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Metabolt Syndrome 2005 Björn Carlsson

Metabolt Syndrome 2005 Björn Carlsson. Biovetenskapliga Läkemedelsprogrammet/Apex Block III, delkurs IV HT 2005. INTER-HEART: Population-attributable risk of acute MI in the overall population. ” Disease” related risk factors Diabetes Hypertension Abdominal obesity ApoB/ApoA 1

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Metabolt Syndrome 2005 Björn Carlsson

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  1. Metabolt Syndrome 2005 Björn Carlsson Biovetenskapliga Läkemedelsprogrammet/Apex Block III, delkurs IV HT 2005

  2. INTER-HEART: Population-attributable risk of acute MI in the overall population • ”Disease” related risk factors • Diabetes • Hypertension • Abdominal obesity • ApoB/ApoA1 • Behaviour related risk factors Alcohol intake Exercise Psychosocial stress Current smoking

  3. Excessivefood intake Physicalinactivity Smoking Stress Obesity Atherosclerosis Atherosclerosis Hypertension Diabetes Dyslipidaemia Arterial & venous thrombosis/ cardiac & cerebral events Arrhythmia Chronic heart failure Life style is a Driver of CVD Life style intervention Risk factor modification

  4. Obesity in the US 1985

  5. Obesity in the US 1990

  6. Obesity in the US 1993

  7. Obesity in the US 1998

  8. Obesity in the US 2001 Today 30% of adults in the US are obese and >65% are overweight

  9. Obesity is a major driver of obesity and diabetes From Mokdad et al, JAMA 2003

  10. Diabetes/obesity • Pandemic of obesity and type 2 diabetes mellitus continues • Foreseen effects in the USA • Life time risk of developing diabetes for individuals born in 2000 • Men 32.8% • Women 38.5% • Life expectancy reduction if diabetes diagnosed at age <40 • Men: loss of 11.6 life years • Women: 14.3 life years Ref. JAMA. 2003;209:1884-90.

  11. Metabolic Syndrome 2005 • A cluster of “non-typical” CV risk factors • Increases lifetime risk of developing type II diabetes and cardiovascular diasese • Controversial disease etiology • Insulin resistance • Visceral obesity

  12. IDF Consensus definition (a) ATPIII: the metabolic syndrome (b) WHO (c) EGIR (d) Hyper TG waist (e) AACC (f) International Diabetes Federation & input from IAS/NCEP National Cholesterol Education Program – Adult Treatment Panel III 1999 World Health Organization definition of the metabolic syndrome European Group for the Study of Insulin Resistance (IR) The Hypertriglyceridemic Waist in Men American Association of Clinical Endocrinologists** Defined as abdominal obesity (as measured by waist circumference against ethnic and gender specific cut-points) plus any two of the following: ·Hypertriglyceridemia (> 150 mg/dl; 1.7mmol/l) ·Low HDLc (<40 mg/dl or <1.03mmol/l for men and <50 mg/dl or 1.29 mmol/l) for women) or on treatment for low HDL ·Hypertension (SBP > 130 mmHg DBP > 85 mmHg or on treatment ·Hyperglycemia – Fasting Plasma Glucose > 100 mg/dl or 5.6 mmol/l or IGT or pre-existing diabetes mellitus) Diagnosis is established when > 3 of these risk factors are present ·Abdominal obesity (waist circumference) Men >102 cm (>40 in)Women >88 cm (>35 in) ·Hypertriglyceridemia > 150 mg/dL ·Low HDLcMen <40 mg/dLWomen <50 g/dL ·Hypertension>130/>85 mm Hg ·HypergylcemiaFasting Plasma Glucose >110 mg/dL Defined as Insulin Resistance (IR)* plus any two of the following: ·Obesity BMI (>30 kg/m2) and/or WHR (>0.90 in men, >0.85 in women) ·Hypertriglyceridemia (>1.7 mmol/l) and/or low HDL cholesterol (<0.9 mmol/l in men, <1.0 mmol/l in women) ·Hypertensive . antihypertensive treatment and/or elevated blood pressure (>140 mmHg systolic or >90 mmHg diastolic) ·Microalbuminuria (urinary albumin excretion rate (AER) >30 µg/min ·IR: Fasting insulin highest 25% of population Plus two of the following: ·Abdominal obesity (waist circumference) Men >94 cm: women >80 cm ·Hypertriglyceridemia >2 mmol/l ·And/or low HDLc <1 mmol/l ·Hypertension >140/90 mm Hg ·Hyperglycaemia Fasting plasma glucose >6.1 mmol/l ·Triglyceride >2.0 mmol/l ·Waist >90 cm ·BMI >25 kg/m2 ·Tg >150 mg/dl ·HDLcMen <40 mg/dl Women <50 mg/dl ·Bp >130/85 mmHg ·2 hours post glucose challenge BS >140 mg/dl ·Fasting glucose 110-126 mg/dl ·Others ·Family history T2DM, HTN or CVD ·PCO ·Sedentary ·Advancing Age ·Ethnic group at high risk Metabolic Syndrome 2005

