SAJDVD Vol 10 no 3

SAJDVD

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

The South African Journal of Diabetes & Vascular Disease

September 2013

Volume 10 Number 3

Featured in this issue: The diet for patients with type 2 diabetes The diet and polycystic ovarian syndrome Diabetes and cardiometabolic disease with polycystic ovary syndrome Intermittent fasting for prevention of diabetes and cardiovascular disease Tolerability and safety of DPP-4 inhibitors Burnout among healthcare workers

Reviews

Ethics Focus

Achieving Best Practice

Diabetes Educator’s Focus

News

ISSN 1811-6515

THE SOUTH AFRICAN JOURNAL OF HYPE

RINSULINAEMIA

Diabetes & vascular disease VOLUME 10 NUMBER 3 • SEPTMBER 2013 www.diabetesjournal.co.za

Corresponding Editor Dr L Lombard Netcare, Kuilsriver Hospital, Cape Town Consulting Editor PROF J-C MBANYA DR F MAHOMED National Editorial Board DR A AMOD Centre for Diabetes, Endocrinology and Metabolic Diseases, Life Healthcare, Chatsmed Gardens Hospital, Durban SR K BECKERT Diabetes Nurse, Paarl

CONTENTS

Editorial

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The diet – central in the treatment of diabetes and polycystic ovarian syndrome

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

L Lombard

PROF R DELPORT Department of Family Medicine, University of Pretoria

Research Article

DR L DISTILLER Director of the Centre of Diabetes and Endocrinology, Houghton, Johannesburg

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The tolerability and safety of DPP-4 inhibitors for the treatment of older people with type 2 diabetes mellitus: an observational study.

DR F MAHOMED Department of Endocrinology, Grey’s Hospital, Pietermaritzburg PROF WF MOLLENTZE Head of Department of Internal Medicine, University of the Free State, Bloemfontein PROF CD POTGIETER Specialist Nephrologist, University of Pretoria and Jakaranda Hospital, Pretoria PROF K SLIWA Associate Professor of Medicine and Cardiology, Baragwanath Hospital, University of the Witwatersrand, Johannesburg PROF YK SEEDAT Emeritus Professor of Medicine and Honorary Research Associate, University of Natal, Durban

A Viljoen, CL Meek, R Gadsby, S Viljoen, H Langerman, AJ Sinclair

Reviews

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Is there an optimal diet for patients with type 2 diabetes? Yes, the one that works for them!

JD Krebs, A Parry-Strong

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JA Tomlinson, JH Pinkney, P Evans, A Millward, E Stenhouse

100

International Editorial Board PROF IW CAMPBELL Physician, Victoria Hospital, Kircaldy, Scotland, UK PROF PJ GRANT Professor of Medicine and head of Academic Unit of Molecular Vascular Medicine, Faculty of Medicine and Health, University of Leeds; honorary consultant physician, United Leeds Teaching Hospitals NHS Trust, UK PROF J-C MBANYA Professor of Endocrinology, Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Cameroon and President, International Diabetes Federation PROF N POULTER Professor of Preventive Cardiovascular Medicine, Imperial College, School of Medicine, London, UK DR H PURCELL Senior Research Fellow in Cardiology, Royal Brompton National Heart and

Screening for diabetes and cardiometabolic disease in women with polycystic ovary syndrome Intermittent fasting: a dietary intervention for prevention of diabetes and cardiovascular disease?

JE Brown, M Mosley, S Aldred

Diabetes Educator’s Focus

103

Burnout: a critical problem among healthcare workers P Wagenaar

Patient Information Leaflet

105

Making good nutritional choices

Reports

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ADA Watch, 2013 update from Chicago, USA G Hardy

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EASD Watch, 2013 update from Barcelona, Spain

Managing Editor: GLENDA HARDY TEL: 021 976 8129 CELL: 071 819 6425 FAX: 086 610 3395 e-mail: glenda@clinicscardive.com Production Editor SHAUNA GERMISHUIZEN TEL: 021 785 7178 FAX: 086 628 1197 e-mail: shauna@clinicscardive.com Financial & Production Co-ordinator ELSABÉ BURMEISTER TEL: 021 976 8129 CELL: 082 775 6808 FAX: 086 664 4202 e-mail: elsabe@clinicscardive.com

Drug Trends

Content Manager MICHAEL MEADON (Design Connection) TEL: 021 976 8129 FAX: 086 655 7149 e-mail: michael@clinicscardive.com

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Novo Nordisk Incretin and Cardiovascular summit

Gauteng Contributor PETER WAGENAAR CELL: 082 413 9954 e-mail: skylark65@myconnection.co.za

G Hardy

Page 103

P Wagenaar

Layout RYKIM TEL: 021 715 2449 e-mail: rykim@mweb.co.za

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

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Articles in this Journal are sourced as per agreement with the British Journal of Diabetes and Vascular Disease All correspondence to be directed to: THE EDITOR PO BOX 1013 DURBANVILLE 7551 or info@clinicscardive.com TEL: 021 976 8129 FAX: 086 664 4202 INT: +27 (0)21 976-8129 To subscribe to the journal or change address, email elsabe@clinicscardive.com Full text articles available on: www.diabetesjournal.co.za via www.sabinet.co.za

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The opinions, data and statements that appear in any articles published in this journal are those of the contributors.

The publisher, editors and members of the editorial board do not necessarily share the views expressed herein.

Although every effort is made to ensure accuracy and avoid mistakes, no liability on the part of the publisher, editors, the editorial board or their agents or employees is accepted for the consequences of any inaccurate or misleading information.

SA JOURNAL OF DIABETES & VASCULAR DISEASE

EDITORIAL

The diet – central in the treatment of diabetes and polycystic ovarian syndrome LANDI LOMBARD

T

he diet is a topic discussed and written about extensively.

It plays a pivotal role in the management of diabetes, both type 1 and type 2, as well as in polycystic ovarian syndrome (PCOS). PCOS can be seen as a major risk factor and probably a marker of future risk for the development of diabetes.

Unfortunately, patients often don’t cope well with our dietary recommendations, which probably contributes more to poor control than any other aspect of diabetes. It is also well recognised that a drastic improvement in diet can improve diabetes control in type 2 diabetes (as measured by plasma HbA1c level) more than any medication, only rivaled by insulin.

Patients are however particularly lax in complying with their diets, especially over time, contributing to progressive worsening of glycaemic control. Many diabetics have been admitted to metabolic units with very poor HbA1c levels, and yet they had perfect control documented in hospital on unchanged regimes. The problem – the diet at home!

Unfortunately, studying diet in official studies is very difficult. It is surprising how weak the evidence is on which we base the most important component of our treatment.

In recent years there has been a movement towards higher protein diets, which in the short term led to better weight control and compliance. This was often driven by people outside the diabetes field and in South Africa; the example of Prof Tim Noakes jumps to mind. In PCOS the diet should probably be similar to that of a diabetic, except that weight loss is even more important and it has been well documented to reverse this syndrome.

It makes sense for diabetics to restrict their carbohydrate intake as this can contribute to improvement in glycaemic control. Recently published studies confirm this, showing that diabetes can be cured through a strict diet (very low calorie diet) in a significant percentage of patients. It was unfortunate that the Look AHEAD study could not show cardiovascular benefit with lifestyle intervention.

In this issue, Krebs and colleagues discuss different diets and the available data in diabetes. They try to answer the question: What is the optimal diet for a diabetic?

Tomlinsen and co-workers present an informative article on the cardiometabolic risk of PCOS and how screening for this risk should be assessed. This common condition is under-diagnosed and therefore practitioners also miss the associated cardiovascular risk.

Viljoen et al. discuss the safety and efficacy of DPP-4 inhibitor use in the elderly. The DPP-4 inhibitors are currently topical and underused in South Africa, largely due to funder restrictions.

References 1. Iris Shai RD. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet.

New Engl J Med 2008; 359(3): 229–341.

2. The Look AHEAD research group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369: 145–154.

3. Lim EL, Hollingsworth KG, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol.

Diabetologia 2011; 54(10): 2506–2514.

Correspondence to: Dr Landi Lombard Netcare Kuils River Hospital, Cape Town Tel: +27 0(21) 900-6350 e-mail: lclombard@mweb.co.za S Afr J Diabetes Vasc Dis 2013; 10: 83

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RESEARCH ARTICLE

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The tolerability and safety of DPP-4 inhibitors for the treatment of older people with type 2 diabetes mellitus: an observational study Adie Viljoen, Claire L Meek, Roger Gadsby, Sumarie Viljoen, Haya Langerman, Alan J Sinclair Abstract Aims/introduction: Despite type 2 diabetes mellitus being up to five times more prevalent in patients aged ≥ 65 years compared with patients < 65 years of age, this population is surprisingly less well studied. Dipeptidyl peptidase (DPP)-4 inhibitor treatment is an option for this older patient group, but clinical practice data for this drug class are sparse in this population. The study examined the efficacy and tolerability of DPP-4 inhibitors in older patients with type 2 diabetes whilst focusing on particular pertinent aspects relevant to care of older persons.

Materials and methods: The medical records of 431 randomly selected patients (median age 74 years) were reviewed and two cohorts (DPP-4-inhibitor-treated and non-DPP-4-inhibitortreated) were compared.

Results: Both groups had a similar duration of diabetes (8 years) and comparable glycated haemoglobin A1C concentrations (7.4% and 7.2%). Hypoglycaemia was less common in the DPP-4 inhibitor group (3%) compared with the medically treated non-DPP-4 inhibitor group (8%), p < 0.02. Despite significantly more patients in the non-DPP-4 inhibitor group living in cared accommodation (9 vs 2%) this group received significantly more insulin (30 vs 7%) Conclusion: Clinicians need to consider the specific clinical issues relevant to older diabetic patients when taking complex treatment decisions.

Keywords: diabetes in elderly, dipeptidylpeptidase, DPP-4 inhibitors, hypoglycaemia Correspondence to: Dr Adie Viljoen Institute of Diabetes for Older People, University of Bedford, Putteridge Bury Campus, Luton, and Department of Chemical Pathology, Lister Hospital, Stevenope, UK email: adie.viljoen@nhs.net Claire L Meek Department of Chemical Pathology, Lister Hospital, Stevenope, UK Roger Gadsby Institute of Clinical Education, Medical School Building, University of Norwick, UK. Institute of Diabetes for Older People, University of Bedford, Putteridge Bury Campus, Luton, UK. Sumarie Viljoen and Alan J Sinclair Institute of Diabetes for Older People, University of Bedford, Putteridge Bury Campus, Luton, UK. Haya Langerman Institute of Diabetes for Older People, University of Bedford, Putteridge Bury Campus, Luton, UK. Originally in: Br J Diabetes Vasc Dis 2013; 13(4): 187–191.

S Afr J Diabetes Vasc Dis 2013; 10: 84–87

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Abbreviations: ADA American Diabetes Association EASD European Association for the Study of Diabetes DPP dipeptidylpeptidase eGFR estimated glomerular filtration rate GLP-1 glucagon like polypeptide HbA1c glycated haemoglobin NHS National Health Service MDRD Modification of Diet in Renal Disease NICE National Institute for Health and Care Excellence

Introduction Diabetes is up to five times more prevalent in patients aged 65 years or older than in patients below the age of 65.1 Indeed up to one in five older people have diabetes and a similar proportion may have undiagnosed diabetes.2 It has been clearly demonstrated that medical intervention which lowers blood glucose can lower the risk of future complications, most notably, microvascular complications.3 The side effects of glucose lowering treatments include weight gain and hypoglycaemia with sulphonylureas and insulin, increased of risk of fractures, congestive heart failure, weight gain and increased risk of bladder cancer with pioglitazone and gastrointestinal side effects related to acarbose and metformin. The newer drug classes acting on the GLP-1 axis namely DPP-4 inhibitors (gliptins) and GLP-1 analogues have had fewer years of post-marketing surveillance and fewer patients taking these medications have been studied in both clinical trials and in clinical practice compared with insulin, metformin, sulphonylureas and pioglitazone. Their safety with respect to their potential link to pancreatitis and pancreatic cancer remains under scrutiny.4 These medications do however have advantages in terms of weight management, namely weight neutrality (DPP-4 inhibitors) and weight reduction (GLP-1 analogues), and a lower risk of hypoglycaemia when compared with insulin and sulphonylureas.

DPP-4 inhibitors can be taken orally whereas GLP-1 analogues require injection. DPP-4 inhibitors are generally well tolerated whereas GLP-1 analogues are associated with nausea and vomiting (especially in the first few weeks of treatment) but DPP-4 inhibitors are less efficacious in terms of HbA1C reduction than GLP-1 analogues.

As highlighted by the NICE guidelines for type 2 diabetes,5 the risk of hypoglycaemia is of particular concern in the older population. Older patients are at higher risk of hypoglycaemia, whose symptoms may be mistaken for other conditions associated more commonly with advanced age. In addition, older patients often require more support with their diabetes management than younger patients and more commonly suffer from other

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co-morbidities, such as renal impairment, which may increase their susceptibility to hypoglycaemia.6 The higher risk of hypoglycaemia associated with sulphonylureas (when compared with non-insulin therapies) may limit their overall clinical utility in this group. They do however offer a cheaper treatment per unit price. DPP-4 inhibitors have some characteristics which may be of particular value in older patients. They can be taken orally, as opposed to insulin or GLP-1 analogues, and they are comparatively well tolerated. Indeed, the most recent ADA-EASD position statement specifically lists their advantage as rarely having severe side effects as opposed to the other treatment options.7 We set out to study the DPP-4 inhibitor class in the clinical practice setting due to the paucity of data for this class and population.

Aim The aim of the study was to examine the efficacy and tolerability of DPP-4 inhibitors in older patients with type 2 diabetes mellitus whilst focusing on particular pertinent aspects relevant to care of older persons. Patients who had received treatment with DPP-4 inhibitors were compared with a control group of patients with type 2 diabetes mellitus who had never been treated with DPP-4 inhibitors.

Methods Patients with a diagnosis of type 2 diabetes mellitus over 60 years of age were randomly selected from primary and secondary care settings in England (in the counties of Warwickshire, Hertfordshire, Bedfordshire, Cambridgeshire, Suffolk and Greater London). This included nine separate GP practices and three NHS Trust Hospitals.

This study was approved as an audit by the regional ethics committee. The investigators liaised with the relevant Caldicott guardians in primary care and the audit departments of hospitals to gain authorised access to the data. Encrypted data storage devices were used to protect data during data transfer and analysis of results. Data were collected by reviewing the electronic medical records, clinical hospital notes and laboratory results. For blood results to be included in the study, the patient had to have received three months’ continuous treatment with the medication before the test was performed. Statistical analysis was performed using Microsoft Excel (Microsoft, Reading, UK) and SPSS software (IBM, Middlesex, UK).

Categorical variables were described using number and percentage and analysed for significance using Pearson’s chisquared (χ2) test. Continuous variables were described using medians and ranges, and were analysed for significance using the Mann-Whitney U test (two tailed), for non-parametric variables.

Chronic kidney disease was defined as an eGFR < 60 ml/min as calculated according to the MDRD equation.8 Hypoglycaemia was recorded when this was documented in the clinical patient records.

Mild hypoglycaemia was defined as hypoglycaemia documented in the medical records which did not require additional support.

Severe hypoglycaemia was defined as when subjects required assistance to recover (e.g. ambulance call-out, hospitalisation, supporter/relative assistance to aid recovery).

Results The analysed data-set included 431 randomly selected patients with 129 patients in the DPP-4 group and 302 in the control group (i.e. never treated with DPP-4 inhibitors). Demographic and

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Table 1. Demographic and cardiovascular factor risk data.

DPP-4 treated group (n = 129)

Control group (n = 302)

p-value for comparison

Age (median, range)

70 (60–92)

77 (60–95)

< 0.001

Male

82 (64%)

165 (54%)

NS

Treated primary care

104 (81%)

243 (81%)

NA

Body mass index (kg/m2)

29

30

NS

9 (7%) 58 (45%) 146 (48%)

15 (5%) 67 (48%) 141 (47%)

Blood pressure (mmHg)

130/72

131/75

NS

Total cholesterol (mmol/l)

3.8

3.8

NS

LDL-cholesterol (mmol/l)

2.0

1.8

NS

HbA1C (%) (median, range)

7.4 (5.7–10.3)

7.2 (5.1–12.6)

NS

Duration diabetes (years)

8

8

NS

CKD (eGFR < 60 ml/ min)

25 (20%)

100 (33%)

0.004

Microalbuminuria

11 (9%)

27 (9%)

NS

Retinopathy

36 (28%)

61 (20%)

NS

Neuropathy

18 (14%)

95 (31%)

< 0.001

Ischaemic heart disease

28 (21%)

88 (29%)

NS

Stroke

10 (8%)

33 (10%)

NS

Peripheral arterial disease

5 (4%)

23 (8%)

NS

Smoking status: • Current • Ex-smokers • Never

NS

CKD: chronic kidney disease; DPP: dipeptidylpeptidase; eGFR: estimated glomerular filtration rate; HbA1c: glycated haemoglobin; LDL: low-density lipoprotein cholesterol; NA: not applicable; NS: not significant, p values >0.05.

cardiovascular risk factor data are shown in Table 1. The median age (range) for the DPP-4 inhibitors group was 70 (60–92) years compared with 77 years (60–95) years (p < 0.001). All other parameters did not differ significantly.

Statistically significant diabetic complication rates in DPP-4 inhibitors vs. control were 14% vs. 31% for neuropathy (p < 0.001); 20 vs 33% for chronic kidney disease (p = 0.004).

The respective treatments (shown in Table 2) in the DPP-4 inhibitors and control groups were diet control only 0 vs 24%; metformin 88 vs. 47% (p < 0.001); sulphonylurea 53 vs 25% (p < 0.001); insulin 7 vs 30% (p < 0.001); and for pioglitazone 17 vs 6% (p < 0.001).

No severe hypoglycaemic events were recorded (i.e. there was no specific mention of these events in the clinical notes as defined). Mild hypoglycaemia in DPP-4 inhibitors versus control (defined as health care professional documented hypoglycaemia in the patient clinical records) was 3 vs 8% (p = 0.062) and no patients required admission in the last year as a consequence of hypoglycaemia. The incidence of hypoglycaemia and risk factors for developing hypoglycaemia are shown in Table 3. In the DPP-4 inhibitors group the 4 out of

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Table 2. Comparison of glucose lowering treatments.

