: www.kalahari.com and www.nutritionalsolutions.co.za.

To win a copy of The Complete Nutritional Solution to Diabe-tes, simply e-mail Wendy on [email protected] with your name, speciality and address by 20 October 2009.

Congratulations to Dr D Craven and Mrs M van Wyk, who won the June book giveaway of the South Afri-can Cookbook for Diabetes and Insulin Resistance 1 by Hilda Lategan.

GIVEAWAY

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EURO

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09/E

2009 UPDATE FROM NEW ORLEANSAmerican Diabetes Association June 2009

SUMMARIES

ADA WATCH

AdA WATCh SA JOURNAL OF dIABETES & VASCULAR dISEASE


Diabetic patients with stable ischaemic heart disease benefit from CABG (BARI-2)Insulin sensitisers are as good as insulin in this patient groupThe long-awaited five-year BARI-2 trial (Bypass Angioplasty Revascularisation Inves-tigation), a collaborative effort between cardiologists and diabetologists, has shown that there was no significant difference in the rates of death and major cardiovascu-lar events between patients undergoing prompt revascularisation (PCI or CABG) and those undergoing medical therapy. Further-more there were no significant differences in the rates of death and major cardio-vascular events between strategies using insulin sensitisation and insulin provision.1

however, those diabetic patients ran-domised by the cardiologist, based on his/her clinical assessment to the CABG ran-domisation arm and immediately operated on, experienced fewer non-fatal myocar-dial infarctions.

Prof Trevor Orchard (Pittsburgh) and dr Robert Frye (National heart, Lung and Blood Institute, Bethesda) pointed out that BARI-2 did not compare PCI versus CABG and the results from this study should not be interpreted that CABG delivers better results than PCI. ‘The CABG patients were at higher CV risk than those randomised to PCI’, dr Orchard noted.

For cardiology, this is the first demonstra-tion that in diabetic patients requiring CABG, it is better to do the procedure early and then continue with intensive cardiovascular risk management. In this study, for exam-ple, 95% of the patients were on statins.

It is important to note that patients were excluded from BARI-2 if they required immediate revascularisation or if they had left main coronary artery disease (all under-went coronary angiography), a creatinine level of more than 2.0 mg/dl, an hbA1c of more than 13%, heart failure or hepatic dysfunction, or if they had undergone PCI/CABG in the previous six months. (These represented some 50% of the patients

screened for entry into the study and there-after they were excluded.)

In an accompanying editorial,2 Drs Boden and Taggart pointed out that the pre-specified analyses of the secondary composite endpoint (death, myocardial infarction or stroke) provided potentially important scientific insights of firstly, insu-lin-sensitising therapy benefits above insu-lin, especially among patients undergoing CABG. Secondly, that the CABG patients operated on early experienced fewer non-fatal myocardial infarctions than those on medical therapy alone.

Crossover therapy was high how-ever with 42% of patients in the medical therapy arms requiring revascularisation, athough, as Prof Orchard pointed out, this meant that 60% of patients did not require revascularisation in the five years of follow-up. The BARI-2 data adds to other scientific evidence supporting CABG over PCI in patients with diabetes and multi-vessel coronary artery disease.

The study was performed in 49 clinical

sites in the USA, Canada, Brazil, Mexico, the Czech Republic and Austria.

References1. Frye RL, August P, Brooks MM, hardison RM,

et al. A randomized trial of therapies for type 2 diabetes and coronary artery diease. N Engl J Med 2009; 360: 2503–2515.

2. Boden WE, Taggart dP. diabetes with coronary disease – a moving target amid evolving thera-pies? 10.1056/NEJME0904090. 7 June 2009.

Rosiglitazone increases risk of heart failure and fractures of arm and lower leg (RECORD trial) while confirming cardiovascular safetyRosiglitazone in combination with met-formin or a sulphonylurea was shown not to increase the risk of cardiovascular disease or death but to double the risk of heart failure. It also increased the risk of arm and lower leg fractures by 57% and the increased risk for women (82%) was much higher than for men (23%).1

RECORd was an open-label, prospective

TABLE OF CONTENTS

Diabetic patients with stable ischaemic heart disease benefit from CABG (BARI-2) ...................................................1

Rosiglitazone increases risk of heart failure and fractures of arm and lower leg (RECORD trial) while confirming cardiovascular safety ...............................1

Insulin glargine extends benefits to more patients .....................................................2

Further evaluation of the ACCORD data 2

VADT (Veterans Administration Diabetes trial) highlights factors affecting benefit/harm in older diabetic patients with established diabetes .................................2

Liraglutide more effective at lowering blood sugar than glimepiride ..................3

Insulin glargine of greater benefit in older patients .....................................................3

Expert committee recommends HbA1c for diabetes diagnoses to replace FPG and 2HPG ........................................................3

Glycaemic control in type 1 diabetes is influenced by specific genes1 ....................3

CDT metformin use associated with B12 deficiency and neuropathy ......................4

Internet medicine + simple photos = faster eye screening .............................................4

Safety and satisfaction with insulin ..........4

Quit smoking for the health of your kidneys ......................................................4

Challenge to healthcare funders to be proactive and reduce long-term costs ....4

Deafness – a new focus for diabetes health educators ..................................................4

SA JOURNAL OF dIABETES & VASCULAR dISEASE AdA WATCh


multicentre trial undertaken to assess the overall cardiovascular safety of rosiglita-zone when added to either metformin or sulfonylurea treatment. A total of 4 447 patients with type 2 diabetes were includ-ed in the study.

The investigators noted that rosiglita-zone performed better in controlling glu-cose levels in the longer term (the median study period was 5.5 years) than the other oral agents plus insulin.

This study supports current prudent advice not to use rosiglitazone in patients with a history of heart failure or with previ-ous problems that might lead to myocar-dial dysfunction. In addition, half-maximal doses, which provide more than half-max-imal therapeutic effects could reduce the magnitude of unwanted side effects and may be the way forward for this agent.

Reference1. home Pd, Pocock SJ, Beck-Nielsen h, et al.

