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Updates in Metabolic Syndrome

Updates in Metabolic Syndrome. Omer Junaidi, M.D. Amanda Ryan, D.O. Internal Medicine Chief Residents. Group of Metabolic Risk Factors. Abdominal obesity Atherogenic dyslipidemia Elevated blood pressure Insulin resistance or glucose intolerance Prothrombotic state

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Updates in Metabolic Syndrome

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  1. Updates in Metabolic Syndrome Omer Junaidi, M.D. Amanda Ryan, D.O. Internal Medicine Chief Residents

  2. Group of Metabolic Risk Factors • Abdominal obesity • Atherogenic dyslipidemia • Elevated blood pressure • Insulin resistance or glucose intolerance • Prothrombotic state • Proinflammatory state

  3. Objectives • Defining and classifying metabolic syndrome • Understanding the basic science • Learning the prevalence and incidence • Reviewing the clinical relevance • Discussing treatment options

  4. WHO Criteria 1999 • Insulin resistance (type 2 diabetes, IFG, IGT) • Plus any 2 of the following: • Elevated BP (>140/90 or drug Rx) • Plasma TG >150 mg/dL • HDL <35 mg/dL in men and 40 in women • BMI >30 and/or W/H ratio >0.9 men and 0.85 women • Urinary albumin >20mcg/min or Alb/Cr >30mcg/g

  5. NCEP – ATP III Guidelines

  6. AHA Guidelines for Diagnosis Three of More of the Following Components: • Elevated waist circumference:Men — Equal to or greater than 40 inches (102 cm)Women — Equal to or greater than 35 inches (88 cm) • Elevated triglycerides:Equal to or greater than 150 mg/dL • Reduced HDL cholesterol:Men — Less than 40 mg/dLWomen — Less than 50 mg/dL • Elevated blood pressure:Equal to or greater than 130/85 mm Hg • Elevated fasting glucose:Equal to or greater than 100 mg/dL

  7. New Guidelines Needed • Identify those at high risk for developing cardiovascular disease and diabetes • Be useful for international comparisons • Be useful for clinicians

  8. International Diabetes Federation 2005 Consensus

  9. IDF Waist Circumference

  10. Prevalence of Metabolic Syndrome • 3rd National Health and Nutrition Examination Survey • Data collected between 1988-1994 • 3 or more of the following criteria: • Abdominal obesity: waist circumference >102cm in men and >88cm win women • Hypertriglyceridemia: >150mg/dL • HDL <40 in men and <50 in women • High blood pressure: >130/85 mm Hg • High fasting glucose: >110mg/dL • 8814 men and women >20 years old studied Ford, E et al Prevalence of the Metabolic Syndrome Among US Adults. JAMA 2002;297:356-59.

  11. Prevalence of Metabolic Syndrome • Results indicated 22-24% prevalence • 6.7% among 20-29 year olds • 43% among 60-69 year olds • Similar for men and women: 24 and 23.4% • African American women compared to men had a 57% higher prevalence • Mexican American women compared to men had a 26% increase • Using these numbers, approximately 47 million US residents have metabolic syndrome

  12. Clinical Implications • Cardiovascular disease • Diabetes • Liver Disease • Cognitive Function

  13. NHANES Applied to MS & CV Risk • Logistic regression was used to estimate the cross-sectional association of the syndrome and each of its 5 component conditions separately with history of myocardial infarction (MI), stroke, and either MI or stroke (MI/stroke). • Models were adjusted for age, sex, race, and cigarette smoking. The metabolic syndrome was significantly related in multivariate analysis to MI. The syndrome was significantly associated with MI/stroke in both women and men. Ninomiya et al. Association of the Metabolic syndrome with history of myocardial infarction and stroke in the third national health and nutrition examination survey. Circulation 2004;109:42-46.

  14. INTERHEART • Purpose of this trial was to assess if common risk factors identified in developed countries can be appropriately applied on a global scale. • Smoking, hx of HTN of DM, W/H ratio, dietary patterns, physical activity, consumption of EtOH, apolipoproteins, and psychosocial factors all studied. • Included nearly 15,000 both case and control Yusuf et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937-44.