  13. Targeting cardiometabolic risk in patients withintra-abdominal adiposity and related comorbidities

  14. Summary • Despite therapeutic advances, cardiovascular disease remains the leading cause of death worldwide • Current treatments generally target individual risk factors and do not propose a comprehensive approach to the management of cardiometabolic disease • An increased risk of developing cardiometabolic disease can be attributed to abdominal obesity (as measured by waist circumference) • A major cause of cardiometabolic disorders (including dyslipidaemia, insulin resistance, type 2 diabetes, metabolic syndrome, inflammation and thrombosis) is thought to be intra-abdominal adiposity (IAA) • Waist circumference provides a simple and practical diagnosis of IAA in patients at elevated CV risk theheart.org

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

  16. Multiple cardiovascular risk factors drive adverse clinical outcomes Increased Cardiometabolic Risk Abdominal obesity Dyslipidaemia Hypertension Glucose intolerance Insulin resistance Metabolic Syndrome

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

  18. HDL-C TNF IL-6 Insulin AbdominalObesity Glu TG PAI-1 Unmet clinical needs to address in the next decade Major Unmet Clinical Need Novel Risk Factors Classical Risk Factors Metabolic syndrome  LDL-C  BP Smoking T2DM CARDIOVASCULAR DISEASE

  19. Management of the metabolic syndrome • Appropriate and aggressive therapy is essential for reducing patient risk of cardiovascular disease • Lifestyle measures should be the first action • Pharmacotherapy should have beneficial effects on • Glucose intolerance / diabetes • Obesity • Hypertension • Dyslipidemia • Ideally, treatment should address all of the components of the syndrome and not the individual components International Diabetes Federation, 1st International Congress on “Prediabetes” and Metabolic Syndrome (2005)

  20. Abdominal obesity: required for diagnosing the metabolic syndrome IDF criteria of the metabolic syndrome • High waist circumference Plus any two of •  Triglycerides ( 1.7 mmol/L [150 mg/dL])‡ •  HDL cholesterol‡ • Men < 1.0 mmol/L (40 mg/dL) • Women < 1.3 mmol/L (50 mg/dL) •  Blood pressure  130 / >85 mm Hg‡ •  FPG ( 5.6 mmol/L [100 mg/dL]), or diabetes ‡or specific treatment for these conditions International Diabetes Federation (2005)

  21. Abdominal obesity and waist circumference thresholds • New IDF criteria: • Current NCEP ATP-III criteria • >102 cm (>40 in) in men, >88 cm (>35 in) in women NCEP 2002; International Diabetes Federation (2005)

  22. High waist circumference is associated with multiple cardio vascular risk factors US population age >20 years 30 20 Prevalence of high waistcircumferenceassociated with (%) 10 0 LowHDL-Ca HighTGb HighFPGc HighBPd >2 riskfactorse a<40 mg/dL (men) or <50 mg/dL (women); b>150 mg/dL; c>110 mg/dL; d>130/85 mmHg; eNCEP/ATP III metabolic syndrome NHANES 1999–2000 cohort; data on file

  23. Unmet clinical need associated with abdominal obesity CV risk factors in a typical patient with abdominal obesity Patients with abdominal obesity (high waist circumference) often present with one or more additional CV risk factors

  24. Abdominal obesity has reached epidemic proportions worldwide Men (%) Women (%) Total(%) USa 36.9 55.1 46.0 Spainb 30.5 37.8 34.7 Italyc 24.0 37.0 31.5 UKd 29.0 26.0 27.5 Francee––26.3 Netherlandsf 14.8 21.1 18.2 Germanyg 20.0 20.5 20.3 High waist circumference: >102 cm (>40 in) in men or >88 cm (>35 in) in womenexcept in Germany (>103 cm [41 in] and >92 cm [36 in], respectively) aFord et al 2003; bAlvarez-Leon et al 2003; cOECI 2004; dRuston et al 2004; eObepi 2003; fVisscher & Seidell 2004; gLiese et al 2001