Glucose-lowering medication

DPP-4 treated Group (n =129)

Control group (n = 302)

p-value for comparison

Metformin

113 (88%)

142 (47%)

< 0.001

Sulphonylurea

69 (53%)

75 (25%)

< 0.001

GLP-1 analogue

3 (2%)

9 (3%)

NS

Pioglitazone

22 (17%)

17 (6%)

< 0.001

Short-acting insulin secretagogues

1 (1%)

1(<1%)

NA

Acarbose

2 (2%)

0 (0%)

NA

Insulin

9 (7%)

91 (30%)

< 0.001

DPP-4 inhibitor

129 (100%)

0 (0%)

NA

Monotherapy

3 (2%)

2 (1%)

NS

Dual therapy

44 (34%)

140 (46%)

0.019

Triple therapy

71 (55%)

68 (23%)

< 0.001

Four or more medications

11 (9%)

19 (6%)

NS

DPP: dipeptidylpeptidase; GLP: glucagon like peptide; NA: not applicable; NS: not significant, p > 0.05.

129 patients who experienced documented hypoglycaemic events were also on sulphonylurea treatment. In the control group, of the 24 patients who had documented hypoglycaemia in the past year, 17 patients were on insulin, 6 patients were on sulphonylurea treatment and one patient, who was on diet control only and who was not on any glucose lowering medication, experienced clinical symptoms of hypoglycaemia post-prandially which were subsequently documented as hypoglycaemia.

In the control group, for those patients who did received glucose lowering therapy (n = 229), documented hypoglycaemia in last year was 10% (n = 23) compared with the DPP-4 inhibitors group (p < 0.02). There was no report of pancreatitis or pancreatic cancer in either group.

Comparing the social support structures in the two groups, 9% of the patients in the DPP-4 inhibitors group lived alone compared with 11% in the control group. Significantly fewer people in the DPP-4 group lived in sheltered accommodation, residential home or care home than the control group, 2% vs. 9% respectively (p = 0.011).

The DPP-4 inhibitor group had a significantly lower (p = 0.013) incidence of dementia (3%) than the control group (10%).

With respect to the patients in the DPP-4 inhibitor group, 74.3% received sitagliptin, 21.8% vildagliptin and 3.9% received saxagliptin. The pre-treatment median (range) HbA1C was 8.3% (5.5–12.7) and the post-treatment HbA1C was 7.4% (5.7–10.3). For blood results to be included in the study, the patient had to have received three months of continuous treatment with the medication prior to the test being performed.

Discussion Treating older patients with type 2 diabetes remains a challenge.

Older patients often have multiple co-morbidities, are more prone to polypharmacy and more often require support in the administration of their medication than younger adults. As age and frailty are known risk factors for hypoglycaemia, the choice of treatment for these patients becomes more limited due to safety concerns.

DPP-4 inhibitors provide a potential attractive treatment option for

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older persons. However, despite its niche appeal, this drug class has not been as extensively studied as in both younger and older populations either. We are not aware of any specific data which assess their utility in this population in a clinical practice setting.

Our results showed that patients who had been prescribed DDP-4 inhibitors had evidence of improved glycaemic control following the initiation of treatment (median HbA1C improved from 8.3 to 7.4%). In addition, this group also had a lower rate of documented hypoglycaemia than the non-DPP-4 inhibitors treated group (3 vs 8%). We defined hypoglycaemia as an event which had occurred in the past year and which was documented in the patients’ medical records. This is likely an underestimate of the true incidence of hypoglycaemia in our cohort when compared with other reports,9 due to the potential reporting bias in our population and due to the limitations of the retrospective nature of our study.

It does however highlight the nature of hypoglycaemia reporting in current clinical practice.

A recent study which specifically observed older adults assessed the frequency and rates of hospitalisation after emergency department visits for adverse drug events. It reported that insulin and oral hypoglycaemic drugs were the second and fourth most common culprits leading to 14 and 11% of all admissions.10 Our study had a control group of individuals who were older and more likely to be treated with injectable treatments such as insulin. Moreover, more patients in this group lived alone or in a care setting and had a higher incidence of dementia and chronic kidney disease, all additional risk factors for hypoglycaemic events.

As clinicians have to weigh up the risks and benefits of treatments, these factors may require re-evaluation.

In those patients in the control group who were controlled by diet alone, 17 of the 72 (25%) had HbA1C concentrations > 6.5% and 10% had HbA1C concentrations > 7%. Whilst recognising that care needs to be individualised for patients, in particular for the elderly, a potential treatment gap was identified between patients who would otherwise be eligible for antidiabetic treatment and those that actually receive this treatment.

The limitations of this study need to be considered and these include the retrospective nature of data collection, the absence of specific data on the reasons for prescribing of particular drugs Table 3. Incidence of hypoglycaemia and risk factors for events.

DPP-4 treated group (n =129)

Control group (n = 302)

p-value for comparison

Documented hypoglycaemia (in the last year)

4 (3%)

24 (8%)

0.062

Hypoglycaemia requiring admission to hospital (in the last year)

0 (0%)

0 (0%)

NA

Lives alone

11 (9%)

32 (11%)

0.51

Lives in own home

126 (98%)

274 (91%)

NA

Lives in sheltered accommodation, residential home or care home

3 (2%)

28 (9%)

0.011

Dementia

4 (3%)

31 (10%)

0.013

NA: not applicable.

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as well as incomplete data on the durations of treatments. In addition, the consistency of hypoglycaemia reporting could not be verified due to the retrospective nature of our study. We do however believe that there were differences in reporting which we did not investigate further; for example, secondary care databases have specific prompting questions on hypoglycaemia as opposed to primary care reporting which does not include this facility. The other limitation is that the use of metformin, sulphonylureas and insulin were significantly different between the groups, which may influence our observations and broad conclusions. However, our findings are supported that these data depict real-life clinical prescribing patterns in both primary and secondary care. We specifically focused and reported on other aspects pertinent to care of older patients such as accommodation and support structures, and our data on HbA1C levels and other patient characteristics, risk factors and complications were well-documented. Our two cohorts had similar durations of diabetes, which reinforces our observations.

In the light of the recent ADA–EASD clinical guidelines for type 2 diabetes mellitus,7 and the European Diabetes Working Party for Older People position statement,2 where individualised treatment plans are emphasised, clinicians should consider the risks and benefits to the individual patient, ensuring optimal risk reduction whilst maximising patient safety.

Declaration of conflicting interest The author declares that there is no conflict of interest.

Funding This study was conducted with the support from an unrestricted educational grant from Merck Sharp and Dohme. A.V., R.G. and A.S. have received consultancy fees, speakers fees, travel support

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and/or are involved in clinical research trials sponsored by Astra Zeneca, Novo Nordisk, Sanofi Aventis, Eli Lilly, Takeda, Merck Sharp Dohme and Pfizer. C.L. is an employee of Merck Sharp and Dohme.

C.M. and S.V.. have no conflicts of interest.

References 1. Fagot-Campagna A, Bourdel-Marchasson I, Simon D. Burden of diabetes in an aging population: prevalence, incidence, mortality, characteristics and quality of care. Diabetes Metab 2005; 31: 5S35–52.

2. Sinclair A, Morley JE, Rodriguez-Mañas L et al. Diabetes mellitus in older people: position statement on behalf of the International Association of Gerontology and Geriatrics (IAGG), the European Diabetes Working Party for Older People (EDWPOP), and the International Task Force of Experts in Diabetes. J Am Med Dir Assoc 2012; 13: 497–502.

3. Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577–89.

4. Butler PC, Elashoff M, Elashoff R, Gale EA. A Critical Analysis of the Clinical Use of Incretin-Based Therapies: Are the GLP-1 therapies safe? Diabetes Care 2013; 36: 2118–25.

5. National Institute for Health and Clinical Excellence. Type 2 diabetes: newer agents. NICE CG87. London: Nice, 2009. http://www.nice.org.uk/nicemedia/ live/12165/ 44318/44318.pdf. Accessed July 2013.

6. Kirkman MS, Briscoe VJ, Clark N et al. Diabetes in older adults. Diabetes Care 2012; 35: 2650–64.

7. Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycemia in type 2 diabetes: A patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35:1354–79.

8. Levey AS, Coresh J, Greene T et al. Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Int Med 2006; 145: 247–54.

9. Donnelly LA, Morris AD, Frier BM et al. DARTS/MEMO Collaboration. Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study. Diabet Med 2005; 22: 749–55.

10. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011; 365: 2002–12.

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REVIEW

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Is there an optimal diet for patients with type 2 diabetes?

Yes, the one that works for them!

Jeremy D Krebs, Amber Parry-Strong Abstract Diet is fundamental in the aetiology and management of type 2 diabetes. The optimal diet remains unclear and the EASD and ADA have recently adopted increased flexibility with dietary composition, whilst maintaining a focus on reduced energy, reduced saturated fat and increased dietary fibre. This review draws three conclusions on the current evidence for three dietary approaches; high protein diets, very low carbohydrate diets and the Mediterranean diet, specifically for the management of weight, glycaemic control and cardiovascular risk in patients with type 2 diabetes. First, unless energy intake is reduced below energy expenditure over a sustained period of time, weight loss will not occur.

Second, weight loss achieved with any dietary approach over the long-term is modest, though compared with the natural history of weight gain in obesity is clinically important. Third, the evidence supports flexibility in dietary composition with no approach superior to another for weight loss, glycaemic control or cardiovascular risk management. Most importantly there is evidence that adherence to any given dietary approach is more important than the macronutrient prescription. So the best diet for those with type 2 diabetes is the one that works for them, and critically the one that they can maintain in the long term.

Keywords: Diabetes mellitus, type 2, randomised controlled trial, diet, carbohydrate-restricted, weight loss

Background Type 2 diabetes (T2DM) is a complex and multifactorial disease which is defined by abnormalities in circulating glucose concentrations, or more recently HbA1c, a measure of long term glycaemic burden.1 A family history of T2DM, obesity, sedentary lifestyle and dietary saturated fat are the key risk factors for the development of T2DM. The pathogenesis is still not completely understood despite decades of research. However, both abnormalities in insulin production and/ or release and impairment of insulin action are required before diabetes ensues.

Diet is fundamental in the aetiology and the management of T2DM. Energy intake is a critical component of energy balance and body weight. Specific dietary components are implicated in diabetes Correspondence to: Dr Jeremy Krebs Endocrine, Diabetes and Research Centre, Capital and Coast Health, Department of Medicine, University of Otago, Wellington, New Zealand. e-mail: jeremy.krebs@ccdhb.org.nz Originally in: Br J Diabetes Vasc Dis 2013; 13(2): 60–66 S Afr J Diabetes Vasc Dis 2013; 10: 88–92

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Abbreviations: ADA American CVD EASD

HC HP LC T2DM

Diabetes Association cardiovascular disease European Association for the Study of Diabetes High carbohydrate High protein Low carbohydrate Type 2 diabetes mellitus

pathogenesis and manipulation of these mooted as means to modify both weight and metabolic parameters. Thus whilst diet and lifestyle modification are the cornerstone of the management of type 2 diabetes, despite an enormous amount of research the optimal approach for this has not been defined. This is reflected in the dietary recommendations from the EASD and the ADA which have both recently adopted increased flexibility with dietary composition, whilst maintaining a focus on reduced energy, reduced saturated fat and increased dietary fibre.1,2 Furthermore achieving sustained changes in diet and lifestyle remain a significant challenge for patients and healthcare professional alike. This review will focus on what the current evidence is for three of the many dietary approaches (Table 1), specifically for the management of weight, glycaemic control and cardiovascular risk in patients with T2DM. Historic recommendations for diet and type 2 diabetes The earliest dietary treatment for T2DM, prior to the availability of antidiabetic agents, was to restrict carbohydrate in the hope of reducing the demand on endogenous insulin.3 Even in the 1970s Truswell et al. reported from a survey of clinics in the United Kingdom that 92% of overweight people with T2DM were prescribed a low carbohydrate diet.4 Around this time research groups were starting to experiment with high complex or unrefined carbohydrate diets that were lower in total fat, higher in polyunsaturated fats and included large quantities of fibre (up to 105 g per day).5–7 This type of diet, later known as the “high carbohydrate–low fat” diet, was shown to be as good as or better than a low carbohydrate Table 1. Typical macronutrient comparison of popular diets.

Diet

Carbohydrate (%TE)

Protein (%TE)

Fat (%TE)

High protein

40

30

30

Very low carbohydrate, high fat

10

40

50

High carbohydrate, High fibre

55

15

30

45–55

15

30–40

Mediterranean

Other

Fibre ≥ 30 g High fibre High MUFA

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diet for blood glucose control and had the added benefit of reducing total cholesterol with the fat manipulation. By the 1980s, a high carbohydrate high fibre diet had become the standard recommendation for T2DM.8 The comparison HC control diets in later studies examining the effect of the HP and low carbohydrate diets have aimed to be high in complex or unrefined carbohydrates, high fibre, and in some studies, also low glycaemic index.

The western population however continued to gain weight and the incidence of T2DM continued to rise. Therefore it was assumed that either a high carbohydrate–low fat approach did not work, or patients could not comply. Attention was turned to other dietary approaches that might be more favourable to patients. Studies then aimed to manipulate dietary fat intake9,10 or carbohydrate intake11,12 with varying degrees of success regarding both compliance and maintenance of weight loss. A more recent approach is to increase protein intake in both absolute amount and relative to fat and carbohydrate.

High-protein diets High protein diets (> 25% total energy) have attained popularity recently, as a less extreme dietary manipulation to aid weight loss, while maintaining glycaemic control and optimal cholesterol profiles, and appealing to patients for better compliance. Most high protein diets consist of around 40% carbohydrate, 30% protein and 30% fat. A high protein (HP) diet is hypothesised to be beneficial in facilitating weight loss due to increased satiety,13–19 diet induced thermogenesis, and in maintaining lean body mass relative to fat mass during weight loss.20–23 There is also a proposed benefit of HP diets reducing post-prandial glucose excursions compared with high carbohydrate diets.24,25 Weight loss To date seven studies have considered the effect of a high protein diet on weight loss in those with T2DM.26–32 Of these, only one study demonstrated a significantly greater weight loss for the HP group.31 The remaining studies observed no difference between diet groups, suggesting that total calorie restriction is more important than macronutrient manipulation. One study did observe a greater weight loss for a HP diet plus resistance training vs a conventional low fat diet plus resistance training, but in the non-exercising arms there was no difference in weight loss.32 Glycaemic control A study of subjects with hyperinsulinaemia, but without diabetes, suggested that protein may blunt the post-prandial glucose rise which in a person with diabetes may improve glucose handling and glycaemic control.33 The specific impact of a HP diet on glycaemic control in subjects with T2DM has generally been disappointing.26,27,29– 32,34 Most studies report no difference between HP and control diets in measures of glycaemia, despite greater weight loss in the HP group in one of these studies.26,27,29,31,32 In a very small and short study, Gannon et al used a cross over design to experiment with a 30% protein, 20% carbohydrate and 50% fat diet (n = 8). After five weeks on the HP diet, fasting glucose and glycosylated haemoglobin were significantly lower than after a HC diet.34 However the carbohydrate level was also lower and fat much higher than other studies making interpretation of which macronutrient manipulation was most important very difficult. In contrast, Sargrad et al. randomised 12 subjects with diabetes to an

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energy restricted HP or HC diet for eight weeks.30 No differences were observed in weight loss or energy intake between diets but significant decreases in HbA1c and fasting glucose concentrations occurred in the HC group only. The recently published DEWL trial is the largest and longest (n = 419 individuals over 2 years) randomised controlled trial published to date to explore this, and did not demonstrate any difference between a HP or a HC diets on either weight or glycaemic control.26 The strength of this study was that it was conducted in a “real world” setting with the large numbers and long duration, using resources that could be translated to typical clinical practice. However this was also a limitation, in that participants struggled to achieve protein intake targets and tended to drift back to habitual diets over time. This highlights the difficulty with any dietary approach over the long term in real clinical practice.

CVD risk factors Despite concerns, none of the HP studies in type 2 diabetes showed an overall detrimental effect of a high protein diet on lipids. Evangelista et al favoured the HP diet for better HDL results, dependant on the type of protein and fat encouraged by the study with a differential benefit for plant derived protein and fats over animal sources.31 This study also recorded a greater decrease in LDL on the HP diet.31 The most consistent results for the HP diet (in populations with and without diabetes) appear to be in the effect on triglycerides, with two of the studies in diabetes demonstrating a significantly greater decrease on the HP diet compared to the HC diet.31,35 High carbohydrate diets have been shown to increase plasma triglycerides however, so this effect is likely due to the reciprocal reduction in carbohydrate, rather than the increase in protein.36,37 There is no consistent effect of a HP diet on blood pressure in those with diabetes. Neither Evangelista, Krebs nor Larsen et al. reported an effect of diet on blood pressure.26,27,31 A larger decrease was noted for the HP group by Sargrad et al. with systolic BP decreasing by 10.5 mmHg and diastolic by 18 mmHg.30 This effect was independent of weight loss but seems remarkable for the 8-week duration of the study, in contrast to the long-term DEWL study with similar weight loss where blood pressure change was minimal and no different from a HC diet.26 The only data on long-term cardiovascular outcomes are from observational studies rather than randomised controlled trials, and in general populations rather than specifically those with type 2 diabetes. In a large Greek cohort study (subgroup of the European Prospective Investigation into Cancer and nutrition study EPIC) higher protein intake particularly if combined with low carbohydrate intake was associated with increased mortality.38 A similar association was observed in the Women’s Lifestyle and Health study, a 12-year observational follow up in Swedish women.39 This association is supported by evidence of worsening of regional blood flow on myocardial perfusion imaging in individuals after 12 months on a high protein diet.40 In contrast, in the Nurses’ Health Study, which controlled for age, smoking, total energy intake, type of fat and other coronary risk factors, higher protein intake was associated with lower relative risk of cardiovascular mortality.41 This is also supported in the Iowa Women’s Health Study where higher vegetable protein consumption was associated with reduced mortality compared with an energy equivalent amount of carbohydrate.42 Therefore whilst some observational studies raise concern about either high protein or low carbohydrate diets, they do not answer the question whether

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a person with diabetes prescribed an energy restricted high protein diet has an increased or decreased risk of cardiovascular mortality. A long-term randomised controlled trial, taking into account the type of carbohydrate, glycaemic load, source of protein and amount of fibre, is required to address this.

