Metabolic Syndrome Evaluation and treatment strategies

1. Metabolic SyndromeEvaluation and treatment strategies John Hyer University of Georgia College of Pharmacy Doctor of Pharmacy Candidate, 2012 Preceptor: Ali R. Rahimi, MD, FACP, AGSF

2. Objectives • Define metabolic syndrome (MetS) • Examine the risk and prevalence associated with Metabolic syndrome (MetS) • Evaluate current treatment strategies for efficacy • Our role in prevention

3. Epidemiology • Approximately 25% of the world’s population has metabolic syndrome • Interestingly enough (but not surprisingly), more than half of the adults in U.S. are overweight or obese • Same or greater primary risk factor as smoking for CVD (cardiovascular disease) • Numbers will increase with aging population and increasing rates of childhood obesity • Peaks in mid to late 60’s

4. Epidemiology • Most common in men and Hispanics • Increases with age • Native Americans have highest recorded prevalence of MetS • 60% or women aged 45-49 • 45% of men aged 45-49 • Cardio-Metabolic Syndrome risk is based on global risk of metabolic syndrome

5. Risk factors • Central adiposity (waist circumference) • Better association with MetS than BMI • Peripheral adiposity is a weaker predictor of MetS • Obesity • Sedentary lifestyle • Type 2 diabetes mellitus (T2DM) • Est. that up to 75% of patients with T2DM or impaired glucose tolerance have MetS • Lipodystrophy • Genetic or HAART induced • Aging • Postmenopausal status • Smoking • Low household income • Antipsychotic medications • Clozapine • Olanzapine

7. Pathophysiology of MetS • Widely debated • Most accepted hypothesis is insulin resistance • Insulin resistance precluded by: • Postprandial hyperinsulinemia followed by • Fasting hyperinsulinemia and hyperglycemia

9. Insulin resistance • Increases with increasing body fat • Excess adipose tissue releases • Nonesterified fatty acids (NEFA) • High level overloads muscle and liver with lipids • Cytokines – • Increase glucose and VLDL-C production by liver • Plasminogen activator inhibitor-1 (PAI-1) • High levels contribute to a prothrombotic state • Adiponectin • Plays a role as an anti-inflammatory and insulin sensitizing agent • Reduced • Interleukin (IL)-6 elevation • Stimulate insulin resistance and lypolysis of adipose tissue TG • C-reactive protein (CRP) • Signifies cytokine excess and a proinflammatory state

10. Insulin resistance • Free fatty acids - contributor • Released from enlarged adipose tissue mass • Insulin responsible for • Antilipolysis • Most sensitive pathway of insulin action • Stimulation of hormone sensitive lipoprotein lipase • Mobilizes fatty acids from triglyceride rich stores • Insulin resistance = increased lipolysis produces more FFA= further decreases antipolytic effect of insulin

11. Insulin resistance -FFAs • In muscle • High NEFA levels in muscle are diverted to the liver • Promoting fatty liver and atherogenicdyslipidemia • In the liver increases production of • Glucose • Triglycerides • Secretion of very-low-density lipoproteins

12. Insulin resistance • In muscle • FFA’s reduce insulin sensitivity by inhibiting insulin-mediated glucose uptake • Leads to increased circulating glucose • Increases pancreatic insulin secretion – hyperinsulinemia • Results in enhanced sodium reabsorption and increased sympathetic nervous system activity • Hypertension? • Take home Point!!! • Insulin resistance leads to oxidative stress which leads to endothelial cell dysfunction, promoting vascular damage and atheroma formation

13. Diagnosing Metabolic Syndrome

15. Metabolic Syndrome Defined • According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) presence 0f 3 of the following:

16. Evaluation • The American Heart Association • Recommends measurement of high-sensitivity CRP for risk stratification in patients at high risk of CVD • Is patient ready to make therapeutic lifestyle modifications? (i.e. reduce dietary fat) • Fasting glucose • Fasting lipid panel • Waist circumference • Height and weight (BMI) • Frammingham Risk Assessment for 10 Year CVD risk • Coronary Artery Calcium (CAC) scan (AHA/ACC) • Good in asymptomatic low-risk patients

17. Clinical ConsequencesMetS CVD and T2DM • Cardiovascular Disease (CVD) • High risk for developing CVD • MetS and the Framingham Risk Score • Which is better at predicting CVD? • Evidence for both camps in the literature • Relative risk for CVD events or death is 1.78 in patients with MetS

