1. Cardiometabolic Syndrome Dr. Nabil Sulaiman HOD Family and Community Medicine, Sharjah University and University of Melbourne & Dr Dhafir A. Mahmood Consultant Endocrinologist Al- Qassimi & Al-Kuwait Hospital Sharjah

2. Agenda • History & Definition • Clustering component of Metabolic Syndrome • Cardiovascular disease worldwide • Global cardiometabolic risks • Abdominal obesity prevalence ( National & International ) • Intra Abdominal Adiposity & associated risks • Targeting Cardiometabolic Risk factors • Multiple Risk Factor management • A Critical Look at the Metabolic Syndrome

3. 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

4. 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 • Reaven now prefers the name, Insulin-Resistance Syndrome - feels insulin resistance is the common denominator for Metabolic Syndrome • Literature now extensive

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

6. Clustering of Components: • Hypertension: BP. > 140/90 • Dyslipidemia: TG > 150 mg/ dL ( 1.7 mmol/L ) HDL- C < 35 mg/ dL (0.9 mmol/L) • Obesity (central): BMI > 30 kg/M2 Waist girth > 94 cm (37 inch) Waist/Hip ratio > 0.9 • Impaired Glucose Handling: IR , IGT or DM FPG > 110 mg/dL (6.1mmol/L) 2hr.PG >200 mg/dL(11.1mmol/L) • Microalbuninuria (WHO)

7. Necessary Criteria to Make Diagnosis • WHO: Impaired G handling + 2 other criteria. • Also requires microalbuminuria - Albumen/ creatinine ratio >30 mg/gm creatinine • IDF: • Require central obesity plus two of the other abnormalities • NCEP/ATP III: • Require three or more of the five criteria

8. What is cardiometabolic risk?* • Global cardiometabolic risk represents the overall risk of developing type 2 diabetes and/or cardiovascular disease (including MI and stroke), which is due to a cluster of modifiable risk factors/markers • These include classical risk factors such as smoking, high LDL, hypertension, elevated blood glucose and emerging risk factors closely related to abdominal obesity (especially intra-abdominal adiposity), such as insulin resistance, low HDL, high triglycerides and inflammatory markers • Cardiometabolic risk is based on the concept of risk continuum MI: myocardial infarction; LDL: low-density lipoprotein; HDL: high-density lipoprotein * working definition

9. Global cardiometabolic risk* Gelfand EV et al, 2006; Vasudevan AR et al, 2005 * working definition

10. Male Female 35 30 25 20 15 10 5 0 Despite therapeutic advances, CV disease remains the leading cause of death (USA) Data for 2002 No. of deaths(left axis) Number of deaths (thousands) % All deaths (male + female) % of all deaths(right axis) National Center for Health Statistics, 2004

11. Substantial residual cardiovascular risk in statin-treated patients The MRC/BHF Heart Protection Study 30 Placebo Statin 20 Risk reduction=24% (p<0.0001) 19.8% of statin-treatedpatients had a majorcardiovascular event by 5 years % patients 10 0 0 1 2 3 4 5 6 Year of follow-up Heart Protection Study Collaborative Group, 2002

12. Abdominal obesity has reached epidemic proportions worldwide Prevalence of abdominal obesity by region 1. Ford ES et al, 2003; 2 Haftenberger M et al, 2002; 3. Kim MH et al 2004; 4. Cameron AJ et al, 2003; 5. Puoane T et al, 2002

13. Targeting Cardiometaboilc RiskDefining cardiometabolic Risk • What is Abdominal Obesity ? • Can be defined by Waist Circumference;

14. Fat Topography In Type 2 Diabetic Subjects FFA* TNF-alpha* Leptin* IL-6 (CRP)* Tissue Factor* PAI-1* Angiotensinogen* Intramuscular Subcutaneous Intrahepatic Intra- abdominal

15. Abdominal obesity is linked to multiple cardiometabolic risk factors Patients with abdominal obesity often present with one or more additional cardiovascular risk factors (NCEP ATP III criteria) HDL: high-density lipoprotein; BP: blood pressure National Cholesterol Education Panel/Adult Treatment Panel III, 2002

16. Targeting Cardiometaboilc RiskDefining cardiometabolic Risk 86% At least 1 additional CM risk factor 24% 2 or more additional CM risk factors