Rosiglitazone evaluated for cardiovascular out-comes in oral agent combination therapy for type 2 diabetes (RECORd): a multicentre, ran-domised open-label trial. Lancet 5 June 2009. dOI:10.1016/S0140-6736(09) 60953-3.

Insulin glargine extends benefits to more patientsIn a symposium on insulin glargine, and Sa-nofi Aventis’ contribution to diabetes man-agement, Mr Pierre Chancel, vice-president of Sanofi Aventis and Prof Philip home from Newcastle, UK emphasised the important contribution insulin glargine is making to delivering real patient benefit.

Insulin glargine is the major insulin used in type 2 diabetes in the USA and with the expected increase in type 2 diabetes in Chi-na (48%), India (73%) and Africa (80%), there is a great need for affordable, effec-tive insulins and a larger choice of glucose-lowering agents.

Prof home presented and discussed the results of a number of recent trials at the AdA. his meta-analysis of insulin glargine compared to NPh insulin with regard to nocturnal hypoglycaemia included five re-cent trials. Importantly, this meta-analysis has shown that one needs eight patients to be treated with insulin glargine for six to nine months to save one hypoglycaemic event, and 112 patients to avoid a severe hypoglycaemic event (< 2.0 mmol/l). Severe hypoglycaemic events are directly related to cardiovascular events and mortality, ac-cording also to recent additional investiga-tions in the ACCORD trial.

Prof home also referred to the increas-ing number of in-practice trials of insulin glargine being conducted in Europe and Asia. Of interest was the recent trial of type 2 diabetic patients who were poorly con-trolled on pre-mix insulin and, on switch-ing to insulin glargine, achieved significant benefits (figure 1).

Further evaluation of the ACCORD data

Excess mortality in intensive glucose-lowering arm of ACCORD attributable to poor glucose control, not to low glucose levelsThe excess mortality in the intensive arm of ACCORd occurred in those patients who, despite receiving intensive therapy, failed to reach a target hbA1c of less than 7%. Patients who reached 7% or lower in the first three to six months experienced a low-er risk, whether they were in the intensive or standard arm.

While severe hypoglycaemia (< 50 mg/dl) occurred more frequently in the inten-sive arm of ACCORd (2–3%) than in the standard-therapy arm (1%), the excess mortality was not due to hypoglycaemia, according to the additional investigations announced at ADA.

Severe hypoglycaemia occurred more frequently in women, Africans, older pa-tients and those who had had a longer du-ration of diabetes or had entered the study already receiving insulin. The occurrence of a severe hypoglycaemic event did however relate to an increased risk of a cardiovascular events and/or death in the particular patient.

A total of 451 deaths occurred in the

ACCORD standard and intensive groups combined; 7% of these individuals had at least one severe hypoglycaemic event re-quiring medical assistance. Those who had severe hypoglycaemia in the intensive arm experienced a lower risk of death compared to those who had severe hypoglycaemia in the standard group. The reason for this is currently not known, but the patients in the intensive arm were more closely moni-tored and received more support from the healthcare team.

The ACCORd group also adjudicated each death for the potential role of hy-poglycaemia. Of the 451 deaths, only one case was adjudicated as potentially due to hypoglycaemia.

Further evaluation of the ACCORD data is ongoing to try and pinpoint further as-pects of importance to clinical manage-ment of these type 2 diabetic patients.

VADT (Veterans Administration Dia-betes trial) highlights factors affect-ing benefit/harm in older diabetic patients with established diabetesEvaluation of the duration of diabetes and the implementation of intensive glucose control has shown cardiovascular benefit in the first 15 years following diagnosis. Af-ter 16 to 20 years, there was no additional benefit from initiating intensive glucose control. however, initiation of intensive control 20 or more years after diagnosis in-creased the risk of cardiovascular events in patients in the VADT trial.

Other major risk factors potentially pre-cipitating a primary cardiovascular event or total mortality were hypoglycaemia, a previ-

Figure 1. GINGER: basal bolus vs premixed insulins.

AdA WATCh SA JOURNAL OF dIABETES & VASCULAR dISEASE


ous cardiovascular event, older age and im-paired kidney function. Interestingly, hdL-C levels played a role in this population, which included older and sicker patients than in the ACCORd study. For every 10-mg in-crease in hdL-C above the individual’s base-line, there was an 80% decrease in risk of cardiovascular events, including mortality.

Severe hypoglycaemia (probably ranked as more severe than in the ACCORD study as it was defined as changes in conscious-ness) resulted in an 88% increase in prima-ry cardiovascular events and a three-fold increase in cardiovascular death. This was true for both the intensive and standard arms of the study.

The presenters concluded that hbA1c levels should be adjusted according to the individual, with particular care being taken with older patients, with diabetes of longer duration, and with prior cardiovascular dis-ease or renal dysfunction where intensive glucose control could be deleterious.

Liraglutide more effective at lower-ing blood sugar than glimepirideOnce-daily liraglutide, taken as mono-therapy leads to statistically significant and sustained reductions in blood sugar and weight after two years of treatment. In the study, 58% of patients treated with liraglu-tide 1.8 mg once daily reached and main-tained the AdA’s target of hbA1C less than 7%, versus 37% of patients treated with glimepiride 8 mg once daily.1

‘The fact that liraglutide continues to effectively lower blood sugar after two years of treatment is consistent with its other long-term clinical benefits, such as continued reductions in fasting blood sugar and weight’, said dr Alan Garber, Baylor College of Medicine, houston, and a LEAd™ 3 principal study investigator. ‘Even with available treatments, many type 2 dia-betes patients still struggle to control their blood sugar while losing weight. Liraglu-tide represents an important advance for these patients.’

The LEAD™ 3 extension study also documented that treatment with liraglu-tide leads to early and lasting weight loss. Many currently available diabetes treat-ments lead to weight gain, a concern for type 2 diabetes patients, most of whom are already overweight. After two years of treatment with 1.8 mg of liraglutide, mean body weight decreased significantly (–2.7 kg) compared to overall weight increase in the glimepiride group (+1.1 kg).