18. Clinical Consequences • Type II Diabetes Mellitus (T2DM) • Presence of MetS is highly predictive of developing new-onset T2DM • 75-85% of patients with MetS will progress to T2DM • Relative risk of 3.53-5.17 for development of diabetes

19. Therapy • Difficult • No randomized controlled trials for specific treatment options • Goal • Reduce the risk for or preventing CVD and T2DM NCEP ATP III Major Therapeutic Goals in Patients with MetS • Treat underlying causes (overweight/obesity and physical inactivity) by intensifying weight management and increasing physical activity • Treating cardiovascular risk factors if they persist despite lifestyle modification *** lifestyle modifications, pharmacologic therapy, and bariatric surgery***

20. Lifestyle Modifications

21. Lifestyle Modifications • Diet • Even a modest weight loss significantly reduced prevalence of MetS • Diet rich in complex, unrefined carbs, high in fiber (14 g/1000 cal consumed daily), and low in added sugar (<25% of caloric intake) • Recommended by Diabetes Prevention Program • Fat • Saturated fat <7% of caloric intake • Increase of unsaturated fat • linoleic acid should be 5-10% of caloric intake (i.e. safflower oil) • alpha-linolenic acid 0.7-1.6% of calories (i.e. kiwifruit seeds and flax)

22. Lifestyle Modifications • Sodium • DASH (Dietary Approaches to Stop Hypertension) • Restrict sodium intake to no more than 1500 to 2000mg/day

23. Lifestyle Modifications • Physical activity • Improves glucose transport and insulin action in working skeletal muscle • AHA guidelines on exercise • ≥ 30 min/day most days of the week (brisk activity; 5 days) • Dose-response effect of aerobic exercise on visceral adiposity • 7-10% reduction in BW during one year of therapy

24. Pharmacologic Therapy • Lifestyle modifications can have amazing clinical benefits… but often met with failure • Noncompliance • Journal keeping and classes? • Excess adiposity • Currently only one FDA drug approved for long term management – Orlistat (Rx - Xenical, OTC - Alli) • The National Institutes of Health guidelines • BMI ≥ 30 kg/m2

25. Pharmacologic Therapy • Insulin resistance/hyperglycemia • First line treatment • Weight loss – 5-10% of baseline weight • Lifestyle modifications • Metformin – indicated for patients with both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) • DPP study found metformin reduced progression of diabetes by 31% for those at risk (53% whom had MetS) • Also reduced incidence of MetS by 17% • Pioglitazone – increase BW, but reduces waist to hip ratio • Improves: BP, TGs, HDL-C, carotid intima-media thickness • Acarbose – STOP-NIDDM trial – many benefits, but very poor patient tolerability (FLUTALANCE, abdominal pain)

26. Pharmacologic Therapy • Dyslipidemia • Elevated TGs, low HDL-C, and small, dense LDL-C • MetS is not currently a coronary risk equivalent for managing lipid goals • Calculate LDL goal and secondary Non-HDL goal using ATP III guidelines • Very high risk – LDL < 70 mg/dL • Moderate high risk LDL < 100 mg/dL • Moderate risk LDL < 130mg/dL

27. Pharmacologic Therapy • Dyslipidemia – treatment • Statins • Reduce LDL-C 15 to 60% • Increase HDL-C 5 to 10% • Reduce triglycerides 7 – 30% • Pleiotropic effects on inflammation, endothelial function, and CVD events • 4S* trial- Those with MetS had both the highest risk of major coronary events and the greatest benefit from statin therapy *Scandinavian Simvastatin Survival Study

28. Pharmacologic Therapy • Dyslipidemia • Bile acid sequestrants (Welchol, Questran, Colestid) • LDL-C reduction of 15 to 30% • Ezetimibe (Zetia) • LDL-C reduction of 15 to 25% ***CONTROVERSY*** • ENHANCE study showed no differences in carotid intima-media thickness when given with simvastatin; no reduction in events… • ARBITER 6-HALTS trial • Showed that ezetimibeincreased carotid intima-media artery wall thickness compared to niacin • SHARP study – Simvastatin and ezetimibe in renal disease • Upcoming IMPROVE-IT Trial

