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The IDF consensus worldwide de nition of the METABOLIC SYNDROME No part of this publication may be reproduced or transmitted in any form or by any means without the prior written permission of the International Federation (IDF). Requests to reproduce or translate IDF publications should be addressed to: IDF Communications Avenue Emile De Mot 19, B-1000 Brussels, Belgium by fax at +32-2-5385114 or by e-mail at [email protected]

© International Diabetes Federation, 2006

2 The IDF worldwide defi nition of the metabolic syndrome was developed during a unique consensus workshop on the initiative of Professors Sir George Alberti and Paul Zimmet. The workshop was held on behalf of the IDF Task Force on Epidemiology and Prevention.

After the meeting, a writing group was convened including: Sir George Alberti, London, UK Paul Zimmet, Melbourne, Australia Jonathan Shaw, Melbourne, Australia Scott M. Grundy, Dallas, USA, Consultant to Writing Group

The IDF metabolic syndrome consensus defi nition process (workshop) was supported by an educational grant from AstraZeneca Pharmaceuticals. AstraZeneca had no role in the development of the consensus defi nition, or in the review or approval of the manuscript.

This publication has been funded by IDF.

The IDF also gratefully acknowledges the contribution of: Pablo Aschner - Bogotá, Columbia Beverley Balkau - France Philip Barter - Sydney, Australia Peter Bennett - Phoenix, USA Edward Boyko - Seattle, USA John Brunzell - Seattle, USA Juliana Chan - Hong Kong, SAR China Ralph DeFronzo - San Antonio, USA Jean-Pierre Després - Québec, Canada Leif Groop - Lund, Sweden Markku Laakso - Kuopio, Finland Pierre Lefèbvre - Liège, Belgium Yuji Matsuzawa - Osaka, Japan Jean Claude Mbanya - Yaounde, Cameroon Chang Yu Pan - Beijing, China Ambady Ramachandran - Chennai, India Eberhard Standl - Munich, Germany Michael Stern - San Antonio, USA Jaakko Tuomilehto - Helsinki, Finland Nigel Unwin - Geneva, Switzerland

Colette Kon, Rapporteur IDF Executive Offi ce: Anne Pierson

3 The metabolic syndrome © Tihis | Dreamstime.com

The metabolic syndrome is a cluster In addition, people with metabolic of the most dangerous heart attack syndrome have a fi vefold greater risk factors: diabetes and raised risk of developing .5 fasting plasma , abdominal They would add to the 230 million , high cholesterol and high people worldwide who already have blood pressure.1-4 diabetes6a, one of the most common chronic diseases worldwide and It is estimated that around 20-25 per the fourth or fi fth leading cause of cent of the world’s adult population in the developed world. The have the metabolic syndrome and clustering of they are twice as likely to die from (CVD) risk factors that typifi es and three times as likely to have a the metabolic syndrome is now heart attack or compared considered to be the driving force for with people without the syndrome. a new CVD epidemic.

4 Diabetes and the metabolic syndrome– driving the CVD epidemic

Each year, 3.2 million people around what is now known as the ‘Metabolic the world die from complications Syndrome’. This ‘clustering’ of associated with diabetes. In countries metabolic abnormalities that occur with a high diabetes incidence, such in the same individual appear to as those in the Pacifi c and the Middle confer a substantial additional East, as many as one in four cardiovascular risk over and above in adults aged between 35 and 64 the sum of the risk associated with years is due to the disease. Type 2 each abnormality.8,9 diabetes, which accounts for 90 per cent of all diabetes, has become one However, even before levels of of the major causes of premature blood glucose are high enough illness and death, mainly through for a person to be diagnosed with the increased risk of CVD which is diabetes, hyperglycaemia and related responsible for up to 80 per cent of changes in blood lipids (increase in these deaths.6b,7 and decrease in the ‘good’ cholesterol HDL-c) increase In most people with glucose a person’s risk of CVD.8 The more intolerance or type 2 diabetes, there components of the metabolic is a multiple set of risk factors that syndrome that are evident, the higher commonly appear together, forming is the cardiovascular mortality rate.10

