Pharmacologic Treatment of Obesity: What is the skinny on diet pills?

1. Pharmacologic Treatment of Obesity: What is the skinny on diet pills? Stephanie E. Freeman, MD Department of Internal Medicine Resident Grand Rounds May 6, 2003

2. Patient 1 40 year old female, 400+ pounds PMH: CHF, HTN, OSA “Doc, I know I need to lose weight. I am desperate. How about diet pills? Patient 2 30 year old female, 5’ 4”, 130 pounds PMH: none “I’m taking these diet pills I bought at the drug store. Are these safe ?” Cases

3. Statistics • More than 60 million Americans are overweight. • Overweight and obesity cause 300,000 deaths each year. • 50% of all women and 25% of all men report that they are trying to lose weight. • $30 billion dollars spent on weight loss products each year.

4. Definitions • Body Mass Index • Weight in kilograms/ (height in meters)2 • Normal: BMI 18.5-24.9 • Overweight: BMI 25-29.9 • Obese: BMI greater than 30 • Morbid Obesity: BMI greater than 40

5. Obesity-Associated Medical Conditions • Type II Diabetes • Hypertension • Asthma • Obstructive sleep apnea • Dyslipidemia

6. Treatment of Obesity • NIH recommends non-pharmacologic therapy (dietary modification and exercise) initially for six months • If weight loss less than 0.45 kg/month, consider addition of weight loss medications.

7. Indications for treatment with weight loss medications • BMI greater than 30 • BMI greater than 27 with 2 or more obesity-related conditions

8. Mechanisms of Action • Suppress Appetite • Inhibit digestion • Increase Metabolism

9. Appetite Suppressants • Noradrenergic Agents • Phentermine • Serotonergic Agents • Fenfluramine • Dexfenfluramine • Noradrenergic/Serotonergic Agents • Sibutramine

10. Phentermine • Noradrenergic Agent • Activates central alpha and dopamine receptors in the hypothalamus. • Enhances catecholamine transmission. • Increases sympathetic activity. • Decreases appetite. • The only FDA approved weight loss medication in this class.

11. Phentermine • Munro et al. 1968 • The only long term, randomized double blind placebo controlled trial of phentermine. • 108 obese women for nine months • Phentermine 30 mg daily or • Intermittent phentermine or • Placebo • Weight Loss • Daily phentermine: 12.2 kg • Intermittent phentermine: 13.0 kg • Placebo: 4.8 kg

12. Side Effects Agitation Insomnia Irritability Nervousness Headache Tachycardia Hypertension Contraindications Hyperthyroidism Glaucoma Agitated states Advanced arteriosclerosis Cardiovascular disease Moderate-severe hypertension Drug abuse Phentermine

13. Serotonergic Agents • Inhibit reuptake of serotonin. • Cause release of serotonin. • Decrease food-seeking behavior and food consumption. • Fenfluramine and Dexfenfluramine

14. Fenfluramine • Removed from market in 1997. • Associated with valvular heart damage. • Serotonin agonist activity responsible for valve damage. • Fenfluramine, dexfenfluramine, and phentermine-fenfluramine “phen-fen” withdrawn from market. • Dexfenfluramine also associated with primary pulmonary hypertension.

15. Serotonergic/Noradrenergic Agents • Sibutramine (Meridia) • Inhibits the uptake of serotonin and norepinephrine • Increases satiety • May increase metabolic rate Yanovski and Yanovski. N Eng J Med. Feb 2002;346:591-602.

16. Sibutramine • Bray et al. • Design • 1047 obese subjects with BMIs between 30 and 40 • After two-week run-in period, randomized to placebo or sibutramine (1mg, 5mg, 10 mg, 20 mg, or 30mg). • Hypocaloric diet and daily exercise • Trial lasted 24 weeks.

17. Sibutramine • Bray et al. • Results • Placebo group lost 1.3 kg. • Sibutramine group • 1mg, 2.4kg • 5mg, 3.7 kg • 10mg, 5.7kg • 15mg, 7.0 kg • 20mg, 8.2 kg • 30mg, 9.0kg

18. Sibutramine • Bray et al. • Exclusions • Hypertension • Diabetes • Cardiovascular disease

19. Sibutramine • Serrano-Rios et al. • Goal • Assess efficacy of sibutramine in type II diabetics • Design • 134 type II diabetic patients on sulphonylureas • BMIs greater than 27 • Randomized to placebo or sibutramine 15mg daily • Six months

20. Sibutramine • Serrano-Rios et al. • Results • Weight loss • Placebo group lost 1.7 kg • Sibutramine group lost 4.5 kg • Hemoglobin A1C • Sibutramine group • Those losing >10%, HgA1C fell by 1.8% • Placebo group • HgA1C fell 0.7%

21. Sibutramine • James et al. • Goal • To assess the long term efficacy of sibutramine for weight loss and weight maintenance. • Design • 605 patients with BMIs between 30 and 45 • Six month weight loss phase • All patients received sibutramine 15 mg daily. • 18 month weight maintenance phase • Patients received placebo or sibutramine 15 mg daily.

22. Sibutramine • James et al. • Results • 261 patients completed the study. • Sibutramine group • 43% maintained 80% or more of weight loss. • Placebo group • 16% maintained 80% or more of weight loss.