Very low-carbohydrate, high-fat diets There has been a resurgence in interest over the last decade on reducing carbohydrate intake. This stems to some extent from the perceived lack of effect of the low-fat high-carbohydrate approach.

However, it ignores that central to a high carbohydrate diet is a focus on dietary fibre and avoiding large amounts of refined carbohydrate, neither of which are achieved in most westernised diets. In the more extreme versions such as the “Atkins diet”, the aim of the very low-carbohydrate, high-fat diet is to reduce initial carbohydrate content to 20 g per day and thus induce ketosis.43 The theory follows that this allows an individual to use fat stores for energy instead of glucose. Variations in fat and protein content abound, but generally the aim is 10% from carbohydrate, and 50% or more from fat, with protein intake making the up the balance. The literature is complicated by inconsistent definitions of low carbohydrate diet, very low carbohydrate diet and inadequate reporting of actual intakes.

Weight loss Studies in those with diabetes are limited, with few over a duration longer than 12 weeks, but indicate potentially initial greater weight loss but no difference over the longer term.44 One non-randomised study comparing a ketogenic very low-carbohydrate diet with a low-calorie diet over 24 weeks did demonstrate greater weight loss, improvements in glycaemic control and lipid profile with the very low-carbohydrate approach.45 However no long-term or randomised controlled trials have demonstrated any superiority.46 It has been hypothesised that the generation of ketosis is central to facilitating weight loss with a low-carbohydrate diet, however this is not supported by Boden47 or Krebs et al.48 who showed that weight loss was directly related to the reduction of total energy intake achieved by removing one macronutrient from the diet without appreciable compensatory increase in actual fat or protein intake.

Glycaemic control Significantly restricting carbohydrate in the diet has profound effects on glucose metabolism. Several small and very short studies ranging from seven days to five weeks have variably demonstrated reduced glucose and insulin concentrations and improved glycaemic control.34,47,49,50 In short-term studies people with T2DM require less antidiabetic agents to control glucose levels and achieve improvements in HbA1c.45,46,48 In some studies these improvements are greater with a very low-carbohydrate diet compared with other approaches,51 but data are not consistent and there are no long term studies convincingly demonstrating any greater benefit. Davis et al. demonstrated similar modest weight loss but no significant improvement in glycaemic control in those with type 2 diabetes on a low-fat or low-carbohydrate diet after one year.52 In the longest very low-carbohydrate diet trial currently reported, a very low-carbohydrate diet achieved a –0.9% reduction in HbA1c at 2 years compared with –0.5% in a Mediterranean diet and –0.4 % in a low fat diet, however the difference between groups was not significant.53

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CVD risk factors One of the concerns raised about very low carbohydrate diets is the potential for increases in dietary saturated fat that may accompany the foods chosen as part of this diet, will adversely affect lipid profile. However this has not been generally observed when weight loss is achieved, though can be seen in isolated individuals who do not lose weight.48 Hussein et al. demonstrate significant reduction in triglycerides, total and LDL cholesterol and an increase in HDL cholesterol over 24 weeks.45 This global benefit is not observed in all trials with increases in HDL cholesterol being the most consistent observation.52 Blood pressure has been shown to be reduced more with very low carbohydrate diets compared with alternatives over 3 months, but no difference after 12 months.52 Once again the only data on long-term cardiovascular outcomes are from observational studies rather than randomised controlled trials. These are reciprocal analyses of the protein intake as described above.38,39,41 One study showed impairment of flowmediated dilatation, but improvements in other endothelial function markers, after 12 months on a very low-carbohydrate diet in overweight and obese patients, but this was not specifically in those with diabetes.54

The Mediterranean diet There is increasing interest in the Mediterranean diet in type 2 diabetes as results of studies such as PREDIMED become available.

The Mediterranean diet is characterised by replacing most red meat with fish and poultry, including wine in moderation and plenty of vegetables, legumes, grains, fruit, nuts and olive oil.55 Impressive evidence from the PREDIMED-Reus trial in diabetes prevention demonstrated a diabetes incidence of 10.1% (5.1–15.1%) in the diet plus olive oil group and 11.0% (5.9–16.1) in the diet plus nuts group compared to 17.9% (11.4–24.4%) in the control group.55 The EPIC-Interact project also demonstrated a positive effect, where high adherence to the Mediterranean diet was associated with a hazard ratio of 0.88 (0.79–0.97), compared with low adherence, in participants over 50 years of age.56 Weight loss There have only been two studies examining the use of a Mediterranean diet for weight loss in participants with type 2 diabetes.57,58 Both studies favoured the Mediterranean diet for greater weight loss but in one study the Mediterranean diet also had a reduced carbohydrate content which may have had a confounding effect.

Glycaemic control Two cross-sectional studies analysing adherence to a Mediterranean diet and Hba1c level have been conducted in Mediterranean populations. In the Campanian Postprandial Hyperglycemia Study (n = 901), high diet adherence was associated with significantly lower HbA1c and 2-hour post-meal glucose concentrations (difference: HbA1c 0.9%, CI 0.5–1.2%, p < 0.001; 2-hour glucose 2.2 mmol/l, 95% CI 0.8–2.9 mmol/l, p < 0.001).59 In the PREDIMED study (n = 262), while a trend toward an inverse relationship between diet adherence score and HbA1c was identified, it was not statistically significant.60 A small cross-over study (n = 27) compared 12 weeks on a Mediterranean diet (key foods provided) with 12 weeks on their usual diet. Compared with usual diet, the ad libitum Mediterranean diet resulted in a fall in HbA1c from 7.1% (6.5–7.7)

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to 6.8% (6.3–7.3) (p = 0.012).61 Finally, newly diagnosed patients were randomised to either a low-fat or a Mediterranean diet, and time to initiation of antidiabetic therapy measured. After four years significantly fewer in the Mediterranean diet group (44% c.f. 70%, p < 0.001) had needed to start antidiabetic therapy.58 Cardiovascular risk Positive results have also been reported for Mediterranean diets and cardiovascular risk.58,62 In the Melbourne Collaborative Study, participants of Greek or Italian heritage with diabetes were assessed for level of adherence to a Mediterranean diet and followed for a minimum of ten years.63 In that time the hazard ratios for CVD mortality per unit of Mediterranean diet score were 0.94 (95% CI 0.89–0.99) in men and 0.94 (95% CI 0.87–1.01) in women. The study found those with higher diet scores had higher intakes of MUFA, fibre, omega-3 fatty acids, fruit and vegetables and lower intakes of saturated fat. Improvements in endothelial function have also been demonstrated in a group with the metabolic syndrome in a study over 2 years of a Mediterranean diet.64

Conclusion There is an abundance of literature examining the effectiveness of various dietary interventions and approaches, including “fad diets”, for weight management and impact on metabolic and cardiovascular markers and outcomes in obese individuals with and without diabetes.3,65,66 This area is a minefield to interpret due to reciprocal changes in macronutrient composition, differences in degree of energy restriction, confounding with changes in physical activity, additional effects of behavioural change intervention, difficulty in accurately measuring dietary intake particularly over extended periods, and differences between highly controlled studies and free living studies to name a few of the challenges. Despite this three things are very clear. First, the simple truth of the first law of thermodynamics over-rides all of this discussion. Unless energy intake is reduced below energy expenditure over a sustained period of time, weight loss will not occur. Second, is that weight loss achieved with any dietary approach over the long-term is modest, though compared with the natural history of weight gain in obesity is clinically important. Third, that evidence supports flexibility in dietary composition with no single dietary approach superior to another. Most importantly there is evidence that adherence to any given dietary approach is more important than the macronutrient prescription.67 So the best diet for those with type 2 diabetes is the one that works for them, and most importantly the one that they can maintain in the long term.

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32. Wycherley TP, Noakes M, Clifton PM, et al. A high-protein diet with resistance exercise training improves weight loss and body composition in overweight and obese patients with type 2 diabetes. Diabetes Care 2010; 33:969–76.

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62. Elhayany A, Lustman A, Abel R, et al. A low carbohydrate Mediterranean diet improves cardiovascular risk factors and diabetes control among overweight patients with type 2 diabetes mellitus: a 1-year prospective randomized intervention study. Diabetes Obes Metab 2010; 12: 204–9.

63. Hodge AM, English DR, Itsiopoulos C, et al. Does a Mediterranean diet reduce the mortality risk associated with diabetes: evidence from the Melbourne Collaborative Cohort Study. Nutr Metab Cardiovasc Dis 2011; 21: 733–9.

64. Esposito K, Marfella R, Ciotola M, et al. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. J Am Med Assoc 2004; 292: 1440–6.

65. Day C, Bailey CJ. Editorial: Which weight loss diet? Br J Diabetes Vasc Dis 2009; 9: 43.

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Screening for diabetes and cardiometabolic disease in women with polycystic ovary syndrome Julie A Tomlinson, Jonathan H Pinkney, Phil Evans, Ann Millward, Elizabeth Stenhouse Abstract Polycystic ovary syndrome (PCOS) is a significant risk factor for developing type 2 diabetes and increased cardiovascular disease risk (together referred to as ‘cardiometabolic disease’, CMD). Primary prevention of CMD may be possible in women with PCOS but the diagnostic criteria for PCOS are controversial and this often hampers optimal clinical management. PCOS affects as many as 18% of women of reproductive age, and at least 70% remain undiagnosed in primary care. Screening women with PCOS for diabetes is seldom undertaken, largely through difficulties in diagnosis due to identification and management of PCOS continuing to focus on treatment of infertility and hirsutism. This article focuses on the diagnostic challenges of making the initial diagnosis of PCOS and considers how screening, detection and prevention of CMD might become routine clinical practice. It explores the unique challenges associated with PCOS and highlights the need for better evidence to justify screening and intervention. Finally, a pragmatic approach to assessing women with PCOS is suggested for use within primary care.

Keywords: cardiometabolic disease, cardiovascular risk, CMD, CVR, PCOS, polycystic ovary syndrome, primary care, primary prevention, screening for type 2 diabetes

Introduction PCOS affects as many as 18% of women of reproductive age, but at least 70% of PCOS remains undiagnosed in primary care.1 Although screening women with PCOS for diabetes and diabetes risk has been recommended,2–4 this is seldom undertaken routinely in clinical Correspondence to: Julie Tomlinson Plymouth University Peninsula Schools of Medicine & Dentistry, Pool Health Centre, Station Road, Pool, Redruth, Cornwall TR15 3DU, UK. e-mail: Julie.Tomlinson@pms.ac.uk Jonathan H Pinkney Plymouth University Peninsula Schools Medicine & Dentistry, University Medicine, Level 7 Derriford Hospital, Crownhill, Plymouth, Devon, UK Phil Evans St Leonard’s Practice, Exeter and University of Exeter Medical School (Primary Care), Athelstan Road, Exeter, UK Anne Millward Plymouth University Peninsula Schools Medicine and Dentistry, Plymouth, Devon, UK Elizabeth Stenhouse School of Nursing and Midwifery, Faculty of Health, University of Plymouth, Derriford, Plymouth, Devon, UK Originally in: Br J Diabetes Vasc Dis 2013; 13 (3): 115–123.

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Abbreviations: ADA AES ASRM BH BMI CH CMD COC CVD DUK ESHRE

FAI FG f-T HbA1C IGR IGT NIH OGTT PCO PCOS SHBG s-T t-T WHO

American Diabetes Association Androgen Excess Society American Society for Reproductive Medicine biochemical hyperandrogenism body mass index clinical hyperandrogenism cardiometabolic disease combined oral contraceptives cardiovascular disease Diabetes UK European Society for Human Reproduction and Embryology free androgen index Ferriman Gallwey free testosterone glycated haemoglobin A1C impaired glucose regulation impaired glucose tolerance National Institutes of Health oral glucose tolerance test polycystic ovaries polycystic ovary syndrome sex hormone binding globulin serum testosterone total testosterone World Health Organisation

practice, largely through difficulties in diagnosis. Identification and management of PCOS continues to focus on treatment of infertility and hirsutism with little regard to opportunities for primary prevention of CMD.5 PCOS carries a substantial risk of developing type 2 diabetes and is a risk factor for CVD.6 These are collectively referred to as CMD. Several studies from the USA report 7.5–10% of women with PCOS have type 2 diabetes and 31–35% with IGT7,8 although in Italy, lower rates of 6.4% with IGT and 0% with type 2 diabetes were observed.9 The wide variations in prevalence are generally considered to reflect different populations and varying diagnostic criteria. Although the principal clinical features of PCOS are oligomenorrhoea, infertility and clinical evidence of hyperandrogenism including hirsutism and acne,5,10 symptoms are variable, and in their absence, PCOS is often unrecognised.

The aim of this article is to consider the problem of how to identify women with PCOS in the community, who could then be screened for CMD. There is already good evidence for increased CMD in women with PCOS and this has been reviewed previously.6 Prevalence of PCOS The reported prevalence of PCOS in young women in the USA was 6–10%.11–14 However, European and Australian data suggest this is an underestimate. A cross-sectional study of 230 women aged

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suggests screening if women have a BMI ≥ 25 kg/m,2 whereas DUK suggest screening if BMI ≥ 30 kg/m2.2,3 Currently, neither DUK nor ADA provide guidance on the optimal screening test for type 2 diabetes in women with PCOS, the screening interval or interventions to reduce women’s health risks. There is a need for evidence-based guidelines on screening, diagnosis and interventions to reduce CMD specifically in women with PCOS. Current screening guidelines are based upon evidence extrapolated from studies of older, mixed sex populations whereas PCOS is a condition of women in reproductive years and therefore quite clearly distinct.

Controversies in screening and diagnosis of PCOS Several different sets of diagnostic criteria are used to define PCOS, and the lack of consensus causes confusion and undoubtedly contributes to under-diagnosis and difficulties in determining whom to screen for CMD. The three main sets of criteria are as follows.

IcebergTomlinson and Pinkney ©2013

Figure 1. Polycystic ovary syndrome (PCOS) iceberg.

18–25 years in Oxford found rates of 8–26%, depending upon the diagnostic criteria used for PCOS.15 More recently, an Australian community study (n=728) compared PCOS prevalence using three different sets of diagnostic criteria: the NIH 1990,16 Rotterdam Consensus17 and the Androgen Excess Society.18 The women were predominantly European (94%) with a mean BMI of 25.7 kg/m.2 Prevalence rates were 17.8% using Rotterdam criteria, and 70% of these women were previously undiagnosed.1 The findings suggest that the actual prevalence of PCOS could be considerably higher than the frequently quoted 6–10% figure, due to different diagnostic criteria and under-diagnosis in primary care. This poses a considerable obstacle if PCOS is to be used as a basis for CMD screening in clinical practice.

PCOS and obesity Numbers of women with PCOS appear to be increasing, and this might indicate increasing prevalence.19 A link has been reported between the increasing incidence of obesity, IGT and type 2 diabetes amongst adolescent girls with PCOS.20 It is therefore plausible that the population rise in BMI might be increasing the prevalence of PCOS, since obesity is known to increase hyperandrogenism21 and menstrual irregularity.21,22 Of potential significance is the associated increase in insulin resistance observed in these women.23–25 Several studies suggest that PCOS may be a specific manifestation of insulin resistance,6 and that insulin resistance is present in the majority.26 Thus, it would not be surprising if the global rise in obesity is increasing the prevalence of PCOS and associated CMD linked to insulin resistance. However, it is likely that women currently diagnosed with PCOS are the tip of a very large iceberg with the majority of PCOS and the co-existing CMD unrecognised and untreated (Figure 1).

Current guidance on screening for type 2 diabetes in women with PCOS Both DUK and the ADA recommend that women diagnosed with PCOS are screened for type 2 diabetes, although US guidance

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The NIH 1990 criteria There was no agreed definition of PCOS until the NIH 1990 conference sought consensus expert opinion through questionnaires and debate, producing the first PCOS diagnostic criteria.16 Although the term ‘PCOS’ itself implies that PCO should be an essential feature for diagnosis, this was controversial and ‘polycystic ovaries’ were not included in the final NIH criteria (Table 1).

Using NIH classification, women with hyperandrogenism and regular menstrual cycles, and women with PCO, irregular menstrual cycle but no hyperandrogenism, would not be diagnosed as having PCOS. There was concern that these criteria could result in false negative diagnoses, missing those with regular cycles, hyperandrogenism and PCO. The debate over the use of ‘polycystic ovaries’ as a diagnostic criterion continued until 2003 when a conference in Rotterdam proposed different criteria.17 The Rotterdam (ESHRE) 2003 criteria. In 2003 the ESHRE/ASRM developed what are now known as the ‘Rotterdam criteria’. These added two new phenotypes by including the feature of PCO in the diagnostic criteria (Table 2): Table 1. The NIH 1990 criteria for the diagnosis of PCOS. A diagnosis of PCOS may be made if there is both: i. Presence of hyperandrogenism with either clinical signs (hirsutism, acne, or male pattern balding) or biochemical signs of hyperandrogenemia (high serum androgen concentrations) and ii. Presence of chronic menstrual irregularity due to oligomenorrhoea/ amenorrohoea after iii. Excluding other known disorders such as Cushing’s syndrome, Congenital Adrenal Hyperplasia, androgen-secreting tumours, and hyperprolactinaemia PCOS: polycystic ovary syndrome.

Table 2. The Rotterdam 2003 criteria for the diagnosis of PCOS. A diagnosis of PCOS may be made if any two of the following features are present: i. The presence of menstrual irregularities – oligomenorrhoea and/or annovulation ii. The presence of clinical and/or biochemical signs of hyperandrogenism iii. The presence of polycystic ovaries after iv. Excluding other potential causes of menstrual irregularity or hyperandrogenism

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• PCO, androgen excess (but normal ovulation and menstrual cycles), • PCO, abnormal ovulation and menstrual cycles (without evidence of hyperandrogenism).27 The Rotterdam criteria increase the number of women meeting criteria for PCOS, although ovarian ultrasound would be required if these criteria were to be fully adopted in primary care. Thus, despite Rotterdam criteria being widely recommended in the UK, in the absence of ultrasound data many women can only be diagnosed using the NIH features of oligomenorrhoea and hyperandrogenism.

This would lead to failure to diagnose women with PCO and either hyperandrogenism or oligomenorrhoea.

