Cardiometabolic Syndrome Nabil Sulaiman Dr Dhafir A Mahmood

Cardiometabolic Syndrome Nabil Sulaiman Dr. Dhafir A. Mahmood

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

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

Clustering of Components o Hypertension: BP. > 140/90 o Dyslipidemia: TG > 150 mg/d. L ( 1. 7 mmol/L ) HDL- C < 35 mg/d. L (0. 9 mmol/L) o Obesity (central): BMI > 30 kg/M 2 Waist girth > 94 cm (37 inch) Waist/Hip ratio > 0. 9 o Impaired Glucose Handling: IR, IGT or DM FPG > 110 mg/d. L (6. 1 mmol/L) 2 hr. PG >200 mg/d. L (11. 1 mmol/L) o Microalbuninuria (WHO)

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

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

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

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

Abdominal obesity and increased risk of cardiovascular events Adjusted relative risk The HOPE study Waist circumference (cm): 1. 4 Tertile 1 Men <95 Women <87 Tertile 2 Tertile 3 95– 103 >103 87– 98 >98 1. 29 1 0. 8 1. 27 1. 17 1. 2 1 1. 16 1 CVD death 1. 35 1. 14 1 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

Abdominal obesity increases the risk of developing type 2 diabetes 24 Relative risk 20 16 12 8 4 0 <71 71– 75. 9 76– 81 81. 1– 86 86. 1– 91 91. 1– 96. 3 Waist circumference (cm) Carey VJ et al, 1997 >96. 3

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 3. 0 Relative risk 2. 5 p for trend = 0. 007 2. 06 2. 0 1. 5 2. 31 2. 44 1. 27 1. 0 0. 5 0. 0 <69. 8 <74. 2 <79. 2 <86. 3 <139. 7 Quintiles of waist circumference (cm) CHD: coronary heart disease; BMI: body mass index Rexrode KM et al, 1998

Diabetes in the new millennium Interdisciplinary problem Diabetes

Diabetes in the new millennium Interdisciplinary problem OBESITY

Diabetes in the new millennium Interdisciplinary problem DIAB ESITY

Targeting Cardiometabolic Risk

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

Insulin Resistance: Associated Conditions

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

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

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

Glucose Abnormalities: o IDF: – FPG >100 mg/d. L (5. 6 mmol. L) or previously diagnosed type 2 diabetes – (ADA: FBS >100 mg/d. L [ 5. 6 mmol/L ])

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

Dyslipidemia: o IDF: – Triglycerides - >150 mg/d. L (1. 7 mmol /L) – HDL - <40 mg/d. L (men), <50 mg/d. L (women)

Public Health Approach

Screening/Public Health Approach o Public Education o Screening for at risk individuals: – Blood Sugar/ Hb. A 1 c – Lipids – Blood pressure – Tobacco use – Body habitus – Family history

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

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

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

Lifestyle modification • • Diet Exercise Weight loss Smoking cessation If a 1% reduction in Hb. A 1 c is achieved, you could expect a reduction in risk of: • 21% for any diabetesrelated endpoint • 37% for microvascular complications • 14% for myocardial infarction However, compliance is poor and most patients will require oral pharmacotherapy within a few years of diagnosis Stratton IM et al. BMJ 2000; 321: 405– 412.

Overcome Insulin Resistance/ Diabetes: o Insulin Sensitizers: – Biguanides – metformin – Glitazones, Gltazars – Can be used in combination o Insulin Secretagogues: – Sulfonylurea - glipizide, glyburide, glimeparide, glibenclamide – Meglitinides - repaglanide, netiglamide

BP Control - How Important? o Goal: BP. <130/80 o 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 o Precedes literature on Metabolic Syndrome

Lipid Control - How Important? o Goals: HDL >40 mg% (>1. 1 mmol /l) LDL <100 mg/d. L (<3. 0 mmol /l) TG <150 mg% (<1. 7 mmol /l) o. Multiple major studies show 24 - 37% reductions in cardiovascular disease risk with use of statins and fibrates in the control of hyperlipidemia.

Substantial residual cardiovascular risk in statin-treated patients The MRC/BHF Heart Protection Study % patients 30 Placebo Statin 20 Risk reduction=24% (p<0. 0001) 19. 8% of statin-treated patients had a major cardiovascular event by 5 years 10 0 0 1 2 3 4 Year of follow-up 5 6 Heart Protection Study Collaborative Group, 2002

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

Individual metabolic abnormalities among Qatari population according to gender (Musallam et al 08) Men (n = 405) Variable ATP III n(%) Women (n=412) p-Value Abdominal obesity 227(56. 0) Hypertension Diabetes 143(35. 3) 77(19. 0) 308(74. 8) 156(37. 9) <0. 001 0. 448 107(26. 0) 0. 017 Hypertriglyceridemia 113(27. 9) 83(20. 1) Low HDL 121(29. 4) 0. 055 95(23. 5) 0. 009

Individual metabolic abnormalities among Qatari population according to gender No of components of ATP III Men (n = 405) Women (n = 412) Variable 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) –

Prevalence of Me. S in different Countries Country Year Sample Prevalence (%) Arab Americans 2003 542 23 Oman 2001 1419 21 Jordan 2002 1121 36 Saudi Arabia 2004 2250 20. 8 Palestine 1998 Qatar 2007 817 27. 6 Turkey 2004 1637 33. 4* ? 10368 33. 7 Iran * Crude rates 17* Mussallam et al. Int J Food Safety and PH 2008

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

A Critical Look at the Metabolic Syndrome Research o “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 ‘metabolic syndrome’. ”

A Critical Look at the Metabolic Syndrome Lifestyle o The advice remains to treat individual risk factors when present & to prescribe therapeutic lifestyle changes & weight management for obese patients with multiple risk factors.