  25. Growing prevalence of abdominal obesity US National Health andNutrition Examination Survey (NHANES) NHANES III (1988–1994) NHANES (1999–2000) Relative change Men 29.5% 36.9% + 28% Women 46.7% 55.1% + 18% Abdominal obesity defined as waist circumference: >102 cm (>40 in)in men or >88 cm (>35 in) in women Ford et al 2003

  26. Abdominal obesity increases the risk of developing type 2 diabetes 24 20 16 Relative risk 12 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 et al 1997

  27. Metabolic syndrome has a negative impact on CV health and mortality No metabolic syndrome Metabolic syndrome 25 25 * *p<0.001 20 20 *p<0.001 * 15 15 Mortality rate (%) Prevalence (%) * 10 10 * * 5 5 0 0 Cardiovascular mortality All-cause mortality CHD MI Stroke Isomaa et al 2001

  28. 49 20 18 10 HTN Diabetes Abdom. Abn Lipids Obesity Abdominal obesity: a major underlying cause of acute myocardial infarction Cardiometabolic risk factors in the InterHeart Study 60 Abdominal obesity predicts the risk of CVD beyond BMI 40 PAR (%)a 20 0 aProportion of MI in the total population attributable to a specific risk factor Yusuf et al 2004

  29. Men Women Tertile 1 <95 <87 Waistcirc. (cm): Tertile 2 95–103 87–98 Tertile 3 >103 >98 Abdominal obesity and increased risk of cardiovascular events The HOPE Study 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-C, total-C Dagenais et al 2005

  30. Quintile 1 2 3 4 5 SAD (cm) 12–19 20–21 22–23 24 25–35 BMI (kg/m2) <23.2 23.2–24.9 25.0–26.6 26.7–28.4 28.5–47.7 Abdominal obesity predicts adverse outcomes such as sudden death The Paris Prospective Study 4 4 SAD is a better predictor ofrisk of sudden death than BMI p for trend=0.0003 3 3 Age-adjustedrelative risk Age-adjustedrelative risk 2 2 1 1 0 0 1 2 3 4 5 1 2 3 4 5 Quintile of BMI Quintile of sagittalabdominal diameter (SAD) Empana et al 2004

  31. Abdominal obesity andincreased risk of CHD Waist circumference was independently associated with increased age-adjusted risk of CHD, even after adjusting for BMI and other CV risk factors 3.0 2.44 2.31 p for trend = 0.007 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) Rexrode et al 1998

  32. Why is abdominal obesity harmful? • Abdominal obesity • is often associated with other CV risk factors • is an independent CV risk factor • Adipocytes are metabolically active endocrine organs, not simply inert fat storage Wajchenberg 2000

  33. Health threat from abdominal obesity is largely due to intra-abdominal adiposity Increased Cardiometabolic Risk Abdominal Obesity Dyslipidemia Hypertension Glucose Intolerance Insulin Resistance Intra-Abdominal Adiposity Adapted from Eckel et al 2005

  34. Intra-abdominal adiposity: a root cause of cardiometabolic disease Intra-abdominal adiposity is characterised by accumulation offat around and inside abdominal organs Cardiovascular risk factors Abdominal obesity (High waist circumference) Indirect Intra-abdominal adiposity Direct CVdisease Frayn 2002; Caballero 2003; Misra & Vikram 2003

  35. The evolving view of adipose tissue:an endocrine organ Current View: secretory/endocrine organ Old View: inert storage depot Fatty acids Glucose Fed Fasted Tg Multiple secretory products Tg Tg Muscle Fatty acids Glycerol Vasculature Liver Pancreas Lyon CJ et al 2003

  36. Intra-abdominal adiposity promotes insulin resistance and increased CV risk  Secretion ofmetabolically activesubstances (adipokines)  Hepatic FFA flux(portal hypothesis)  Intra-abdominaladiposity  PAI-1  Adiponectin  IL-6  TNFa  suppression of lipolysis by insulin  FFA  Insulin resistance  Dyslipidaemia Net result:  Insulin resistance  Inflammation Pro-atherogenic Heilbronn et al 2004; Coppack 2001; Skurk & Hauner 2004