It remains debatable whether NIH or Rotterdam are the appropriate diagnostic criteria for PCOS as each definition gives two overlapping, yet phenotypically different sets of women. Although Rotterdam criteria include a wider range of phenotypes, in terms of CMD and insulin resistance, NIH phenotypes (hyperandrogenism and chronic anovulation) probably carry greater CMD risk28 than those who would only be diagnosed through Rotterdam criteria.

Clearly, there remain inherent problems with both criteria and there is no accepted ‘gold standard’. Supporters of Rotterdam argue that NIH fails to identify some PCOS, whereas others argue that Rotterdam has broadened the diagnostic criteria too far. This lack of consensus has substantial implications for diabetes screening and potential CMD risk reduction in women with PCOS. The AES recommendations This diagnostic controversy prompted the AES to make its own recommendations for diagnostic criteria (Table 3).

The AES criteria. AES allow the use of ultrasound, but unlike Rotterdam, hyperandrogenism is regarded as essential for diagnosis.

However, a minority still considered that some women may have PCOS in the absence of hyperandrogenism, and so the definition is likely to continue to evolve as more evidence becomes available.27 What is apparent is that until there is a universally accepted definition of PCOS, it will be difficult to fully resolve which women to screen for type 2 diabetes and who might benefit from measures to reduce CMD risk.

Difficulties using clinical features in the diagnosis of PCOS PCO Ultrasound examinations demonstrate that PCO are present in 32–33% of young women, are not necessarily related to other symptoms or metabolic dysfunction15,29 and are especially unreliable for diagnosing PCOS in adolescents.30 A diagnosis of PCOS using PCO as a criterion, and without evidence of hyperandrogenism, is therefore controversial. Despite inclusion of PCO in the Rotterdam Table 3. The Androgen Excess Society criteria for the diagnosis of PCOS. A diagnosis of PCOS may be made if the following features are present: i.

The presence of hyperandrogenism (clinical and/or biochemical) and

ii. The presence of ovarian dysfunction (oligo-anovulation and/or polycystic ovaries) after: iii. Excluding other causes

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criteria, requests for ultrasounds are often not accepted by imaging departments in the UK for diagnosis of PCOS. This leaves clinicians with no alternative than to use NIH criteria, unless previous scans are available or if secondary care specialists make requests. Where ultrasound information is available, clinicians should be wary of relying on interpretive comments of non-expert reporters such as ‘consistent with PCOS’. Clinical reports often lack standardisation in the interpretation with only poor to moderate levels of interobserver agreement.31 Thus, there should be reliable evidence of the size and number of ovarian cysts before an ovarian scan report can be considered reliable for diagnosis. In addition, ovarian ultrasounds are often performed trans-abdominally, rather than transvaginally, and can be of inferior quality.32,33 Transvaginal scans (although more invasive than trans-abdominal) have been found to be superior to transabdominal for identifying ovarian cysts in obese women.33 They are therefore the preferred modality for ovarian imaging in women with suspected PCOS. In summary, limited access to high quality ultrasound examination in primary care is one of the factors constraining the identification and classification of women with PCOS, and therefore has implications for identifying the population to be screened for type 2 diabetes and CMD risk.

Hyperandrogenism: biochemical There are also difficulties in using hyperandrogenism as a guide to potential PCOS. Further challenges are found in the assessment of hyperandrogenism (CH and BH). BH can be assessed in several different ways and there is no agreed standard biochemical test, or reference range. It is widely considered that the most informative index of BH is a combined measurement of a raised total s-T and a decrease in its principal binding protein – SHBG, although these measurements in isolation are not always indicative of PCOS. A low SHBG is a marker of insulin resistance, and can be of use for identifying insulin-resistant individuals34 which may help to identify those with greatest CMD risk. However, reduced levels of SHBG are certainly not specific to PCOS. Total s-T measurements do not provide information on testosterone bioavailability. Some laboratories offer measurements of f-T, although this is relatively expensive and not widely available.

The FAI is an alternative index of hyperandrogenism, calculated by dividing the t-T measurement by the SHBG and multiplying by 100 to obtain an estimate of the f-T level. As hyperandrogenism is often difficult to fully assess in women who are taking oestrogen containing contraception, guidelines recommend measuring s-T prior to initiating COC or after a 3-month washout.30 The role of SHBG in the diagnosis of hyperandrogenism is also not straightforward. Serum SHBG levels are inversely associated with insulin levels.35 Thus, low SHBG levels and consequently elevated FAI are often found in insulin-resistant women, including those with PCOS. The pathogenesis of hyperandrogenism is often considered likely to result from obesity-induced hyperinsulinaemia and suppression of SHBG production by the liver. The reverse may then be seen when weight loss triggers a reduction in insulin, elevation of SHBG and drop in the FAI. These effects have been noted when women who have PCOS lose significant amounts of weight after bariatric surgery, indicating that obesity exacerbates hyperandrogenism, increased fasting insulin and reducing SHBG.36,37 Hyperandrogenism: clinical The diagnosis of CH is also complicated by subjectivity and wide interindividual variation. Hirsutism is a good marker for hyperandrogenism

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and is present in 70% of women with PCOS, and likewise 70% of hirsutism is associated with PCOS.38 Yet there is wide variation in grading of hirsutism by clinicians.38,39 The FG score (or modified mFG version) can be used to quantify female hirsutism,40 especially in research where it has been found to provide results equivalent to measures of hair diameter.41 However, FG lacks objectivity and reproducibility38 and is therefore seldom used in clinical practice.

Furthermore, as hirsutism often increases in postmenopausal or obese women, and varies across ethnic groups, FG interpretations must be population specific.39 In the absence of a standardised hirsutism measure, clinical assessment is largely subjective and so hyperandrogenism should also be evaluated biochemically.28 The usefulness of acne as a marker of CH is highly variable. In teenagers it becomes totally unreliable and thus should be avoided as a criterion for diagnosing PCOS in young women and used with caution subsequently.28,30 Furthermore, 50% of healthy women with acne do not have hyperandrogenism, and hirsutism in PCOS is often not associated with acne.28 Therefore, acne is probably an unreliable feature for diagnosis of PCOS. Likewise, care should also be used when assessing CH using malepattern baldness (central alopecia and hair recession). Interestingly, evidence links premature baldness in men with female relatives who have PCOS.42 However, this marker is expressed differently in diverse populations and so cannot be applied universally. In conclusion, without robust guidelines enabling clinicians to measure these features, acne and alopecia are less frequently used to diagnose PCOS, despite their inclusion in the Rotterdam criteria.

Oligo/amenorrhoea In principle, a history of oligo/amenorrhoea may be used as a simple screening question to identify women who might have PCOS, and who, subject to confirmation of the diagnosis, could be screened for CMD. However, this is also constrained by difficulties in determining cut-offs for the ‘normal’ menstrual cycle.

Amenorrhoea has been defined as intervals between periods of greater than 199 days, whereas oligomenorrhoea is intervals of 35–199 days.28 There is debate whether short cycles of < 21 days should be regarded as oligomenorrhoea, and there is evidence for both long43 and short30 cycles being associated with increased CMD risk. However, cycle lengths vary amongst healthy women

and women who meet the Rotterdam criteria for a diagnosis of PCOS can also have regular cycles. Currently, Australian guidelines include both short cycles < 21 days and cycles >35 days in their classification of oligomenorrhoea30 but European guidance defines oligomenorrhoea as cycles of 35–199 days.28 The largest survey of menstrual cycle regularity was undertaken in the 1982 Nurses’ Health Study where 82 439 women were given questionnaires about their prior menstrual regularity between the ages of 22 and 35 years. Of these, 84.8% reported very regular or usually regular cycles, 15.2% reported usually irregular or very irregular cycles.43 The women who reported usually irregular or very irregular cycles, tended to have higher BMIs than those with regular cycles. This study suggests that oligomenorrhoea is a relatively frequent finding in the general population (especially amongst women with high BMI) and the ‘normal cycle length’ of 24–35 days often quoted from a study in the 1960s44 might need to be reviewed in light of increasing obesity levels over recent decades and the association between adiposity and menstrual irregularity. Nevertheless, oligomenorrhoea is commonly defined as 35 to 199 day cycles for the purpose of PCOS diagnosis. In summary, in addition to the different sets of diagnostic criteria for PCOS, there are also difficulties and inconsistencies in the definitions of all of the component clinical features, including PCO, CH and BH, and oligomenorrhoea.

Differential diagnoses Further complicating the identification of women with PCOS in the community, whichever set of diagnostic criteria are used, it is necessary to exclude differential diagnoses that present similar features to PCOS. Table 4 summarises some of the clinical features of diagnoses that must be excluded prior to a PCOS diagnosis.

Recommendations for clinical practice It is widely considered that PCOS is a significant risk factor for CMD6 – making it as important to consider as dyslipidaemia or hypertension. While primary care focuses largely on hirsutism and fertility issues in PCOS management,5 the question of identifying all women with PCOS, and offering general screening for type 2 diabetes and CVD risk assessment is currently not addressed.

Table 4. Differential diagnoses of PCOS features.

Condition

Hirsutism

Biochemical hyperandrogenism

Amenorrhoea/oligomenorrhoea

Congenital adrenal hyperplasia

3

3

3

Cushing’s syndrome

3

3

3

Hypothyroidism

3

3

3

Obesity

3

3

3

Adrenal neoplasms

3

3

3

Hyperandrogenic insulin-resistant acanthosis nigricans (HAIR-AN syndrome)

3

3

3

Hyperprolactinaemia

–

–

3

Pregnancy

–

–

3

Anorexia nervosa/weight related amenorrhoea

3

–

3

Turner’s syndrome

–

–

3

‘Stress’

–

–

3

Peri/post-menopausal

3

–

3

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among women, (ii) increased symptom enquiry by primary care professionals, and (iii) greater attention given to the investigation of oligomenorrhoea or hirsutism by simple blood tests. Women who meet the clinical/biochemical diagnostic criteria for PCOS may need investigation to exclude other diagnoses, through discussion with, or referral to an endocrinologist. Most of the differential diagnoses are relatively uncommon or rare. Differential diagnoses may be excluded (see table 4) and CMD risk may be determined through the following investigations (Table 5).

Table 5. Recommended Investigations for PCOS. Serum Testosterone or Free Androgen Index Sex hormone binding globulin (SHBG) Thyroid stimulating hormone (TSH) Prolactin Ultrasound ovaries (transvaginal better than abdominal) LH and FSH* 17-OH progesterone** Dehydroepianderosterone sulphate (DHEAS)*** 2-hour oral glucose tolerance test**** Lipid profile *Can be performed as an additional tool to aid diagnosis. PCOS often results in an increased LH/FSH ratio. Tests also relevant to exclude other causes of amenorrhoea. **To exclude congenital adrenal hyperplasia (CAH). ***A second-line measure of adrenal hyperandrogenism. ****HbA1C and fasting plasma glucose have not been shown to be reliable measures for determining abnormal glucose regulation in PCOS. FSH: follicle stimulating hormone, LH: luteinising hormone.

However, we propose that interim clinical recommendations can and should be made.

1. Improve the identification of women with PCOS in primary care This could be achieved through (i) greater public awareness of PCOS

2. Standardisation of the PCOS definition The identification of women with PCOS, who then could be screened for type 2 diabetes, would be helped considerably if there were a universally accepted definition. Current discrepancies between definitions lead to uncertainty in primary care. Using the NIH classification which does not require ultrasound, will result in missing the diagnosis of some PCOS phenotypes and perpetuating low detection rates. Yet, even in the UK where the Rotterdam criteria are used to diagnose this condition, unless women with either oligomenorrhoea or hyperandrogenism are referred for ultrasound investigation, clinicians are essentially basing their diagnosis upon the NIH criteria. It would be pragmatic therefore to first identify if a woman has hyperandrogenism and oligomenorrhoea and when only one criteria is found, to refer for a transvaginal ultrasound to confirm diagnosis.

Table 6. Recommendations for the clinical assessment of CMD in women with PCOS. Clinical assessment

Recommendation

Minimum frequency

Diagnosis

Diagnose by Rotterdam Criteria. Caution in diagnosis teenagers < 18 years or if menarche < 2 years ago

Once

Additional information

Glucose tolerance

2-h oral glucose tolerance test

Every 2 years.

Annually if PCOS and additional risk factors*

*Additional risk factors: Increased age, ethnicity, parental history of diabetes, history hypertension, use of antihypertensives, smoker, physical inactivity, increased waist circumference

Cardiovascular risk

Body mass index (and weight loss advice where appropriate)

Annually

BMI 18.5–24.9 kg/m2 = healthy 25–29.9 kg/m2 = overweight 30+ kg/m2 = obese Aim for 5–10% weight loss as initial goal

Waist circumference

Annually

> 80 cm increased metabolic risk > 88 cm high metabolic risk

Smoking status (advice if smoker)

At each visit

Physical activity status (and advice)

Annually

Blood pressure

Annually

Lipid profile

Annually if abnormal or obese. Every two years if found normal.

Recommendation of 150 minutes physical activity/week Goals: PCOS only: • Total cholesterol < 4 mmol/l, • LDL-C < 3.4, HDL-C > 1.0 triglycerides < 1.7 mmol/l PCOS and metabolic risk: • Total cholesterol < 4 mmol/l, • LDL-C < 1.8–2.6, HDL-C > 1.0,triglycerides < 1.7 mmol/l PCOS and diabetes: • Total cholesterol < 4 mmol/l, • LDL-C < 1.8, HDL-C > 1.0, triglycerides < 1.7 mmol/l

Adapted from: Teede H et. al. (2011) and Fauser et. al (2012).

HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol.

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Laboratory referral guidelines would need to reflect this and also ensure that reporting detail is sufficient to base a diagnosis upon.

3. Standardisation of PCOS screening recommendation PCOS is a common condition which identifies many women at risk of CMD. Diabetes screening protocols for women with PCOS need agreement. Fasting glucose will miss 80% of pre-diabetes30 but whilst the WHO45 and ADA4 now recommend the use of HbA1C to diagnose diabetes they acknowledge the limitations of this test. This includes the poor sensitivity in identifying IGR in PCOS, making the test unsuitable for identifying small degrees of IGR in this population.46 It is noted, therefore, that despite a general move towards using HbA1C, the OGTT remains the only proven test for accurate classification of IGR and potentially for the diagnosis of type 2 diabetes in PCOS. For this to work successfully in primary care settings, disease registers and recall systems would be required to ensure that regular type 2 diabetes screening and CVD risk assessment can be undertaken.

Until there is formal UK guidance a pragmatic approach is required to ensure that women with PCOS are recognised, diagnosed and their CMD risk managed. European guidelines recommend screening for diabetes in women with PCOS who have a BMI > 30 kg/m2,28 despite evidence of profound insulin resistance in lean women with PCOS47 and the guidance of screening PCOS with a BMI ≥ 25 kg/m2 by the ADA.3 Australian guidelines address this by recommending an OGTT every two years on all women with PCOS or annually in those with other risk factors including pre-existing IGR. Table 6 provides suggestions for CMD assessment based upon information provided by these sources (Table 6).30 Standardisation of clinical assessment The wide range of PCOS phenotypes and women’s own concerns suggest that clinical management should be individualised according to symptoms and risks. However, whether it is treating hyperandrogenism, managing infertility or screening for CMD, it would be in the interests of the woman involved and their healthcare professionals to have evidenced-based guidelines to improve quality and equity of care.

Many of the issues raised in this article have been addressed recently, although it should be noted that whilst adopting the Rotterdam diagnostic criteria, the authors of the Australian guidelines30 are not in complete concordance with the recommendations of the 3rd ESHRE consensus workshop28 in terms of defining oligomenorrhoea and recommendations to screen for CMD.

Conclusion Whilst PCOS is a common condition it remains under-diagnosed in primary care and its cardiometabolic consequences neglected.

Although controversies persist regarding diagnostic criteria and the optimal screening and management guidelines for CMD, relatively simple steps would improve the recognition of PCOS and opportunities for primary prevention of CMD. General practitioners and their teams are ideally placed to undertake this work and to ensure that these women are no-longer disadvantaged.

Declaration of conflicting interest The author declares that there is no conflict of interest.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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26. Panidis D, Tziomalos K, Misichronis G et al. Insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study. Hum Reprod 2012; 27: 541â&#x20AC;&#x201C;9.

27. Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab 2006; 91: 781â&#x20AC;&#x201C;5. PubMed PMID: 16418211.

28. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R et al. Consensus on womenâ&#x20AC;&#x2122;s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 2012; 97: 28â&#x20AC;&#x201C;38 e25.

29. Johnstone EB, Rosen MP, Neril R, Trevithick D, Sternfeld B, Murphy R et al. The Polycystic Ovary Post-Rotterdam: A Common, Age-Dependent Finding in Ovulatory Women without Metabolic Significance. J Clin Endocrinol Metab 2010.

30. Teede H, Michelmore J, McAllister V, Norman R. Evidence-based guideline for the assessment and management of polycystic ovary syndrome. 2011. PCOS Australian Alliance. Available at: http://www.nhmrc.gov.au/_files_nhmrc/ publications/attachments/ext_2_ext_0002.pdf (Accessed 8 July 2013).

31. Lujan ME, Chizen DR, Peppin AK, Dhir A, Pierson RA. Assessment of ultrasonographic features of polycystic ovaries is associated with modest levels of inter-observer agreement. J Ovarian Res 2009; 2: 6.

32. Fleischer AC, Gordon AN, Entman SS. Transabdominal and transvaginal sonography of pelvic masses. Ultrasound Med Biol 1989; 15: 529â&#x20AC;&#x201C;33.

33. Leibman AJ, Kruse B, McSweeney MB. Transvaginal sonography: comparison with transabdominal sonography in the diagnosis of pelvic masses. Am J Roentgenol 1988; 151: 89â&#x20AC;&#x201C;92.

34. Jayagopal V, Kilpatrick ES, Jennings PE et al. The biological variation of testosterone and sex hormone-binding globulin (SHBG) in polycystic ovarian syndrome: implications for SHBG as a surrogate marker of insulin resistance. J Clin Endocrinol Metab 2003; 88: 1528â&#x20AC;&#x201C;33.

35. Pugeat M, Moulin P, Cousin P et al. Interrelations between sex hormone-binding

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globulin (SHBG), plasma lipoproteins and cardiovascular risk. J Steroid Biochem Mol Biol 1995; 53: 567â&#x20AC;&#x201C;72.

36. Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F et al. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J Clin Endocrinol Metab 2005; 90: 6364â&#x20AC;&#x201C;9.

37. Eid GM, Cottam DR, Velcu LM et al. Effective treatment of polycystic ovarian syndrome with Roux-en-Y gastric bypass. Surg Obes Relat Dis 2005; 1: 77â&#x20AC;&#x201C;80.

38. Wild RA, Vesely S, Beebe L et al. Ferriman Gallwey self-scoring I: performance assessment in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90: 4112â&#x20AC;&#x201C;4.

39. Api M, Badoglu B, Akca A et al. Interobserver variability of modified Ferriman-Gallwey hirsutism score in a Turkish population. Arch Gynecol Obstet 2009; 279: 473â&#x20AC;&#x201C;9.

40. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961; 21: 1440â&#x20AC;&#x201C;7.

41. Barth JH. Semi-quantitative measurements of body hair in hirsute women compare well with direct diameter measurements of hair shafts. Acta Derm Venereol 1997; 77: 317â&#x20AC;&#x201C;8.

42. Govind A, Obhrai MS, Clayton RN. Polycystic ovaries are inherited as an autosomal dominant trait: analysis of 29 polycystic ovary syndrome and 10 control families.

J Clin Endocrinol Metab 1999; 84: 38â&#x20AC;&#x201C;43.

43. Solomon CG, Hu FB, Dunaif A et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab 2002; 87: 2013â&#x20AC;&#x201C;7.

44. Treloar AE, Boynton RE, Behn BG, Brown BW. Variation of the human menstrual cycle through reproductive life. Int J Fertil 1967; 12(1 Pt 2): 77â&#x20AC;&#x201C;126.

45. World Health Organisation. Use of Glycated Haemoglobin (HbA1C) in the Diagnosis of Diabetes Mellitus: Abbreviated report of a WHO consultation. Geneva: WHO, 2011; WHO/NMH/CHP/CPM/11.1.

46. Aye M, Kahal H, Hooson F et al. Haemoglobin A1C in diagnosis of impaired glucose regulation in polycystic ovary syndrome. Endocrine Abstracts 2012; 28: 217.

47. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989; 38: 1165â&#x20AC;&#x201C;74.

Submit case reports to the South African Journal of Diabetes and Vascular Disease: www.diabetesjournal.co.za Specifications: Total word count 1 500; maximum three illustrations/images Title Abstract t JODMVEJOH XIZ UIF DBTF JT OPWFM PS NFSJUT SFWJFX Describe the case according to timeline t NFEJDBM IJTUPSZ t SFMFWBOU EBUB GSPN DMJOJDBM JOWFTUJHBUJPOT t JOUFSWFOUJPOT Discussion on clinical relevance t XIZ UIJT JT OPWFM PS XPSUI SFWJFX t DPNQSFIFOTJWF MJUFSBUVSF SFWJFX t EFSJWF OFX LOPXMFEHF t QSPWJEF SFDPNNFOEBUJPOT References Types of case report 1. Diagnosis related t VOVTVBM PS OFX EJTFBTF t VOVTVBM QSFTFOUBUJPO PG LOPXO EJTFBTF t OFX NFUIPET PG EJBHOPTJT t VOVTVBM PS OFX BFUJPMPHZ t VOFYQFDUFE BTTPDJBUJPO CFUXFFO EJTFBTFT PS TZNQUPNT VOLUME 10 NUMBER 3 â&#x20AC;˘ SEPTEMBER 2013

2. Management related t OFX PS JNQSPWFE USFBUNFOU UZQF t OFX PS SBSF TJEF FòFDUT PS DPNQMJDBUJPO PG USFBUNFOU Common problems with case reports t UJUMF JODMVEFT SFEVOEBOU XPSET F H ADBTF SFQPSU BOE SFWJFX PG UIF MJUFSBUVSF t DBTF JT OPU XPSUI SFQPSUJOH o POMZ TMJHIU WBSJBUJPO JO EJBHOPTUJD PS UIFSBQFVUJD BQQSPBDI t UIFSBQFVUJD BQQSPBDI XJUIPVU TUSPOH SBUJPOBMF BOE OP JNQBDU PO PVUDPNF t FYDFTTJWFMZ MPOH NBOVTDSJQU t FYDFTTJWFMZ DPNQMJDBUFE DBTF t MBDLT TDJFOUJÜD FWJEFODF t OP QSPPG PG EJBHOPTJT t OP BEEJUJPOBM PS JODSFNFOUBM LOPXMFEHF t PWFS HFOFSBMJTBUJPO t PWFS BNCJUJPVT DPODMVTJPO OPU TVQQPSUFE CZ FWJEFODF

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Intermittent fasting: a dietary intervention for prevention of diabetes and cardiovascular disease?

James E Brown, Michael Mosley, Sarah Aldred Abstract Intermittent fasting, in which individuals fast on consecutive or alternate days, has been reported to facilitate weight loss and improve cardiovascular risk. This review evaluates the various approaches to intermittent fasting and examines the advantages and limitations for use of this approach in the treatment of obesity and type 2 diabetes.

Keywords: diet, fasting, intermittent fasting, obesity, type 2 diabetes, weight loss

Introduction The increasing prevalence of obesity and type 2 diabetes in recent decades has been associated with increased comorbidities including atherosclerotic macrovascular disease and premature mortality.1–3 Individuals with sub-diabetic degrees of hyperglycaemia, such as impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are also at increased risk of premature cardiovascular disease, emphasising the importance of interventions to improve glucose homeostasis in pre-diabetic, as well as diabetic individuals.4–5 Several large studies have identified pre-diabetic individuals as subjects in whom to investigate lifestyle changes to prevent the progression to a fulminant diabetic state.6–10 However, there is considerable debate regarding the most effective manner in which lifestyle changes such as diet and/or exercise should be implemented.11 The approach of intermittent fasting is currently generating particular interest.

Intermittent fasting Extensive evidence suggests that imposing fasting periods upon experimental laboratory animals increases longevity, improves health and reduces disease, including such diverse morbidities as cancer,12,13 neurological disorders 14-17 and disorders of circadian rhythm.18,19 The specific benefit of intermittent fasting as a health-giving therapeutic approach has been recognised since the 1940s.20

Day 1

Day 2

Day 3

Day 4

Normal TDEE

Normal

Fasting

TDEE

500 (female) 600 (male)

Sarah Aldred School of Sport and Exercise Sciences, College of Life and Environmental Sciences, University of Birmingham, UK Originally in: Br J Diabetes Vasc Dis 2013; 13(2): 68–72 S Afr J Diabetes Vasc Dis 2013; 10: 100–102

100

Day 6

Day 7

Normal

Fasting

Normal

Normal

TDEE

500 (female) 600 (male)

TDEE

TDEE

Calories (per day) TDEE = total daily energy expenditure

Figure 1. Diagrammatic representation of a typical intermittent fasting plan.

Subjects who undertake this form of diet are required to limit their calorie intake for two days, consecutively or otherwise each week. The calorie limit for fasting days is approximately 25% of TDEE or 600 calories for men and 500 for women. On non-fasting days subjects can eat normally to their TDEE calorie level (approximately 2 500 for men and 2 000 for women).

Intermittent fasting can be undertaken in several ways but the basic format alternates days of ‘normal’ calorie consumption with days when calorie consumption is severely restricted. This can either be done on an alternating day basis, or more recently a 5:2 strategy has been developed (Figure 1), where two days each week are classed as ‘fasting days’ (with < 600 calories consumed for men, < 500 for women). Importantly, this type of intermittent fasting has been shown to be similarly effective or more effective than continuous modest calorie restriction with regard to weight loss, improved insulin sensitivity and other health biomarkers.1,21 Fasting has been used in religion for centuries. For example, the Daniel fast is a biblical partial fast that is typically undertaken for three weeks, and during Ramadan, the ninth month of the Muslim calendar, there is a month of fasting during daylight hours, during which some observers also refrain from fluid consumption.22 Such periods of fasting can limit inflammation,23 improve circulating glucose and lipid levels24–27 and reduce blood pressure,28 even when total calorie intake per day does not change, or is only slightly reduced. Ethical and logistical constraints have restricted most caloric deprivation studies to six months, although some have assessed the effects for longer.29–31 The majority of studies show positive effects on markers of metabolic health and body composition, in part due to the demonstrated effects intermittent fasting has on metabolic tissues (Figure 2). In addition caloric restriction studies undertaken

Correspondence to: Dr James E Brown Aston Research Centre for Healthy Ageing and School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK. e-mail: j.e.p.brown@aston.ac.uk Michael Mosley Aston Research Centre for Healthy Ageing & School of Life and Health Sciences, Aston University, Birmingham, UK

Day 5

Fasting/calorie restriction

Liver i Fatty liver h Insulin sensitivity

Blood vessels h No i Oxidative stress

Adipose tissue

Pancreatic islet

h Tag deposition i Age related h Insulin sensitivity decline

Skeletal muscle h Glucose uptake i Insulin resistance

Figure 2. Tissue-specific effects of intermittent fasting and calorie restriction.

Research has identified several biological effects of intermittent fasting and/or calorie restriction on tissues that are central to metabolic and cardiovascular health. NO: nitric oxide, TAG: triacylglycerides.

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in animals and humans have suggested that fuel selection is altered and efficiency of metabolism is improved32,33 while oxidative stress is reduced.34 It is possible that short periods of fasting mobilise ectopic triacylglyceride (TAG) in non-adipose depots, reducing the detrimental effects of intra-myocellular and intra-hepatic TAG deposition19,35 and redistributing TAG into adipose tissue.

Intermittent fasting and obesity Obesity comprises multiple genetic, metabolic and behavioural abnormalities that complicate treatment. Most pharmaceutical therapies that promote weight loss have been discontinued, and at the time of writing the only licensed anti-obesity drug on the UK market is orlistat.1 Increasing numbers of obese individuals are undergoing bariatric surgery, but this remains a restricted minority treatment.36 The mainstay of treatment for obesity therefore remains lifestyle intervention based around dietary changes37-40 which generally form the first step in any weight-loss programme.

Intermittent fasting is known to be useful in the treatment of intractable obesity,41 and morbidly obese individuals.42 Original treatment regimens were based upon intermittent starving as opposed to restricting calories43,44 a harsh regime that must have challenged adherence. Despite the seemingly strict nature of the fasting days, intermittent fasting has a generally good adherence record and can cause significant reductions in body weight in individuals with obesity,45-46 suggesting that this is a clinically relevant therapeutic approach.

Intermittent fasting and type 2 diabetes Since obesity commonly co-exists with type 2 diabetes1 patients are usually initially assigned lifestyle interventions aimed at reducing body weight.46 Most obese type 2 diabetes patients however will progress onto drug-based therapies, some of which can exacerbate their existing obesity.1 Intermittent fasting can reduce the incidence of diabetes in experimental animals47–49 and there is evidence that this type of fasting may also slow the progression of type 2 diabetes in obese individuals.

Indeed, a recent study confirmed earlier reports of a reversal of type 2 diabetes through daily calorie restriction, with improvement of pancreatic function and a reduction of occult triglyceride deposition.50 The particular diet employed a maximum of 600 calories every day, which may prove too severe for many type 2 diabetes patients, but an intermittent fasting strategy may be more acceptable and still improve metabolic parameters, insulin levels and insulin sensitivity51,52 and prevent the development of diabetic complications.53 Indeed, intermittent fasting might achieve much of the benefit seen with bariatric surgery,65 but without the costs, restriction on numbers and risks associated with surgery.

Whether intermittent fasting can be used as a tool to prevent diabetes in those with IGT or IFG, or to prevent progression in those recently diagnosed with type 2 diabetes remains a tantalising notion.

Intermittent fasting and cardiovascular disease Although with up to 80% of obese type 2 diabetes patients die from cardiovascular complications,54,55 and the benefits of weight loss are well recognised56 it is also known to be more difficult for individuals with type 2 diabetes to lose weight.57,58 Intermittent represents a potential therapy for those at high cardiovascular risk. Intermittent fasting in animal models can reproduce some of the cardiovascular benefits such as improvements

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in blood pressure and heart rate that are seen with physical exercise.59 Caloric restriction studies have shown improvements in circulating cholesterol, triglycerides, improved blood pressure, and reduced carotid intima–media thickness.28,60 Also, improvements in physiological cardiovascular parameters are associated with intermittent fasting and survival from l myocardial ischaemia61 through pro-angiogenic, anti-apoptotic and anti-remodelling effects.

Intermittent fasting also appears to be cardioprotective, providing experimental animals with resistance to ischaemic injury,62 in a manner possibly associated with increases in levels of the adipokine adiponectin.63 Adiponectin is a unique adipokine that appears to have beneficial effects but has circulating levels that are negatively correlated with body composition.64,65 However, intermittent fasting modulates the levels of visceral fat and several additional adipokines, including leptin, interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α) and IGF-1.66 These changes are responsible for a reduction in low-density lipoprotein cholesterol (LDL-C) and total cholesterol, consistent with a potentially beneficial effect on cardiovascular risk. Although most fasting is generally regarded to reduce cardiovascular risk, over-zealous fasting for protracted periods is not without risks of reducing myocardial mass alongside reductions in other components of reduced lean body mass.

Conclusion The use of intermittent fasting offers the potential to improve weight loss and enhance the cardiovascular health of overweight and obese individuals with type 2 diabetes and reduces cardiovascular risk. Limiting calories in this way can reverse diabetes. This type of intervention is cost-effective and associated with a low risk of adverse events.

Declaration of conflicting interests The authors declare no conflicts of interest in preparing this article.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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29. Dewanti L, Watanabe C, Sulistiawati et al. Unexpected changes in blood pressure and hematological parameters among fasting and nonfasting workers during Ramadan in Indonesia. Eur J Clin Nutrit 2006; 60: 877–81.

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31. Fontana L, Klein S, Holloszy JO et al. Effect of long-term calorie restriction with adequate protein and micronutrients on thyroid hormones. J Clin Endocrinol Metab 2006; 91: 3232–5.

32. Meyer TE, Kovacs SJ, Ehsani AA et al. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol 2006; 47: 398–402.

33. Sanz A, Caro P, Ibanez J et al. Dietary restriction at old age lowers mitochondrial oxygen radical production and leak at complex I and oxidative DNA damage in rat brain. J Bioenerg Biomembranes 2005; 37: 83–90.

34. Heilbronn LK, de Jonge L, Frisard MI et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 2006; 295: 1539–48.

35. Lignot J-H, LeMaho Y. A history of modern research into fasting, starvation and food inanition. In MD McCue (ed). Compariative Physiology of fasting, starvation and food limitation. Springer-Verlag, Berlin 2012,17–23.

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finds review. Br Med J 2012; 345: e6890.

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50. Lim EL, Hollingsworth KG, Aribisala BS et al. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54: 2506–14.

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54. Mccallum RW, Fisher M. Review: Comparing cardiovascular outcomes in diabetes studies. Br J Diabetes Vasc Dis 2006; 6: 111–8.

55. Wilding J, Finer N. Weight management and cardiovascular disease: implications of recent and ongoing clinical trials. Br J Diabetes Vasc Dis 2008; 8: 170–6.

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59. Fontana L, Villareal DT, Weiss EP et al. Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial. Am J Physiol Endocrinol Metab 2007; 293: E197–202.

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62. Wan R, Ahmet I, Brown M et al. Cardioprotective effect of intermittent fasting is associated with an elevation of adiponectin levels in rats. J Nutrit Biochem 2010; 21: 413–7.

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64. Dunmore SJ, Brown JE. The role of adipokines in beta-cell failure of type 2 diabetes. J Endocrinol 2013; 216: T37–45.

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Diabetes Educator’s Focus BURNOUT: A CRITICAL PROBLEM AMONG HEALTHCARE WORKERS P Wagenaar Gauteng correspondent

S Afr J Diabetes Vasc Dis 2013; 10: 103–104

A

n online survey has revealed that 60% of healthcare workers experience burnout, with 21% always or often feeling burned out, according to an article published earlier this year on the website, Health IT News.1 Heavy patient loads, smaller staff complements and higher stress levels are responsible, according to the survey by the American recruiting firm, CareerBuilder, which was conducted between 11 February and 6 March 2013. It involved more than 500 US healthcare workers and more than 240 employers.

Thirty-four per cent of healthcare worker respondents plan to look for a new job in 2013, up from 24% in 2012. Nearly half (45%) plan to look for a new job over the next two years. Eighty-two per cent said that while they are not actively looking for a job, they would be open to a new position if the right opportunity came along.

Jason Lovelace, president of CareerBuilder Healthcare, said in a statement, ‘Long hours and juggling multiple patient needs are taking their toll on morale and retention. The survey shows that healthcare workers are seeking a more manageable work experience.’

WHAT INFLUENCES JOB SATISFACTION? According to survey findings, there are four key factors influencing job satisfaction and retention (Table 1). The survey bears out the feelings of Candace Plattor, a registered clinical counsellor based in Vancouver, Canada.

‘Burnout among healthcare professionals has become a common and critical problem. As a therapist working in the healthcare system for over 20 years,

VOLUME 10 NUMBER 3 • SEPTEMBER 2013

I have seen a great many of my colleagues suffer from the various types of stress that can adversely affect workers in this field. I have watched some of them “burn out”, using up their paid sick leave, taking stress leave, resorting to unhealthy coping behaviours and sometimes leaving the profession altogether. I have also seen others deal with their stresses in healthier ways, choosing self-care strategies such as seeking out personal counselling and taking refreshing holidays.’2 Plattor maintains that burnout is not inevitable, though it is relatively common. In her opinion, the key lies in the willingness to become self-aware and make the changes necessary to remain holistically healthy. She believes it is incumbent upon healers to serve as guides and role models for their clients/patients. ‘As such, we must be doing our own personal work in order to most effectively assist our clients to do theirs’, she says.

Table 1. Key factors impacting on job satisfaction and retention.

• Pay: 75% of healthcare workers say they do not earn their desired salary, with 29% saying not anywhere near it.

• Work–life balance: 18% of workers say they are dissatisfied with their work–life balance; the highest percentage cites a workload that is too heavy (44%), followed by their employer’s unwillingness to provide flexible work schedules (21%).

