1. In Search of the Magic Pill: Current and Developing Agents in Weight Management Donna Mojdami, PGY-4

2. Outline Current role for pharmacologic agents in obesity management – Canadian Guidelines 2007 Brief history of weight loss agents Review the major classes of anti-obesity drugs Currently approved agents for weight management – Orlistat Off-label use of known agents Drug therapy in development

3. CMAJ 2007;176(8 suppl):Online-1–117

4. The Role for Pharmacotherapy Realistic goals must be established – Return to normal body weight is an unrealistic expectation – Drug therapy is not a cure to obesity Success must be measured not only by degree of weight loss but also health benefits – Weight loss of 5-10% reduces risk of DM and CVD – Weight loss of 1 lbs per week, 5% below baseline at 3-6 mo and maintained considered effective

5. History of Weight Loss Drugs Late 1800s - Thyroid extract was used as a remedy for obesity but resulted in hyperthyroidism and other serious side effects. 1930s - Dinitrophenol reduced weight but sped up metabolism so much that it led to nerve malfunction. It was sold legally before the FDA had the power to regulate drugs. 1940s - Amphetamine was used as an obesity drug, though it proved addictive. 1960s - Rainbow pills, a combination of amphetamine, digitalis and diuretics, were linked to several deaths. 1971 - Aminorex, an appetite suppressant, was linked to cases of high blood pressure. September 1997 - Fenfluramine, part of the "fen-phen" drug combination, was withdrawn from the market because of heart valve problems. Redux, also contained a related chemical dexfenfluramine and also was taken off the market in 1997. November 2008 - Sanofi-Aventis pulled the plug on diet drug rimonabant, never won U.S. approval after a panel of experts rejected it amid fears it may cause suicidal thoughts. May 2009 - Widely used Hydroxycut-brand diet supplements were pulled from store shelves after reports of liver damage. FACTBOX-A troubled history for weight-loss drugs. Reuters. February 1, 2011.

6. History of Weight Loss Drugs October 2010 - Abbott Laboratories Inc pulled sibutramine from the U.S. market. Approved in November 1997, carried warnings about high blood pressure and a risk of heart attack and stroke in cardiovascular patients. October 2010 - Arena Pharmaceuticals Inc announced that the FDA rejected its drug, lorcaserin, seeking an independent review of the data and possibly more studies to assess cancer risk after tumors were found in animals. October 2010 - The FDA rejected Qnexa, a diet pill made by Vivus Inc and asked for more data on heart risks and other issues. January 2011 - Orexigen Therapeutics said the FDA rejected its diet drug candidate, Contrave, and requested a clinical trial to resolve concerns about heart risks. FACTBOX-A troubled history for weight-loss drugs. Reuters. February 1, 2011.

7. The Fen Phen Story Fenfluramine first introduced in 1970’s – Only modest effects on weight Fenfluramine combined with phentermine in 1990s Several cases of pulmonary hypertension known, but product labelling only mentioned 4 cases NEJM case-control study in 1996 showed 23-fold increase in risk of pulmonary hypertension FDA asked MDs to report valvular problems in their patients receiving treatment – 66 additional reports of valve disease received FDA requests company remove drug from market in 1997 More than 50,000 liability suits filed against Wyeth, approximately $14 billion

8. Major Classes of Anti-Obesity Drugs Sympathomimetic drugs – Reduce food intake by inducing early satiety, increase resting energy expenditure – Stimulate release of NE or inhibit its reuptake e.g. Phentermine – Block serotonin reuptake e.g Sibutramine (now discontinued)

9. Major Classes of Anti-Obesity Drugs Drugs altering fat digestion - Orlistat – Inhibits pancreatic lipases therefore fats not hydrolyzed and fecal fat excretion is increased

10. Major Classes of Anti-Obesity Drugs Antidepressants – SSRIs e.g. Fluoxetine, sertraline – Bupropion – believed to modulate action of NE Antiepileptic Drugs – Topiramate – Zonisamide – serotonergic and dopaminergic activity

11. Major Classes of Anti-Obesity Drugs Diabetes Agents – Metformin – Pramlintide – GLP-1 Receptor Agonists Exenatide, liraglutide