17. Abdominal obesity and increased risk of cardiovascular events The HOPE study Men Women Tertile 1 <95 <87 Waistcircumference (cm): Tertile 2 95–103 87–98 Tertile 3 >103 >98 1.4 1.35 1.29 1.27 1.17 1.2 1.16 1.14 Adjusted relative risk 1 1 1 1 0.8 CVD death MI All-cause deaths Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-C; CVD: cardiovascular disease; MI: myocardial infarction; BMI: body mass index; DM: diabetes mellitus; HDL: high-density lipoprotein cholesterol Dagenais GR et al, 2005

18. Abdominal obesity increases the risk of developing type 2 diabetes 24 20 16 12 Relative risk 8 4 0 <71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 >96.3 Waist circumference (cm) Carey VJ et al, 1997

19. 3.0 2.44 p for trend = 0.007 2.31 2.5 2.06 2.0 Relative risk 1.5 1.27 1.0 0.5 0.0 <69.8 69.8<74.2 74.2<79.2 79.2<86.3 86.3<139.7 Quintiles of waist circumference (cm) Abdominal obesity is linked to an increased risk of coronary heart disease Waist circumference has been shown to be independently associated with increased age-adjusted risk of CHD, even after adjusting for BMI and other cardiovascular risk factors CHD: coronary heart disease; BMI: body mass index Rexrode KM et al, 1998

20. Diabetes in the new millenniumInterdisciplinary problem Diabetes

21. Diabetes in the new millenniumInterdisciplinary problem OBESITY

22. Diabetes in the new millenniumInterdisciplinary problem DIAB ESITY

23. Targeting Cardiometabolic Risk

24. Linked Metabolic Abnormalities: • Impaired glucose handling/ insulin resistance • Atherogenic dyslipidemia • Endothelial dysfunction • Prothrombotic state • Hemodynamic changes • Proinflammatory state • Excess ovarian testosterone production • Sleep-disordered breathing

25. Resulting Clinical Conditions: • Type 2 diabetes • Essential hypertension • Polycystic ovary syndrome (PCOS) • Nonalcoholic fatty liver disease • Sleep apnea • Cardiovascular Disease (MI, PVD, Stroke) • Cancer (Breast, Prostate, Colorectal, Liver)

26. Multiple Risk Factor Management • Obesity • Glucose Intolerance • Insulin Resistance • Lipid Disorders • Hypertension • Goals: Minimize Risk of Type 2 Diabetes and Cardiovascular Disease

27. Glucose Abnormalities: • IDF: • FPG >100 mg/dL (5.6 mmol. L) or previously diagnosed type 2 diabetes • WHO: • Presence of diabetes, IGT, IFG, insulin resistance • ATP III: • FBS >110 mg/dL, <126 mg/dL (6.1-7.1 mmol/L ) • (ADA: FBS >100 mg/dL [ 5.6 mmol/L ])

28. Hypertension: • IDF: • BP >130/85 or on Rx for previously diagnosed hypertension • WHO: • BP >140/90 • NCEP ATP III: • BP >130/80

29. Dyslipidemia: • IDF: • Triglycerides - >150mg/dL (1.7 mmol /L) • HDL - <40 mg/dL (men), <50 mg/dL (women) • WHO: • Triglycerides - >150 mg/dL (1.7 mmol/L) • HDL - <35 mg/dL (men), >39 mg/dL) women • ATP III: • Same as IDF

30. Screening/Public Health Approach • Public Education • Screening for at risk individuals: • Blood Sugar/ HbA1c • Lipids • Blood pressure • Tobacco use • Body habitus • Family history

31. Life-Style Modification: Is it Important? • Exercise • Improves CV fitness, weight control, sensitivity to insulin, reduces incidence of diabetes • Weight loss • Improves lipids, insulin sensitivity, BP levels, reduces incidence of diabetes • Goals: Brisk walking - 30 min./day 10% reduction in body wt.

32. Smoking Cessation / Avoidance: • A risk factor for development in children and adults • Both passive and active exposure harmful • A majorrisk factorfor: • insulin resistance and metabolic syndrome • macrovascular disease (PVD, MI, Stroke) • microvascular complications of diabetes • pulmonary disease, etc.