• Career advancement: nearly a quarter (24%) of healthcare workers is not satisfied with their career progress. A lack of upward mobility is also one of the top reasons for seeking alternative employment opportunities.

• Switching industries: nearly three in 10 (29%) healthcare workers say they are currently trying to acquire skills in a new industry or field. Of these, 54% are going back to study, 18% are volunteering and 7% are taking on temporary or contract work.

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EDUCATOR’S FOCUS

THE PROBLEM The nature of the work dictates that the giving and receiving of support between client and counsellor is not an equitable dynamic. One reason burnout occurs is because healers sometimes lose sight of this, becoming depleted and defensive, and taking it personally when clients are demanding or manipulative. This can leave them feeling emotionally drained. Emotional exhaustion, coupled with the high ethical and moral standards they often set for themselves, can lead to feelings of frustration, anger and resentment.

If there appears to be no respite from the seemingly ever-present stress, healthcare workers could well be on the road to severe burnout.

It is therefore imperative that they take a proactive stance by broadening their understanding of what burnout is, why it develops, how it can manifest and what can be done to counteract it before it gets out of control.

An appreciation of the elements of healthy and appropriate self-care is an essential tool for the prevention of burnout.

CAUSES OF BURNOUT In talking with other healers, Plattor has discovered that there seem to be as many definitions of burnout as there are people defining it.

‘Despite these variations, however, it would appear that burnout has, at its core, three features in common: physical fatigue, emotional exhaustion and gradual disillusionment with the work itself. Other contributing factors that can lead to burnout may include work overload, lack of appreciation and recognition, strained relationships among colleagues and/or supervisors, and job dissatisfaction. As healers become disillusioned, they may become self-critical and feel as if they are not doing enough to help other people.’

MANIFESTATIONS OF BURNOUT There are many ways that the symptoms of occupational stress and burnout can manifest. These include physical symptoms such as headaches, gastrointestinal disturbances, chronic colds, changes in appetite and sleep difficulties. Emotional manifestations can include feelings of depression, helplessness, anxiety, nervousness, guilt, irritability and emotional depletion. Behavioural symptoms may show up as tardiness, absenteeism and poor work performance.

If burnout persists, the affected healthcare workers may develop negative attitudes toward the work, themselves, their clients and/or life in general. They may withdraw from clients, friends and family members, preferring to engage in such solitary activities as isolative substance use, excessive reading, watching too much television or spending inordinate amounts of time online.

‘It is important to remember that clients who come to healthcare professionals for assistance often have narcissistic needs.’ Plattor therefore

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SA JOURNAL OF DIABETES & VASCULAR DISEASE

feels strongly that therapists who expect to have any of their own needs met by clients are at risk of burnout.

‘Countertransference can develop when the healer’s own unresolved conflicts and defences are triggered by “difficult” clients. When exploring various occupational hazards of the healthcare professional, it is vital to understand and acknowledge that the healer’s emotional investment may be quite high, thus making it easy to feel disappointed. In addition, healers who work in isolation may not have opportunities to debrief with colleagues or supervisors when they find themselves triggered. Ongoing self-awareness is therefore essential; healthcare workers need to seek the support necessary to prevent symptoms of burnout from taking over their lives.’

PREVENTION OF BURNOUT Plattor thinks it unfortunate that many healthcare professionals believe that practising ‘self-care’ is equivalent to being ‘selfish’, rather than seeing healthy self-care as vitally important in terms of a well-rounded, holistic plan for burnout prevention.

‘Choosing to practise healthy self-care can incorporate a great many alternative types of coping responses. For example, having insight into one’s own “compassion fatigue” is crucial to the prevention of burnout.

It is also necessary for healers to establish and maintain a balance between their personal and professional lives and to find ways to interact with each other. In addition, healers need to pursue extracurricular activities and find ways to enjoy themselves. These include hobbies, sport, cultural events, socialising with friends and family, taking vacations and/ or engaging in coursework outside their area of professional expertise.

Holistic self-care also includes eating well, getting regular exercise, getting enough rest and sleep, having reflective time alone, engaging in spiritual pursuits and having fun!’

CONCLUSION ‘It is essential that we pursue our own healing, because it is only when we are self-aware and comfortable with our own unique personhood that we can effectively assist clients to become comfortable exploring theirs’, concludes Plattor. She cautions, however, that it is unrealistic to think that burnout can be completely eliminated. ‘Internal and external stressors will always affect people from time to time. However, when we are aware of occupational stress and its causes and manifestations, we can develop and implement preventative strategies that will greatly decrease unnecessary burnout among healthcare professionals.’

References 1.

2.

Monegain B. Burnout rampant in healthcare. http://www.health careitnews.com/ news/burnout-rampant-health care (Last accessed 4 October 2013).

Plattor C. When healers burn out: Causes and prevention of occupational stress among healthcare professionals. http://www.candaceplattor.com/articles/when_ healers_burn_out.htm (Last accessed 4 October 2013).

VOLUME 10 NUMBER 3 • SEPTEMBER 2013

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Patient information leaflet

Keep and Copy Series MAKING GOOD NUTRITIONAL CHOICES

S Afr J Diabetes Vasc Dis 2013; 10: 105–108

VOLUME 10 NUMBER 3 • SEPTEMBER 2013

G

ood nutrition is important throughout life, to help with feeling your best and staying strong. Good nutrition can also prevent the risk of developing some diseases and help to manage the symptoms of existing health issues.

Although understanding our nutritional needs may seem complicated, food labelling legislation helps us to know what the nutrient content of packaged foodstuffs is. Fortunately, vegetables and fruit don’t come with nutrition facts stamped into their skins.

For the nutrient content of fresh fruit and vegetables, see Tables 1 and 2.

Understanding the information on food labels can help in making healthier food choices and assist in achieving the goals of diabetes management. Food labels are astonishingly crammed with what can be confusing information. Aside from the listed ingredients of the product, there are usually two other broad categories of information included on the packaging; nutritional facts and nutritional claims.

example, should include the nutritional information per serving size to determine how many nutrients and how much energy are being consumed, as well as the per 100-g values to enable comparison between products and food types.

LISTED INGREDIENTS Ingredients are listed in order from the largest to the smallest amount used, based on the weight of the ingredients. Usually, the first three on the list are the major ingredients of the product.

Food additives such as flavourants, colourants or preservatives will also be included. These help you to compare similar products and avoid ingredients that you don’t want to eat. See Table 3 for some of the listed ingredients you may encounter on food labels that can be interpreted to mean fat, or sugar, or salt.

The serving size information should not be ignored! Packaged foods often include more than one portion or serving. A box of breakfast cereal, for

Calorie/kilojoule content This tells how much energy there is in one portion/ recommended serving size.

NUTRITIONAL CONTENT The nutritional content is the section of the food label that elaborates on the specific nutrients contained in a product, usually being the fat, carbohydrate, protein, vitamin and mineral content per serving size, and weight in grams.

These contents will also be expressed as a percentage of daily nutrient reference value (%NRV), which is the amount of that nutrient required in order to stay healthy. A %NRV < 5% is considered low, whereas a %NRV > 20% is considered high. These figures are based on the average population, and ill health may require modification of daily nutrient needs.

Fat The right kind of fat provides energy and nutrition to the body, but too much fat or the wrong types of fat can increase risk for the development of diabetes and cardiovascular disease. South African guidelines for diabetes recommend a fat intake of < 35% of total energy intake.

Total fat: This is the total of all the different types of fats that may be in the foodstuff (saturated, unsaturated, trans, cholesterol). Choose ‘low-fat’ or

105

Calcium

Iron

%NRV

mg

%NRV

g

%NRV

g

%NRV

g

%NRV

g

g

%NRV

%NRV

%NRV

%NRV

Protein

g

Sugars

Vitamin C

Dietary fibre

Vitamin A

Serving Size (gram weight)

Total carbohydrates

on a 2 000-calorie diet

Potassium

Value (%NRV) based

Sodium

Nutrient Reference

Calories

portion. Percentage

Total fat

Raw, edible weight

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Calories from fat

PATIENT INFORMATION LEAFLET

Asparagus 5 spears – 93 g

20

0

0

0

0

0

230

7

4

1

2

8

2

2

10

15

2

2

Bell pepper 1 medium – 148 g

25

0

0

0

40

2

220

6

6

2

2

8

4

1

4

190

2

4

Broccolli 1 medium stalk – 148 g

45

0

0.5

1

80

3

460

13

8

3

3

12

2

4

6

220

6

6

Carrot 1 medium – 78 g

30

0

0

0

60

3

250

7

7

2

2

8

5

1

110

10

2

2

Cauliflower 1/6 medium head – 99 g

25

0

0

0

30

1

270

8

5

2

2

8

2

2

0

100

2

2

Celery 2 medium stalks – 99 g

15

0

0

0

115

5

260

7

4

1

2

8

2

0

10

15

4

2

Cucumber 1/3 medium – 99 g

10

0

0

0

0

0

140

4

2

1

1

4

1

1

4

10

2

2

Green beans 3/4 cup cut – 83 g

20

0

0

0

0

0

200

6

5

2

3

12

2

1

4

10

4

2

Green cabbage 1/12 medium head – 84 g

25

0

0

0

20

1

190

5

5

2

2

8

3

1

0

70

4

2

Iceberg lettuce 1/6 medium head – 89 g

10

0

0

0

10

0

125

4

2

1

1

4

2

1

6

6

2

2

Leaf lettuce 1 1/2 cups shredded – 85 g

15

0

0

0

35

1

170

5

2

1

1

4

1

1

130

6

2

2

Mushrooms 5 medium – 84 g

20

0

0

0

15

0

300

9

3

1

1

4

0

3

0

2

0

2

Onion 1 medium – 148 g

45

0

0

0

5

0

190

5

11

4

3

12

9

1

0

20

4

4

Potato 1 medium – 148 g

110

0

0

0

0

0

620

18

26

9

2

8

1

3

0

45

2

6

Radishes 7 radishes – 85 g

10

0

0

0

55

2

190

5

3

1

1

4

2

0

0

30

2

2

Mielies kernels from 1 medium ear – 90 g

90

20

2.5

4

0

0

250

7

18

6

2

8

5

4

2

10

0

2

Sweet Potato 1 medium – 130 g

100

0

0

0

70

3

440

13

23

8

4

16

7

2

120

30

4

4

Tomato 1 medium – 148 g

25

0

0

0

20

1

340

10

5

2

1

4

3

1

20

40

2

4

Table 1. Vegetable nutrition facts (adapted from US Food and Drug Administration Vegetables nutrition facts, 1 January, 2008).

‘fat-free’ products. Some fat-free foods can be very high in sugar and

Unsaturated fat (mono- or polyunsaturated fat): These are termed ‘good’

total energy, so pay attention to these values if weight loss is a goal. Low-

fats and come from plant sources such as nuts, seeds and other plant

fat products have a fat content of below or equal to 3 g per 100 g solids

oils. These fats may help reduce the risk of heart disease.

or 1.5 g per 100 ml liquids. Try to choose products with less than 5% total fat and the lowest saturated fat content.

Trans fat: These fats form in the process of hydrogenation, a manufacturing technique that converts liquid oils into partially solid products. Trans

Saturated fat: This type of fat is the key player in raising cholesterol levels. It

fats lower HDL (good) cholesterol levels. Look out for partially hydrogen-

is mostly found in animal fats and dairy products (as well as hard brick mar-

ated fats on the ingredients list as they are the main source of trans fat.

garines), but may also be found in some tropical plant fats such as coconut

Cut down on processed foods and commercially baked products (e.g.

or palm kernel oil (in coffee creamers, tea whiteners, artificial cream, ice

biscuits, crackers, cakes), and choose products that are free of trans

cream and chocolate, for example). Low saturated fat values are 1.5 g per

fats, as indicated by values of less than 1 g per 100 g of fat/oil in the

100 g or 0.75 g per 100 ml, and not more than 10% of total energy.

product.

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VOLUME 10 NUMBER 3 • SEPTEMBER 2013

Calcium

Iron

%NRV

mg

%NRV

g

%NRV

g

%NRV

g

%NRV

g

g

%NRV

%NRV

%NRV

%NRV

Protein

g

Sugars

Vitamin C

Dietary fibre

Vitamin A

Serving Size (gram weight)

Total carbohydrates

on a 2 000-calorie diet

Potassium

Value (%NRV) based

Sodium

Nutrient Reference

Calories

portion. Percentage

PATIENT INFORMATION LEAFLET

Total fat

Raw, edible weight

Calories from fat

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Apple 1 large – 242 g

130

0

0

0

0

0

260

7

34

11

5

20

25

1

2

8

2

2

Avocado 1/5 medium – 30 g

50

35

4.5

7

0

0

140

4

3

1

1

4

0

1

0

4

0

2

Banana 1 medium – 126 g

110

0

0

0

0

0

450

13

30

10

3

12

19

1

2

15

0

2

Sweet melon/spanspek 1/4 medium – 134 g

50

0

0

0

20

1

240

7

12

4

1

4

11

1

120

80

2

2

Grapefruit 1/2 medium – 154 g

60

0

0

0

0

0

160

5

15

15

2

8

11

1

35

100

4

0

Grapes 3/4 cup – 126 g

90

0

0

0

15

1

240

7

23

8

1

4

20

0

0

2

2

0

Kiwifruit 2 medium – 148 g

90

10

1

2

0

0

450

13

20

7

4

16

13

1

2

240

4

2

Lemon 1 medium – 58 g

15

0

0

0

0

0

75

2

5

2

2

8

2

0

0

40

2

0

Lime 1 medium – 67 g

20

0

0

0

0

0

75

2

7

2

2

8

0

0

0

35

0

0

Nectarine 1 medium – 140 g

60

5

0.5

1

0

0

250

7

15

5

2

8

11

1

8

15

0

2

Orange 1 medium – 154 g

80

0

0

0

0

0

250

7

19

6

3

12

14

1

2

130

6

0

Peach 1 medium – 147 g

60

0

0.5

1

0

0

230

7

15

5

2

8

13

1

6

15

0

2

Pear 1 medium – 166 g

100

0

0

0

0

0

190

5

26

9

6

24

16

1

0

10

2

0

Pineapple 2 slices – 112 g

50

0

0

0

10

0

120

3

13

4

1

4

10

1

2

50

2

2

Plums 2 medium – 151 g

70

0

0

0

0

0

230

7

19

6

2

8

16

1

8

10

0

2

Strawberries 8 medium – 147 g

50

0

0

0

0

0

170

5

11

4

2

8

8

1

0

160

2

2

Cherries 1 cup – 140 g

100

0

0

0

0

0

350

10

26

9

1

4

16

1

2

15

2

2

Watermelon 2 cups diced – 280 g

80

0

0

0

0

0

270

8

21

7

1

4

20

1

30

25

2

4

Table 2. Fruit nutrition facts (adapted from US Food and Drug Administration Fruits nutrition facts, 1 January, 2008).

Cholesterol: This is found only in animal products. Aim for less than 300 mg dietary cholesterol per day. Bear in mind that vegetable oil is still 100% fat even though it is cholesterol free, so it will still contribute to your total fat intake. Low-cholesterol foodstuffs have values of less than 20 mg per 100 g or 10 mg per 100 ml.

but are often high in fat. Sugar-free foods are those with less than 0.5 g sugar per 100 g/ml.

Carbohydrates For people with diabetes, this is one of the most important sections of the food label. Blood sugar can be better controlled by dividing carbohydrate intake evenly over the snacks and meals of the day, and by eating fibrerich foods. South African guidelines recommend a carbohydrate intake of 45–60% total energy intake.

Protein Protein builds muscle, bone and teeth, and should make up 15–20% of the diet in people with diabetes.

Sugar (mono- or disaccharides): Many products may contain natural sugars that are not suitable for diabetics or for those who are watching their weight. Also look out for ‘diabetic’ products which claim to be sugar free,

VOLUME 10 NUMBER 3 • SEPTEMBER 2013

Fibre: High-fibre foods are those with a content of 3–6 g per 100 g. Aim for products with the highest fibre content.

Sodium (Na) Salt helps to balance the fluids in the body, but too much is harmful. A high sodium intake has been linked to high blood pressure, with table salt (sodium chloride/NaCl) being the source of sodium. Keep sodium intake to less than 2 000 mg per day (5 g table salt). Low-sodium foods have values of less than120 mg Na (305 mg salt) per 100 g, very low is less

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PATIENT INFORMATION LEAFLET

SA JOURNAL OF DIABETES & VASCULAR DISEASE

Table 3. Words that mean fat, sugar or salt.

FAT

SUGAR

SALT

Vegetable oil/fat Animal fat/oils Shortening Copha Lard Palm oil Coconut oil Butter Milk solids Monoglycerides Diglycerides Coconut

Sucrose Maltose Lactose Dextrose Fructose Mannitol Sorbitol Xylitol Glucose syrup Corn syrup Dissaccharides Honey

Sodium Na Monosodium glutamate (MSG) Sodium bicarbonate Sodium ascorbate Sodium lactate Yeast extracts Baking soda Vegetable salt

than 40 mg Na (102 mg salt) per 100 g, and virtually free values are less than 5 mg Na (13 mg salt) per 100 g.

Vitamins and minerals Vitamins and minerals are essential for a healthy and functioning body.

Different vitamins have different functions in maintaining a healthy body and it is advisable to obtain a range of vitamins from the foods you eat.

Remember that it is possible to take too much of some vitamins, so speak to your doctor before supplementing or substantially increasing vitamin intake.

NUTRITIONAL CLAIMS Nutritional claims on food labels can easily be confusing and even misleading. Some packaged foods will make claims of being healthy because, for example, the contents are sugar free; however, these foods may have an unhealthily high salt or fat content.

Watch out for words, statements and misleading descriptions which include ‘natural’ (on a processed food label), ‘healthy’, ‘wholesome’, ‘nutritious’, ‘heal’ and ‘cure’. Also be aware of claims stating that a foodstuff provides complete or balanced nutrition. You’ll recognise some of the nutrition claims below. What do they really mean?

Reduced fat: At least 25% less fat than the original product in the same brand, but the food may still have a high fat content. % Fat free: This can only be used for ‘low-fat’ products, the percentage based on the weight of fat in 100 grams of food; 98% fat free implies 2% fat content.

Cholesterol free: Do not confuse cholesterol free with low fat. Cholesterol is only found in foods containing animal fats. However, vegetable oils (e.g. canola, olive, sunflower) are 100% fat despite being cholesterol free.