Reference1. Garber A, henry R, Ratner R, et al. Monothera-

py with liraglutide, a once-daily human GLP-1 analog, provides sustained reductions in hBh-BA1C, FPG and weight compared with glimepir-ide in type 2 diabetes: LEAd-3 mono 2-year results. Presented at the American diabetes As-sociation annual congress, 6 June 2009, New Orleans, USA.

Insulin glargine of greater benefit in older patientsSanofi Aventis presented the results of a new study, Safety and Efficacy of Insulin Glargine Compared with NPh Insulin in Old-er Adults with Type 2 diabetes: Results from a Pooled Analysis, which examined the safe-ty and efficacy of Lantus® [insulin glargine (rdNA origin) injection] compared to insulin NPh in older adults with type 2 diabetes.

The study, presented as a poster,1 found that among patients 65 years or younger, there was no significant difference between insulin glargine and NPh insulin treatment in hbA1c reduction (1.26% for insulin glargine, 1.20% for NPh insulin) or fasting blood glucose (FBG) reduction (86 mg/dl for insulin glargine, 84 mg/dl for NPh in-sulin) after 24 weeks of treatment. Similar results were also found for daytime symp-tomatic hypoglycaemic events per patient year in patients younger than 65 years (2.4 for insulin glargine and 2.6 for NPh insulin) and severe hypoglycaemic events (0.03 for insulin glargine and 0.04 for NPh insulin).

Patients over 65 years old who received insulin glargine had statistically significantly greater hbA1c reductions, with an average decrease of 1.21% in the insulin glargine group versus 0.99% in the NPh insulin group (p < 0.05). These older patients also experienced statistically significantly great-er FBG reductions with insulin glargine treatment than with NPh insulin (92 mg/dl versus 85 mg/dl, p < 0.05). The number of symptomatic hypoglycaemic events per patient year in these older patients was 2.2 for insulin glargine and 2.4 for NPh insulin, with 0.01 severe hypoglycaemic events for insulin glargine and 0.03 for NPh insulin.

The rate of nocturnal hypoglycaemia was statistically significantly lower with in-sulin glargine than with NPh insulin in both age groups [1.1 versus 2.3 average events per patient year (p < 0.0001) in patients younger than 65 years; and 1.3 versus 2.7 average events per patient year (p < 0.005) in patients older than 65 years].

Twenty-two Sanofi Aventis-sponsored randomised clinical trials in patients with

type 2 diabetes were screened. Studies were included in the analysis if: all patients in these trials were insulin naïve, had diag-nosed type 2 diabetes, and were treated with a basal insulin only (insulin glargine or NPh insulin). duration of treatment in all studies was 24 weeks.

Reference1. Oral presentation, 2009 AdA conference

Expert committee recommends HbA1c for diabetes diagnoses to replace FPG and 2HPGAn expert committee appointed by the AdA, IdF and EASd has recommended us-ing the hbA1c assay as the new defining test for the diagnosis of diabetes. This will align diagnosis with the accepted measure for glycaemic control, hbA1c. These recom-mendations released at the ADA have not yet been accepted by the commissioning organisations.1

hbA1c varies less than fasting blood glu-cose (FPG) values and the assay for hbA1c has technical advantages compared with the glucose assay, according to chairman Dr David N Nathan from Massachusetts General hospital and professor of Medicine at harvard Medical School. The test is also easier for patients who will no longer be re-quired to perform a fasting or oral glucose tolerance test.

The suggested definitive level to de-fine diabetes has been set at ≥ 6.5% as it is regarded as sufficiently sensitive and specific to identify people who have dia-betes. The cut-off point should however not be construed as an absolute divid-ing line between normal glycaemia and diabetes, dr david Nathan noted. Glu-cose impairment runs on a continuum and this needs to be taken into account when determining level of individual risk.

Reference1. AdA media release.

Glycaemic control in type 1 diabe-tes is influenced by specific genes1

Evaluation of the patients within the DCCT trial has identified four major gene loci re-lated to hbA1c levels. Those genotypes con-taining SORCS1 gene 10q 25.1 were asso-ciated with hypoglycaemia, and a second single nucleotide polymorphism (SNPS, also referred to as snips) was associated with kidney, eye and cardiovascular disease.

At this stage the data are primarily of

SA JOURNAL OF dIABETES & VASCULAR dISEASE AdA WATCh


research interest but the finding may con-tribute to better understanding of the mechanism of diabetes control. In the fu-ture, these genetic variations may point to individuals who will be particularly prone to hypoglycaemia and micro- and macro- vascular complications of diabetes and who may require special efforts.

Reference1. Abstract 58-OR, AdA 69th scientific meeting.

CDT metformin use associated with B12 deficiency and neuropathyMetformin is a first-line treatment for type 2 diabetes but this study1 showed that 40% of users had B12 deficiency or were in the low-normal range. Further, peripheral neuropathy (PN) was found in 7% of the normal, 23% of the low normal, and 77% of those in the deficiency state. Since PN is such a major and intractable problem in people with type 2 diabetes, the research-ers recommended that those on metformin for a year either be screened for B12 defi-ciency or supplemented with B12, and that anyone on metformin with PN be screened for the deficiency.

Reference1. Poster 569. AdA 2009 congress.

Internet medicine + simple photos = faster eye screeninghere’s a clue for community health systems or hospitals that need to screen people for retinopathy in a more efficient way.1 Get-ting diabetic patients to follow up on a referral for such screening is a major prob-lem in diabetes care. It’s even worse in low-income/poverty populations such as those in this study. Instead of sending patients elsewhere for screening, researchers brought mobile three-field non-mydriatic

(non-dilated) retinal photographic equip-ment to community clinics, together with a trained technician, to read the photo-graphs and store them on internet servers, from where they could later be retrieved and checked by a specialist.


Safety and satisfaction with insulindoctors and patients with type 2 diabe-tes often resist moving on to insulin when it is needed due to fears of weight gain, hypoglycaemia and diminished quality of life. This study shows those fears to be un-founded.1 Newly diagnosed patients were started on insulin and metformin and then randomised to continue that regimen or switch to a triple-therapy regimen. After three years, and quarterly monitoring visit, quality of life and treatment satisfaction were similar in both groups, and 100% of those on insulin were willing to continue. hbA1c levels were almost identical; weight increased three times as much in the pill group as in the insulin group, and the pill users had slightly more hypoglycaemia.