5 Global burden

The cardiovascular complications of The annual direct healthcare cost diabetes, which is also a leading cause of diabetes worldwide for this age of blindness, amputation and kidney group is conservatively estimated failure, account for much of the social to be as much as 286 billion ID, or and fi nancial burden of the disease.11 even more. If diabetes prevalence The prediction that diabetes incidence continues to rise as anticipated, it is will double by 2025 indicates a parallel likely that this fi gure will increase to rise in cardiovascular-related illness and 396 billion ID by 2025. This will mean death, with an inevitable and profound an expenditure of up to 13 per cent impact on global healthcare systems. of the world’s healthcare budget on diabetes care, with high prevalence With a rise in comorbid disease on countries spending up to 40 per cent this scale, the burden on national of their budget.6b healthcare systems and budgets is enormous. It was estimated that It is important to note that these in 2003 for the 25 European Union estimates of burden on national countries the total direct healthcare healthcare systems are for type 2 costs of all diabetes in 20 to 79 diabetes only and do not, as yet, year olds was up to 64.9 billion estimate the additional burden of international dollars (ID), equivalent CVD associated with metabolic to 7.2 per cent of the total health syndrome where clinical diabetes is expenditure for these countries.6b,12 not yet present.

6 What causes the metabolic syndrome?

The underlying cause of the much glucose in the blood) and will metabolic syndrome continues to be diagnosed with type 2 diabetes. challenge the experts but both Even before this happens, damage resistance and central obesity are is occurring to the body, including a considered signifi cant factors.13,14 build-up of triglycerides which further Genetics, physical inactivity, ageing, a impairs insulin sensitivity. proinfl ammatory state and hormonal changes may also have a causal Central obesity effect, but the role of these may vary Obesity is associated with insulin depending on ethnic group.15,16 resistance and the metabolic syndrome. Obesity contributes to , high serum cholesterol, Insulin resistance occurs when cells low HDL-c and hyperglycaemia, and is in the body (liver, skeletal muscle independently associated with higher and adipose/fat tissue) become less CVD risk.13,17,18 The risk of serious sensitive and eventually resistant health consequences in the form to insulin, the hormone which of type 2 diabetes, coronary heart is produced by the beta cells in disease (CHD) and a range of other the pancreas to facilitate glucose conditions, including some forms absorption. Glucose can no longer of cancer, has been shown to rise be absorbed by the cells but with an increase in remains in the blood, triggering (BMI),19 but it is an excess of body fat the need for more and more insulin in the abdomen, measured simply (hyperinsulinaemia) to be produced by circumference, that is more in an attempt to process the glucose. indicative of the metabolic syndrome The production of ever-increasing profi le than BMI.20-22 The International amounts of insulin weakens and may Obesity Task Force (IOTF) reports that eventually wear out the beta cells. 1.7 billion of the world’s population Once the pancreas is no longer able is already at a heightened risk of to produce enough insulin then a weight-related, non-communicable person becomes hyperglycaemic (too diseases such as type 2 diabetes.23

7 The need for early diagnosis and treatment: the IDF worldwide de nition of metabolic syndrome

With the metabolic syndrome driving Furthermore, the existence of the twin global epidemics of type 2 multiple defi nitions for the metabolic diabetes and CVD there is an syndrome has caused confusion overwhelming moral, medical and and has resulted in many studies economic imperative to identify those and research papers comparing individuals with metabolic syndrome the merits of each defi nition. It has early, so that lifestyle interventions also proved diffi cult to make direct and treatment may prevent the comparisons between the data from development of diabetes and/or studies where different defi nitions cardiovascular disease. have been used to identify the syndrome. A number of expert groups have developed clinical criteria for the IDF experts recognized that there was metabolic syndrome. The most widely a stark need for a single, universally accepted of these were produced by the accepted diagnostic tool that is easy World Health Organization (WHO), the to use in clinical practice and that European Group for the Study of Insulin does not rely upon measurements Resistance (EGIR), and the National only available in research settings. Cholesterol Education Program – Third Adult Treatment Panel (NCEP ATP The new IDF defi nition addresses III).24-26 All groups agreed on the core both clinical and research needs, components of the metabolic syndrome: providing an accessible, diagnostic obesity, insulin resistance, dyslipidaemia tool suitable for worldwide use and hypertension. However, the existing and establishing a comprehensive guidelines were either diffi cult to use or ‘platinum standard’ list of additional gave confl icting results when attempting criteria that should be included in to identify individuals with the metabolic epidemiological studies and other syndrome in clinical practice. research into the metabolic syndrome.

