1. Metabolic Syndrome Malek M., MD Associated Professor of Endocrinology and Metabolism Semnan University of Medical Sciences

3. METABOLIC SYNDROME HISTORY DEFINITIONS PREVALANCE IMPORTANCE OF METABOLIC SYNDROME CRITICAL LOOK AT THE METABOLIC SYNDROME TREATMENT

4. “ Metabolic syndrome is a cluster of the most dangerous cardiovascular risk factors namely diabetes, abdominal obesity, high lipid and elevated blood pressure”. METABOLIC SYNDROME

5. Other Names Used Syndrome X Cardiometabolic Syndrome Cardiovascular Dysmetabolic Syndrome Insulin-Resistance Syndrome Metabolic Syndrome Reaven’s Syndrome etc.

6. Metabolic Syndrome (History) 1923 - Kylin first to describe the clustering of hypertension, hyperglycemia, hyperuricemia 1936 - Himsworth first reported Insulin insensitivity in diabetics 1965 - Yalow and Berson developed insulin assay and correlated insulin levels & glucose lowering effects in resistant and non-resistant individuals

7. Metabolic Syndrome History (cont.) 1988 - Reaven in his Banting lecture at the ADA meeting coined the term Syndrome X and brought into focus the clustering of features of Metabolic Syndrome

8. World Health Organization (WHO) 1998 Adult Treatment Panel III, 2001 American Association of Clinical Endocrinologists (AACE2003) International Diabetes Foundation (IDF 2005) European Group for the Study of Insulin Resistance, EGIR American Heart Association (AHA) and National Heart, Lung and Blood Institute (NHLBI), 2005 Metabolic Syndrome (History)

9. Definitions & Criteria of Diagnosis

10. WHO definition of ‘Metabolic Syndrome’ AT LEAST ONE OF: glucose intolerance IFG type 2 diabetes insulin resistance* AT LEAST TWO OF:  arterial pressure  140/90 mmHg  plasma triglycerides  1.7 mmol/l or 150 mg/dl and/or  HDL cholesterol < 0.9 mmol/l or 35 mg/dl for men; < 1.0 mmol/l or 39 mg/dl for women central obesity waist:hip ratio > 0.90 for men, > 0.85 for women; and/or BMI > 30 kg/m 2 microalbuminuria urinary albumin excretion rate  20  g/min or albumin to creatinine ratio  30 mg/g * Insulin resistance defined under hyperinsulinemic, euglycemic conditions as glucose uptake below the lowest quartile for the background population under investigation + World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: Diagnosis and classification of diabetes mellitus. WHO Department of Noncommunicable Disease Surveillance; 1999.

11. Draw backs in the WHO Definition 1- BMI is not a reliable measure to obesity 2- Microalbuminuria is very rarely found in absence of diabetes. 3- Euglyc. clamp is not practically applicable (clinically or epidem.)

12. Risk FactorCriterion Abdominal Obesity Men Women Waist Circumference >102 cm (>40 in) >88 cm (>35 in) Triglycerides  150 mg/dL HDL-Cholesterol Men Women <40 mg/dL <50 mg/dL Blood Pressure  130/  85 mm Hg Fasting Glucose  110 mg/dL NCEP ATP III. JAMA. 2001;285:2486-2497. The Metabolic Syndrome (ATP III) & Criteria

13. The ATP III Definition 2001( cont. ) Draw back - absence of ethnic consideration in the cut-off points.

14. International Diabetes Federation (IDF) Consensus Definition 2005 Central Obesity Waist circumference – ethnicity specific* – for Europids: Male > 94 cm Female > 80 cm plus any two of the following: Raised triglycerides> 150 mg/dL (1.7 mmol/L) or specific treatment for this lipid abnormality Reduced HDL cholesterol< 40 mg/dL (1.03 mmol/L) in males < 50 mg/dL (1.29 mmol/L) in females or specific treatment for this lipid abnormality Raised blood pressureSystolic : > 130 mmHg or Diastolic: > 85 mmHg or Treatment of previously diagnosed hypertension Raised fasting plasma glucose Fasting plasma glucose > 100 mg/dL (5.6 mmol/L) or Previously diagnosed type 2 diabetes If above 5.6 mmol/L or 100 mg/dL, OGTT is strongly recommended but is not necessary to define presence of the syndrome.

