The Metabolic Syndrome 1 Jean-Pierre Després, Ph.D., FAHA, FIAS Quebec Heart and Lung Institute Department of Medicine Université Laval Québec, Canada Reaven s syndrome X Triglycerides HDL cholesterol Insulin resistance Insulin Hypertension 2 Adapted from Reaven GM, Diabetes(1988) 37: 1595-1607 CHD odds ratio according to plasma insulin levels and triglyceride or Apo B concentrations in the 5-year follow-up of the Québec Cardiovascular Study Odds ratio 8,0 6,0 4,0 2,0 0,0 1.5 5.4 p=0.002 4.6 p=0.005 1.0 <12 12-15 >15 Insulin (mu/ml) 6.7 5.3 Odds ratio 15,0 12,0 9,0 6,0 3,0 0,0 11.0 9.7 1.8 1.0 3.0 p=0.04 3.2 p=0.04 <12 12-15 >15 Insulin (mu/ml) Low Triglycerides Low Apo B High Triglycerides High Apo B 3 From Després JP et al. NEJM (1996) 334: 952-957 1
Our "toxic" lifestyle 4 The changing landscape of modifiable CVD risk factors Smoking Type 2 diabetes Hypercholesterolemia Abdominal obesity Hypertension Metabolic syndrome 1950 60 1990 00 Statins HT medication Smoking cessation 5 Sedentariness Energy density of food An early finding from our lab 25 yrs ago! Fat mass: 19.8 kg Visceral AT: 155 cm 2 Fat mass: 19.8 kg Visceral AT: 96 cm 2 6 Obesity cannot be defined by excess body weight/body fat 2
Visceral obesity is associated with the cluster of metabolic abnormalities often described as the insulin resistance syndrome Hypertriglyceridemia Low HDL-cholesterol Elevated apolipoprotein B Small, dense LDL particles Inflammatory profile Insulin resistance Hyperinsulinemia Glucose intolerance Impaired fibrinolysis Endothelial dysfunction These features lead to type 2 diabetes and cardiovascular disease 7 Adapted from Lamarche B et al. JAMA (1998) 279: 1955-1961 Després JP et al. NEJM (1996) 334: 952-957 Risk of IHD according to the cumulative number of traditional and non-traditional risk factors Odds ratio* 30 25 20 15 10 5 0 The Québec Cardiovascular Study Traditional risk factors Non-traditional risk factors 1.0 1.0 4.7 1.8 2.8 9.1 (0.01) 4.4 (0.01) 0 1 2 3 20.8 (<0.001) Traditional: LDL-cholesterol, triglycerides and HDL-cholesterol Non-traditional: Insulin, apolipoprotein B and small, dense LDL particles * Odds ratios are adjusted for systolic blood pressure, family history of IHD and medication use 8 From Lamarche B et al. JAMA (1998) 279: 1955-1961 Triglycerides HDL cholesterol Insulin resistance Insulin Hypertension 9 Adapted from Reaven GM, Diabetes(1988) 37: 1595-1607 3
How to find insulin resistant individuals with simple screening tools? The metabolic syndrome a star is born! 10 Clinical identification of the metabolic syndrome according to NCEP-ATP III criteria Waist circumference 1 Men > 102 cm Women > 88 cm Triglycerides 2 1.69 mmol/l HDL-cholesterol 3 Men < 1.03 mmol/l Women < 1.29 mmol/l Blood pressure 4 130/85 mm Hg Fasting glucose 5 6.1 mmol/l (now 5.6) 11 1 Population-specific cut-off values have been proposed in the International Diabetes Federation guidelines 2 Or treatment for hypertriglyceridemia; 3 Or treatment for low HDL-cholesterol 4 Or treatment for hypertension; 5 Or treatment with a hypoglycemic agent Presence of 3 or more of the above risk determinants Adapted from JAMA (2001) 285: 2486-2497 Grundy SM et al. J Am Coll Cardiol(2006) 47: 1093-1100 2009 harmonized definition for the clinical identification of the metabolic syndrome 3 risk determinants are present Abdominal obesity Europids Men 94 cm Women 80 cm Non-Europids Men 90 cm Women 80 cm Triglycerides 1 1.70 mmol/l HDL-cholesterol 2 Men < 1.0 mmol/l Women < 1.3 mmol/l Blood pressure 3 130/85 mmhg Fasting plasma glucose 4 5.6 mmol/l 12 1 Or treated for elevated triglycerides 2 Or treated for low HDL-cholesterol 3 Or treated for hypertension 4 Or treated for elevated fasting plasma glucose Alberti KG, Eckel RH, Grundy SM et al., Circulation (2009) 120: 1640-45 4