8 © Jxpfeer | Dreamstime.com

9 Worldwide de nition for use in clinical practice

While the pathogenesis of the Central (abdominal) obesity, easily metabolic syndrome and each of its assessed using waist circumference components is complex and not well and independently associated with understood, central obesity and each of the other metabolic syndrome insulin resistance are acknowledged components including insulin as important causative factors.15,16,27-29 resistance, is a prerequisite risk factor

Table 1: The new International Diabetes Federation (IDF) de nition

According to the new IDF defi nition, for a person to be defi ned as having the metabolic syndrome they must have:

Central obesity (defi ned as waist circumference* with ethnicity specifi c values)

plus any two of the following four factors: Raised ≥ 150 mg/dL (1.7 mmol/L) triglycerides or specifi c treatment for this lipid abnormality < 40 mg/dL (1.03 mmol/L) in males Reduced HDL < 50 mg/dL (1.29 mmol/L) in females cholesterol or specifi c treatment for this lipid abnormality Raised blood systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg pressure or treatment of previously diagnosed hypertension (FPG) ≥ 100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes Raised fasting If above 5.6 mmol/L or 100 mg/dL, OGTT is strongly plasma glucose recommended but is not necessary to defi ne presence of the syndrome.

* If BMI is >30kg/m², central obesity can be assumed and waist circumference does not need to be measured.

10 for the diagnosis of the syndrome in (ApoB), small dense LDL and small the new defi nition. Insulin resistance, HDL particles, all of which are which is diffi cult to measure in day-to- independently atherogenic30, and day clinical practice, is not an essential which is commonly observed in requirement. people with both type 2 diabetes and the metabolic syndrome. Atherogenic dyslipidaemia Low HDL-c and high TG levels describes the combination of are frequently found with insulin raised triglycerides (TG) and low resistance, with or without type 2 concentrations of HDL-c together diabetes31, and both are risk factors with elevated apolipoprotein B for coronary heart disease (CHD).32,33

Table 2: Ethnic speci c values for waist circumference

Waist Country/Ethnic group circumference Europids* Male ≥ 94 cm In the USA, the ATP III values (102 cm male; 88 cm female) are likely to continue to be used for Female ≥ 80 cm clinical purposes South Asians Male ≥ 90 cm Based on a Chinese, Malay and Asian-Indian population Female ≥ 80 cm Male ≥ 90 cm Chinese Female ≥ 80 cm Male ≥ 90 cm Japanese** Female ≥ 80 cm Ethnic South and Central Use South Asian recommendations until more Americans specifi c data are available Use European data until more specifi c data Sub-Saharan Africans are available Eastern Mediterranean and Use European data until more specifi c data Middle East (Arab) populations are available * In future epidemiological studies of populations of Europid origin, prevalence should be given using both European and North American cut-points to allow better comparisons. ** Originally different values were proposed for Japanese people but new data support the use of the values shown above.

11 © 2005 CE/A Martinez Alonso Central obesity is most easily in the USA for clinical diagnosis, measured by waist circumference it is strongly recommended that using the guidelines in Table 2 which for epidemiological studies and, are gender and ethnic-group (not wherever possible, for case detection, country of residence) specifi c. The ethnic group specifi c cut-points consensus group acknowledges that should be used for people of the these are pragmatic cut-points taken same ethnic group wherever they are from various different data sources found. Thus the criteria recommended and that better data will be needed for Japan would also be used in to link these to risk. expatriate Japanese communities, as would those for South Asian males Although a higher cut-point is and females regardless of place and currently used for all ethnic groups country of residence.34

12 ‘Platinum standard’ de nition– additional metabolic measurements for research

Table 3: Additional metabolic measurements for research

General body fat distribution (DEXA) Central fat distribution (CT/MRI) Abnormal body fat distribution biomarkers: , Liver fat content (MRS) Atherogenic dyslipidaemia ApoB (or non-HDL-c) (beyond elevated and low HDL) Small LDL particles Dysglycaemia OGTT Fasting insulin/proinsulin levels HOMA-IR Insulin resistance by Bergman Minimal Insulin resistance Model (other than elevated fasting glucose) Elevated free fatty acids (fasting and during OGTT) M value from clamp Vascular dysregulation Measurement of endothelial dysfunction (beyond elevated blood pressure) Elevated high sensitivity C-reactive protein Elevated infl ammatory (eg TNF- Proinfl ammatory state alpha, IL-6) Decrease in adiponectin plasma levels Fibrinolytic factors (PAI-1, etc) Prothrombotic state Clotting factors (fi brinogen, etc) Hormonal factors Pituitary-adrenal axis