  15. Results • Everything except alcohol was a significant risk factor for acute MI across all groups • Smoking and raised ApoB/ApoA1 ratio were two strongest predictors • DM, HTN, and psychosocial factors were next strongest. • W/H ratio stronger than BMI

  16. Metabolic Syndrome & Hypertension • Randomized prospective study in Italy with >1700 people with HTN (mean 155/95) & no CVD, followed for a mean of 4 years • During follow up, 162 pts developed CV events, a total of 593 pts had metabolic syndrome using NCEP guidelines • Those with MS had an almost double CV event rate 3.23 vs 1.76per 100pt years.

  17. Metabolic Syndrome & Hypertension • This increase remained after adjustment for all traditional cardiovascular risk factors with a hazard ratio of 1.73. • Metabolic syndrome was an independent predictor of both cardiac and cerebrovascular events. Schillaci et al. Prognostic value of the metabolic syndrome in essential hypertension J. Am. Coll. Cardiol., May 2004; 43: 1817 - 1822.

  18. Risks with # of MS characteristics

  19. Metabolic Syndrome + Aortic Stenosis • Aortic valves sclerosis and progression to aortic stenosis may be caused by an atherosclerotic process • 105 consecutive patients with at least moderate AS were enrolled and 40 of them had MS per NCEP-ATP III. • End-points included hemodynamic progression of AS (per echo) and cardiovascular death and AVR

  20. Metabolic Syndrome + Aortic Stenosis • Hemodynamic progression to AS was twice as fast in those with MS • Three year event free survival was markedly lower with 44% (those with metabolic syndrome) vs 69% with p 0.002 • In multivariate analysis, MS was found to be a strong independent predictor of both stenosis progression (p = 0.006) and event-free survival odd (p < 0.001) Briand et al. Metabolic syndrome negatively influences disease progression and prognosis in aortic stenosis. Journal of American College of Cardiology 2006; 47:2229.

  21. Insulin Resistance • Numerous trials have demonstrated the relationship between impaired glucose tolerance, development of DM, and cardiovascular risk. • Some studies have decreased the fasting glucose cutoff to 100mg/dL.

  22. Metabolic Syndrome, Inflammation, and Cognitive Decline • Cardiovascular and metabolic risk factors are hypothesized to play a role in the pathogenesis of Alzheimer’s and vascular dementia. • Study designed to test hypothesis that metabolic syndrome is a risk factor for cognitive decline and whether this association is modified by inflammation Yaffe et al The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004;292:2237-42.

  23. Cognitive Effects cont • 5 year prospective observational study conducted from 1997 to 2002 • Total of 2632 patients aged 70-79 • Exclusion criteria included clinical dementia, inability to communicate with the interviewer, difficulty with ADL’s, cancer tx within 3 years • Modified mini-mental state exam (3MS) given at baseline and repeated at 3 and 5 year visits • Cognitive impairment defined as a 3MS change of 5 or more • Metabolic syndrome defined using NCEP guidelines • Inflammatory markers included measurements for IL-6 and CRP • Covariates included characteristics previously shown in the literature to be associated with cognitive function or metabolic syndrome

  24. Results • Mean age 73.6; 52% women, 40% black, 25% high markers of inflammation • Compared with participants without metabolic syndrome (n=1616), those with metabolic syndrome (n=1016) were more likely to be: • women and white • to smoke • have higher depression scores • higher BMI • hx of MI • to use statins and NSAIDS • have higher markers of inflammation

  25. More Results • Cognitive decline occurred in 598 participants (23%) • Baseline cognitive scores similar for those with (90.6) or without (90.4) metabolic syndrome RISK OF DEVELOPING COGNITIVE IMPAIRMENT OVER 4 YEARS ACCORDING TO THE METABOLIC SYNDROME AND INFLAMMATION

  26. Conclusion • Among high functioning elders, those with metabolic syndrome showed an increased risk of developing cognitive impairment and decline over four years.