RR of M&M associated with metabolic syndrome (meta-analysis) All cause death No. studies 6 RR (95 % CI) 1.35 (1.17 1.56) CVD death 6 1.74 (1.29 2.35) CVD CHD 8 8 1.53 (1.26 1.87) 1.52 (1.37 1.69) Stroke 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 3 1.76 (1.37 2.23) 13 Adapted from Galassi A et al., Am J Med (2006) 119: 812-819 Metabolic syndrome: some issues Clinical evaluation vs. definition (pathophysiology) Heterogeneous (3 out of 5 criteria) Yes or no: does not assess its severity Cannot assess absolute CVD risk As an entity, cannot be a therapeutic target Added value? 14 Després JP, Cartier A, Côté M, Arsenault BJ. Ann Med.(2008) 40(7): 514-23 A Genetic and environmental determinants Energy dense diet Genetic variation Age and Gender Lack of physical activity Smoking Stress Neuroendocrine abnormalities Steroid hormones Susceptible endocannabinoid system Drugs B Visceral obesity/ Ectopic fat Adipokines Insulin resistance/ Insulin Impaired Inflammation fibrinolysis Syndrome X (Reaven) Insulin resistance syndrome Blood pressure Atherogenic dyslipidemia Dysglycemia Based on key pathophysiological markers C 15 Metabolic syndrome (NCEP-ATP III or IDF) Based on clinical tools: Waist girth Triglycerides HDL-cholesterol Glucose Blood pressure Després JP et al., ATVB (2008)28: 1039-1049 5
How prevalent is the metabolic syndrome among nonobese individuals? 16 Waist girth among men of the Québec Health Survey characterized by different combinations of features of the metabolic syndrome (NCEP-ATPIII) 130 125 123.0 120 115.8 115 113.2 110 106.7 105 103.4 104.0 100 95 90 87.7 85 80 Waist girth > 102 cm X X X X X X Triglycerides 1.7 mmol/l X X X X HDL cholesterol < 1.03 mmol/l X X X X Blood pressure 130/85 mmhg X X X Fasting glucose 6.1 mmol/l X X X X Waist girth (cm) 100.2 X X X X X X 104.9 X X X 17 From Després JP, et al., Eur Heart J (2008) 10(Suppl B): B24-B33 18 6
Abdominal obesity is the most prevalent form of the metabolic syndrome Endothelial dysfunction Atherogenic dyslipidemia Hypertension ( ( Inflammatory profile Insulin resistance Pro-thrombotic state 19 From Després JP, Lemieux I. Nature (2006) 444: 881-887 Excess liver fat: another characteristic of visceral obesity associated with features of the metabolic syndrome 20 Liver fat: an important partner in crime in the link between visceral fat and cardiometabolic risk? Increased liver fat deposition Positive energy balance? Expanded visceral fat depot Cardiometabolic risk 21 Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org 7
22 From Guerrero R. et al., Hepatology (2009)49: 791-801 Sex differences in liver fat content are largely explained by differences in visceral adiposity Figure 3. Relationship Between Hepatic Triglyceride Content and Total/Regional Adiposity by Gender Hepatic triglyceride content (HTGC) was log transformed to meet assumptions of ANCOVA analysis. As expected, HTGC increased as a function of total and regional adiposity in both sexes. (A) The plot of HTGC vs. percent body fat (%BF) in men and women. The slopes of this relationship were significantly different (Slopemen 0.06 vs. Slopewomen 0.05 P=0.019). (B) The plot of HTGC vs. percent intraperitoneal fat (%IP) (intraperitoneal fat mass / total body mass) in men and women. The slopes of this relationship were significantly different (Slopeme n 0.66 vs. Slopewomen, 0.81 P=0.022). Adjustment for subcutaneous fat yielded resultssimilar to adjustment for %BF. 23 From Guerrero R. et al., Hepatology (2009)49: 791-801 There is, however, a lack of international data on the contribution of excess visceral adiposity/liver fat to the cardiometabolic risk profile of patients with: Impaired glucose homeostasis Type 2 diabetes Cardiovascular disease 24 8
