John Hyer University of Georgia College of Pharmacy Doctor of Pharmacy Candidate, 2012 Preceptor: Ali R. Rahimi, MD, FACP, AGSF 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 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 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 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 Pathophysiology of MetS Widely debated Most accepted hypothesis is insulin resistance Insulin resistance precluded by: Postprandial hyperinsulinemia followed by Fasting hyperinsulinemia and hyperglycemia Diabetes obesity diabesity 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 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 Insulin resistance -FFAs In muscle High NEFA levels in muscle are diverted to the liver Promoting fatty liver and atherogenic dyslipidemia In the liver increases production of Glucose Triglycerides Secretion of very-low-density lipoproteins Insulin resistance In muscle FFA’s reduce insulin sensitivity by inhibiting insulinmediated 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 Diagnosing Metabolic Syndrome Metabolic Syndrome Defined According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) presence 0f 3 of the following: ATP III Criteria Abdominal Obesity Waist circumference > 40 inches in men and 35 inches in female Fasting plasma glucose (FPG) FPG ≥ 100 mg/dL or drug treatment for elevated blood glucose Blood pressure (BP) BP > 130/85 mmHg or drug treatment for blood pressure Serum high-density lipoprotein cholesterol (HDL-C) HDL-C < 40 mg/dL in men and < 50 mg/dL in women Serum triglycerides ≥ 150 mg/dL or drug treatment for elevated triglycerides 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 Clinical Consequences MetS 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 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 T2DM Insulin resistance Hyperinsulinemia Dyslipidemia Obesity 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 1. Treat underlying causes (overweight/obesity and physical inactivity) by intensifying weight management and increasing physical activity 2. Treating cardiovascular risk factors if they persist despite lifestyle modification *** lifestyle modifications, pharmacologic therapy, and bariatric surgery*** Lifestyle Modifications 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) Lifestyle Modifications Sodium DASH (Dietary Approaches to Stop Hypertension) Restrict sodium intake to no more than 1500 to 2000mg/day 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 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 Pharmacologic Therapy Insulin resistance/hyperglycemia First line treatment 1. 2. 3. • • 4. • 5. 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) 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 Pharmacologic Therapy Dyslipidemia – treatment 1. 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 • 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 ezetimibe increased carotid intima-media artery wall thickness compared to niacin SHARP study – Simvastatin and ezetimibe in renal disease Upcoming IMPROVE-IT Trial 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 Pharmacologic Therapy • Hypertension/Elevated Blood Pressure • First line – in patients with MetS, especially in setting of CVD or T2DM 1. 2. A. • • 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 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 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 Controversy About MetS 1. The definition 2. 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? • • • Weakness: • • i.e. greater risk than its individual abnormalities Treatment is no different than treatment for each of its components NCEP ATP III associates MetS with a 2-fold increase in CVD 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 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 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.f ull 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 Association 285 (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/diseasesconditions/metabolic-syndrome-shown-to-increase-risk-ofkidney-problems/ References Sulaiman N, Mahmood DA. Cardiometabolic Syndrome. HOD Family and Community Medicine, Sharjah University of Melbourne. Access 10 March 2012.