Quit smoking to save your kidneysSmoking is an independent risk factor for the development of microalbuminuria in people with type 2 diabetes. It may be the first step on the road towards nephropathy and end-stage kidney disease. This study as-sessed the effect smoking cessation might have on people newly diagnosed with type 2 diabetes and who had microalbuminuria.1 Quitting smoking was associated with less microalbuminuria, and improved glycaemic control and lipid profiles.


Challenge to healthcare funders to be proactive and reduce long-term costsMedco, a health maintenance funder, iden-tified 3 836 type 2 diabetes patients with a pharmacy claim for a diabetes medication but with no active pharmacy prescription for an ACE inhibitor or an angiotensin recep-tor blocker (which are often prescribed to treat hypertension or kidney problems in people with diabetes). Faxes were sent to the physicians of 1 771 patients, summa-rising ADA recommendations for the use of ACE inhibitors and angiotensin recep-tor blockers. They provided a list of them and a prescription form pre-filled in with patient information that could be faxed back. Twenty-four per cent in the faxed group were prescribed one of the drugs in the next four months compared to 9% in the non-contacted group.


Deafness – a new focus for diabe-tes health educatorsPeople with diabetes who have poor gly-caemic control, vascular or neuropathic complications may also be prone to high-frequency hearing loss.1 What can be done? Just tell the patients to be aware of it and get their hearing tested if they notice changes, and to discuss how to improve glycaemic control and address possible underlying vascular or neuropathic prob-lems with their doctors.


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

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

EURO

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SA JOURNAL OF DIABETES & VASCULAR DISEASE DRUG TRENDS


Lessons from the BEAUTIfUL trial Heart rate targets for coronary patients

T he benefit of lowering heart rate (hR) in post myocardial

infarction (MI) patients is now well accepted and included in all major guidelines. however, until the recent publication of the BEAUTIfUL [morbidity–mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary artery disease (CAD) and left-ventricULar dysfunction] study, the target hR had not been established in prospective outcome stud-ies. The target is usually deter-mined at the discretion of the physician and influenced by the dose tolerated and the

presence of side effects and concomitant disease.

Recently, retrospective analysis from the CASS study (25 000 patients) has shown better outcome in patients with hR below 62 beats per minute (bpm) compared to those with hR above 85 bpm, independent of other risk fac-tors.1 Also the impact of rest-ing hR in hypertensive patients with coronary artery disease, included in the INVEST trial, was evaluated. This study showed an increased risk of cardiovascular (CV) events with elevated resting hR from 75

bpm upwards.2

The BEAUTIfUL trial tested whether hR lowering with ivabradine (Coralan®) reduced CV events in coronary patients with left ventricular dysfunc-tion (LVD).3 Ivabradine, recently launched as Coralan® in South Africa, specifically inhibits the If current in the sino-atrial node to lower hR without negatively affecting other aspects of car-diac function.3

The study enrolled 10 917 eligible patients (mean age 65.2 years, mean ejection frac-tion 32.4%) in a randomised, double-blind, parallel group

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design; 5 479 received ivabra-dine 5 to 7.5 mg twice daily, and 5 438 received matched placebo, in addition to guide-line-recommended CV treat-ments (aspirin/anti-thrombotic 94%; statins 72%; RAAS inhibitor 90%; beta-blocker 84%). The average follow up was 19 months.3

A sub-analysis of the pla-cebo group was performed to test the hypothesis that elevated resting hR at base-line is a marker for subsequent CV death and morbidity. The patients were divided into two groups using a pre-specified

Figure 1. Kaplan-Meier time-to-event plots split by heart rate for (A) cardiovascular death, (B) admission to hospital for heart failure, (C) admission to hospital for myocardial infarction, and (d) coronary revascularisation.

ACV deathHR 1.34

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DRUG TRENDS SA JOURNAL OF DIABETES & VASCULAR DISEASE


hR cut-off of 70 bpm (≥ 70 bpm in 2 693 patients vs 2 745 patients with hR < 70 bpm).4

The difference in hR between the groups was 79.2 versus 64.1 bpm. This resulted in a significant and marked increase in CV death (34%, p = 0.0041) and admission to hos-pital for myocardial infarction (46%, p = 0.0066), coronary revascularisation (38%, p =

0.037) and heart failure (53%, p < 0.0001) (figure 1).4

Furthermore figure 1 shows an immediate and dramatic divergence of the Kaplan-Meier time-to-event plots. This early divergence in the curves high-lights the need for the clinician to act sooner rather than later, to gain the potential benefit of early hR lowering.

Figure 2 shows the crude

event rate and hazard ratio according to the hR groups. It indicates different hR tar-gets for prevention of coro-nary events (hR ≤ 65 bpm) and worsening of heart failure (hR ≤ 70 bpm).4 The authors concluded that there are ‘dif-ferential effects of outcomes associated with heart failure and with coronary events’.4

The primary endpoint in the BEAUTIfUL trial was a compos-ite of CV death and admission to hospital for new-onset or worsening hF, and for acute MI. The primary endpoint was neutral. The sub-analysis above sheds light on the results of the BEAUTIfUL study.

When patients were divided according to hR as described above, the fact that the start-ing/resting hR (73 bpm) was already close to the target hR for heart failure of 70 bpm explains why further lower-ing of the hR by 7 bpm with ivabradine resulted in a neutral

outcome. At the same time, as expected, this lowering of the hR with ivabradine resulted in a significant reduction in coro-nary events where the target was 65 bpm.3

Therefore the authors con-cluded ‘reduction in hR with ivabradine does not improve cardiac outcomes in all patients with stable CAd and LVd, but could be used to reduce the incidence of CAD outcomes in a subgroup of patients who have hRs of 70 bpm or above’.3 Furthermore, the good safety profile and excellent tolerabil-ity of ivabradine, alone or in combination with beta-block-ers, has now been established in this large, landmark trial.

1. diaz A, et al. Eur Heart J 2005; 26: 867–874.