25 Adapted from Smith JD et al., J Clin Endocrinol Metab (2012)97(5): 1517-1525 Overall objectives of INSPIRE ME IAA 26 Cross-sectionally: To determine the relationship between visceral adiposity and: Cardiometabolic risk markers/factors including waist circumference History of ischemic cardiovascular events and type 2 diabetes Prospectively: To determine the relationship between visceral adiposity and incidence of ischemic cardiovascular events and type 2 diabetes over a 3-year follow-up period General information 29 countries; 4277 patients ( 52%; 48%) First patients in: 30 June 2006, last patient in: 30 May 2008 North America n=701 patients Latin America n=885 patients Asia n=1636 patients Europe n=1055 patients Mean age: 57 years Hypertension: 60% Type 2 diabetes fasting glucose 7 mmol/l or glucose 11.1 mmol/l 120 or treatment for diabetes or history of diabetes: 39% Metabolic syndrome (AHA/NHLBI): 62% Cardiovascular disease (CAD, CRVD, PAD): 24% 27 9
Visceral adipose tissue measurement Vertebrae Ribs L4-L5 Muscle Visceral fat Visceral fat Visceral fat Subcutaneous fat Subcutaneous fat 28 L4-L5 inter-vertebral space Liver fat measurement (Th12-L1) Subject A Lean liver CTL-Liver Liver fat CTS-Spleen CTL: 79.4 HU CTS: 59.6 HU Subject B Fatty liver Liver attenuation value (CTL) CTL: 14.8 HU CTS: 60.7 HU 29 Visceral Adiposity Type 2 Diabetes Cardiometabolic risk? 30 10
Categorization by presence/absence of type 2 diabetes and tertiles of VAT 1 st tertile of VAT: low VAT Low VAT without T2D (386 m, 457 w) Low VAT with T2D (273 m, 149 w) All patients (with and without T2D) 2 nd tertile of VAT: mid VAT Mid VAT without T2D (356 m, 334 w) Mid VAT with T2D (309 m, 252 w) 31 3 rd tertile of VAT: high VAT High VAT without T2D (258 m, 221 w) High VAT with T2D (403 m, 371 w) Triglyceride concentrations across visceral adipose tissue tertiles in men without and with type 2 diabetes Triglycerides (mmol/l) 2.5 2.0 1.5 1.0 0.5 Without type 2 diabetes With type 2 diabetes 0.0 138.9 138.9-204.9 >204.9 Visceral adipose tissue tertiles (cm 2 ) p<0.0001 for visceral AT, p=0.6 for type 2 diabetes, p=0.2 for interaction 32 Adapted from Smith JD et al., J Clin Endocrinol Metab (2012)97(5): 1517-1525 Triglyceride concentrations across visceral adipose tissue tertiles in women without and with type 2 diabetes Triglycerides (mmol/l) 2.5 2.0 1.5 1.0 0.5 Without type 2 diabetes With type 2 diabetes 0.0 113.6 113.6-167.3 >167.3 Visceral adipose tissue tertiles (cm 2 ) 33 p<0.0001 for visceral AT, p<0.0001 for type 2 diabetes, p=0.002 for interaction Adapted from Smith JD et al., J Clin Endocrinol Metab (2012)97(5): 1517-1525 11
HDL cholesterol concentrations across visceral adipose tissue tertiles in men without and with type 2 diabetes HDl cholesterol (mmol/l) 1.40 1.30 1.20 1.10 1.00 Without type 2 diabetes With type 2 diabetes 0.90 138.9 138.9-204.9 >204.9 Visceral adipose tissue tertiles (cm 2 ) 34 p<0.0001 for visceral AT, p=0.05 for type 2 diabetes, p=0.6 for interaction Adapted from Smith JD et al., J Clin Endocrinol Metab (2012)97(5): 1517-1525 HDL cholesterol concentrations across visceral adipose tissue tertiles in women without and with type 2 diabetes HDl cholesterol (mmol/l) 1.70 1.60 1.50 1.40 1.30 1.20 Without type 2 diabetes With type 2 diabetes 1.10 113.6 113.6-167.3 >167.3 Visceral adipose tissue tertiles (cm 2 ) 35 p<0.0001 for visceral AT, p<0.0001 for type 2 diabetes, p=0.0006 for interaction Adapted from Smith JD et al., J Clin Endocrinol Metab (2012)97(5): 1517-1525 Inflammatory factors increased with both visceral adiposity and type 2 diabetes Men lowvat medvat highvat lowvat medvat highvat Type 2 diabetes No diabetes 36 lowvat medvat highvat Adjusted for: age, physician s specialty, region, BMI There was a similar pattern in women 12