The IDF consensus group has criteria for CVD and/or diabetes. highlighted a number of other The use of these additional factors parameters that appear to be related in research will also allow further to the metabolic syndrome (Table 3) modifi cation of the defi nition if which should be included in research necessary and the validation of the studies to help determine the new clinical defi nition in different predictive power of these extra ethnic groups.

13 14 © Marilyna | Dreamstime.com Recommendations for treatment

Once a diagnosis of the metabolic conversion to type 2 diabetes among syndrome is made, the future high-risk individuals with glucose management of the condition should intolerance who were, generally, be aggressive and uncompromising obese.35,36 in its aim to reduce the risk of CVD and type 2 diabetes. Patients should Secondary intervention undergo a full cardiovascular risk In people for whom lifestyle assessment (including smoking status) change is not enough and who in conjunction with the following: are considered to be at high risk for CVD, drug may be Primary intervention required to treat the metabolic IDF recommends that primary syndrome. There is a defi nite need management for the metabolic for a treatment that could modulate syndrome is a healthy lifestyle. This the underlying mechanisms of the includes: metabolic syndrome as a whole moderate calorie restriction (to and thereby reduce the impact achieve a 5–10 per cent loss of of all the risk factors and the long body weight in the fi rst year) term metabolic and cardiovascular moderate increase in physical consequences. However, these activity mechanisms are currently unknown change in dietary composition. and specifi c pharmacological agents are therefore not yet available. As The results of Finnish and American defi ned in Table 4, it is currently prevention of diabetes studies have necessary instead to treat the shown the marked clinical benefi ts individual components of the associated with a small weight syndrome in order that a lower loss (as well as increased physical individual risk associated with each activity) in terms of preventing (or at component will reduce the overall least delaying by several years) the impact on CVD and diabetes risk.

15 Table 4: IDF recommended treatment of the individual components of the metabolic syndrome Atherogenic dyslipidaemia Primary aims for therapy: Lower TG (as well as lowering ApoB and non-HDL cholesterol) Raise HDL-c levels Reduce LDL-c levels (elevated levels represent a high risk in the metabolic syndrome) Options: (PPAR alpha agonists) improve all components of atherogenic dyslipidaemia and appear to reduce the risk for CVD in people with metabolic syndrome. The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) showed that raising HDL-c concentrations using a fi brate in patients with well-established CHD and both a low HDL-c and a low LDL-c level will signifi cantly reduce the incidence of major coronary events.31 Statins to reduce all ApoB-containing lipoproteins and to achieve ATP III goals for LDL-c as well as for non-HDL-c (ATP III, 2001). Several clinical studies have confi rmed the benefi ts of statin therapy.37–39 Fibrates in combination with statins but may be complicated by side effects.

Elevated blood pressure Categorical hypertension (BP ≥ 140/≥ 90 mm Hg) should be treated according to the USA Seventh Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure (JNC 7) recommendations.40 In patients with established diabetes, antihypertensive therapy should be introduced at BP ≥ 130/≥ 80 mm Hg. Options: Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are useful antihypertensive drugs, with some clinical trials (but not all) suggesting they carry advantages over other drugs in people with diabetes. At this time, however, the majority of clinical trials suggest that the risk reduction associated with antihypertensive drugs is the result of blood pressure lowering per se and not due to a particular type of drug. No particular agents have been identifi ed as being preferable for hypertensive patients who also have the metabolic syndrome.

Insulin resistance and hyperglycaemia

There is growing interest in the possibility that drugs that reduce insulin resistance will delay the onset of type 2 diabetes and will reduce CVD risk when metabolic syndrome is present. The Diabetes Prevention Program (DPP) showed that metformin therapy in people with will prevent or delay the development of diabetes and recent thiazolidinedione studies have also demonstrated effi cacy in delaying or preventing type 2 diabetes in people with impaired glucose tolerance (IGT) and insulin resistance.41-43 Similarly, other studies have shown that both acarbose and orlistat can be used to delay the development of type 2 diabetes in people with IGT.44,45 Data do not yet exist to show whether any of the currently available thiazolidinediones reduce the risk of CVD in those with the metabolic syndrome, IGT or diabetes.

