1. The Obesity/Diabetes Epidemic: Adiposopathy & ‘Obesity’- The New Disease! Weight Management in Obesity and DM: Emphasis on New Medical Therapies Stan Schwartz MD, FACP, FACE Private Practice, Ardmore Obesity Program Cardiometabolic Diabetes Center and Affiliate, Main Line Health System Emeritus, Clinical Associate Professor University of Pennsylvania Part 4

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8. DRUGS

9. Long-Term Pharmacotherapy Pharmacotherapy typically used to induce weight loss but greater benefit may be for maintenance of weight loss Use weight loss medication chronically, in same manner as medications for other chronic conditions Orlistat, a lipase inhibitor: 8% loss at 2 years

10. Medications Short-term obesity management Sympathomimetics (Phentermine, Diethylpropion, Benzphetamine) Long-term obesity management Lipase inhibitors (Orlistat) Recently approved obesity medications Serotonin agonists (Locaserin)- BELVIQ Combination agents (Phentermine-topiramate)-QSYMIA

11. Phentermine (Suprenza) Type: sympathomimetic Mechanism of action: stimulates the hypothalamus to suppress appetite Year of approval: 1959 FDA approved indication: short-term (< 12 weeks) adjunct to exercise and caloric restriction for BMI ≥ 30 or ≥ 27 in the presence of other risk factors such as hypertension, diabetes or hyperlipidemia Efficacy: 3.6 kg mean weight loss beyond that achieved by placebo at 2-24 weeks (meta-analysis of six placebo-controlled trials; Int J Obes Relat Metab Disord 2002;26:262-73) Adverse effects: risk of dependence and abuse, hypertension, dry mouth, insomnia, tremor, GI disturbance, primary pulmonary hypertension (rare, associated with combined use of fenfluramine in “fen-phen”), valvular heart disease (rare), psychosis (rare) Contraindications: history of CV disease, MAOIs, hyperthyroidism, glaucoma, history of drug abuse, pregnancy, breastfeeding

12. Treatment of Obesity with Phentermine Munro JF, et al. Br Med J. 1968;1:352-4.

13. Orlistat (Xenical, Alli) Type: lipase inhibitor Mechanism of action: inhibits the breakdown of triglycerides into absorbable free fatty acids by lipase enzymes in the stomach and pancreas, resulting in less fat being absorbed Year of approval: 1999 (Xenical – prescription 120 mg TID), 2007 (Alli – OTC 60 mg) FDA approved indication: as an adjunct to a reduced-calorie and low-fat diet for weight loss or to lower the risk of regaining weight after prior weight loss Efficacy: 2.9 kg mean weight loss (Xenical) beyond that achieved by placebo at one year (meta- analysis of 15 trials; Ann Intern Med 2005;142:532-46) Adverse effects: significant diarrhea, fecal incontinence, oily spotting, flatulence, bloating, dyspepsia (all can be reduced with avoidance of fat-rich foods), reduced absorption of fat-soluble vitamins, serious liver injury (rare) Contraindications: malabsorption, cholestasis, impaired liver function, pancreatic disease, pregnancy (added in 2012)

14. Weight Change With Orlistat vs Placebo

15. Lorcaserin (Belviq) Type: serotonin agonist Mechanism of action: activates 5-HT 2C receptors in the hypothalamus, resulting in increased proopiomelanocortin (POMC) production, which promotes satiety Year of approval: 2012 FDA approved indication: treatment of obesity for adults with BMI ≥ 30 or ≥ 27 in the presence of other risk factors such as hypertension, diabetes or hyperlipidemia Efficacy: 3.6 kg mean weight loss beyond that achieved by placebo (5.8 kg vs. 2.2 kg) at one year (Phase 3 RCT; N Engl J Med 2010; 363:245-256) Adverse effects: headache, nasopharyngitis Contraindications: pregnancy, MAOIs, SSRIs (caution)

16. Phentermine-topiramate (Qsymia) Year of approval: 2012 FDA approved indication: chronic weight management, as an adjunct to a reduced-calorie diet and exercise, for BMI ≥ 30 or ≥ 27, in the presence of other risk factors such as hypertension, diabetes or hyperlipidemia Efficacy: 10.7 kg mean weight loss beyond that achieved by placebo (12.6 kg vs. 1.9 kg) at one year (Phase 3 RCT; Obesity (2012); 20 2, 330–342) Adverse effects: tachycardia, insomnia, paresthesias, dizziness, distorted taste sensation, constipation, dry mouth, anxiety, suicidality (rare), acute angle closure glaucoma (rare), metabolic acidosis (rare), increased serum creatinine (rare) Contraindications: pregnancy, glaucoma, hyperthyroidism, MAOIs, history of suicide attempt

17. Comparative Drug Efficacy