15. Ethnic specific values for waist circumference Waist circumference Country / Ethnic group 94 cm 80 cm Male Female Europids* In the USA, the ATP III values ( 102 cm male; 88 cm female) are likely to continue to be used for clinical purposes 90 cm 80 cm Male Female South Asians Based on a Chinese, Malay and Asian-Indian population 90 cm 80 cm Male Female Chinese 90 cm 80 cm Male Female Japanese** Use South Asian recommendations until more specific data are available Ethnic South and Central Americans Use European data until more specific data are available Sub-Saharan Africans Use South Asian recommendations until more specific data are available EMME ( Arab) populations

16. Waist circumference cut-off points for the diagnosis of metabolic syndrome in Iranian adults. 91.5cm in men 85.5cm in women Esteghamatit A et al. Diabetes Res Clin Pract. 2008 Oct;82(1):104-7.

17. The IDF Definition does not have the final word 1- more research will possibly reveal more accurate predictive indices. 2- other major risk factors for CVD ( e.g. smoking & LDL cholesterol ) must be taken in consideration

20. Prevalence of the Metabolic Syndrome

21. 50 40 30 20 10 0 Prevalence (%) Years of age 20-70+20-2930-3940-4950-5960-6970+ Metabolic syndrome was defined according to NCEP ATP III criteria. Ford ES JAMA 2002;287:356-9 Men Women Prevalence of the Metabolic Syndrome according to age

22. Prevalence of ATP III metabolic syndrome among subjects in the NHANES III survey by race/ethnicity and sex Ford, ES. JAMA 2002; 287:356.

23. Comparing criteria in defining populations Using data from the National Health and Nutrition Examination Survey 1999-2002 database;  1- IDF criteria: 39 percent ATP III criteria: 34.5 percent  2- the IDF criteria categorized 15 to 20 percent more adults with the metabolic syndrome than the ATP III criteria. 1-Ford, ESDiabetes Care 2005; 28:2745. 2-Adams, RJ. Diabetes Care 2005; 28:2777.

24. Why is MetS Important?

25. Causes 2-3 fold increase in cardiovascular risk of mortality. Considered as a risk factor for Diabetes mellitus (up to 5% fold increase in risk). Even with 2 components- increased mortality from CVD and CHD. Risk of stroke increases 3 fold. Reduced cardiorespiratory fitness. Associated with: Essential hypertension, Polycystic ovarian syndrome, Nonalcoholic fatty liver disease Gallstone disease, Cancer (i.e., breast cancer), Sleep apnea Why is MetS Important?

27. Risk of CVD Three meta-analyses found that the metabolic syndrome increases the risk for incident cardiovascular disease (CVD) (RRs ranging from 1.53 to 2.18) and all cause mortality (RRs 1.27 to 1.60) [1] Ford, ES. Diabetes Care 2005; 28:1769. [2] Galassi, A, Reynolds, K, He, J. Am J Med 2006; 119:812. [3] Gami, AS, Witt, BJ, Howard, DE.J Am Coll Cardiol 2007; 49:403.

28. Prediction of cardiovascular disease by metabolic syndrome in individuals aged over 40 yrs according to the ATP III and IDF definition: Tehran Lipid and Glucose Study (45%) MS according to the ATP III and (50%) IDF criteria The ATP III and IDF similarly predict CVD neither of the 2 definitions had this predictive power after adjustment of their components in addition to the earlier mentioned ones. Malek et al.IJEM.2006

29. Prevalence of Metabolic Syndrome by the ATPIII, DF, and WHO Definitions and their Association with CHD in an Elderly Iranian Population ATPIII and WHO definitions seem to be more pertinent than IDF for screening CHD risk. None of these definitions showed association with CHD when considering their components. prevalence of MS was 50.8%, 41.8% and 41.9% based on the (ATPIII),(WHO), and (IDF) definitions, respectively Hadaegh,Ann Acad Med Singapore 2009;38:142-9

30. Predictive value for diabetes strong predictive value of MetS for diabetes with both the NCEP and the WHO definition. (1)Edelstein SL, Diabetes 1997;46(4):701–10. (2) Ohlson LO,. Diabetes 1985;34(10):1055–8. (3) Haffner SM.Diabetes Care 1986;9(2):153–61. (4) Kaye SA. J Clin Epidemiol 1991;44(3):329–34. (5) Despre´ s JP. Diabetes 1989;38(3):304–9.