  37. Adverse cardiometabolic effects of products of adipocytes ↑ Lipoprotein lipase Hypertension ↑ Agiotensinogen ↑ IL-6 Inflammation Atherogenicdyslipidaemia ↑ Insulin ↑ FFA Adiposetissue ↑ TNFα ↑ Resistin ↑ Leptin ↑ Adipsin(Complement D) ↑ Lactate Type2 diabetes ↑ Plasminogenactivator inhibitor-1(PAI-1) ↓ Adiponectin Atherosclerosis Thrombosis Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

  38. Properties of key adipokines IAA: intra-abdominal adiposity Marette 2002

  39. Suggested role of intra-abdominal adiposity and FFA in insulin resistance  Hepaticinsulinresistance  Hepaticglucoseoutput  Small,denseLDL-C Intra abdominal adiposity Lipolysis  TG-richVLDL-C  FFA Portal circulation LowHDL-C CETP,lipolysis Systemic circulation  Glucose utilisation FFA: free fatty acidsCETP: cholesteryl estertransfer protein  Insulin resistance Lam et al 2003; Carr et al 2004; Eckel et al 2005

  40. Intra abdominal adiposity impairs pancreatic b-cell function  FFA Splanchnic & systemic circulation Intra abdominal adiposity Short-termstimulationof insulinsecretion Long-term damageto b-cells Decreased insulinsecretion FFA: Free fatty acids Haber et al 2003; Zraika et al 2002

  41. Systemic inflammation and adverse cardiovascular outcomes Physicians' Health Study: 9-year follow-up 4.4 2.8 3.4 2.8 Relative risk of MI 2.5 1.3 1.1 1.2 1.0 High Medium hs-CRP Low Low Medium High Cholesterol/HDL cholesterol ratio Ridker et al 1998

  42. Triglycerides HDL-cholesterol 310 60 248 186 mg/dL mg/dL 45 124 62 30 0 Low High Lean Low High Lean Visceral fat(obese subjects) Visceral fat(obese subjects) Intra-abdominal adiposity and dyslipidaemia Pouliot et al 1992

  43. 1 Intra-abdominal adiposity and glucose metabolism Glucose Insulin 1,2 15 1200 1,2 1,2 Area Area 12 1 1,2 1,2 1 1 1,2 800 9 1,2 1 mmol/L 1 pmol/L 1 1,2 1 1,2 1 6 400 1,2 3 1,2 0 0 0 60 120 180 0 60 120 180 Time (min) Time (min) Non-obese Obese low IAA Obese high IAA IAA: intra-abdominal adipositySignificantly different from 1non-obese, 2obese with low intra-abdominal adiposity levels Pouliot et al 1992

  44. Pathophysiology of the metabolic syndrome leading to atherosclerotic CV disease Genetic variation Environmental factors Abdominal obesity Adipokines Cytokines Adipocyte Monocyte/ macrophage Inflammatory markers Insulin resistance  Tg Metabolic syndrome  HDL  BP Atherosclerosis Plaque rupture/thrombosis Reilly & Rader 2003; Eckel et al 2005 Cardiovascular events

  45. Summary • Despite therapeutic advances, cardiovascular disease remains the leading cause of death worldwide • Current treatments generally target individual risk factors and do not propose a comprehensive approach to the management of cardiometabolic disease • An increased risk of developing cardiometabolic disease can be attributed to abdominal obesity (as measured by waist circumference) • A major cause of cardiometabolic disorders (including dyslipidaemia, insulin resistance, type 2 diabetes, metabolic syndrome, inflammation and thrombosis) is thought to be intra-abdominal adiposity (IAA) • Waist circumference provides a simple and practical diagnosis of IAA in patients at elevated CV risk

  46. Excessivefood intake Physicalinactivity Smoking Stress Obesity Atherosclerosis Atherosclerosis Hypertension Diabetes Dyslipidaemia Arterial & venous thrombosis/ cardiac & cerebral events Arrhythmia Chronic heart failure A Broad Approach to Prevention and Treament of Cardiovascular Disease Life style intervention Risk factor modification Disease intervention/ secondary prevention

  47. Can we change our life-style? Buy a dog!

  48. Thank you for your attention!

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