12. Major Classes of Anti-Obesity Drugs Cannabinoid-1 Receptor Antagonist – E.g. Rimonabant – now discontinued

13. Approved Agents in Canada Orlistat (Xenical®) Sibutramine Withdrawn from market in October 2010 SCOUT trial showed increased risk of cardiovascular events

14. Orlistat Alters fat digestion by inhibiting pancreatic lipases Primary site of action in the gut – Only 1% of the drug is absorbed Dose-dependent effect that peaks when 30% of dietary fat not absorbed

15. Orlistat – Side Effects GI side effects most common – Cramps, flatus, fecal incontinence – Improved by adhering to diet with <30% fat Absorption of fat-soluble vitamins slightly reduced – Vitamin D most frequently affected – Vitamin supplementation advisable Rare but serious liver injury (13 reports over 10 years) Very little effect on absorption of other drugs except for cyclosporine

16. 16 trials analyzed All studies showed greater weight loss than placebo Long-term Pharmacotherapy for Obesity and Overweight

17. Orlistat – Cochrane Review 2009 Weight Loss Orlistat treated subjects lost 2.9kg more weight than placebo (95% CI 2.5-3.2 kg)

18. Orlistat – Cochrane Review 2009 Change in Waist Circumference (cm) Significant reduction in circumference 2.1 cm (95% CI 1.3-2.9cm)

19. Orlistat – Cochrane Review 2009 Change in BMI (kg/m²) Significant reduction in BMI 1.1 kg/m² (95% CI 0.7 - 1.4 kg/m²)

20. Orlistat – Cochrane Review 2009 Change in SBP (mmHg) Placebo-subtracted SBP reduction 1.5mmHg (95% CI 0.9 – 2.2mmHg)

21. Orlistat – Cochrane Review 2009 Change in LDL Reduction in LDL by 0.26mmol/L (95% CI 0.22 – 0.3mmol/L)

22. Orlistat – Cochrane Review 2009 Change in HDL Reduction in HDL by 0.03mmol/L (95% CI 0.02-0.04mmol/L)

23. Orlistat – Cochrane Review 2009 Reduction in T2DM In the XENDOS trial, reduction in incidence of T2DM from 9.0% to 6.2% Benefit seen primarily in those with impaired glucose tolerance

24. Orlistat – Cochrane Review 2009 Change in Weight in Diabetics (kg) Weight reduced by 2.3kg (95% CI 1.6 – 3kg)

25. Orlistat – Cochrane Review 2009 Change in FBG in Diabetics (mmol/L) In trials with both diabetics and non- diabetics, FBG reduced by 0.1 – 0.5mmol/L In patients with diabetes, FBG reduced by 1.0mmol/L (95% CI 0.6-1.5mmol/L)

26. Orlistat – Cochrane Review 2009 Change in HbA1c in Diabetics Reduction in HbA1c of 0.4% (95% CI 0.2 – 0.6%)

27. Orlistat – Cochrane Review 2009 Discontinuation Due to GI Side-Effects

28. Orlistat – Cochrane Review 2009 Largest limitation in most studies is high attrition rates – 14 of 16 studies had attrition rates >20% – Only two trials had true intention-to-treat analysis – In the longest and largest trial, XENDOS, 60% of patients dropped out over 4 year follow-up Most common reasons for drop out: Treatment refusal Loss to follow up Adverse effects

29. FDA Approved Agents Orlistat (Xenical®) Diethylpropion (Tenuate®, Tenuate Dospan®) Phentermine (Adipex®, Ionamin Slow Release®) Benzphetamine (Didrex®) Phendimetrazine (Bontril®, Prelu-2®) Orlistat (Xenical®) Diethylpropion (Tenuate®, Tenuate Dospan®) Phentermine (Adipex®, Ionamin Slow Release®) Benzphetamine (Didrex®) Phendimetrazine (Bontril®, Prelu-2®)

30. Sympathomimetic Drugs Stimulate release of norepinephrine or inhibit its reuptake into nerve terminals Approved for short-term use – Typically 12 weeks Phentermine and diethylpropion are Schedule IV drugs – potential for abuse

31. Phentermine The better half of Fen-phen Most widely prescribed weight loss agent in U.S. – Use >12 weeks considered off-label Adverse effects – Elevated BP, tachycardia, palpitations, constipation, headache, insomnia

32. Phentermine A mean placebo-subtracted weight loss of 7.5kg Figure from UptoDate. Data from Munro, JF, MacCuish, AC, Wilson, EM, Duncan, LJ, BMJ 1968; 1:352.