23. Sibutramine • Studies demonstrate that sibutramine effective for weight loss. • Studies had drop-out rates of about 20%. • Exclusion criteria • Hypertension, diabetes, heart disease, and other serious medical conditions

24. Side effects Dry mouth Insomnia Hypertension Palpitations Tachycardia Dyspnea Other Effects Lower total cholesterol, LDL, triglyceride, and gout levels Usage Starting dose 10 mg daily Increase to 15 or 20mg Use longer than 2 years not recommended. Sibutramine

25. Digestive Inhibitors • Orlistat (Xenical) • Inhibits lipase • Decreases absorption of dietary fat • Leads to decreased absorption of calories • Leads to decreased body weight

26. Orlistat - Mechanism Yanovski and Yanovski. N Eng J Med. Feb 2002;346:591-602.

27. Orlistat • Sjostrom et al. • Goal • Demonstrate efficacy for weight loss and slowing of weight regain • Design • 2 year study • 743 patients with BMIs between 28 and 47 • Hypocaloric diet with 30% energy as fat • 4 week run in period with placebo

28. Orlistat • Sjostrom et al. • Design-continued • Weight loss phase • Randomized to placebo or orlistat 120 mg TID for 52 weeks. • Weight maintenance phase • At end of year one, randomized to continue current regimen or to switch regimens for 52 weeks.

29. Orlistat • Sjostrom et al. • Results • Year one (weight loss phase) • Placebo group lost 6.1 kg • Orlistat group lost 10.3 kg • Year two (weight maintenance phase) • Placebo-Orlistat group lost 3.6 kg • Placebo-Placebo group regained 2% of weight • Orlistat-Placebo group regained 4% of weight • Orlistat-Orlistat group regained 2% of weight • Continuous Orlistat • 57% maintained weight loss > 5% • Continuous Placebo • 37% maintained weight loss > 5%

30. Orlistat Sjostrom et al. Lancet. July 18, 1998;352:167-172.

31. Orlistat • Hanefeld et al. • Goal • To show efficacy of orlistat in Type II DM • Design • 492 Type II DM patients with BMIs greater than 27 who were receiving treatment with sulphonylureas or no treatment for their diabetes • Randomized to receive placebo or Orlistat 120 mg tid

32. Orlistat • Hanefeld et al. • Results • Weight loss • Placebo group • lost 3.7 kg • 31.6% lost more than 5% • Orlistat group • lost 5.7 kg • 51.3% lost more than 5% • Glycemic Control • Placebo group • Hemoglobin A1C 8.6 to 8.1 • Orlistat group • Hemoglobin A1C 8.6 to 7.7

33. Studies Demonstrate efficacy Have drop-out rates of about 20-25% Extensive exclusion criteria Hypertension Diabetes mellitus (except study by Hanefeld et al) Cardiovascular disease Other effects Decreased total cholesterol Decreased LDL Improved glycemic control Side effects Abdominal pain Flatulence Greasy stools Lasts < 4 days Orlistat

34. Orlistat • May decrease absorption of fat-soluble vitamins. • The dose is 120 mg tid with meals. • May be taken up to one hour after meals. • Use for longer than two years not recommended.

35. Ephedrine Increases the release of norepinephrine Suppresses appetite Increases metabolism Synthetic form of ephedra Ma Huang Caffeine Often combined with ephedrine/ephedra Decreases the breakdown of NE Acts in synergy with ephedrine/ephedra Ephedrine/Ephedra

36. Ephedrine/Ephedra • Metabolife • Ingredients • Ephedra alkaloids • 12 mg • Caffeine • 40 mg • Directions • One to two caplets • BID-TID or every 4 hours • On empty stomach • One hour before meal • Do not exceed 8 caps/day

37. Ephedrine/Ephedra • Shekelle et al. • Meta-analysis • Goal • Review the safety and efficacy of ephedrine and ephedra

38. Ephedrine/Ephedra Shekelle et al. JAMA. March 26, 2003;289:537-1545.

39. Ephedrine/Ephedra • Shekelle et al. • Adverse events • Examined 50 trials • Grouped events into categories • Psychiatric symptoms • Autonomic hyperactivity • Upper GI symptoms • Palpitations • Hypertension • Headaches

40. Ephedrine Three deaths Two myocardial infarctions One psychiatric event One seizure Ephedra Two deaths Three Myocardial infarctions Nine strokes Three psychiatric events Shekelle et al. Serious Adverse Events

41. Ephedrine/Ephedra • Serious Adverse Events • ½ occurred in people younger than 30 • Steve Bechler • 23 year-old baseball player • Died 2/17/03 after collapsing in spring training • Had been taking Xenadrine RFA-1 • Contains ephedra • Coroner links death to the drug.

42. Ephedrine/Ephedra • Effective for short term (less than six months) weight loss • Not FDA approved • Side effects • Psychiatric disturbances, autonomic hyperactivity, upper GI symptoms • Case reports • Death, MI, CVA

43. Weight-loss Medications Conclusions • There are only three FDA-approved weight loss medications • Phentermine • Sibutramine (Meridia) • Orlistat (Xenical) • Must be used in conjunction with diet and exercise

44. Conclusions • Reassess if weight loss is less than 2.0 kg in the first month. • The average weight loss attributed to weight loss medications is 5% of initial body weight. • Use for longer than 2 years is not recommended.

45. Conclusions • “Although weight loss drugs produce clinically important weight loss, the magnitude of weight loss with pharmacotherapy is rarely sufficient to bring the morbidly obese down to a healthy weight.” Glazer, Gary. Arch Intern Med. Aug 13/27 2002;1814-1823.