Insulin Resistance: Associated Conditions

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

Determinants and dynamics of the CVD Epidemic in the developing Countries Other Possible factors o 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 o 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)

CVD epidemic in developing & developed countries. Are they same? o Urban populations have higher levels of CVD risk factors related to diet and physical activity (overweight, hypertension, dyslipidaemia and diabetes) o Tobacco consumption is more widely prevalent in rural population o The social gradient will reverse as the epidemics mature. o The poor will become progressively vulnerable to the ravages of these diseases and will have little access to the expensive and technology-curative care. o The scarce societal resources to the treatment of these disorders dangerously depletes the resources available for the ‘unfinished agenda’ of infectious and nutritional disorders that almost exclusively afflict the poor

Burden of CVD in Pakistan o Coronary heart disease o Mortality statistics o Specific mortality data ideal for making comparisons with other countries are not available o Inadequate and inappropriate death certification, and multiple concurrent causes of death

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

Why people physically inactive? o Lack of awareness regarding the physical activity for health fitness and prevention of diseases o Social values and traditions regarding physical exercise (women, restriction). o Non-availability public places suitable for physical activity (walking and cycling path, gymnasium). o Modernization of life that reduce physical activity (sedentary life, TV, Computers, tel, cars).

Insulin Resistance: Associated Conditions

Prevalence (%) Prevalence of the Metabolic Syndrome Among US Adults NHANES 1988 -1994 45 40 35 30 25 20 15 10 5 0 Men Women 20 -29 30 -39 40 -49 50 -59 60 -69 > 70 Age (years) Ford E et al. JAMA. 2002(287): 356. 1999 -2002 Prevalence by IDF vs. NCEP Definitions (Ford ES, Diabetes Care 2005; 28: 2745 -9) (unadjusted, age 20+) NCEP : 33. 7% in men and 35. 4% in women IDF: 39. 9% in men and 38. 1% in women

Prevention of CVD o There is an urgent need to establish appropriate research studies, increase awareness of the CVD burden, and develop preventive strategies. o Prevention and treatment strategies that have been proven to be effective in developed countries should be adapted for developing countries. o Prevention is the best option as an approach to reduce CVD burden. o Do we know enough to prevent this CVD Epidemic in the first place.

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

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/d. L (1. 7 mmol/L) or specific treatment for this lipid abnormality Reduced HDL cholesterol < 40 mg/d. L (1. 03 mmol/L) in males < 50 mg/d. L (1. 29 mmol/L) in females or specific treatment for this lipid abnormality Raised blood pressure Systolic : > 130 mm. Hg or Diastolic: > 85 mm. Hg or Treatment of previously diagnosed hypertension Raised fasting plasma glucose Fasting plasma glucose > 100 mg/d. L (5. 6 mmol/L) or Previously diagnosed type 2 diabetes If above 5. 6 mmol/L or 100 mg/d. L, OGTT is strongly recommended but is not necessary to define presence of the syndrome.

Treatment of Metabolic Syndrome: 2005 Stop smoking Oral hypoglycaemics ACEI &/or A 2 receptor blockers Diet, Exercise, Lifestyle change Insulin Statins & Fibrates Aspirin CB 1 Receptor Blocker Antihypertensives

Recommendations for treatment Primary management for the Metabolic Syndrome is healthy lifestyle promotion. This includes: o. Moderate calorie restriction (to achieve a 5 -10% loss of body weight in the first year) o. Moderate increases in physical activity o. Change dietary composition to reduce saturated fat and total intake, increase fibre and, if appropriate, reduce salt intake.

Management of the Metabolic Syndrome o Appropriate & aggressive therapy is essential for reducing patient risk of cardiovascular disease o Lifestyle measures should be the first action o Pharmacotherapy should have beneficial effects on – – Glucose intolerance/diabetes Obesity Hypertension Dyslipidaemia o Ideally, treatment should address all of the components of the syndrome and not the individual components

Summary: new IDF definition for the Metabolic Syndrome The new IDF definition addresses both clinical and research needs: • Provides a simple entry point for primary care physicians to diagnose the Metabolic Syndrome • Providing an accessible, diagnostic tool suitable for worldwide use, taking into account ethnic differences • Establishing a comprehensive ‘platinum standard’ list of additional criteria that should be included in epidemiological studies and other research into the Metabolic Syndrome

Contact Information Nabil Sulaiman nsulaiman@sharjah. ac. ae