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Metabola Syndromet 2006 Björn Carlsson Apex Block III, delkurs IV HT 2006.

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Presentation on theme: "Metabola Syndromet 2006 Björn Carlsson Apex Block III, delkurs IV HT 2006."— Presentation transcript:

1 Metabola Syndromet 2006 Björn Carlsson Apex Block III, delkurs IV HT 2006

2 INTER-HEART: Population-attributable risk of acute MI in the overall population ”Disease” related risk factors -Diabetes -Hypertension -Abdominal obesity -ApoB/ApoA 1 Behaviour related risk factors Alcohol intake Exercise Psychosocial stress Current smoking

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

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

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:

11 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 Metabolic Syndrome 2005

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)  Hypertriglycerid emia > 150 mg/dL  Low HDLc Men <40 mg/dL Women <50 g/dL  Hypertension >130/>85 mm Hg  Hypergylcemia Fasting 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)  Hypertriglyceride mia (>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  Hypertriglyceride mia >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 mg/dl  Others  Family history T2DM, HTN or CVD  PCO  Sedentary  Advancing Age  Ethnic group at high risk

13 Targeting cardiometabolic risk in patients with intra-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 Despite therapeutic advances, cardiovascular disease remains the leading cause of death (USA) Number of deaths (thousands) Male Female % of all deaths (right axis) No. of deaths (left axis) % All deaths (male + female) National Center for Health Statistics 2004 Data for 2002

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

17 Substantial residual cardiovascular risk in statin-treated patients Placebo Statin Year of follow-up % Patients Risk reduction=24% (p<0.0001) The MRC/BHF Heart Protection Study Heart Protection Study Collaborative Group (2002) 19.8% of statin-treated patients had a major CV event by 5 years

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

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 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 IDF criteria of the metabolic syndrome Abdominal obesity: required for diagnosing the metabolic syndrome International Diabetes Federation (2005) ‡ or specific treatment for these conditions

21 Abdominal obesity and waist circumference thresholds New IDF criteria: NCEP 2002; International Diabetes Federation (2005) Current NCEP ATP-III criteria >102 cm (>40 in) in men, >88 cm (>35 in) in women MenWomen Europid>94 cm (37.0 in)>80 cm (31.5 in) South Asian>90 cm (35.4 in)>80 cm (31.5 in) Chinese>90 cm (35.4 in)>80 cm (31.5 in) Japanese>85 cm (33.5 in)>90 cm (35.4 in)

22 High waist circumference is associated with multiple cardio vascular risk factors Low HDL-C a High TG b High FPG c High BP d >2 risk factors e Prevalence of high waist circumference associated with (%) a 150 mg/dL; c >110 mg/dL; d >130/85 mmHg; e NCEP/ATP III metabolic syndrome US population age >20 years NHANES 1999–2000 cohort; data on file

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

24 US a Spain b Italy c UK d France e – – 26.3 Netherlands f Germany g Abdominal obesity has reached epidemic proportions worldwide a Ford et al 2003; b Alvarez-Leon et al 2003; c OECI 2004; d Ruston et al 2004; e Obepi 2003; f Visscher & Seidell 2004; g Liese et al 2001 Men (%)Women (%)Total (%) High waist circumference: >102 cm (>40 in) in men or >88 cm (>35 in) in women except in Germany (>103 cm [41 in] and >92 cm [36 in], respectively)

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

26 Abdominal obesity increases the risk of developing type 2 diabetes <7171–75.976–8181.1–8686.1–9191.1–96.3> Relative risk Waist circumference (cm) Carey et al 1997

27 Metabolic syndrome has a negative impact on CV health and mortality CHDMI Stroke Prevalence (%) No metabolic syndrome Metabolic syndrome *p<0.001 Isomaa et al 2001 * All-cause mortality Cardiovascular mortality Mortality rate (%) * * * * *p<0.001

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

29 Abdominal obesity and increased risk of cardiovascular events Dagenais et al 2005 Adjusted relative risk CVD deathMI All-cause deaths Tertile 1 Tertile 2 Tertile 3 MenWomen <95 95–103 >103 <87 87–98 >98 Waist circ. (cm): Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-C, total-C The HOPE Study

30 Abdominal obesity predicts adverse outcomes such as sudden death Age-adjusted relative risk Quintile of sagittal abdominal diameter (SAD) Quintile of BMI p for trend = The Paris Prospective Study Empana et al 2004 Quintile SAD (cm)12–1920–2122–232425–35 BMI (kg/m 2 )< – – – –47.7 SAD is a better predictor of risk of sudden death than BMI

31 Abdominal obesity and increased 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 < < < < < p for trend = Relative risk Rexrode et al 1998 Quintiles of waist circumference (cm)

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 Abdominal Obesity Dyslipidemia Hypertension Glucose Intolerance Insulin Resistance Increased Cardiometabolic Risk Intra-Abdominal Adiposity Adapted from Eckel et al 2005

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

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

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

37 Adverse cardiometabolic effects of products of adipocytes Adipose tissue ↑ IL-6 ↓ Adiponectin ↑ Leptin ↑ TNF α ↑ Adipsin (Complement D) ↑ Plasminogen activator inhibitor-1 (PAI-1) ↑ Resistin ↑ FFA ↑ Insulin ↑ Agiotensinogen ↑ Lipoprotein lipase ↑ Lactate Inflammation Type 2 diabetes Hypertension Atherogenic dyslipidaemia Thrombosis Atherosclerosis Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

38 Adiponectin  in IAA Anti-atherogenic/antidiabetic:  foam cells  vascular remodelling  insulin sensitivity  hepatic glucose output IL-6  in IAA Pro-atherogenic/pro-diabetic:  vascular inflammation  insulin signalling TNF   in IAA Pro-atherogenic/pro-diabetic:  insulin sensitivity in adipocytes (paracrine) PAI-1  in IAA Pro-atherogenic:  atherothrombotic risk Properties of key adipokines IAA: intra-abdominal adiposity Marette 2002

39 Suggested role of intra-abdominal adiposity and FFA in insulin resistance FFA: free fatty acids CETP: cholesteryl ester transfer protein Intra abdominal adiposity Portal circulation  Hepatic glucose output  Hepatic insulin resistance Systemic circulation  TG-rich VLDL-C  Small, dense LDL-C Lipolysis Low HDL-C CETP, lipolysis  Glucose utilisation  Insulin resistance  FFA Lam et al 2003; Carr et al 2004; Eckel et al 2005

40 Intra abdominal adiposity impairs pancreatic b-cell function Haber et al 2003; Zraika et al 2002  FFA Long-term damage to  -cells Decreased insulin secretion Short-term stimulation of insulin secretion Intra abdominal adiposity FFA: Free fatty acids Splanchnic & systemic circulation

41 Systemic inflammation and adverse cardiovascular outcomes Relative risk of MI Cholesterol/HDL cholesterol ratio hs-CRP Low Medium High MediumHigh Physicians' Health Study: 9-year follow-up Ridker et al

42 Intra-abdominal adiposity and dyslipidaemia Pouliot et al mg/dL Triglycerides Lean HDL-cholesterol Visceral fat (obese subjects) LowHigh Lean Visceral fat (obese subjects) LowHigh

43 Intra-abdominal adiposity and glucose metabolism Pouliot et al 1992 IAA: intra-abdominal adiposity Significantly different from 1 non-obese, 2 obese with low intra-abdominal adiposity levels Time (min) , mmol/L , ,2 1 Area 1,2 Area pmol/L InsulinGlucose Non-obese Obese low IAA Obese high IAA

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

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

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

48 Thank you for your attention!


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