Liver fat was related to both visceral adiposity and type 2 diabetes Men Women lowvat midvat highvat lowvat midvat highvat 37 Adjusted for age, physician s specialty, region, BMI Type 2 diabetes No diabetes Frequency of prevalent CVD in men and women without and with type 2 diabetes A Men Women lowvat midvat highvat lowvat midvat highvat CVD: history of current symptoms of carotid revascularization, carotid stenosis, lower limb amputation due to ischemic disease, lower limb revascularization, myocardial infarction or unstable angina, myocardial revascularization, or stroke Statistical significance was calculated using a logistic model including VAT tertiles, type 2 diabetes status, and their interaction as well as age, BMI, patient s geographical region, and the recruiting physician s specialty 38 Adapted from Smith JD et al., J Clin Endocrinol Metab (2012)97(5): 1517-1525 Odds ratios for type 2 diabetes associated with a 1-SD change in cardiometabolic risk factors C Men Statistical model 2 D Women Statistical model 2 SBP SBP DPB log (TG) HDL-C SAT VAT liver attenuation DPB log (TG) HDL-C SAT liver attenuation VAT Men and women report odds ratios after adjustment for one another as well as for the following confounding variables: Age, geographical region, and recruiting physician s specialty 39 Adapted from Smith JD et al., J Clin Endocrinol Metab (2012)97(5): 1517-1525 13
Conclusion Visceral Adiposity Type 2 Diabetes 40 Cardiometabolic risk? Excess visceral adiposity/liver is a key correlate of metabolic abnormalities in both patients with/without type 2 diabetes Excess visceral/liver fat redefines what is high risk overweight/obesity Increased liver fat deposition Positive energy balance? Expanded visceral fat depot Cardiometabolic risk 41 Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Visceral obesity = dysfunctional adipose tissue? A Insulin resistant Portal circulation Altered FFA metabolism Hyperinsulinemia Glucose intolerance Hypertriglyceridemia Etc. B Release of cytokines IL-6 TNF-a Adiponectin Other adipokines Altered metabolic profile: Insulin resistant milieu Pro-inflammatory state Pro-thrombotic state Pro-hypertensive state C Ectopic fat deposition 42 Lack of or dysfunctional subcutaneous fat Impaired Clearance and storage of TG in subcutaneous AT From Després JP, Lemieux I. Nature (2006)444:881-887,Després JP et al., ATVB (2008)28: 1039-1049 14
How to find insulin resistant individuals with excess visceral adipose tissue/liver fat with simple screening tools? «Hypertriglyceridemic waist» 43 Hypertriglyceridemic waist as a screening tool for visceral obesity/ectopic fat Waist* + Triglycerides* Good < 90 cm < 2.0 mmol/l ~10% Bad > 90 cm > 2.0 mmol/l ~80% * 85 cm and 1.5 mmol/l in women 44 Adapted from Lemieux I et al., Circulation(2000) 102: 179-184 HyperTG waist and CHD risk in the EPIC-Norfolk Study PIs: Wareham NJ, Khaw KT (Cambridge) European Prospective Investigation into Cancer and nutrition - Norfolk study 21,758 subjects (9,496 men and 12,262 women) aged 45 to 79 years Mean follow-up 8.2 ± 1.4 years 1387 CHD events (854 men and 533 women) 45 Arsenault B et al, CMAJ. (2010) 183: 1427-1432 15
150 145 140 135 130 Without Hypertriglyceridemic waist: an important clinical phenotype in men of the EPIC-Norfolk study Systolic BP With 90 88 86 84 82 80 Without Diastolic BP With 1,5 1,4 1,3 1,2 1,1 1,0 HDL-cholesterol Without With CRP LDL particle size Apolipoprotein B 4,0 3,5 p=0.007 265 260 150 140 3,0 130 2,5 255 120 2,0 46 Without With 250 Without 110 With Without With Arsenault B et al, CMAJ. (2010) 183: 1427-1432 150 145 140 135 130 Without Hypertriglyceridemic waist: an important clinical phenotype in women of the EPIC-Norfolk study Systolic BP With 90 88 86 84 82 80 78 Without Diastolic BP With 2,0 1,8 1,6 1,4 1,2 1,0 HDL-cholesterol Without With CRP LDL particle size Apolipoprotein B 6,0 5,0 265 260 150 140 4,0 3,0 255 130 120 2,0 47 Without With 250 Without 110 With Without With Arsenault B et al, CMAJ. (2010) 183: 1427-1432 Kaplan-Meir survival curves according to subgroups of hypertriglyceridemic waist in men (1993-2003) 1.00 Men Event-free survival 0.95 0.90 0.85 0 WC<90 cm, TG<2.0 mmol/l WC<90 cm, TG>2.0 mmol/l WC>90 cm, TG<2.0 mmol/l WC>90 cm, TG>2.0 mmol/l 3 6 9 12 Follow-up (years) 48 Arsenault B et al, CMAJ. (2010) 183: 1427-1432 16
