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What is the metabolic syndrome? Simon Thom Lipid Update VI Stratford-upon-Avon, 20/11/2006.

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Presentation on theme: "What is the metabolic syndrome? Simon Thom Lipid Update VI Stratford-upon-Avon, 20/11/2006."— Presentation transcript:

1 What is the metabolic syndrome? Simon Thom Lipid Update VI Stratford-upon-Avon, 20/11/2006

2 Diabetes Obesity Hypertension Overlap of diabetes 2 obesity & essential hypertension Squares are roughly proportional to prevalence of the 3 conditions in a middle-aged westernized population Ferrannini E. J Nephrol 1989; 1: 3-15

3 The metabolic syndrome / insulin resistance syndrome / Reaven’s syndrome / syndrome ‘X’  Resistance to insulin-stimulated glucose uptake  Glucose intolerance  Hyperinsulinemia  VLDL triglyceride  HDL cholesterol  Hypertension  Central obesity, waist-hip ratio Reaven G, Diabetes 1988; 37:1595

4 Metabolic syndrome definitions NCEP-ATP III definition Any 3 or more of the following criteria: 1.Waist circumference >102 men & >88 cm in women 2.Serum triglycerides Blood pressure >130/85 4.HDL cholesterol <1.0 men and <1.3 women 5.Serum glucose 6.1 (5.6 may be applicable) WHO definition Diabetes, IFG, IGT, or insulin resistance (clamp studies) & at least 2 of the following criteria: 1.Waist-hip ratio >0.90 men or >0.85 women 2.Serum triglycerides 1.7 or HDL cholesterol <0.9 men & <1.0 women 3.Blood pressure 140/90 4.Urinary albumin excretion >20 µg/min or albumin- creatinine ratio >30 mg/g JAMA 2001; 285: 2486 Circulation 2004; 109: 433 WHO Geneva potential defining combinations!

5 IDF 2005 worldwide metabolic syndrome definition  Central obesity  Waist circumference ≥94 cm for men and ≥80 cm for women (Europid values)  Plus ≥2 of the following:  TG level ≥150 mg/dL (1.7 mmol/L) or treatment for hypertriglyceridemia  HDL-C <40 mg/dL (1.03 mmol/L) in males and <50 mg/dL (1.29 mmol/L) in females or treatment for reduced HDL-C  Systolic BP ≥130 mmHg or diastolic BP ≥85 mmHg or treatment for hypertension  Fasting plasma glucose ≥100 mg/dL (5.6 mmol/L) or Type 2 diabetes Alberti KGMM et al. Lancet 2005; 366: 1059

6 Hazard ratio & 95% CI Total strokeTotal IHDCardiovascular death Asia Pacific Cohort Studies Collaboration. Diabetes Care 2004; 27: 2836 Usual fasting glucose & risk of CV end points 237,468 participants (14,282 Chinese); ~1.2 million person-years follow-up 1,661 strokes & 816 IHD events Each 1 mmol/l ↓ fasting glucose associated with ~20% ↓ risk of CVD death Usual fasting glucose, mmol/l

7 CHD: risk accumulates with additional CV risk factors Dyslipidemia TC 260 mg/dL X2.3 Hypertension SBP 150 mmHg X1.5 Glucose intolerance X1.8 X3.5 X6.2 X2.8 X4 Risk shown above is compared with baseline risk for a 40-year-old male non-smoker with TC 4.7 mmol/L (185 mg/dL), SBP 120 mmHg, and no glucose intolerance, who is ECG-LVH negative and whose probability of developing CVD is 15/1000 (1.5%) in 8 years Kannel WB. In Hypertension: Physiopathology & Treatment 1977 : 888–910

8 ATP III definition; adapted from: Gu D. Lancet 2005; 365:1398. Eckel R. Lancet. 2005; 365:1415. Ford E. Diabetes Care. 2004; 27: International prevalence of the metabolic syndrome Reynolds K. Am J Med Sci, 2005; 330: 273

9 Prevalence of the metabolic syndrome in USA & China USAChina Prevalence, % Gu D. InterASIA Lancet 2005; 365: 1398 Ford ES. JAMA 2002; 287: 356

10 Does the metabolic syndrome predict CVD risk?

11 Pyorala M. ATVB 2000; 20: 538 Kaplan-Meier curves for remaining free of CHD and stroke by tertiles of insulin resistance Metabolic syndrome predicts risk of CHD & stroke in healthy middle-aged men 22-Year follow-up, Helsinki Policemen Study CHDStroke

12 Sattar N. Circulation 2003; 108: 414 Kaplan-Meier curves for CHD events in men with zero, 1, 2, 3, or >=4 characteristics of the metabolic syndrome at baseline Years % with events Metabolic syndrome: CHD death or non-fatal MI with different numbers of factors men followed for 5 yrs