29. Pharmacologic Therapy • Dyslipidemia • Fibrates • Reduce triglycerides 25 to 50% • Increase HDL-C 5 to 15% • Reduce LDL 0 to 30% • Useful to reach non-HDL-C goal when statins are not enough • Niacin • Most effective FDA approved agent for raising HDL-C and increasing HDL-C particle size • 15-35% • Lowers TGs 20 to 50% • Reduction of LDL-C 5 to 25% • Note: caution in liver dx, gout, DM (hyperglycemia and hyperuricemia) • AIM-HIGH trial – halted prematurely • No benefit over statin alone in reduction CV related complications, despite increases in HDL and decreases in triglycerides • A small and unexplained increase in ischemic stroke rates in high dose niacin group

30. Pharmacologic Therapy • Hypertension/Elevated Blood Pressure • First line – in patients with MetS, especially in setting of CVD or T2DM • Angiotensin-converting enzyme (ACE) inhibitors • Angiotensin receptor blockers (ARB) Shown to be effective in reducing rates of albuminuria or progression of nephropathy in patients with diabetes • Thiazide type diuretic • ALLHAT* trial – superior CVD outcomes compared to CCB, B-B, or ACE-I; even in diabetes • *Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

31. Pharmacologic Therapy • Antiplatelets (ASA) • Treating the prothrombotic state of MetS • low-dose aspirin reduces CVD events in both secondary and primary prevention • Favorable efficacy/side effect ratio when 10-year risk for CVD is ≥10%. • AHA/ACC class 1b recommendation for women less than 65 years old with intermediate risk

32. Bariatric Surgery • In a recent meta-analysis of 22,094 morbidly obese patients: • T2DM resolved in 76.8% and improved in 86% of cases • Swedish Obese Subjects study – 10 year follow up surgery • Overall reduction in mortality due to CVD and T2DM • Associated with improvement and/or resolution of multiple comorbidities associated with obesity

33. Controversy About MetS • The definition • The ability or inability of MetS to predict CVD or T2DM • Should T2DM be part of the definition? • Is MetS greater than the sum of its parts? • i.e. greater risk than its individual abnormalities • Weakness: • Treatment is no different than treatment for each of its components • NCEP ATP III associates MetS with a 2-fold increase in CVD

34. Conclusion • Treatment strategies must focus on identifying and managing individual components of metabolic syndrome • Aggressive therapy must be optimized for each individual patient and characteristics to reduce risk • No direct marker for insulin resistance to diagnose metabolic syndrome • Further research is needed to better define metabolic syndrome, the exact pathophysiology, and treatment algorithms • Use care with lipid lowering agents

37. References • Prasad, H, et al. Metabolic Syndrome: Definition and Therapeutic Implications. Postgraduate Medicine 2012; Jan. vol. 124, issue I. Pg. 21-30. • Well, CC, et al. Obesity, race, and risk for death or functional decline among Medicare beneficiaries. Annals. 2011 May; Vol 154, num 10: 645-654. • SHARP Collaborative Group. Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9438 patients with chronic kidney disease. Am Heart J 2010; DOI:10.1016/j.ahj.2010.08.012.  • The AIM-HIGH investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med2011; DOI:10.1056/oa1107579

38. References • Taylor AJ, Villines TC, Stanck EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009; DOI:10.1056/NEJMoa907569 • National Health Disparities Research Center of Excellence Meharry Medical College. Cardio Metabolic. Accessed March 2012. http://www.hdrcoe.org/CardioMetabolic.html • Bruce Goldfarb. Metabolic Syndrome Debate Defused. Diabetes Journals. March 2012. http://docnews.diabetesjournals.org/content/3/9/1.1.full

39. References • Expert Panel On Detection, Evaluation, And Treatment Of High Blood Cholesterol In Adults (May 2001). "Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)". JAMA: the Journal of the American Medical Association285 (19): 2486–9 • Ashen, DM. Management of cardiometabolic syndrome in the primary and secondary prevention of cardiovascular disease. Journal for Nurse Practitioners. 2008;4(9):673-680. • Metabolic syndrome shown to increase risk of kidney problems. Worldwide-Medicine.com. Aug 26, 2011. Accessed 10 March 2012. http://www.worldwide-medicine.com/diseases-conditions/metabolic-syndrome-shown-to-increase-risk-of-kidney-problems/

40. References • Sulaiman N, Mahmood DA. Cardiometabolic Syndrome. HOD Family and Community Medicine, Sharjah University of Melbourne. Access 10 March 2012.