2. Kolloch R, et al. Eur Heart J 2008; 29: 1327–1334.

3. Fox K, et al. Lancet 2008; 372: 817–821.

4. Fox K, et al. Lancet 2008; 372: 807–816.

Figure 2. Crude event rates and hazard ratios according to heart rate group. Crude event rates (bars; left-hand scale) and hazard ratios (and 95% CI; right-hand scale) according to heart rate group relative to heart rate of less than 65 bpm for (A) cardiovascular death, (B) admission to hospital for heart failure, (C) admission to hospital for myocardial infarction, and (d) coronary revascularisation. horizontal line corresponds to the hazard ratio of 1. hazard ratios adjusted for all variables with nominal difference at baseline (p < 0.05).

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Take-home message • despite being optimally treated with guideline-recom-

mended therapy, the risk associated with a hR ≥ 70 bpm is substantially higher for all coronary and heart failure outcomes.

• The BEAUTIfUL trial showed a differential effect of reducing hR on outcomes associated with hF (target > 70 bpm) and those associated with coronary events (target < 65 bpm).

• There are now two proven modalities to reduce heart rate in these patients. The difference in the manner in which they reduce heart rate has clinical consequences. Coralan specifically inhibits the If current in the sino-atrial node to lower the heart rate, without negatively affecting other aspects of cardiac function. The choice of agent remains at the discretion of the physician.



Drug TrendsImportance of HbA1c assay in the diagnosis of diabetes mellitusReport from the 11th CDE Postgraduate Forum in Diabetes Management, held in Johannesburg from 7–10 August 2009

T he publication in June 2009 of an article on this subject

– representing a consensus opinion by European and American experts – potentially represents a major paradigm shift away from the reliance on only blood glucose meas-ures for a diagnosis of diabetes mellitus. Speaking at the 11th Centre for Diabetes and Endo-crinology (CdE) Postgraduate Forum in Diabetes Manage-ment, held in Johannesburg in August, durban-based endo-crinologist Dr Aslam Amod appraised this expert opinion, but found it lacking in some respects.

Tracing the history of diabe-tes diagnosis, he cited several milestones, starting with the National Diabetes Data Group (NddG) criteria in 1979, which formalised diagnosis by means of blood glucose levels in the general population, and criteria based on population statistics and the likelihood of decom-pensation to diabetes.

In 1997, the American dia-betes Association (ADA) and the World health Organisation (WhO) focused attention on the relationship between blood glucose levels and long-term complications of diabetes. Evi-dence that diabetic retinopathy increased linearly relative to increased fasting plasma glu-cose (FPG) levels, two-hour glu-cose readings and hbA1c levels, caused an increased focus on the latter’s utility in the context of diabetes diagnosis.

The hbA1c assay’s cause was

helped by the fact that FPG and the oral glucose tolerance test (OGTT) are discordant and don’t necessarily identify the same set of patients as having diabetes. The concordance rate is only 28%. The AdA opted to favour the former because it is faster, cheaper and more reproducible, while the WhO continued to regard the latter as the gold standard.

When the ADA lowered its definition of impaired FPG to make it more comparable with impaired glucose toler-ance (IGT), as assessed by the OGTT, it not only improved the concordance, but also inad-vertently increased the number of patients with impaired FPG but without impaired glucose tolerance (IGT), by 300%. The potential economic impact of this meant that the rest of the world did not follow the AdA’s lead in this regard.

HbA1c assay in diabetes managementAt present, the hbA1c assay is not used for diagnosis for a number of reasons, among them that the test is not yet internationally standardised and not globally available. ‘The new expert opinion starts by making the point that instru-ment bias misclassifies 12% of patients when it comes to blood glucose management’, said dr Amod, ‘which essen-tially implies that using blood glucose levels to diagnose dia-betes is bad’.

‘It then argues that diabetes is a chronic disease and that the hbA1c level is a more relia-ble guide to managing chronic hyperglycaemia. It is already used to guide treatment, so why not diagnosis? There is a strong correlation between hbA1c levels and complications. Standardisation and accuracy of the assays have improved greatly in recent years, and there is less biological vari-ability than with blood glucose measures. It is also unaffected by acute changes in blood glu-cose.’

‘When it came to appropri-ate cut-off points for diagno-sis, the panel chose specificity over sensitivity (on the basis that its use was being recom-mended for diagnosis and not for screening) and opted for ≥ 6.5%, given that values below this are associated with mini-mal clinical consequences.’

however, there are many limitations, including that the cost is higher, standardised assays are not universally avail-able and the fact that various conditions can interfere with readings, some of them spe-cific to certain populations.

Dr Amod is therefore con-cerned that while glucose measures are not being aban-doned for now, the intention is ultimately to phase out terms like ‘impaired glucose toler-ance’, ‘impaired fasting glu-cose’ and ‘pre-diabetes’. ‘The article states that those people with hbA1c levels ≥ 6.0% are at considerable risk for future

diabetes and require ‘effective interventions’, to be guided by the presence of other compo-nents of the metabolic syn-drome.

There is however no men-tion of whether hbA1c level will become a diagnostic criterion for the metabolic syndrome itself. There is also no evidence that proven interventions for IGT are applicable to individu-als with hbA1c values between 6.0 and 6.5%, yet the commit-tee recommends this without discussion.

Limitations of HbA1c as a diagnostic measure in SA: the need for an HbA1c committee to set standards‘From a South African view-point, it is easy to dismiss this opinion as not really applicable to us’, continued dr Amod. ‘We have little information on inter-ethnic variations in hbA1c levels, the impact of hIV/AIdS and antiretroviral treatments (which are known to have haematological effects), and the prevalence and effects of various types of anaemia. The article is also unclear on the dif-ference between diagnosis and screening. The hbA1c assay is recommended for the former, but not the latter. how does one distinguish (in a particu-lar individual) where screening ends and diagnosis begins?’