Kaplan-Meir survival curves according to subgroups of hypertriglyceridemic waist in women (1993-2003) 1.00 Women Event-free survival 0.95 0.90 WC<85 cm, TG<1.5 mmol/l WC<85 cm, TG>1.5 mmol/l WC>85 cm, TG<1.5 mmol/l WC>85 cm, TG>1.5 mmol/l 0.85 0 3 6 9 12 Follow-up (years) 49 Arsenault B et al, CMAJ. (2010) 183: 1427-1432 Limitations of a clinical diagnosis of the metabolic syndrome in absolute CVD risk assessment 50 CASE #1 Nondiabetic man 30 years of age Normal blood pressure Nonsmoker Waist circumference = 104 cm Triglycerides = 2.50 mmol/l LDL-cholesterol = 3.00 mmol/l HDL-cholesterol = 0.85 mmol/l 51 Framingham 10-year CHD risk= 4% Metabolic syndrome 10-year CHD risk 8 4 Relative risk of CHD by 2 fold Relative risk of CHD 2X 0 Absence Presence Metabolic syndrome From Després JP, Lemieux I. Nature (2006) 444: 881-887 CASE #2 Nondiabetic man 55 years of age Blood pressure = 170/95 mmhg Smoker Waist circumference = 104 cm Triglycerides = 2.50 mmol/l LDL-cholesterol = 4.00 mmol/l HDL-cholesterol = 0.85 mmol/l Framingham 10-year CHD risk= 33% Metabolic syndrome 10-year CHD risk Relative risk of CHD 66 33 Relative risk of CHD by 2 fold 2X 0 AbsencePresence Metabolic syndrome 17
Risk of CHD associated with the metabolic syndrome: relative risk vs. absolute risk 52 Absolute 10-year CHD risk (%) 70 60 50 40 30 20 10 0 AbsencePresence AbsencePresence Metabolic syndrome? Metabolic syndrome Case #1 Case #2 From Després JP, Lemieux I. Nature (2006) 444: 881-887 Metabolic syndrome: one component of global CMR + = 53 From Després JP, Lemieux I. Nature (2006) 444: 881-887 Incorporating visceral adiposity/ectopic fat into improved global risk assessment algorithms? HyperTG-waist Visceral Ectopic fat Insulin resistance LDL HDL Hypertension Diabetes Age Male gender Smoking Others (genetic factors) Global cardiometabolic risk 54 From Després JP, Lemieux I. Nature (2006) 444: 881-887 18
Management of the metabolic syndrome: the medical approach 55 We have good news your cholesterol is normal!" "Turbostatins": the medical response to our sedentary atherogenic/pro-inflammatory lifestyle? 56 From Després JP. The Lancet(2009) 379: 1147-9 The abdominally obese patient most often has a sedentary lifestyle and a poor fitness level 57 19
58 Men Women * * ** * * ** 59 Broekhuizen LN et al, Eur J Cardiovasc Prev Rehab (2011) 18: 209-217 Relative CHD risk 12 10 Low cardiorespiratory fitness: a powerful CHD risk factor 8 6 4 2 9.25 3,120 women, 10,224 men ~ 8-year follow-up 1.0 7.93 1.0 60 0 Low High Fitness level Women Low High Fitness level Men From Blair SN et al., JAMA (1989) 262: 2395-2401 20
61 Reshaping lifestyle habits of viscerally obese patients with features of the metabolic syndrome 62 What should our target be? Loss of visceral/liver fat and improving cardiorespiratory fitness? The metabolic syndrome Which variables/factors should be on our radar screen? Lifestyle variables ( the causes of the causes ) Nutritional quality Physical activity/exercise, sedentary time Ecological, socio-economic drivers of unhealthy behaviors Phenotypes: Imaging markers of visceral/ectopic fat Physical activity (pedometers, accelerometers with HR) Cardiorespiratory fitness Anthropometry, blood markers (IR, lipoproteins, inflammation) 63 21
64 22