New Medical Therapies for Obesity and Diabetes Management

1. The Obesity/Diabetes Epidemic:Adiposopathy & ‘Obesity’- The New Disease!Weight Management in Obesity and DM: Emphasis on  New Medical Therapies Part 4 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

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7. DRUGS

8. 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

9. 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

10. Phentermine (Suprenza) Controlled 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

11. 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)

12. Lorcaserin (Belviq) Type: serotonin agonist Mechanism of action: activates 5-HT2C 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)

13. Phentermine-topiramate (Qsymia) Controlled 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

14. Comparative Drug Efficacy