In summary, he feels that the level of evidence offered is not high, the discussion is



superficial, the article is repeti-tive, and the lack of data on Africans and Asians is a criti-cal shortcoming, especially in respect of its value locally. ‘In South Africa we are dealing with multiple racial groups, the prevalence of iron-deficiency anaemia and, in some sections of the community, a thalas-saemia trait that is high. The haematological effects of hIV/AIDS and antiretrovirals on hbA1c levels are unknown, and we do not know which of our many laboratories are offering UKPdS- and dCCT-standard-ised hbA1c measurements.’

Moreover, the prevalence of IGT in South Africa is high and we have proven interven-tions for this, which many practitioners are implement-ing. Patients with IGT would be denied treatment if we were to abandon the glucose toler-ance test in favour of the hbA1c assay, especially because the hbA1c assay and the glucose tolerance test are discordant in that they identify different sets of individuals at high cardio-vascular and diabetes risk.

‘My own recommendation is not to adopt it just yet. We need a local hbA1c committee to ensure national standardisa-tion and validation. For now, in the interests of holistic treat-

ment, we need to continue to encourage the simultaneous measurement of glucose and hbA1c levels’, he concluded.

Dishonest scales or defec-tive goods? Confounding factors in HbA1c assayCDE diabetes educator Michael Brown elaborated on some of the confounding factors that bedevil the hbA1c assay. ‘Over a 40-year period, the hbA1c assay has become an indispen-sable tool for the monitoring of glycaemic control. Its clinical use has continued to improve and it is well established as a long-term measure of glycae-mic control and the effective-ness of therapy and lifestyle interventions. But is it always honest?’

‘The interpretation of what is “normal” can be significantly impacted on by many factors, including differing laboratory results consequent on differ-ent analytical techniques, age of subject, and biological vari-ation between individuals. A “good hbA1c” does not reflect variability in blood glucose levels along with recent hyper- and hypoglycaemic episodes and may not correlate with quality of life.’

Brown pointed out that the

hbA1c assay assumes a stand-ard red cell-aging process and mix of haemoglobin subtypes. Quantitative and qualitative variation in haemoglobin will affect test results. Therefore, to interpret hbA1c results accu-rately, in-depth knowledge of an individual patient’s hae-matological status is required. ‘Patients with the same mean blood glucose values can have greatly differing hbA1c results’, he said. ‘We need to under-stand the impact of these varying factors along with the clinical consequences of false results.’

Broadly speaking, ‘false lows’ can lead to under-treat-ment, with negative impacts on disease management. The over-treatment consequent on ‘false highs’ increases the risk of hypoglycaemia.

Accurate hbA1c measure-ment depends on factors such as red cell survival and turno-ver, glucose concentration and total haemoglobin composi-tion. While intra-individual variation is small, there is sig-nificant variation between dif-ferent individuals, and widely differing rates of red cell sur-vival can still be deemed ‘hae-matologically normal’. ‘Factors affecting red cell survival can therefore produce false hbA1c

results. These include the pres-ence of haemolytic anaemia, chronic malaria, major blood loss, renal and liver disease and blood transfusions.’

haemoglobinopathies, of which there are many variants, can produce false lows and their presence should immedi-ately lead one to suspect prob-lem hbA1c readings. Excessive intake of vitamins C and E are also associated with false lows, possibly because of their inhibition of the glycolation of haemoglobin.

Some of the factors impli-cated in false highs include the following: alcoholism, lead poisoning, opiate addiction, iron-deficiency anaemia, hyper-triglyceridaemia, hyperbilirubin- aemia, pregnancy, vitamin B12 or folate deficiency, and exces-sive use of salicylates.

Awareness of all the above can prompt clinicians to look for problems. Findings derived from careful history taking can then be confirmed in labora-tory tests.

Brown concluded by under-scoring that while hbA1c is a good clinical indicator of gly-caemic control, ‘it may not always reflect true glycaemic status. It is therefore not the only parameter we should be concerned about.’

16th Biennial Congress of the Southern African Hypertension Society

Recent Advances in Hypertension

5 –7 February 2010

Linder Auditorium, University of the Witwatersrand, Johannesburg

For more information or to attend the congress, log on to the website www.hypertension.org.za or contact congress organiser Eileen Shaw on

Tel: (011) 795-3818; Fax: (011) 795-3073e-mail: [email protected]

Save these dates



Generic drug companies need to build brands and consider clinical researchG eneric companies must

stand out above their competitors (other generic companies) in order to capture market share.

‘The increasing competi-tion between generic com-panies has resulted in a move from generic companies to build their own pharmaceuti-cal brands’, noted Mr Rowan Joseph of Van Siedels Patent Attorneys, speaking at the recent Generics Medicine Con-gress held in Johannesburg in August. Also, to differentiate their products within a particu-lar environment, generic com-panies are considering doing clinical research to overcome medical practitioners’ concerns with regard to efficacy.

A South African example of a clinical research initiative by a generics company is that of Ranbaxy. The company was faced with doctors’ concerns as to the efficacy of their mod-ified-release generic antibiotic, based solely on the bioequiva-lence data. Their response was to participate in a prospective, comparative, investigator-blind trial of their modified-release generic clarithromycin (Klari-thran MR) and the origina-tor formulation (KLacid XL) in patients with acute commu-nity-acquired respiratory tract infections.

The study results,1 published in a Pubmed-cited journal, showed that the agents had similar clinical and bacterio-logical cure rates. There were no differences in tolerability in patients. All the adult patients were recruited in Gauteng in a typical community setting.

The reassurance derived from these study results show-ing that this drug was not infe-rior to the originator product

with regard to clinical cure rates and tolerability will cer-tainly assist in the marketing of this product in Southern Africa.

While this may not have been the primary intention, studies of this calibre will help to defuse the often-emotional debate around generic quality in terms of the known results of the originator medication.

Contrasting and integrating the originator and generic companiesAs generic medicines gain ground worldwide, the origi-nator pharmaceutical land-scape is changing. Key trends include generics entering the market much sooner after patent expiry than before – within six months to a year – with originator drugs losing up to 80% of their revenue as a consequence.

Also, the originator pipe-line of blockbuster drugs is declining in the face of esca-lating research and develop-ment costs and ever-tougher approval processes. ‘We can therefore expect a global decline in originator product sales’, Ettiene van heerden, senior manager, KPMG, sug-gested at the congress.