33. Drugs Used Off-label in Obesity Anti-epileptics – Zonisamide – Topiramate Anti-depressants – Bupropion – Fluoxetine – Sertraline

34. Li, Z. et al. Ann Intern Med 2005; 142:532-546.

35. New Drugs in Development for Management of Obesity Gut hormones Combination drugs Tesofensine Cetilistat Lorcaserin Melanocortin-4 receptor agonist

36. Gut Hormones Several gut hormones play a role in energy metabolism regulation – Glucagon-like peptide 1 (GLP-1) – Cholecystikinin – Amylin – Pancreatic polypeptide – Peptide YY – Oxyntomodulin – Ghrelin

37. Glucagon-like Peptide 1 Cobble, M. et al. The Journal of Family Practice Supp. 2008; 57: S1-S31 GLP-1 secreted by L-cells of intestine in response to a meal Suppresses glucagon secretion Enhances insulin secretion Decreases pancreatic beta cell apoptosis Increases satiety in the brain Delays gastric emptying

38. GLP-1 Receptor Agonists Originally developed for management of T2DM Weight loss noticed in trials Liraglutide and exenatide are the most well studied

39. Similar weight loss on either drug - Liraglutide 3.24 kg and exenatide 2.87 kg Similar proportions lost weight – Liraglutide 78% and exenatide 76% Buse, J. et al. Lancet 2009; 374: 39-47

40. 60 overweight non-diabetic women with PCOS Randomized to metformin 1000mg bid, exenatide 10µg bid or combination therapy Secondary outcomes included anthropometric measures

42. Adverse Effects GI effects most common – Constipation, diarrhea, dyspepsia, emesis, nausea

43. Pramlintide Synthetic analogue of human amylin – Peptide hormone secreted from pancreatic β cells in response to food stimuli Slows gastric emptying, improves postprandial BG rise, modest improvement in HbA1c (<1%) Induces modest weight loss ~ 0.4 kg compared to weight gain with placebo in T1DM Whitehouse, F. et al. Diabetes Care 2002; 25: 724

44. Peptide YY Co-secreted with GLP-1 from intestinal L-cells Short-term administration in obese and lean subjects shown to decrease appetite and intake by 30% Batterham, R.L. et al. NEJM 2003; 349: 941 12 week randomized, placebo-controlled trial of 133 obese subjects showed no difference in weight loss Gantz, I. et al. J Clin Endo Metab 2007; 92: 1754 – Weight loss not assessed in the subjects receiving highest dose due to 60% drop-out (nausea, emesis)

45. Peptides – Leptin Primarily produced in adipose tissue Absence of leptin associated with massive obesity in animal models and humans – Administration of leptin induces weight loss Obese adults have leptin resistance associated with high serum leptin levels Recombinant human leptin has modest dose- dependent reduction in weight (-1.4 kg to -7.1kg) in combination with caloric restriction – Heymsfield, S.B. et al. JAMA 1999; 282: 1568

46. Peptides – Melanocortin-4 Receptor Agonist Hypothalamic melanocortin system plays important role in body weight MC4R gene has been the most strongly associated and replicated in obesity Mutations in MC4R accounts for obesity in 1.8% of adults and 6.0% of children

48. Peptides – Melanocortin-4 Receptor Agonist Intranasal administration of melanocortin induced body fat loss of 1.7kg in healthy subjects Fehm, H.L. et al. J Clin Endo Metab 2001; 86: 1144 Same melanocortin compound in overweight subjects did not induce significant changes in body weight or fat Hallschmid, M. et al. J Clin Endo Metab 2006; 91:522

49. Combination Agents Benefit of targeting multiple pathways involved in energy homeostasis Reduced doses of individual drugs decreases risk of potential side-effects