31. Framingham Offspring Study:  the NCEP definition showed a 6.9 fold risk and the WHO definition a 6.1 fold risk for type 2 diabetes Insulin Resistance Atherosclerosis Study; the NCEP, WHO, and IDF definitions of the MetS had similar predictive values for the incidence of type 2 diabetes, with adjusted odds ratios of 4.1, 3.7, and 3.4, respectively [1] Wilson PW. Circulation 2005;112(20):3066–72. [2] Hanley AJCirculation 2005;112(24):3713–21. Predictive value for diabetes

32. 1- IDF definition is not better in predicting cardiovascular disease than the NCEP definition in the Japanese Diabetes Complication Study 2-IDF definition is not superior to either the NCEP or the WHO definitions in predicting diabetes in the Insulin Resistance and Atherosclerosis Study (IRAS) population. 1- Sone H. Diabetes Care 2006;29(1):145–7. 2- Hanley AJ. Circulation 2005;112(24):3713–21. IDF definition was compared with the NCEP definition :

33. Mortality Associated With Metabolic Syndrome LakkaH-M et al. JAMA. 2002;288:2709-2716. 18 9 6 8 3 2 0 2 4 6 8 10 12 14 16 18 20 All-cause mortality*CVD mortality*CHD mortality* Metabolic syndrome No metabolic syndrome Mortality (% of patients)  2003 PPS ® *Adjusted for known CHD risk factors. POWERSEARCH PLUG-IN™ 2.0 Copyright © 2001-02 Accent Graphics, Inc. Slide Source: "R:\NDEI-2\2004 Grant\T108\ARS\T095 ARS Case 2 FINAL-Baton Rouge 12-09-03.ppt" <OPEN> Last Modified: December 9, 2003 2:17:25 PM Slide Number: 19 POWERSEARCH PLUG-IN™ 2.0 Copyright © 2001-02 Accent Graphics, Inc. Slide Source: "R:\NDEI-2\2004 Grant\T108\ARS\T095 ARS Case 2 FINAL-Baton Rouge 12-09-03.ppt" <OPEN> Last Modified: December 9, 2003 2:17:25 PM Slide Number: 19

34. Sattar Circulation 2003;108:414-419 Heart Disease 3.7 Fold Increase Heart Disease Risk with 4-5 Features of the Metabolic Syndrome

35. Sattar Circulation 2003;108:414-419 Diabetes 24.5 Fold Increase Risk of New Onset DM with 4-5 Features of the Metabolic Syndrome

36. PATHOGENESIS

37. Generalized Metabolic Derangement (Insulin Resistance) Obesity Physical Inactivity Adipose Tissue Disorders Genetic Insulin Resistance Endocrine Dysfunction Drugs Genetics & Ethnicity Race and Ethnicity Risk Factor Specific Metabolic Derangement Ethnic and Individual Variation Multiple Metabolic Risk Factors

38. Confusion results from different definitions Why ? differences in 1- the components of the MTS 2- the cut- off points This causes difficulties in : 1- identifying the MTS i.e. diagnosing 2- interpretation of its causation 3- comparing its burden in different populations

39. A CRITICAL LOOK AT THE METABOLIC SYNDROME  Lack of clarity of definition, with criteria differing between the ATP, WHO, and other definitions  Multiple different phenotypes included within the metabolic syndrome  Lack of a consistent evidence-base for setting the thresholds for the various components in the definitions Kahn, R. Diabetes Care 2005; 28:2289.

40.  Inclusion of patients with clinical CVD or diabetes as part of the syndrome which is intended to define risk for these diseases   Other risk factors for CVD which are not components of the metabolic syndrome, such as inflammatory markers, smoking and LDL, may have equal or greater bearing on risk. A CRITICAL LOOK AT THE METABOLIC SYNDROME Kahn, R. Diabetes Care 2005; 28:2289.

41.  The CVD risk associated with the metabolic syndrome has not been shown to be greater than the sum of its individual components  The critical weakness of the current metabolic syndrome construct is that treatment of the syndrome is no different than treatment for each of its components. 1- Grundy, SM. Circulation 2005; 112:2735. 2- Sundstrom, J. Diabetes Care 2006; 29:1673. A CRITICAL LOOK AT THE METABOLIC SYNDROME

42. All agree that the presence of one component of the metabolic syndrome should lead to evaluation for other risk factors. Whether patient benefit is gained from diagnosing patients with a syndrome of such uncertain characteristics or predictive value remains an open question.

43. Treatment  lifestyle therapies as first-line management weight reduction increased physical activity  Secondary treatment of individual components

44. Summary 20-25 % of the world adult population have the metabolic syndrome ( MTS), and these are : Metabolic syndrome increases the risk of both CVD and diabetes mellitus. - twice likely to die - 3 times likely to have a heart attack or stroke - 5 times at risk to develop diabetes type 2

45. Insulin resistance and obesity play primary roles. Many of the risk factors are modifiable. Treatment should be initiated for each of the components of metabolic syndrome to lower mortality and morbidity. Summary