Van heerden cited Zocor (simvastatin) as an example of what happens when a drug comes off patent and is generi-cised. ‘Within the first week of a generic competitor enter-ing the market, Zocor’s sales dropped 14%. Within a year, generic versions were being prescribed 200 000 to 300 000 times more often. Origina-tor companies therefore face ongoing top-line pressure, as growth from their existing port-folios fails to keep pace with

loss of revenue to generics.’ As a result, pharmaceutical

companies are implementing cost-cutting measures, such as downsizing their sales forces and outsourcing their manu-facturing to countries where costs are lower, such as India and Brazil. ‘Notably, they are themselves entering the gener-ics market, and we’re seeing large-scale alliances with gener-ics manufacturers, such as that between GSK, dr Reddy’s Lab-oratories and Aspen, locally’, continued van heerden.

‘This is a global trend, with originator and generics com-panies becoming more and more integrated and the lines between them increasingly blurred.’ Other trends include originator pharmaceutical companies entering the bio-tech industry, revisiting pricing of products after patent expiry and focusing on specialist-driven markets.

The future looks bright for the generics market globally. ‘It is estimated that by 2012, the generics market in the USA will be worth $78 billion, rep-resenting a 65% growth rate from 2007. healthy growth is also evident in emerging mar-kets’, said van heerden.

he predicts that the origina-tor pharmaceutical company business model will become increasingly complex, with one of two models adopted:• the specialist model• the diversification model.The former entails a focus on a small number of specialised and complex areas. The latter favours a broad basket of prod-ucts, including patented drugs, generics and biotech products, serving both established and emerging markets. ‘The most successful companies are cur-

rently following one of these models’, said van heerden.

In South Africa, the generics market is expected to grow to R8.34 billion by 2012, repre-senting a growth rate just shy of 70% since 2008. ‘This com-pares well with other emerging markets’, van heerden under-scored. however, this projec-tion does not take into account factors such as price bench-marking and the proposed introduction of national health insurance (NhI), which will offer new opportunities to the whole pharmaceutical industry.

he feels that the pharma-ceutical industry was largely sheltered from the global economic crisis, both locally and internationally. however, higher operating costs have put bottom lines under pres-sure, leading to cost-cutting and re-engineering measures.

he raised a few important issues that need to be con-sidered in times like this. ‘The risk of fraud increases during tough economic times, and because this issue is often not high on a company’s agenda, it can catch one off-guard. Good internal controls are necessary to counter phenomena such as misappropriation of company assets and fraudulent financial reporting.’

It is also important to keep in mind the effect of current market conditions on distribu-tors, wholesalers, joint venture partners and other service pro-viders. ‘There is a tendency to focus on internal issues, rather than those beyond one’s immediate control. however, supply-chain failure is a major concern and contingency plans are necessary to counter this. Finally, working capital is a key consideration, as the strength



of one’s balance sheet impacts on service delivery during tough economic times.’

This environment increases the need for strong regulatory action from the State.

Generics: funders’ perspectivesdr Jonathan Broomberg, gen-eral manager of strategic risk management at Discovery health, told delegates at the congress that his company’s figures showed an increase in generics use in acute condi-tions from 40 to 47% from 2005 to 2008, with spend increasing from 20 to 30% across the same period. ‘It’s a good trend, driven by benefit designs and affordability con-cerns, but we still haven’t gone far enough when you consider cost pressures and government initiatives such as NhI. Other markets have achieved much

higher generics usage, so why not us?’

By way of answers, he mentioned entrenched resist-ance and negative attitudes towards generics on the part of doctors. Another issue is that relative to global trends, the pricing of generics in South Africa is still too close to that of the branded products. ‘These narrow price gaps disincentiv-ise both doctors and patients from switching’, he said, ‘and funders are not in a position to force the issue against their wishes’.

he feels that much greater awareness is needed and that, to date, industry initiatives in this regard are lacking. ‘Why isn’t the industry standing up? Where is a public relations and public awareness campaign, necessary to allay concerns and misperceptions around the efficacy of generics, while

at the same time making the savings known?’

Wimpie du Plessis, CEO of MediKredit Integrated health-care Solutions, observed that MediKredit too has seen a dramatic increase in the use of generics, and that this use is growing constantly. She echoed Broomberg’s call for more doctor and patient edu-cation to counter resistance to generics. ‘Patients need to be aware that generics contain the same active ingredients as the original research and develop-ment products, and are in no way inferior.’

du Plessis also supports the concept of reference pricing to ensure cost-effective com-petition. ‘Most importantly, it allows for choice and flex-ibility and can passively influ-ence those prescribers who are resistant to using formularies.’

‘Part of the resistance to

generics is associated with doctors and patients feeling that they’re being dictated to. Reference pricing gives them the choice – but with a finan-cial consequence. The onus is then on doctor and patient to decide whether to go with a generic, which will be funded in full by the scheme, or the branded drug, which will require a co-payment from the patient. Reference pricing therefore also ensures an envi-ronment in which both types of drug company – ethical and generic – can compete.’

1. Snyman JR, Schoeman hS, Grobusch MP, henning M, et al. Generic versus non-generic formulation of extended-release clarithromycin in patients with community-acquired respiratory tract infections. A prospective, randomized, comparative, investigator-blind, multicentre study. Clin Drug Invest 2009; 29(4): 265–274.

Primary prevention using losartan in type 1 diabetic patients significantly reduces retinopathyT his five-year RASS study

on the effect of blockade of the renin-angiotensin system with an ACE inhibitor (enalapril) or an ARB (losar-tan) was not able to show that primary prevention protects kidney function in normoten-sive, normo-albuminuric type 1 diabetic patients.1 This therapy did however achieve significant beneficial effects on diabetic retinopathy.

In the study, treatment with enalapril and losartan were both associated with a reduc-tion in the progression of dia-betic retinopathy by two or three steps or more. This rep-resents, compared to placebo, an approximate 65% reduction with enalapril and 70% reduc-tion of progression of retinopa-

thy with losartan, independent of adjustments for blood pres-sure changes over the five-year period. These reductions, which were unrelated to gly-caemia, might be partially derived from blood pressure lowering, together with the direct effects of blockage of the retinal renin-angiotensin system.