‘Light’ or ‘Lite’: This does not necessarily mean low in energy or fat.

These words may also be used to mean light in colour, lightly toasted, light in salt, light in taste.

No added sugar: No refined sugars have been added. Remember that the food may be high in natural sugars (e.g. fruit juices).

‘Diet’: Usually means artificially sweetened.

Source of fibre: More than 1 g of fibre per 100 g High fibre: At least 3 g of fibre per 100 g FURTHER RESOURCES 1.

2.

3.

4.

5.

108

The South African Heart and Stroke Foundation. http://www.heartfoundation. co.za/topical-articles/label-reading Candadian Diabetes Association. www.healthyeatingisinstore.ca Diabetes UK. Food labelling. http://www.diabetes.org.uk/MyLife-YoungAdults/ Food-and-diet/Food-labelling/ American Drug Association. Taking a closer look at labels. http://www.diabetes. org/food-and-fitness/food/what-can-i-eat/taking-a-closer-look-at-labels.html Amod A, Ascott-Evans BH, Berg GI et al. The 2012 SEMDSA Guideline for the Management of Type 2 Diabetes (Revised). J Endocrinol Metab Diabetes S Afr 2012; 17(2): S1–S95.

VOLUME 10 NUMBER 3 • SEPTEMBER 2013

SA JOURNAL OF DIABETES & VASCULAR DISEASE

ADA WATCH

ADA WATCH SUMMARIES

2013 UPDATE FROM CHICAGO, USA American Diabetes Association 73rd scientific sessions Contributor: G Hardy

Intensive HbA1c management in type 1 diabetes sees persistent benefit Preliminary results of the latest data from the Diabetes Control and Complications trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) trial were published as abstracts and presented at the recent ADA meeting. The 10-year DCCT, which began in 1983, demonstrated a consistent beneficial effect of intensive therapy on reducing complications compared with conventional therapy.

The DCCT revealed that intensive therapy, lowering HbA1c levels to 7% rather than the 9%, which was standard practice at the time, in patients with type 1 diabetes diminished a range of complications by about 35 to 75%, establishing intensive therapy as the standard of care.

Improved glucose control was achieved with frequent insulin injections or insulin pump therapy, guided by frequent selfmonitoring of blood glucose with fingerprick testing.

The trial was extended into EDIC (now running for a total of 30 years); 95% of trial patients who are still alive continue to participate in the trial. While the initial DCCT results were dramatic, the effect of intensive therapy in reducing the longer-term consequences of complications, including kidney failure, loss of vision, amputations and heart disease, were unknown.

Over 18 years, those patients who had intensive management and maintained an HbA1c target of 7% had a 46% lower risk of retinopathy, a 39% reduced risk of microalbuminuria, and a 61% lower risk of macroalbuminuria (p < 0.0001 for all).

The long-term consequences of intensive therapy have shown a 50% reduction in risk for developing impaired kidney function. Intensive therapy also reduced the incidence of heart disease and stroke by almost 60%.

VOLUME 10 NUMBER 3 • SEPTEMBER 2013

21–25 June 2013

Researchers also reported new data on musculoskeletal complications, particularly cheiroarthropathy, which presents with peri-articular skin thickening of the hands and limited joint mobility. Cheiroarthropathy typically results from the accumulation of advanced glycation end-products in the collagen, and includes carpal tunnel syndrome, adhesive capsulitis, Dupuytren’s contracture, flexor tenosynovitis (or ‘trigger finger’), and prayer sign (or trouble holding the hands flat when palm-to-palm).

Researchers found that a third of about 1 200 patients (33%) had at least one type of this complication, with the most common being adhesive capsulitis, followed by carpal tunnel and then prayer sign. Another 20% of patients had at least two complications, and a further 10% had at least three. About 3% had four or more complications. Risk factors for these conditions included older age, female gender, longer duration of disease, and higher HbA1c levels over time. http://www.medpagetoday.com/MeetingCoverage/ ADA/40047 http://www.diabetes.org/for-media/2013/sci-sessionsdcct-edic.html

New therapeutic targets for type 2 diabetes Recent years have seen a dramatic expansion in the range of pharmacological therapy for type 2 diabetes. A range of new therapeutic targets were under discussion.

Beta-cells The beta-cell plays a crucial role in type 2 diabetes, with beta-cell pathways offering multiple potential drug targets. Free fatty acid receptor 1 (FFAR-1 or GPR40) is one of the most promising targets. Free fatty acids are both metabolic fuels and signalling pathways that are highly expressed in the beta-cells, the hypothalamus and the gut.

The investigational compound TAK-875 has shown reductions in HbA1c levels similar to those with glimepiride; with significantly fewer incidents of hypoglycaemia and no effect on weight, insulin sensitivity, blood pressure or pulse. The compound has also shown no significant drug-related adverse events.

Insulin receptors The most important cause of insulin resistance is obesity and treating obesity is probably the most effective way to treat insulin resistance. Other approaches include enhancing insulin receptor activity and modulating signalling downstream from the receptor. Enhancement and activation of insulin receptors has met with success in rodent models, but none of these compounds appear to be appropriate for human use. Other investigative agents potentiate insulin receptor activity to increase glucose uptake.

Targeting inflammation Reducing inflammation in adipose tissue and skeletal muscle with salsalate has

TABLE OF CONTENTS Intensive HbA1c management in type 1 diabetes sees persistent benefit......................................................... 109 New therapeutic targets for type 2 diabetes.................................................................................................. 109 Look AHEAD: lifestyle intervention in type 2 diabetes offers microvascular benefit but does not lower risk of cardiovascular disease...................................................................................................................... 110 Exercise may be the best medicine for diabetes patients................................................................................ 110 New perspectives on type 2 diabetes risk factors........................................................................................... 110

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ADA WATCH

positive metabolic consequences, including a decrease in numbers of white blood cells, neutrophils and lymphocytes, and HbA1c levels. Another target is the nuclear factor kappa-B, or NF-kB, a pathway that acts as a master regulator of inflammatory signalling in both adipose tissue and skeletal muscle. Pharmacological intervention in this pathway appears to have beneficial effects on the metabolism and inflammation.

Targeting glucose absorption and excretion One of the approaches to targeting glucose absorption and excretion is to enhance the activity of sodium glucose co-transporter 2 (SGLT-2) in order to boost renal glucose excretion. Dapagliflozin and canagliflozin have been approved for use by the Federal Drug Administration, and positive phase 3 data on empagliflozin were presented at the meeting. These agents can be used with other antiglycaemics but safety questions remain.

Look AHEAD: lifestyle intervention in type 2 diabetes offers microvascular benefit but does not lower risk of cardiovascular disease Look AHEAD (Action for Health in Diabetes) is the longest and largest randomised, controlled trial to examine the effects of an intensive lifestyle-intervention programme in overweight and obese participants with type 2 diabetes. Investigators presented 11-year results of lifestyle interventions designed to achieve at least a 7% weight loss, and increase physical activity to 175 minutes per week, implemented through group and individual sessions.

In terms of cardiovascular effects of intensive lifestyle interventions in type 2

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diabetes, the trial was stopped for futility reasons after a median follow up of 9.6 years. The primary outcome was a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for angina during follow up.

An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in the study population. However, it did show benefit of a 31% reduction in the risk of advanced kidney disease and a 14% reduction in the risk of diabetic retinopathy. Also of note was a 20% reduction in new incidence of depression in the intensive lifestyle-intervention arm.

Improvements in fitness levels saw improvements in other markers of metabolic risk, such as HbA1c levels and systolic blood pressure. LDL cholesterol levels were not improved with the intensive lifestyleintervention programme.

The Look AHEAD research group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369: 145–154. http://www.medscape.com/viewarticle/ 806816?t=1

Dr Dagogo-Black is also of the opinion that there are very limited roles for drugs and surgery. ‘Pharmacotherapy can help a very select cohort of patients who fail to respond to exercise and dietary changes, whereas bariatric surgery is appropriate for an even smaller and targeted cohort’.

Dr Barry Braun, associate professor of Kinesiology at the University of Massachusetts, stated that insulin sensitivity is improved dramatically by a single exercise session, and even more by a threemonth training programme. Research into the effects of exercise and metformin in patients with pre-diabetes indicate that while exercise plus metformin is not better than exercise alone, the combination is better than metformin alone.

Dr Paul Coen, assistant professor of Health and Physical Activity at the University of Pittsburgh, says that exercise provides additional benefits to cardiometabolic risk following bariatric surgery. Experts recommend 150 minutes of aerobic exercise a week; however any amount of exercise is better than none.

Exercise may be the best medicine for diabetes patients

New perspectives on type 2 diabetes risk factors

Dr Samuel Dagogo-Black, professor and director of Endocrinology, Diabetes and Metabolism at the University of Tennessee Health Science Centre, said ‘A preponderance of evidence mandates lifestyle change, principally exercise and diet, as the pre-eminent and primary consideration for any and all purposes where the goal is to improve insulin sensitivity, reduce obesity and prevent diabetes. The vast majority of overweight people who are insulin resistant will benefit greatly from a 5 to 10% weight loss.’

Epidemiological research continues to uncover a growing list of novel risk factors that include environmental elements.

Metals, plasticisers and air pollution are not typically considered risk factors for type 2 diabetes; however recent research suggests they should be. Epidemiological data have implicated environmental exposure to arsenic and phthalates, both common compounds used as plasticisers across the globe, as risk factors for the development of type 2 diabetes.

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EASD WATCH

EASD WATCH SUMMARIES

2013 UPDATE FROM BARCELONA, SPAIN European Association for the Study of Diabetes Contributor: G Hardy

Blood sugar control in type 1 diabetes: European study suggests gender bias in adults Analysis of data from 142 260 children and adult patients from 12 countries (predominantly European, also including New Zealand and the United States) has indicated that men with type 1 diabetes were better than women at controlling their blood sugar levels. However there was no significant difference in control between boys and girls.

Retrospective research from populationbased registers and clinical databases analysed blood sugar control over the previous 12 to 24 months, comparing the proportions of women and men with HbA1c levels ≥ 7.5%, adjusted for age and duration of diabetes across three age strata: paediatric (< 15 years), young adult (15–29 years) and adult (≥ 30 years).

Proportions of people with worse control as implied by HbA1c levels ≥ 7.5% ranged from 64.4% in boys to 74.0% in young adult women. No statistically significant gender difference was found in the paediatric population; however young adult women were 8% more likely to miss target than men of the same age, and of those older than 30 years, women were 6% more likely to miss target than men of the same age.

Prof Sarah Wild, University of Edinburgh, commented that one explanation for this phenomenon could be that women tend to have lower haemoglobin levels than men. http://www.sciencedaily.com/releases/2013/09/ 130923200309.htm

23–27 September 2013

in a presentation on behalf of the Scottish Diabetes Research Network, that historically, those with T1DM have been reported to have a reduced life expectancy, but there are little contemporary data available.

Given advances in medical care in recent years, Prof Colhoun and colleagues sought to determine current life expectancy in people with T1DM in Scotland. Nearly all individuals with diabetes in Scotland are registered with the Scottish Care Information – Diabetes Collaboration database. Data extracted from this database was linked with death data from the General Register to assess remaining life expectancy.

For those with T1DM aged 20 to 24 years, remaining life expectancy was 45 years for men and 47 years for women, compared to 56 and 61 years, respectively for the general male and female population. Remaining life expectancy for those aged 65 to 69 years was estimated at 12 years for both men and women, compared to 17 and 19 years, respectively for the general population.

The difference in remaining life expectancy between those with T1DM and the general population reduced with increasing age.

However, the substantial gap in life expectancy between those with T1DM and the general population needs to be addressed. http://www.easdvirtualmeeting.org/resources/4307 http://www.diabetes.co.uk/news/2013/Sep/longer-lifeexpectancy-for-type-1-diabetes-sufferers-in-scotland95744377.html

Social deprivation is a key mortality factor in type 1 diabetes Dr Stephen Thomas of Guy’s and St Thomas’ Hospitals NHS Foundation Trust report that social deprivation is an independent risk factor for mortality in people with type 1 diabetes. Social deprivation represents a combination of poverty, lack of access to healthcare facilities, lack of education, and other factors.

The Diabetes Clinical Academic Group analysed demographic and health resource utilisation data, as well as biochemical data of 1 038 T1DM patients attending two London specialist diabetes outpatient clinics, collected over a 10-year period. Of deceased patients, 61% represented the poorest 20% of the population range, as determined using the index of multiple deprivation (IMD). http://www.easdvirtualmeeting.org/resources/4307 http://www.medpagetoday.com/MeetingCoverage/ EASDEndo/41859

Mortality is increased when using sulfonylureas as first-line therapy in type 2 diabetes Prof Craig Currie, University of Cardiff, says that it may no longer be appropriate to offer sulfonylureas as first-line treatment in the patient with type 2 diabetes. New research indicates a higher mortality rate in

TABLE OF CONTENTS Blood sugar control in type 1 diabetes: European study suggests gender bias in adults...............................111

Improvements in life expectancy in Scottish patients with type 1 diabetes A study from the UK reveals that for people with type 1 diabetes (T1DM) who live in Scotland, life expectancy has improved substantially. Prof Helen Colhoun noted

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Improvements in life expectancy in Scottish patients with type 1 diabetes..................................................111 Social deprivation is a key mortality factor in type 1 diabetes......................................................................111 Mortality is increased when using sulfonylureas as first-line therapy in type 2 diabetes...............................112 Obesity is associated with lower mortality in older patients with type 2 diabetes........................................112 DPP-4 inhibitor trial data............................................................................................................................112 SAVOR TIMI 53 study.................................................................................................................................112 EXAMINE Cardiovascular Safety Outcomes trial..........................................................................................112

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patients receiving sulfonylureas than those receiving metformin.

Data from the Clinical Practice Research Datalink (CPRD) was used to evaluate the comparative risk of all-cause mortality for patients exposed to first-line diabetes monotherapy with either sulfonylureas or metformin. Each arm of the direct-matched cohort included 2 048 patients, with 8 836 patients in each propensity-matched arm.

Those patients prescribed sulfonylureas were 58% more likely to die from any cause than those prescribed metformin.

Additional research presented by Dr Currie indicated that a combination of metformin and a sulfonylurea significantly increased risk for death when compared with combination therapy of metformin and a DPP-4 inhibitor. Important to note, however, is that not all sulfonylureas are the same. Long-term outcomes from the ADVANCE study indicate that modifiedrelease gliclazide is safe. http://www.easdvirtualmeeting.org/resources/3059 http://www.medscape.com/viewarticle/811641

Obesity is associated with lower mortality in older patients with type 2 diabetes The role of obesity in the development of insulin resistance and type 2 diabetes (T2DM) is well recognised. Contrary to what may be expected, recent evidence has suggested that obese patients with type 2 diabetes may have lower morbidity and mortality rates compared to patients of normal weight.

Research by Dr Pierluigi Costanzo and colleagues from the Universities of Hull and York sought to establish the relationship between body mass index (BMI), mortality and cardiovascular morbidity in patients with diabetes. In total, 12 025 patients attending the diabetes service at Hull and East Yorkshire hospitals, NHS Trust, UK were followed for a mean of 10 years. Age, gender, height, weight, blood pressure and information on co-morbidities were recorded, as well as total mortality and hospital admissions for acute coronary syndrome, cerebrovascular accidents and heart failure.

Of the study population (54% men, mean age 60 ± 15 years, 15% T1DM, remainder T2DM), acute coronary syndrome occurred in 9%, cerebrovascular accident in 7% and a heart failure hospitalisation in 6%. Risk of acute coronary syndrome progressively increased with

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BMI, being 49% higher in obese (BMI > 30 kg/m2) patients. Obese patients also faced a 53% higher risk of heart failure.

However, risk of cerebro-vascular accident was 25% higher in overweight (BMI 25–28 kg/m2) patients. Despite increased risk of cardiovascular events with increasing BMI, all-cause mortality showed an inverse relationship with BMI, being 25% lower in obese subjects compared to those of normal weight in older (> 67 years) patients with type 2 diabetes.

Dr Costanzo explains, ‘…diabetes induced by the metabolic stress of obesity may be a fundamentally different problem from diabetes that develops in the absence of the stress of obesity. Alternatively, obesity may provide a protective metabolic reserve in older diabetic patients.’ http://www.easdvirtualmeeting.org/resources/4280 http://www.pri-med.com/pmo/MedicalNewsDetail. aspx?id=10968&topic=mc-topic::JJY7WSLM

DPP-4 inhibitor trial data Trial data on both saxagliptin and alogliptin were presented at the meeting. Neither agent showed an increased risk for pancreatitis or pancreatic cancer. Both drugs showed a modest reduction in HbA1c levels, reduced progression to use of insulin, both had a neutral effect on weight gain and low rates of hypoglycaemia (with the exception of the combination of saxagliptin in combination with sulfonylureas).

SAVOR TIMI 53 study The positive effect of blood glucose lowering on macrovascular complications is still controversial. In most cases, maintaining a target of near normal HbA1c levels requires a combination of several drugs. Recent retrospective analyses of several hypoglycaemic drugs have raised the possibility that they may have a negative effect on the heart.

The SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) TIMI 53 study was designed to assess the cardiovascular safety of saxagliptin, along with the possibility of beneficial cardiovascular effect. Cases of pancreatitis were also adjudicated.

Approximately 16 500 type 2 diabetes patients on any therapy except incretin therapy were randomised to either saxagliptin or placebo. Of those older than 40 years, 80% had known cardiovascular disease and the remainder were at high risk of developing cardiovascular disease.

The primary end-point of a combination of acute myocardial infarction, ischaemic stroke and death was equal in the saxagliptin and placebo arms. Hospitalisation for heart failure was significantly increased in the saxagliptin arm. No increase in death related to heart failure was associated with saxagliptin.

Other study results indicated that treatment with saxagliptin nearly doubled the percentage of patients attaining HbA1c target levels. Attaining target without hypoglycaemia was approximately double in the saxagliptin versus placebo arms in combination with any other agents except sulfonylureas. Major hypoglycaemic events were rare, the most at-risk patient being treated with saxagliptin and sulfonylurea, with HbA1c < 7% at baseline. No significant difference in reports of pancreatitis were evident between the saxagliptin and placebo arms.