16 The group awaits with interest the effects. In addition, emerging results of ongoing thiazolidinedione such as incretin mimetics, and fi brate outcomes studies, as well dipeptidyl peptidase IV inhibitors, as the publication of clinical data for protein tyrosine phosphatase 1B the new generation of PPAR agonists inhibitors, and the endocannabinoid which interact with both PPAR alpha receptor blocking agents offer and gamma receptors, thereby potential as future therapies for the combining lipid and glycaemic metabolic syndrome.

Future work The IDF consensus group hopes that the aetiology of the metabolic this new defi nition, emphasizing the syndrome importance of central obesity with the best and most predictive modifi cations according to ethnic defi nition of the metabolic group, will be adopted worldwide syndrome and its components and prove convenient and useful in the relationship of blood pressure clinical practice and epidemiological to the other components of the studies. This should encourage the syndrome clinical diagnosis of the metabolic the relationship between different syndrome and the identifi cation of constellations of factors to CVD patients at considerably increased outcomes risk of developing CVD and/or type 2 the relationship of simple diabetes. and complex measures of the components of the metabolic A single worldwide defi nition syndrome to clinical events will enable easier comparison of the true impact of effective data from different studies and treatment of all components of an ongoing refi nement as more the syndrome on CVD risk information becomes available and better identifi cation of high risk as the following areas of further patients with metabolic syndrome research are explored: in different populations.

17 Frequently Asked Questions

What is the objective of the What is the pathogenesis of the new defi nition of the metabolic metabolic syndrome? syndrome? The primary underlying causes of To provide a simple diagnostic the metabolic syndrome have been and clinical tool to defi ne those suggested to be central obesity and at greater risk of type 2 diabetes insulin resistance. However, more and CVD, detect them early and research is needed to establish facilitate intervention. The tool will whether there is one single factor be particularly helpful in low-income or several which interact to give the countries where the metabolic characteristic picture of the metabolic syndrome is on an exponential rise. syndrome. Environmental factors such A single worldwide defi nition will as those associated with sedentary also ease comparison of data from lifestyle may be important too. different studies. Is the metabolic syndrome a valid Is the term “syndrome” adapted indicator of cardiovascular risk? to the clustering of metabolic risk The metabolic syndrome is not an factors? absolute risk predictor. However, The term clearly fi ts the defi nition of as a general rule, the risk from the a syndrome. For example, a well- metabolic syndrome for major CVD accepted defi nition of a syndrome events is approximately twice as high is a “group or recognizable pattern as for those without the syndrome. of symptoms or abnormalities that The risk for type 2 diabetes is indicate a particular trait or disease”. approximately fi ve-fold. Finally,

18 people with type 2 diabetes who also In practice: Frequently Asked present the metabolic syndrome carry a much higher risk of CVD than those How is central obesity measured? Questions who have type 2 diabetes alone. Central obesity is a prerequisite risk factor for metabolic syndrome which Is the risk of CVD greater in the can be easily assessed using waist metabolic syndrome than the sum circumference. The waist measurement of its parts? can be taken with a tape measure in Some studies have shown a purely a horizontal plane, midway between additive risk whilst others show a the inferior margin of the ribs and greater interaction. Whichever is true the superior border of the iliac crest. the metabolic syndrome provides Ethnic specifi c values should be taken a useful tool to identify high risk into account (see Table 2). people and to institute treatment. Have criteria been adapted to How can cardiovascular risk be children and adolescents? prevented and treated? A further consensus meeting has been Lifestyle change is the best way held by IDF on this subject and criteria by far to prevent increased risk of to diagnose metabolic syndrome cardiovascular disease and diabetes. in children and adolescents will be If that fails then the individual risk published in late 2006 or 2007. factors will require treatment with appropriate pharmacological agents. Have ATP III come in line with the new IDF criteria? How can the metabolic syndrome Apart from not making waist be diagnosed in clinical practice? circumference the central and The initial step is to measure waist essential component, the most circumference. This can be done by recent ATP III criteria are now in line people themselves. If that is raised with those of IDF. then the factors should be checked: blood pressure and a fasting blood sample for glucose, triglycerides and HDL-cholesterol.