  27. Insulin Resistance, Metabolic Syndrome and NASH • Nonalcoholic fatty liver disease is a common condition compromising a wide spectrum of liver damage strongly associated with type 2 diabetes, obesity, and hyperlipidemia. • Insulin resistance affects 20% of the nondiabetic population and occurs in association with many cardiovascular and metabolic abnormalities

  28. Purpose and Criteria • Study designed to assess the relationship of different degrees of insulin resistance (IR) and fatty liver. • 308 consecutive patients referred to metabolic clinic • Eligible if no excessive alcohol, hep B/C negative, and no US findings of cirrhosis • ALT, HDL, triglycerides, glucose, insulin, and standard glucose tolerance tests Angelico et al. Insulin Resistance, the metabolic syndrome, and nonalcoholic fatty liver disease. Jour Clinical Endocrinology & Metabolism 2005;90:1578-82.

  29. Insulin Resistance • Homeostasis model of IR based on serum fasting glucose and insulin levels was used as a measure of IR. • Liver steatosis was analyzed using ultrasound with grading of 0-3 based on intensity of echoes. • 5% without steatosis • 59% with mild/moderate steatosis • 36% with severe

  30. Insulin Resistance • Per WHO criteria, 193 subjects has a normal glucose tolerance test • 43 subjects had impaired glucose tolerance • 72 subjects had type 2 diabetes • Strong positive correlation found between insulin resistance and severe steatosis

  31. Liver Pathology and the Metabolic Syndrome in Severe Obesity • 580 subjects undergoing gastric bypass surgery had wedge biopsies of liver • Mean age was 36 • 436 were women • Steatosis found in 86%, risk was 2.6 times higher in men • Fibrosis present in 74% of a subgroup of 82 pts, majority with grade 1 Marceau et al Liver pathology and the metabolic syndrome X in severe obesity. Journal of Clinical Endocrinology and Metabolism. 1999;84:1513-17.

  32. Correlations • BMI correlated positively with fasting blood sugars and degree of steatosis, inversely with total and HDL cholesterol. • Serum ALT and AST highly correlated with steatosis. • Four components of metabolic syndrome significantly correlated with grade of fatty infiltration. • Cohort of 104 women with WHR measurements there was significant interaction among fasting blood sugars, WHR, and relative risk of steatosis hepatitis.

  33. Economics of Obesity & Diabetes • Contributing factors that have tipped the balance between caloric intake and expense into an unfavorable area • Expanding labor market for women • Increased consumption of food away from home • Rising cost of healthy foods • Growing quantity of caloric intake with declining overall food prices • Decreased need of occupational and environmental physical activity

  34. Economics • Diabetes in the US, estimated to account for 1.3% of our GDP and 31% of total indirect costs (lost wages, more people on disability, etc) • In five years, cost of treating DM went form $44 to 92 billion in the US. • Estimated prevalence in US of DM in 2000 was 8.8, 2030 estimate is 11.2 Yach et al. Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nature Medicine. 2006;12:62-66.

  35. Primary Intervention • Main principle is healthy lifestyle promotion including: • Moderate caloric restriction (goal 5-10% body weight loss in 1st year) • Moderate increase in physical activity • Change in dietary choices

  36. Diet • Main dietary strategies include adequate omega-3-fatty acids intake, reduction of saturated and trans-fats, consumption of a diet high in fruits, vegetables, nuts, and whole grains and low in refined grains. Each of these strategies may be associated with reducing inflammation. Giugliano et al. The effects of diet on inflammation; focus on metabolic syndrome. Jour Amer Coll Card. 2006;48:677-85.

  37. What to Treat • There is a definite need for a treatment that can modulate the underlying pathophysiologic mechanisms in metabolic syndrome as a whole, these are not yet completely defined and therefore, no specific pharmacotherapy exists • At this point, goal is to treat each individual component to help decrease the cardiovascular and diabetes risk

  38. Metformin (UKPDS, DPP) Acarbose (Stop-NIDDM) Ramipril (HOPE) Pravastatin(WOSCOPS) Losartan (LIFE) Niaspan (HATS) ↓ diabetes, obesity and BP ↓ diabetes, BP, CVD, Lipids ↓ diabetes, CVD ↓ diabetes, CVD ↓ diabetes, CVD, stroke ↓ CVD, TG, ↑ HDL Summary of Current Data

  39. Glitazones • Improve insulin sensitivity • Decrease blood sugar • Increase healthy fats (HDL, adiponectin) • Antiinflammatory, anticlotting, antiproliferating (CRP, PAI-1, MMP9) • Improve endothelial dysfunction • However, may also increase the risk of weight gain, edema, and CHF

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