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What is the metabolic syndrome? Simon Thom

What is the metabolic syndrome? Simon Thom. Lipid Update VI Stratford-upon-Avon, 20/11/2006. Overlap of diabetes 2 obesity & essential hypertension. Diabetes. Obesity. Hypertension. Squares are roughly proportional to prevalence of the 3 conditions in a middle-aged westernized population.

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What is the metabolic syndrome? Simon Thom

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

  2. Overlap of diabetes2 obesity & essential hypertension Diabetes Obesity 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. NCEP-ATP III definition Any 3 or more of the following criteria: Waist circumference >102 men & >88 cm in women Serum triglycerides 1.7 Blood pressure >130/85 HDL cholesterol <1.0 men and <1.3 women 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: Waist-hip ratio >0.90 men or >0.85 women Serum triglycerides 1.7 or HDL cholesterol <0.9 men & <1.0 women Blood pressure 140/90 Urinary albumin excretion >20 µg/min or albumin-creatinine ratio >30 mg/g Metabolic syndrome definitions 16 potential defining combinations! JAMA 2001; 285: 2486 Circulation 2004; 109: 433 WHO Geneva 1999

  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 http://www.idf.org/webdata/docs/IDF_Metasyndrome_definition.pdf Alberti KGMM et al. Lancet 2005; 366: 1059

  6. Usual fasting glucose & risk of CV end points Total stroke Total IHD Cardiovascular death Hazard ratio & 95% CI Usual fasting glucose, mmol/l 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 Asia Pacific Cohort Studies Collaboration. Diabetes Care 2004; 27: 2836

  7. CHD: risk accumulates with additional CV risk factors Hypertension SBP 150 mmHg X1.5 Dyslipidemia TC 260 mg/dL X2.3 X3.5 X6.2 X4 X2.8 Glucose intolerance X1.8 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. International prevalence of the metabolic syndrome ATP III definition; adapted from: Gu D. Lancet 2005; 365:1398. Eckel R. Lancet. 2005; 365:1415. Ford E. Diabetes Care. 2004; 27: 2444. Reynolds K. Am J Med Sci, 2005; 330: 273

  9. Does the metabolic syndrome predict CVD risk?

  10. Metabolic syndrome: CHD death or non-fatal MI with different numbers of factors - 6000 men followed for 5 yrs % with events Years Kaplan-Meier curves for CHD events in men with zero, 1, 2, 3, or >=4 characteristics of the metabolic syndrome at baseline Sattar N. Circulation 2003; 108: 414

  11. The metabolic syndrome and 11-year risk of incident CVD in ARIC 12,089 women & men followed for 11 years The syndrome conferred no greater CHD risk than the sum of its components. Hazard ratio* Components of the ATP III metabolic syndrome 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. McNeill AM, ARIC, Diabetes Care 2005; 28: 385

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

  13. .... in recognising the undoubted risk factor clustering of the metabolic syndrome, we don’t appear to be identifying any particular risk enhancing interaction. .... should this surprise us? 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: 1719

  14. Is there a unifying explanatory mechanism for the metabolic syndrome?

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

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

  17. Relationship between BP & muscle blood flow during hyperinsulinemic clamp 250 200 150 r = - 0.69 p = 0.005 % increase in leg blood flow 100 50 115 95 65 75 105 85 Basal MAP (mmHg) Baron AD, Hypertension 1993; 21:129

  18. 8 wk exercise, one leg opposite leg control In trained muscle : LPL activity VLDL-TG uptake HDL chol production m-LPLA :: a-v D TG Effect of training on skeletal muscle lipoprotein lipase activity - relationship with capillary density 500 400 Capillary density /mm2 300 200 0 20 40 60 80 LP Lipase activity (mU/g w.w.) Kiens B. JCI 1989; 83: 558 - 564

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

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

  21. Linked by association or by mechanism? - a genetic or environmental hook – or both? Ferrannini E. Am Heart J 1991; 121: 1274

  22. Overlap of diabetes2 obesity & essential hypertension Diabetes Obesity 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

  23. Diabetes ? Hypertension Obesity

  24. Diabetes Hypertension Physical inactivity Obesity

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

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

  27. Metabolic syndrome - a clinically useful diagnosis? 11.4 5.8 (mmol/l) 2.2 1.8 * IDF criteria Reaven GM. The metabolic syndrome: is this diagnosis really necessary? Am J Clin Nutr 2006; 83: 1237

  28. Metabolic syndrome: • Deadly trigger – unidentified • Magic bullet – ? … rimonabant, glitazones, telmisartan……… Editorial accompanying ‘Nolan J. NEJM 1994;331:1188 - 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

  29. 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

  30. Thank you for your attention. s.thom@imperial.ac.uk

  31. Link between insulin resistance (IR) & essential hypertension (EH) • Patients with EH (as a group) are relatively insulin resistant with compensatory hyperinsulinemia • Normotensive 1st 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

  32. 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

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

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

  35. The metabolic syndrome:a recent perspective  BMI  Central Adiposity Insulin Resistance + Hyperinsulinemia GlucoseMetabolism Uric AcidMetabolism Dyslipidemia Hemodynamic Novel RiskFactors •  TG •  PP lipemia •  HDL-C •  PHLA • Small, dense LDL •  Uric acid •  Urinary uricacid clearance •  SNS activity •  Na retention • Hypertension •  CRP •  PAI-1 •  Fibrinogen • ± Glucoseintolerance Coronary Heart Disease Reaven G. Drugs. 1999; 58 (S): 19

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

  37. Metabolic syndrome predicting mortality 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) Malik S. Circulation 2004; 110: 1245

  38. Prediction of CHD prevalence using multivariate logistic regression * Significant predictors of prevalent CHD. The syndrome confers no greater information than the sum of its component risk factors. Alexander CM. Diabetes 2003; 52:1210

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

  40. 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 Cardiovascular benefits of exercise

  41. 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: 2596-2598

  42. Grundy Nature Reviews Drug Discovery5, 295–306 (April 2006) | doi:10.1038/nrd2005

  43. Grundy Nature Reviews Drug Discovery5, 295–306 (April 2006) | doi:10.1038/nrd2005

  44. Grundy Nature Reviews Drug Discovery5, 295–306 (April 2006) | doi:10.1038/nrd2005

  45. Grundy Nature Reviews Drug Discovery5, 295–306 (April 2006) | doi:10.1038/nrd2005

  46. Grundy Nature Reviews Drug Discovery5, 295–306 (April 2006) | doi:10.1038/nrd2005

  47. Grundy Nature Reviews Drug Discovery5, 295–306 (April 2006) | doi:10.1038/nrd2005

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