50. Vetter, M. L. et al. Nat. Rev. Endocrinol. 6, 578–588 (2010) Stimulates food intake Inhibits food intake

51. Naltrexone and Bupropion (Contrave®) Bupropion – dopamine and NE reuptake inhibitor – increases firing of POMC neurons Naltrexone – opioid receptor antagonist – inhibits β-endorphin-mediated autoinhibition of POMC neurons – Enhances activity of bupropion Currently in phase III clinical trials

52. Naltrexone & Bupropion

53. Wadden et al. Obesity. 2011; 19:110 -120. -5.2kg -9.3kg

56. Bupropion and Zonisamide (Empatic®) Zonisamide – enhances serotonergic and dopaminergic activity – Incidentally found to induce weight loss in epilepsy trials Phase III trials currently in progress

57. Bupropion and Zonisamide (Empatic®) Drug efficacy and tolerability study combined with hypocaloric diet Landbloom et al. Obesity. 2008; 16:S63- S64 Double-blind, placebo-controlled trial with intention to treat analysis over 24 weeks Combination drug induced 8.6% weight loss vs. 1.1% placebo Frequent side-effects: headache, nausea, insomnia, dry mouth, anxiety

58. Pramlintide and Metreleptin Pramlintide – analogue of amylin Metreleptin – recombinant leptin

59. 24 week, RCT, double-blind, active-drug-controlled trial Enrolled 177 obese or overweight subjects, 25% drop out Study design Ravussin, E. et al. Obesity. 2009; 17: 1736-1743.

61. Trend towards – Lower TGs (- 8%) – Lower total cholesterol (-9%) – Lower LDL (-8%) – Lower insulin resistance – Lower insulinemia (-22%)

63. Lorcaserin: Successor to Dexfenfluramine? Selective serotonin agonist Activates 5-HT2C receptors in the hypothalamus, thalamus, limbic system In theory avoids unwanted valvular effects (re: fenfluramine) since receptors not found peripherally FDA voted against approval in 2010 – Preclinical toxicology studies showing increased risk mammary tumours & astrocytomas

64. Double-blind, randomized, placebo-controlled trial of 3182 obese or overweight subjects In year 1, randomization to lorcaserin or placebo In year 2, those on lorcaserin randomly reassigned to placebo or lorcaserin Subjects received diet and exercise counselling 55.4% completed study (treatment)and 45.1% completed study (placebo) – 7.1% (treatment) and 6.7% (placebo) discontinued because of adverse events

65. - 2.2kg - 5.8kg

67. Secondary end-points

68. Valvulopathy

69. Tesofensine: Successor of Sibutramine? Norepinephrine-, dopamine- and serotonin- reuptake inhibitor Originally developed for treatment Parkinson’s disease Induces weight loss by suppressing appetite

70. Phase II, RCT, double-blind, placebo controlled trial 203 obese subjects on calorie restriction randomized to placebo or various doses tesofensine Treatment for 24 weeks, 79% completed study

71. - 2.2 kg - 6.7 kg - 11.3 kg - 12.8 kg

72. Adverse Effects – GI most common Dry mouth, nausea, abdo pain, constipation, diarrhea – Insomnia, sleep disturbance, dizziness – Increased SBP, DBP (1.0mg dose) - mean increase 6.8/5.8 mmHg – Dose-related effect on HR – Increased anger and hostility (1.0mg dose) – Increased confusion

73. Limitations of Pharmacotherapy Studies investigate efficacy of agents as part of intensive lifestyle and behavioural interventions Safety concerns and tainted reputation limit use of agents Most studies are short-term, long-term outcomes unknown Weight loss is modest compared to patient expectations

74. Limitations of Pharmacotherapy There is a maximum therapeutic effect after which no further weight loss is achieved Weight is regained once drug stopped – Most agents only approved for short-term use Effect of agents on hard outcomes e.g. mortality, cardiovascular events not known

75. Summary Pharmacotherapy should be utilized as adjunct to lifestyle modification only if patient not able to lose 0.5kg/week by 3-6 mo Many classes of drugs available – central and peripheral acting The only drug approved in Canada for weight management is orlistat – Expect 2.9kg weight loss in conjunction with lifestyle modification

76. Summary While many new agents have shown promise in phase II studies, safety concerns limit their development