19 References

1 Alberti KG, Zimmet P, Shaw J; IDF at risk of type 2 diabetes and/or Epidemiology Task Force Consensus cardiovascular disease? Diabetes Care Group. The metabolic syndrome- 2004;27(11):2676-81 a new worldwide defi nition. Lancet 2005;366:1059-62. 6a Diabetes Atlas, third edition, International Diabetes Federation, 2006 (in print) 2 Alberti KG, Zimmet P, Shaw J. Metabolic syndrome-a new world-wide defi nition. 6b Diabetes Atlas, second edition, A Consensus Statement from the International Diabetes Federation, 2003 International Diabetes Federation. Diabet Med 2006 May;23(5):469-80. 7 UKPDS Group. UK Prospective Diabetes Study 17: A nine-year update of a 3 www.idf.org/metabolic_syndrome, website randomized, controlled trial on the of the International Diabetes Federation effect of improved metabolic control on complications in non-insulin-dependent 4 The metabolic syndrome, Diabetes Voice diabetes mellitus. Ann Intern Med special issue, May 2006, 51. 1996;124:136–45

5 Stern M, Williams K, Gonzalez-Villalpando 8 Sattar N, Gaw A, Scherbakova O. C et al. Does the metabolic syndrome Metabolic syndrome with and without c- improve identifi cation of individuals reactive protein as a predictor of coronary

20 heart disease and diabetes in the West 15 Saad MF, Lillioja S, Nyomba BL et al. of Scotland Coronary Prevention Study. Racial differences in the relation between Circulation 2003;108:414-9 blood pressure and insulin resistance. New England Journal of 9 Golden SH, Folsom AR, Coresh J et al. 1991;324:733-9 Risk factor grouping related to insulin resistance and their synergistic effects 16 Anderson PJ, Critchley JAJH, Chan JCN on subclinical : the et al. Factor analysis of the metabolic atherosclerosis risk in communities study. syndrome: obesity vs insulin resistance Diabetes 2002;51:3069-76. as the central abnormality. International Journal of Obesity 2001;25:1782 10 Hu G, Qiao Q, Tuomilehto J et al for the DECODE Study Group. Prevalence of the 17 Zimmet P, Alberti KGMM, Shaw J. Global metabolic syndrome and its relation to and societal implications of the diabetes all-cause and cardiovascular mortality in epidemic. Nature 2001;414:782-7 nondiabetic European men and women. Arch Intern Med 2004;164:1066-76 18 Carey VJ, Walters EE, Colditz GA et al. Body fat distribution and risk of non- 11 World Health Organization. Prevention of insulin-dependent diabetes in women: diabetes mellitus. Technical Report Series the Nurses’ Health Study. Am J Epidemiol no. 844. WHO, Geneva, 1994 1997;145:614-19

12 Williams R. Implications for health 19 Lee IM, Manson JE, Hennekens CH et systems II. The medical and economic al. Body weight and mortality. A 27-year case for prevention of type 2 diabetes follow-up of middle-aged men. JAMA and cardiovascular disease. Presentation 1993;270:2823-8. at the International Diabetes Federation symposium “The Metabolic Syndrome”, 20 Pouliot MC, Després JP, Lemieux Brussels. 1st July, 2004 S et al. Waist circumference and abdominal sagittal diameter: best simple 13 Hu G, Qiao Q, Tuomilehto J et al. Plasma anthropometric indexes of abdominal insulin and cardiovascular mortality in visceral adipose tissue accumulation and non-diabetic European men and women: related cardiovascular risk in men and a meta-analysis of data from eleven women. Am J Cardiol 1994;73:460-8 prospective studies. The DECODE Insulin Study Group. Diabetologia 21 Ohlson LO, Larsson B, Svardsudd K et al. 2004;47:1245–56 The infl uence of body fat distribution on the incidence of diabetes mellitus: 13.5 14 Carr DB, Utzschneider KM, Hull years of follow-up of the participants in RL et al. Intra-abdominal fat is a the study of men born in 1913. Diabetes major determinant of the National 1985;34:1055-8 Cholesterol Education Program Adult Treatment Panel III criteria for 22 Rexrode KM, Carey VJ, Hennekens CH et the metabolic syndrome. Diabetes al. Abdominal adiposity and coronary heart 2004;53(8):2087-94 disease in women. JAMA 1998;280:1843-8.