33. Diabetes Control - How Important? • For every 1% rise in Hb A1c there is an 18% rise in risk of cardiovascular events & a 28% increase in peripheral arterial disease • Evidence is accumulating to show that tight blood sugar control in both Type 1 and Type 2 diabetes reduces risk of CVD • Goals: • FBS - premeal <110, • postmeal<180. • HbA1c <7%

34. Overcome Insulin Resistance/ Diabetes: • Insulin Sensitizers: • Biguanides - metformin • PPAR α, γ & δ agonists – Glitazones, Gltazars Rosiglitazon, Pioglitazon • Can be used in combination • Insulin Secretagogues: • Sulfonylurea - glipizide, glyburide, glimeparide, glibenclamide • Meglitinides - repaglanide, netiglamide

35. BP Control - How Important? • MRFIT and Framingham Heart Studies: • Conclusively proved the increased risk of CVD with long-term sustained hypertension • Demonstrated a 10 year risk of cardiovascular disease in treated patients vs non-treated patients to be 0.40. • 40% reduction in stroke with control of HTN • Precedes literature on Metabolic Syndrome • Goal:BP.<130/80

36. Lipid Control - How Important? • Multiple major studies show 24 - 37% reductions in cardiovascular disease risk with use of statins and fibrates in the control of hyperlipidemia. • Goals:LDL <100 mg/dL (<3.0 mmol /l) (high risk <70 mg/dL- <2.6 mmol/L) TG <150 mg% (<1.7 mmol /l) HDL >40 mg% (>1.1 mmol /l)

37. Medications: • Hypertension: • ACE inhibitors, ARBs • Others - thiazides, calcium channel blockers, beta blockers, alpha blockers • Central acting Alfa agonist : Moxolidin • Dylipidemia: • Statins, Fibrates, Niacin • Platelet inhibitors: • ASA, clopidogrel

38. A Critical Look at the Metabolic Syndrome Is it a Syndrome?* • “…too much clinically important information is missing to warrant its designations as a syndrome.” • Unclear pathogenesis, Insulin resistance may not underlie all factors, & is not a consistent finding in some definitions. • CVD risks associated with metabolic syndrome has not shown to be greater than the sum of it’s individual components. *ADA & EASD

39. A Critical Look at the Metabolic Syndrome • “Until much needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the ‘metabolicsyndrome’.” • The advice remains to treat individual risk factors when present & to prescribe therapeutic lifestyle changes & weight management for obese patients with multiple risk factors.

40. Individual metabolic abnormalities among Qatari population according to gender (Musallam et al 08) Men (n = 405) Women (n=412) Variable n(%) n(%) p-Value ATP III Abdominal obesity 227(56.0) 308(74.8) <0.001 Hypertension 143(35.3) 156(37.9) 0.448 Diabetes 77(19.0) 107(26.0) 0.017 Hypertriglyceridemia 113(27.9) 83(20.1) 0.009 Low HDL 95(23.5) 121(29.4) 0.055

41. Individual metabolic abnormalities among Qatari population according to gender No of components of ATP III Men (n = 405)Women (n=412) Variable n(%) n(%) p-Value None 88(21.7) 74(18.0) – One 103(25.4) 100(24.3) 0.033 Two 125(30.9) 111(26.9) – Three or more 89(22.0) 127(30.8) –

42. Multivariate logistic regression analysis of factors associated with Metabolic Syndrome according to (ATP III criteria) Odds ratio95% CIp-Value Age 1.07 1.05–1.09 <0.001 Female gender 1.86 1.30–2.67 0.001 Body Mass Index 1.05 1.02–1.07 <0.001 Fam his of DM 1.66 1.12–2.44 0.011 Smoking 3.27 1.63–6.55 0.001

43. Prevalence of MeS in different Countries * Crude rates Mussallam et al. Int J Food Safety and PH 2008

44. Prevalence of MeS in different Countries * Crude rates Mussallam et al. Int J Food Safety and PH 2008

48. Thank You

49. Determinants and dynamics of the CVD Epidemic in the developing Countries Data from South Asian Immigrant studies • Excess, early, and extensive CHD in persons of South Asian origin • The excess mortality has not been fully explained by the major conventional risk factors. • Diabetes mellitus and impaired glucose tolerance highly prevalent. (Reddy KS, circ 1998). • Central obesity, ↑triglycerides, ↓HDL with or without glucose intolerance, characterize a phenotype. • genetic factors predispose to ↑lipoprotein(a) levels, the central obesity/glucose intolerance/dyslipidemia complex collectively labeled as the “metabolic syndrome”

50. Determinants and dynamics of the CVD epidemic in the developing countries Other Possible factors • Relationship between early life characteristics and susceptibility to NCD in adult hood ( Barker’s hypothesis) (Baker DJP,BMJ,1993) • Low birth weight associated with increased CVD • Poor infant growth and CVD relation • Genetic–environment interactions (Enas EA, Clin. Cardiol. 1995; 18: 131–5) • Amplification of expression of risk to some environmental changes esp. South Asian population) • Thrifty gene (e.g. in South Asians)