13 HRs of CHD associated with the presence of 1, 2, 3, or 4+ metabolic syndrome components cf. no components; *adjusted for age, race, LDL cholesterol level, and smoking. Components of the ATP III metabolic syndrome Hazard ratio* The syndrome conferred no greater CHD risk than the sum of its components. McNeill AM, ARIC, Diabetes Care 2005; 28: 385 The metabolic syndrome and 11-year risk of incident CVD in ARIC 12,089 women & men followed for 11 years

14 Wannamethee S G et al. Arch Intern Med 2005; 165: 2644 Metabolic syndrome / Framingham risk score & measures of probability (%) for occurrence of CHD event & Type 2 diabetes

15 .... in recognising the undoubted risk factor clustering of the metabolic syndrome, we don’t appear to be identifying any particular risk enhancing interaction. At least 80% of major CHD events in middle aged men can be attributed to the three strongest risk factors (cholesterol, BP & smoking). The residual variation may be explained once changes in smoking habits & other established risk factors such as physical inactivity & obesity have been taken into account. Emberson JR et al. E Heart J 2003; 24: should this surprise us?

16 Is there a unifying explanatory mechanism for the metabolic syndrome?

17 Metabolic syndrome - hypotheses for pathogenesis Sympathetic activation Inflammation Adiponectin deficiency Vascular rarefaction Sodium retention Leptin resistance ……..

18 Sympathetic activation High cardiac ouput - (  adrenergic) Inadequate vasodilatation - (  adrenergic) Stimulated  adrenergic receptors High blood pressure Insulin resistance Vascular hypertrophy Conversion to fast twitch fibres Cardiovascular Skeletal muscle Vascular rarefaction Decreased substrate to muscles Acute Chronic

19 250 Basal MAP (mmHg) % increase in leg blood flow r = p = Relationship between BP & muscle blood flow during hyperinsulinemic clamp Baron AD, Hypertension 1993; 21:129

20 LP Lipase activity (mU/g w.w.) Capillary density /mm 2 Effect of training on skeletal muscle lipoprotein lipase activity - relationship with capillary density Kiens B. JCI 1989; 83: l 8 wk exercise, one leg l opposite leg control In trained muscle : l LPL activity l VLDL-TG uptake l HDL chol production l m-LPLA :: a-v D TG

21 Dandona P. Circulation 2005; 111:1448 Extension of metabolic syndrome on the basis of resistance to the novel actions of insulin

22 Prasad A. Circulation 2004; 110: 1507 Pathophysiology of CVD in the metabolic syndrome

23 Summary of concerns regarding the metabolic syndrome 1.Criteria are ambiguous or incomplete. Rationale for thresholds are ill defined. 2.Value of including diabetes in the definition is questionable. 3.Insulin resistance as the unifying etiology is uncertain. 4.No clear basis for including/excluding other CVD risk factors. 5.CVD risk value is variable and dependent on the specific risk factors present. 6.The CVD risk associated with the "syndrome" appears to be no greater than the sum of its parts. 7.Treatment of the syndrome is no different than the treatment for each of its components. 8.The medical value of diagnosing the syndrome is unclear. Kahn R, et al. Diabetes Care 2005; 28: 2289 Cause? Consequence?

24 Shen BJ. Am J Epi 2003; 157: 701 Factor structure of the metabolic syndrome C a u s e ? C o n s e q u e n c e ?

25 Linked by association or by mechanism? Ferrannini E. Am Heart J 1991; 121: a genetic or environmental hook – or both?

26 Diabetes Obesity Hypertension Overlap of diabetes 2 obesity & essential hypertension Squares are roughly proportional to prevalence of the 3 conditions in a middle-aged westernized population Ferrannini E. J Nephrol 1989; 1: 3-15

27 Diabetes Obesity Hypertension ?

28 Diabetes Obesity Hypertension Physical inactivity


30 Metabolic syndrome – at least a prompt for action? “Units” Diagnostic / therapeutic threshold Khunti K. BMJ 2005; 331: 1154 Alberti KG. Lancet 2005; 366: 1056

31 Metabolic syndrome – at least a prompt for action? “Units” Diagnostic / therapeutic threshold Khunti K. BMJ 2005; 331: 1154 Alberti KG. Lancet 2005; 366: 1056

32 Case 1Case 2 Age 54 Gender Male WC (cm) 9394 Glucose (mg/dl) Trigs (mg/dl) Metabolic syndrome* NoYes Metabolic syndrome - a clinically useful diagnosis? Reaven GM. The metabolic syndrome: is this diagnosis really necessary? Am J Clin Nutr 2006; 83: 1237 * IDF criteria (mmol/l)

