1. Cardiometabolic Syndrome 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. Cardiometabolic Syndrome II Aims Abdominal obesity prevalence Targeting Cardiometabolic Risk factors Multiple Risk Factor management A Critical Look at the Metabolic Syndrome

3. 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)

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

5. The new IDF definition focusses on abdominal obesity rather than insulin resistance International Diabetes Federation (IDF) Consensus Definition 2005

6. Why a New Definition of the MeS: IDF Objectives Needs: To identify individuals at high risk of developing cardiovascular disease (and diabetes) To be useful for clinicians To be useful for international comparisons

7. Central Obesity IDF: IDF: –Central obesity - waist circumference >94 cm for Europid men, >80 Europid women with ethnicity specific values for other groups WHO: WHO: –Waist-hip ratio >0.9 - men or >0.85 - women ATP III: ATP III: –Waist circumference >40 in. - men, > 35 in. - women

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

9. Abdominal obesity and increased risk of cardiovascular events Dagenais GR et al, 2005 Adjusted relative risk 111 1.17 1.16 1.14 1.29 1.27 1.35 0.8 1 1.2 1.4 CVD deathMIAll-cause deaths Tertile 1 Tertile 2 Tertile 3 MenWomen <95 95–103 >103 <87 87–98 >98 Waist circumference (cm): The HOPE study 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

10. Abdominal obesity increases the risk of developing type 2 diabetes <7171–75.976–8181.1–8686.1–9191.1–96.3>96.3 24 20 16 12 8 4 0 Relative risk Waist circumference (cm) Carey VJ et al, 1997

11. 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 0.0 0.5 1.0 1.5 2.0 2.5 3.0 <69.8 69.8  <74.2 74.2  <79.2 79.2  <86.3 86.3  <139.7 1.27 2.06 2.31 2.44 p for trend = 0.007 Relative risk Quintiles of waist circumference (cm) Rexrode KM et al, 1998 CHD: coronary heart disease; BMI: body mass index

12. Diabetes in the new millennium Interdisciplinary problem Diabetes

13. Diabetes in the new millennium Interdisciplinary problem OBESITY

14. Diabetes in the new millennium Interdisciplinary problem DIAB ESITY

15. Targeting Cardiometabolic Risk

16. Central obesity: a driving force for cardiovascular disease & diabetes “Balzac” by Rodin Front Back

17. Intra-abdominal adiposity is closely correlated with abdominal obesity To assess IAA, the simplest measure of abdominal obesity is waist circumference, which is strongly correlated with direct measurement of IAA by CT scan or MRI, considered to be the gold standard Després JP et al, 2001; Pouliot MC et al, 2004 300 200 100 0 r = 0.80 6080100120 IAA Waist circumference (cm) IAA (cm 2 ) IAA: intra-abdominal adiposity; CT: computed tomography; MRI: magnetic resonance imaging

18. Intra-abdominal adiposity is a major contributor to increased cardiometabolic risk Kershaw EE et al, 2004; Lee YH et al, 2005; Boden G et al, 2002 Associated with inflammatory markers (C-reactive protein)  Free fatty acids  Inflammation Insulin resistance Dyslipidaemia Increased cardiometabolic risk IAA = high risk fat Secretion of adipokines ( ↓ adiponectin)  IAA: intra-abdominal adiposity

19. Waist Circumference

20. Intra-abdominal adiposity and dyslipidaemia Pouliot MC et al, 1992 310 248 186 124 62 0 60 45 30 mg/dL Triglycerides Lean HDL-cholesterol Visceral fat (obese subjects) LowHigh Lean Visceral fat (obese subjects) LowHigh HDL: high-density lipoprotein

21. Insulin Resistance: Associated Conditions

22. Targeting Cardiometaboilc Risk Defining cardiometabolic Risk Cardiovascular Disease Abdominal Obesity Glucose intolerance Insulin Resistance Dyslipedemia Hypertension

23. Targeting Cardiometaboilc Risk Defining cardiometabolic Risk Major Unmet Clinical Need Classical Risk Factors Novel Risk Factors Cluster Risk Factors LDL-C BP Smoking DM-2 Insulin HDL-C TNF & IL-6 Abdominal Obesity Glucose PAI-1 TG Cardiovascular Disease

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. Targeting Cardiometaboilc Risk Site of Action Mechanisms Addresses Adipose tissues Adiponectin Dyslipidemia Lipogeenesis Insulin resistance Muscle G uptake Insulin resistance Liver Lipogeenesis Dyslipidemia Insulin resistance GI tract Satiety signals Body weight Waist circumference Hypothalamus Food intake Body weight Waist circumference Genetic?

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

28. Glucose Abnormalities: IDF: IDF: –FPG >100 mg/dL (5.6 mmol. L) or previously diagnosed type 2 diabetes –(ADA: FBS >100 mg/dL [ 5.6 mmol/L ])

29. Hypertension: IDF: IDF: hypertension –BP >130/85 or on Rx for previously diagnosed hypertension

30. Dyslipidemia: IDF: IDF: –Triglycerides - >150mg/dL (1.7 mmol /L) – HDL - <40 mg/dL (men), <50 mg/dL (women)

31. Insulin Resistance: Hyperinsulinemic individuals are at risk for developing Diabetes, Dyslipidemia, Hypertension & ultimately Cardiovascular disease Patients with Metabolic Syndrome are 3.5 times as likely to die from Cardiovascular disease compared to normal people