21 23 Diabetes and Obesity: Time to Act. Insulin resistance and cardiovascular International Diabetes Federation (IDF) events with low HDL cholesterol. The and International Association for the Veterans Affairs HDL Intervention Trial Study of Obesity (IASO), 2004 (VA-HIT). Diabetes Care 2003;26(5):1513-7

24 World Health Organization. Defi nition, 32 Steinmetz A, Fenselau S, Schrezenmeir J. diagnosis and classifi cation of diabetes Treatment of dyslipoproteinemia in the mellitus and its complications. Report of metabolic syndrome. Exp Clin Endocrinol a WHO consultation 1999 Diabetes 2001:109:S548-59

25 Executive summary of the Third Report 33 Robins SJ, Collins D, Wittes JT et al. of The National Cholesterol Education Relation of Gemfi brozil treatment and Program (NCEP) Expert Panel on lipid levels with major coronary events. detection, evaluation, and treatment JAMA 2001;285:1585-91 of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 34 Tan CE, Ma S, Wai D et al. Can we apply 2001;285:2486-97 the National Cholesterol Education Program Adult Treatment Panel defi nition 26 Balkau B, Charles MA. Comment of the metabolic syndrome to Asians? on the provisional report from the Diabetes Care 2004;27:1182-6 WHO consultation. Diabetic Medicine 1999;16:442-3 35 Lindström J, Louheranta A, Mannelin M. The Finnish Diabetes Prevention Study 27 Nakamura T, Tokunga K, Shimomura (DPS): Lifestyle intervention and 3-year I et al. Contribution of visceral fat results on and physical activity. accumulation to the development of Diabetes Care 2003;26:3230-6. in non-obese men. Atherosclerosis 1994;107:239-46 36 Tuomilehto J, Lindström J, Eriksson JG et al. Prevention of Type 2 diabetes mellitus 28 Bonora E, Kiechl S, Willeit J et al. by changes in lifestyle among subjects Prevalence of insulin resistance in with impaired glucose tolerance. NEJM metabolic disorders: the Bruneck Study. 2001;344:1343-50 Diabetes 1998;47(10):1643-9 37 Heart Protection Study Collaborative 29 Nesto RW. The relation of insulin Group, MRC/BHF Heart Protection resistance syndromes to risk of Study of cholesterol-lowering with cardiovascular disease. Rev Cardiovasc simvastatin in 5963 people with diabetes: Med 2003;4(6):S11-S18 a randomised placebo-controlled trial. Lancet 2003;361:2005-16 30 Brunzell JD, Ayyobi AF. in the metabolic syndrome and type 2 38 Haffner SM, Alexander CM, Cook diabetes mellitus. Am J Med 2003 Dec TJ et al. Reduced coronary events in 8;115 Suppl 8A:24S-28S simvastatin-treated patients with coronary heart disease and diabetes mellitus or 31 Robins SJ, Rubins HB, Faas FH et al. levels: subgroup

22 analysis on the Scandinavian Simvastatin 45 Torgerson JS, Hauptman J, Boldrin MN et Survival Study. Arch Intern Med al. XENical in the Prevention of Diabetes 1999;159(22):2661-7 in Obese Subjects (XENDOS) Study. A randomized study of orlistat as an adjunct 39 Goldberg RB, Mellies MJ, Sacks FM to lifestyle changes for the prevention et al. for the CARE investigators. of type 2 diabetes in obese patients. Cardiovascular events and their Diabetes Care 2004;27:155-61. reduction with pravastatin in diabetic and glucose-intolerant survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial. Circulation 1998;98:2513-9.

40 Chobanian AV, Bakris GL, Black HR et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42(6):1206-52

41 Knowler WC, Barrett-Connor E, Fowler SE et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. NEJM 2002;346(6):393-403

42 Buchanan TA, Xiang AH, Peters RK et al. Preservation of pancreatic beta- cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796-803

43 Durbin RJ. Thiazolidinedione therapy in the prevention/delay of type 2 diabetes in patients with impaired glucose tolerance and insulin resistance. Diabetes, Obesity and 2004;6:280-5

44 Chiasson JL, Josse RG, Gomis R et al. STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 2003 Jul 23;290(4):486-94.

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