33 Editorial accompanying ‘Nolan J. NEJM 1994;331: effect of troglitazone on insulin resistance ’ “Medical moralists will despair that pharmacologic inventiveness may now allow people to become even fatter and lazier without having to face their metabolic nemesis.” Harry Keen, NEJM 1994 Metabolic syndrome: Deadly trigger – unidentified Magic bullet – ? … rimonabant, glitazones, telmisartan………

34 Points of agreement around the metabolic syndrome: That certain “metabolic” / cardiovascular risk factors associate with each other more often than chance would dictate. That these factors taken alone or in any possible combination are associated with an elevated risk for CVD & diabetes. That there is no definitive treatment for the “syndrome” per se. Kahn R. Diabetes Care 2006; 29: 1693



37 Thank you for your attention.

38 Link between insulin resistance (IR) & essential hypertension (EH)  Patients with EH (as a group) are relatively insulin resistant with compensatory hyperinsulinemia  Normotensive 1 st degree relatives of patients with EH are more insulin resistant cf. control subjects without FH of EH  IR in population based studies predicts the eventual development of EH

39 ComparisonPoint estimate95% CI Q2 vs. Q – 2.4 Q3 vs. Q – 2.5 Q4 vs. Q – 7.5 RR of hypertension by quartile of baseline fasting insulin 278 adult women age 50, Gothenburg, 12 years follow-up Adjusted for BMI, W/H ratio, weight change Also significant relationship: baseline insulin &  BP Lissner L. Hypertension 1992; 20: 797

40 Defect in insulin action Rising glucose Stimulated insulin secretion Homeostasis at price of hyperinsulinaemia

41 Insulin resistance states:  Obesity  Hyperlipidemia  High blood pressure  IGT  High triglycerides  Diabetes type 2  Smoking  HAART for HIV  …….

42 The metabolic syndrome: a recent perspective Reaven G. Drugs. 1999; 58 (S): 19  BMI  Central Adiposity  BMI  Central Adiposity Glucose Metabolism Uric Acid Metabolism Dyslipidemia Hemodynamic Novel Risk Factors Insulin Resistance Hyperinsulinemia +  TG  PP lipemia  HDL-C  PHLA Small, dense LDL ± Glucose intolerance  Uric acid  Urinary uric acid clearance  SNS activity  Na retention Hypertension  CRP  PAI-1  Fibrinogen Coronary Heart Disease

43 Haffner S. Circulation 2003; 108: 1541 Age-adjusted prevalence of CHD in the US population >50 years with metabolic syndrome & diabetes

44 Malik S. Circulation 2004; 110: 1245 Age- and gender-adjusted CHD, CVD, & total mortality rates in US adults with MetS +/- diabetes & pre-existing CVD in NHANES II (n=6255; mean follow-up, 13.3 years) Metabolic syndrome predicting mortality

45 Prediction of CHD prevalence using multivariate logistic regression * Significant predictors of prevalent CHD. Variable * Odds ratio Lower 95% limit Upper 95% limit Waist circumference Triglycerides HDL cholesterol * Blood pressure * IFG Diabetes * Metabolic syndrome Alexander CM. Diabetes 2003; 52:1210 The syndrome confers no greater information than the sum of its component risk factors.

46 Intracell Ca ++  Vasculopathy* Constriction Rarefaction Symp, Activity/ Tissue Reactivity Central Obesitiy Hyperinsulinemia Insulin resistance Hyperinsulinemia Na + Reabsorption * skeletal muscle Genetics Nutrition

47 Cardiovascular benefits of exercise blood pressure peripheral resistance sympathetic activity fibrinogen & PAI-1 platelet aggregation triglycerides & LDL blood sugar left ventricular mass abdominal obesity endothelial NO HDL insulin sensitivity fibrinolytic activity LV ejection fraction haemodynamics in HF psychological well-being arrhythmia threshold coronary flow

48 Proposed Role of RBP4 in the Pathogenesis of Insulin Resistance and Glucose Intolerance. Insulin resistance in adipose tissue is associated with reduced levels of glucose transporter 4 (GLUT4), which results in the increased production of RBP4. This increased production leads to elevated circulating levels of the protein that causes insulin resistance in muscle, as well as elevated levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase and an increased rate of gluconeogenesis in the liver, causing increased glucose production. These factors increase blood glucose levels, leading to impaired glucose tolerance or diabetes. Polonsky, KS. NEJM 2006; 354:

49 Grundy Nature Reviews Drug Discovery 5, 295–306 (April 2006) | doi: /nrd2005






55 Scripps ghrelin vaccine was injected into male rats. Ghrelin secreted by the rats when they had not eaten is sequestered by vaccine-induced antibodies, reducing the ability of ghrelin to reach the brain, where it acts Zorrilla E. (& Janda). Proc. Natl. Acad. Sci. USA, DOI: /pnas

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