Earlier trials2,3 have shown less progression of diabetic retinopathy in patients with type 2 diabetes who were sub-jected to tight blood pressure control, independent of the use of an ACE inhibitor.

The severity of diabetic retinopathy at baseline in the normotensive RASS patients correlated with the nighttime systolic blood pressure.4

Although the benefit with regard to diabetic retinopathy remained after adjustment for the lower blood pressures recorded during the study in the enalapril and losartan groups, compared to the pla-cebo group, the authors noted that they could not rule out some beneficial effect of blood pressure control on the dia-betic retinopathy outcomes.

The lack of a reliable predic-tor/marker of which patients in this group who did not have clinically detected renal dis-ease at baseline would be at an increased risk of develop-ing nephropathy, reduced the statistical power of the study. This is an arena that requires further research.

Markers of nephropathy

that were used in the study included mesangial frac-tional volume per glomeru-lus, albuminuria, or reduction of glomerular filtration rate. There was a suggestive trend of enalapril reducing progres-sion of mesangial fractional volume by 0.026 units, while losartan reduced this param-eter by 0.005 units.

1. Mauer M, Zinman B, Gardiner R, et al. N Engl J Med 2009; 361: 40–51.

2. Matthews dR, Stratton IM, Aldington SJ, holman RR, Kohner EM. Arch Ophthalmol 2004; 122: 1631–1640.

3. Schrier RW, Estacio RO, Esler A, Mehler P. Kidney Int 2002; 61: 1086–1097.

4. Klein R, Moss E, Sinaiko AR, et al. Ophthalmology 2006; 113: 2231–2236.

SA JOURNAL OF DIABETES & VASCULAR DISEASE DIABETES NEWS


Novo Nordisk meeting

Delegates: Thiloshinie Moodley and Debbie Claassen.

The Novo Nordisk meeting was well attended and focused on exchanging practical experiences in managing diabetes patients.

Lorraine Makhubela, Anelda Moore (Novonordisk), dr Larry distiller and Mr Peter Black (CEO of the CdE diabetes programme) at the registration desk.

Anelda Moore, Zella Young, Cornel Joubert (Potchestroom), Petro Waanders, dr Nelly Silvis (hatfield, Pretoria), dr Adri Kok and Sr Martie Janneke.

delegates: Marilize Jacobs, Rona van Tonder and dr hilton Kaplan.

In serious discussion, dr Nicholas Bernard (Paarl), Sr Maureen Barnard (George) and Rosemary Flynn (CDE).

Gretchen Karin van Wyngaard and Dr Janie van den Berg.

DIABETES NEWS SA JOURNAL OF DIABETES & VASCULAR DISEASE


Lifescan supported the Novo Nordisk meeting. From left: dumisile Kubeka, Bellina Mkhulisi, Sr Sesi Mukwevho and Sipho Radebe.

Diabetes newsSecondary stroke prevention in diabetic patients

T high-length graduated compression stockings (TL-

GCS) do not reduce the risk of blood clots in stroke patients (the CLOTS study included dia-betic patients). Since guidelines in the UK and many developed nations recommend the use of TL-GCS, such guidelines should now be urgently revised.

The findings of the CLOTS trial, written by Prof Martin dennis, University of Edin-burgh, UK and colleagues, were first published in an arti-cle online and now in a recent issue of the Lancet. Most of the study’s funding came from the UK Medical Research Council. The findings were announced during the 2009 European Stroke Conference, in Stock-holm, Sweden.

About two-thirds of stroke patients are unable to walk on admission to hospital, and between 10 and 20% of these will develop a blood clot in the veins of their legs – deep vein thrombosis (dVT). In some, this blood clot will break up and be carried in the blood stream to the heart and lungs. These life-threatening clots (called

pulmonary emboli) can cause severe breathlessness and are an important cause of death among hospitalised patients.

To date, only small trials have reported that TL-GCS reduce the risk of DVT in patients having surgery, but national stroke guidelines recommend their use in patients despite this inadequate evidence.

This randomised, controlled trial analysed 2 518 patients, 15% of whom were diabetic patients,1 from 64 centres in the UK, Italy and Australia. They were admitted to hospital within one week of an acute stroke and were immobile.

Patients received rou-tine care plus TL-GCS (1 256 patients), or routine care only (1 262). Each was then given an ultrasound of both legs at seven to 10 days and again at 25 to 30 days after enroll-ment. The primary outcome was occurrence of DVT in the thigh.

The researchers found that dVT occurred in 10.0% of patients in the TL-GCS group, and 10.5% of patients in the routine-care only group. The

difference was not statistically significant. Furthermore, skin breaks, ulcers, blisters and skin tissue death were significantly more common in patients given TL-GCS than in those given routine care only (5 vs 1%).

Referring to the UK exam-ple, dr dennis says that draft guidelines, out for public con-sultation from the National Institute for health and Clinical Excellence (NICE), recommend that stroke patients should be treated with compression stockings. he says: ‘we can estimate that 80 000 patients with stroke in the UK – about two-thirds of all admissions to hospital with acute stroke – would be treated with stockings if this guideline is followed. Therefore the results of the CLOTS trial 1 will have a major effect on the manage-ment of patients. Given that most national guidelines rec-ommend stockings in at least some patients, the results of

our study will affect the treat-ment of millions of patients each year. Abandoning this ineffective and sometimes uncomfortable treatment will free up significant health resources – both funding and nurse time – which might be better used to help stroke patients.’

he concludes: ‘compression stockings are used in the major-ity of stroke units. In this study, we have shown conclusively that compression stockings do not work for stroke patients. National guidelines need to be revised and we need further research to establish effective treatment in this important group of patients.’

1. The CLOTS trials collaboration. Effectiveness of thigh-length graduated compression stock-ings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre randomised controlled trial. Lancet 2009; 373(9679):1958–1965.

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SAJDVD Volume 6, Issue 3

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Transcript of SAJDVD Volume 6, Issue 3