EXAMINE Cardiovascular Safety Outcomes trial Data from the global EXAMINE (Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) cardiovascular safety outcomes trial indicated that alogliptin did not increase cardiovascular ischaemic events including all-cause mortality, non-fatal myocardial infarction, non-fatal stroke and urgent revascularisation due to unstable angina.

Exploratory data also showed that rates of hospitalisation for heart failure were comparable across alogliptin and placebo groups.

The EXAMINE trial did not have heart failure as a specific pre-specified endpoint on its own. It was included in a composite endpoint with death included, which showed no difference (HR = 1.07; p = 0.657). When a post hoc analysis was done on heart failure admissions only, it showed a clear increased trend, although not significant, with HR = 1.19 and p = 0.222.

The EXAMINE trial evaluated a total of 5 380 patients with type 2 diabetes and a recent acute coronary syndrome (within 15 to 90 days prior to randomisation). Alogliptin doses were adjusted according to renal function, and the median duration of alogliptin exposure was 533 days. At study end, mean HbA1c change from baseline was –0.33% and 0.03% in the alogliptin and placebo groups, respectively. http://www.medscape.com/viewarticle/811921 http://www.epgonline.org/news/2013/oct/savor-studyresults-foronglyza.cfm

VOLUME 10 NUMBER 3 • SEPTEMBER 2013

For people with type 2 diabetes

Do more than lower blood glucose.

Grab diabetes ™ by the roots Victoza® is the first and only human GLP-1 analogue with 97 % homology to natural GLP-11 Reduction in HbA1C2 Reduction in weight1,3 Improvement in beta-cell function3

The ADA / EASD position statement includes use of GLP-1 receptor agonists right after metformin4 References: 1. Victoza® Package Insert. 2. Zinman B., et.al. Achieving a clinically relevant composite outcome of an HbA1c of < 7 % without weight gain or hypoglycaemia in type 2 diabetes: a meta-analysis of the liraglutide clinical trial programme. Diabetes, Obesity and Metabolism. 2012;14:77–82. 3. Pratley R., et.al. One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial. Int J Clin Pract. 2011;65(4):397- 407. 4. Inzucchi S.E., et.al. Management of Hyperglycaemia in Type 2 Diabetes: A Patient-Centered Approach: Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetes Care. 2012;35(6):1364-1379.

Proprietary Name: Victoza®. Scheduling Status: S4 Composition: Liraglutide 6 mg/ml. Indications: As an adjunct to diet and exercise to achieve glycaemic control in patients with type 2 diabetes mellitus.

Registration Number: 43/21.13/0781. For full prescribing information refer to package insert approved by the medicines regulatory authority.

Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. 2nd Floor, Building A, 345 Rivonia Boulevard, Edenburg, Rivonia, Sandton 2128, South Africa. Tel: (011) 202 0500 Fax: (011) 807 7989 www.novonordisk.co.za VIC/ADVERT-MED/MAY/2013/1A CINGULATE 9024

DRUG TRENDS

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Drug Trends

Novo Nordisk Incretin and Cardiovascular summit

A

number of consistent key messages came through at Novo Nordisk’s Incretin and Cardiovascular summit, which took place in Durban on 29 June 2013. Despite some superficially conflicting evidence in clinical studies, early intensive therapy has long-term cardiovascular benefit in diabetes patients, consequent on a legacy effect or ‘metabolic memory’, even though these benefits may take years and even decades to manifest.

When treating patients, it is imperative to individualise treatment and keep cardiovascular safety in mind. While there was some debate as to whether diabetes is indeed a cardiovascular disease (CVD) equivalent, as has been suggested in some quarters, there is no question that people living with diabetes are at high risk of cardiovascular complications. This presents unique treatment challenges.

Incretin-based therapies are taking the management of diabetes in new and encouraging directions, providing optimal HbA1c control, with reduced or no risk of weight gain and reduced hypoglycaemia. Studies are on-going to show cardiovascular safety and, in due course, may even show benefit.

How early and aggressively should diabetes be treated?

Prof Brynne Ascott-Evans, head of the Division of Diabetes and Endocrinology, University of Stellenbosch, Tygerberg According to Prof Ascott-Evans, the answer to the question is ‘very early and very aggressively’. Intervention should begin in the pre-diabetic stage to reduce risk, slow progression to overt diabetes and prevent macrovascular complications. ‘Diabetes is a late manifestation of the metabolic syndrome and a cluster of CVD risk factors is often already present in pre-diabetes’, said Prof Ascott-Evans.

Studies have shown good results with lifestyle modification, but where these fail and/or in high-risk individuals, pharmacotherapy should be introduced early. Prompt tight control of glucose levels has a legacy effect that reduces the risk of complications in the long term.

Insulin can be introduced early too, even though it is not usually recommended as

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first-line therapy. However, Prof AscottEvans feels that there is sometimes a place for temporary insulin therapy at diagnosis in high-risk patients. ‘Several weeks of insulin therapy can help to normalise blood glucose levels, where after the patient can be controlled with diet and metformin.’

Newer therapies such as the incretins have the promise of protecting beta-cell function.

‘Effective treatment usually requires multiple drugs used in combination’, he concluded.

‘We need to intervene early in the natural history of diabetes to prevent progressive beta-cell failure, and that intervention needs to be aggressive.’

Choosing appropriate antidiabetic therapy in patients with CVD Prof Pankaj Joshi, emeritus professor of Medicine, Medical University of South Africa (MEDUNSA) • Type 2 diabetes mellitus is an independent CVD risk factor and should not be viewed only as a disease of blood sugar.

• The risk of CVD increases as glucose metabolism deteriorates.

• Antidiabetic therapy should achieve not only adequate glucose control, but also favourable cardiovascular safety profiles and outcomes.

• Therapy should be selected and individualised appropriately.

• Overall, metformin is still the best choice in respect of cardiovascular protection, but the incretins may show benefits in future.

Is type 2 diabetes really a CVD risk equivalent?

Dr Hoosen Randeree, specialist physician and endocrinologist in private practice, Durban The increase in cardiovascular morbidity and mortality associated with diabetes is well established but ‘equivalence’ implies the same future risk of CVD, with the practical implication that intervention strategies should yield similar benefits.

Answering the question is complicated by the fact that different studies have different endpoints as well as varying definitions of coronary artery disease (CAD)/coronary heart disease (CHD), blurring the associations

seen. Dr Randeree cited as an example the fact that people living with diabetes have a lower risk of future myocardial infarction (MI) than individuals who have had a previous MI. ‘Baseline risk depends on the type of study and is much lower in large population studies than in those evaluating smaller, high-risk populations.’

Many determinants need to be taken into account when looking at the relationship between diabetes and CAD, including regional differences, ethnicity, age threshold for transition to high-risk status, age at diagnosis and duration of diabetes, type of diabetes therapy, risk factors, microvascular disease, family history and dietary/lifestyle habits. ‘There are many confounders in this relationship, which is not a linear one’, he said. ‘You therefore cannot call diabetes a CVD risk equivalent.’

It was a 1998 article by Haffner et al.1 that ‘started all the trouble’ by concluding risk equivalence, even though many other studies have shown this conclusion to be wrong. ‘Although diabetes is a major risk factor requiring aggressive treatment, a blanket approach, irrespective of overall risk may confer little benefit. Many factors influence risk, so treatment therefore needs to be individualised. We need to develop a unique model that takes into account diabetes-specific risk factors in order to risk-stratify diabetics in future. Just as HbA1c targets are individualised, so too must we differentiate patients in respect of future CVD risk.’

1.

Haffner SM, et al. N Engl J Med 1998; 339: 229– 234.

Acute coronary syndrome in diabetes: how do we improve clinical outcomes?

Dr Sajidah Khan, principal specialist in cardiology, Wentworth and Albert Luthuli central hospitals, Durban Acute coronary syndrome (ACS) in diabetics is associated with higher mortality rates, greater morbidity and more co-morbid conditions.

‘Type 2 diabetes is more than hyperglycaemia.

The unified pathophysiology of oxidative stress and subclinical inflammation drives both diabetes and CVD, and diabetics have

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accelerated atherosclerosis, increased rates of stenosis/re-occlusion and exaggerated inflammation.’

The only real difference between STEMI and non-STEMI ACS is that in the former, the thrombus occludes the vessel completely. This means that with STEMI every second counts, whereas one can wait before treating non-STEMI. ‘Symptoms of STEMI are unreliable in those with diabetes, and they may not present with classic chest pain’, said Dr Khan.

‘When performing primary percutaneous intervention (PCI), one should not use baremetal stents in diabetic patients, but rather second-generation drug-eluting stents.

However, the “limos” drugs do not work as well in diabetics as in non-diabetics, failing to inhibit smooth muscle proliferation, so paclitaxel is a better option.’ With regard to adjunctive antiplatelet therapy, prasugrel is more effective than clopidogrel in diabetics.

Many low- and middle-income countries have a shortage of PCI facilities and interventional cardiologists, which makes addressing ACS in these environments challenging, given that it requires prompt action. ‘If PCI is not an option, fibrinolysis is an alternative strategy. Further to this, the patient can be transferred to a PCI-capable facility for angiography and possible PCI if it is still appropriate.’

People living with diabetes are considered at high risk for non-STEMI and may be asymptomatic. ‘Thirty per cent of patients are hyporesponders to clopidogrel and in future, ticagrelor – which will be launched next year – will be a better option. As with diabetic therapies, antiplatelet and antithrombotic regimens are complex.’ People living with diabetes are also more likely to have adverse left ventricular remodelling, and this needs to be borne in mind.

Hyperglycaemia during ACS is a powerful predictor of in-hospital survival, and complications and so-called ‘stress hyperglycaemia’ is common in both diabetics and non-diabetics. Blood glucose control is therefore imperative, but the challenge is to achieve this without inducing hypoglycaemia, which has its own cardiovascular risks in respect of being arrhythmogenic and a precipitator of ischaemia. Symptom status is not a reliable predictor of ischaemia and provocative testing is required to assess the total ischaemic burden, which in turn predicts prognosis.

Summing up, Dr Khan observed that all STEMI patients should be taken to the catheterisation laboratory and that an early invasive strategy is also associated with better

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DRUG TRENDS

survival in non-STEMI. PCI with a drug-eluting stent should be followed by dual antiplatelet therapy for one year, and coronary artery bypass grafting should be undertaken when there is multivessel disease.

‘In developing countries, the progression of insulin resistance to diabetes parallels that of endothelial dysfunction to atherosclerosis.

Primary prevention, in the form of early aggressive diabetes therapy, is therefore important.’

Tailoring antidiabetes treatment in the era of CVD risk management Dr Rajendran Moodley, specialist physician in private practice, Umhlanga Diabetes management needs to move beyond glucose control to embrace multiple risk-factor intervention. ‘We need a broader understanding of diabetes to achieve integrated control of the condition. The traditional glucocentric approach is no longer appropriate,’ said Dr Moodley.

He too underscored the importance of early intensive therapy, pointing out that the apparently confounding results of the ACCORD trial, in which it was shown to be harmful, should not be overestimated. ‘The patients in that study were predominantly older individuals with a history of CVD events and multiple risk factors. They were therefore not representative of all diabetics.

Individualise the control and ensure treatment that is aggressive but tailored to each specific patient. When choosing therapy, consider the mechanism of action, the patient’s cardiovascular profile and any pleiotropic effects the agent(s) may have.’

Paradigms will shift with newer agents, and the incretins show promising cardiovascular benefits, although some of these have yet to be translated into clinical practice. ‘There is evidence that the GLP-1 receptor agonists may have beneficial effects on the myocardium and endothelial function and, in high-risk patients, improve left ventricular function. To improve control, therapy must be intensive, integrated and individualised,’ he concluded.

New antidiabetic drugs and safety: an introduction to the LEADERTM trial Dr Adri Kok, specialist physician in private practice, Alberton Diabetes drugs need to be safe and help prevent CVD. The LEADERTM trial, currently

under way, is a five-year CVD outcomes study evaluating the GLP-1 receptor agonist, liraglutide. It is currently at the three-and-ahalf-year mark.

The trial population comprises people living with diabetes over the age of 50 years with a history of CVD events that puts them at high risk. ‘So far we’re seeing effective HbA1c control along with significant weight reduction and an absence of hypoglycaemic episodes. So there is safety, but not necessarily fewer events. It will be interesting to see what comes out.’

GLP-1: glucose lowering and beyond Prof Jeffrey Wing, chief physician and professor of Medicine, Charlotte Maxeke Johannesburg Hospital Prof Wing underscored the importance of addressing overweight and obesity in diabetes management. ‘Weight is a composite target and the relationship between body mass index (BMI) and diabetes risk is well established. Weight is also linked to other CVD risk factors and co-morbidities, as well as being associated with increased mortality rates.’

Routine lifestyle intervention has shown little benefit in the medium to long term in respect of cardiovascular outcomes.

‘The genetic component of obesity is underestimated. The impact of genes is also underplayed in type 2 diabetes itself, where they have an important role.’

Bariatric surgery in the form of the Rouxen-Y gastric bypass has shown remarkably successful outcomes, with durable weight reduction as well as metabolic, cardiovascular and diabetes mortality benefits. ‘The risk of developing diabetes in obese, non-diabetic individuals was reduced, and blood pressure, lipid levels and general cardiovascular risk scores all improved. There’s no doubt that surgery works and even though it’s an expensive procedure initially, it’s been shown to be cost effective in the long term.

So should it be universally available?’

Current guidelines, however, recommend surgery only in specific patients after failed medical treatment. Yet bariatric surgery reduces appetite, increases satiety and GLP-1 levels. The question then is, ‘Can this be achieved without surgery?’

Yes, injectable GLP-1 analogues can mimic what bariatric surgery can achieve.

Current evidence suggests that they bring about weight reduction that is durable and sustained. They provide a composite

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treatment that lowers both blood glucose levels and weight, while also being safe in respect of another important component of diabetes, namely hypoglycaemia.

Hypoglycaemia and cardiovascular outcomes in diabetes Prof Wolfgang Schmidt, chief of GI/ Hepatology and Diabetes Services and director of the Department of Medicine, St Josef-Hospital, Ruhr-University Medical School, Bochum, Germany Hypoglycaemia is an important confounder in the management of diabetes, and glycaemic control is only a part of the story. To achieve an overall favourable outcome also requires control of CVD risk factors and an avoidance of weight gain and hypoglycaemic episodes.

Multiple studies have shown the benefits of good early glycaemic control and its association with a lower CHD event rate. Its legacy effect confers significant benefit 10 to 15 years later. The challenge in achieving this favourable scenario lies in attaining

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glycaemic control, lowering lipid levels and blood pressure and avoiding hypoglycaemia while not doing harm. Intensive intervention in diabetes and better glycaemic control often come at the price of increased weight gain and more hypoglycaemic episodes, which is a bad risk–benefit ratio. Certain patients are at particular risk, including the elderly, those with diabetes of longer duration and/or a high baseline HbA1c level, and patients with renal dysfunction or peripheral neuropathy.

Severe hypoglycaemic events are associated with a 2.5% higher mortality rate so therapy-induced hypoglycaemia must be avoided. ‘Why is it so dangerous?’ asked Prof Schmidt. ‘It has pro-arrhythmic effects, is associated with cognitive dysfunction and delayed recovery in the elderly and is both pro-thrombotic and pro-inflammatory. In addition it causes increased anxiety in patients, which in turn has a negative impact on compliance.’ So control needs to be both stringent and safe from the time of diagnosis.

‘In 2013, when managing diabetes, we need to avoid hypoglycaemia, especially in

those with cardiovascular risk, avoid weight gain, and reconstitute beta-cell function and stop their loss. Is GLP-1 incretin therapy an option?’

Prof Schmidt feels strongly that it is.

‘GLP-1 normalises glucose levels in poorly controlled patients, without causing hypoglycaemia. Liraglutide improves firstphase insulin secretion and maximal betacell insulin capacity. Importantly, it does not induce insulin secretion when glucose levels are low. Used in combination with metformin, the risk of hypoglycaemia is low, comparable with that of placebo. It also improves biomarkers of CVD risk, notably reducing systolic blood pressure.’

Liraglutide therefore has a favourable impact on the composite endpoint of optimal HbA1c concentrations, weight loss and hypoglycaemia. ‘It shows great promise in helping us get our patients to their individualised HbA1c targets early, without weight gain and hypoglycaemia, while preserving beta-cell function,’ Prof Schmidt concluded.

P Wagenaar

VOLUME 10 NUMBER 3 • SEPTEMBER 2013

EVIDENCE BASED

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References: 1. DeFronzo RA, Hissa MN, Garber AJ, et al. Once-daily saxagliptin added to metformin provides sustained glycaemic control and is well tolerated over 102 weeks in patients with T2D. Abstract.

Presented at ADA 69th ScientiďŹ c Session. New Orleans. 2009. 2. GĂśke B, Gallwitz B, Eriksson JG, et al. Saxagliptin vs. glipizide as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: long-term (52-week) extension of a 52-week randomised controlled trial. Int J Clin Pract 2013;doi: 10.1111/ijcp.12119.

S3 ONGLYZAÂŽ 2.5 (Tablet) . Each ONGLYZAÂŽ 2.5 tablet contains saxagliptin hydrochloride equivalent to 2.5 mg saxagliptin free base. S3 ONGLYZAÂŽ 5 (Tablet). Each ONGLYZAÂŽ 5 tablet contains saxagliptin hydrochloride equivalent to 5 mg saxagliptin free base. Reg. No. ONGLYZAÂŽ 2.5 : 43/21.2/0608. Reg. No. ONGLYZAÂŽ 5 : 43/21.2/0609. ONGLYZAÂŽ is a registered trademark of Bristol-Myers Squibb. For full details relating to any information mentioned above please refer to the package insert. Bristol-Myers Squibb (Pty) Limited. Reg. No. 1956/001115/07. Woodmead North OfďŹ ce Park, 54 Maxwell Drive, Woodmead, 2191. PO Box 227, Sunninghill, 2157. Tel: (011) 808 5000. Fax: (011) 808 5301. AstraZeneca Pharmaceuticals (Pty) Ltd. Reg. No. 1992/005854/07. Building 2, Northdowns OfďŹ ce Park, 17 Georgian Crescent West, Bryanston, 2191. Private Bag X23, Bryanston, 2021. Tel: 011 797-6000. Fax: 011 797-6001. www.astrazeneca.co.za. Expiry Date: August 2015. Log No: ONG 09/13/004