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Pharmacotherapy. Obesity Pharmacotherapy Outline How to apply drug trial data to clinical practice Principles of obesity medication use in clinical practice.

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Presentation on theme: "Pharmacotherapy. Obesity Pharmacotherapy Outline How to apply drug trial data to clinical practice Principles of obesity medication use in clinical practice."— Presentation transcript:

1 Pharmacotherapy

2 Obesity Pharmacotherapy Outline How to apply drug trial data to clinical practice Principles of obesity medication use in clinical practice Medications approved for long-term use –sibutramine (Meridia) –orlistat (Xenical) Medications approved for short term use –phentermine –others rarely used: mazindol, diethylpropion Medications for use in special patients –the depressed obese patient – bupropion (Wellbutrin) and venlafaxine (Effexor) –type 2 diabetes – metformin, pramlintide (Symlin), exendin-4 (Exenatide) –patients with neuropsychiatric problems - topiramate (Topamax) and zonisamide (Zonegran) Medications in development

3 1.Mean responses describe how patients fare on average. 2.The weight loss curves describe the tempo of weight loss. 3.The placebo response indicates the strength of the behavioral approach. –8 –6 –4 – Mean Change in Weight (%) Drug Placebo Treatment Month Note units Note plateau Placebo response indicates behavioral program Applying Pharmacotherapy Trials to the Practice Setting – 6 Tips

4 4.Categorical responses indicate the chance an individual patient has of meeting key response levels, 5% and 10%. 5.Significance levels and n’s are important. *P < 0.01 vs placebo † P < vs placebo (95) (95) (107) Placebo 1 mg 5 mg 10 mg 15 mg (n=87) (99) (99) mg (96) mg (101) Drug (n) * † † † † * † † † † 5% Responders10% Responders Patients (%) (98) (98) Chances of response note

5 Applying Pharmacotherapy Trials to the Practice Setting – 6 Tips 6.There is no placebo effect in weight loss studies. The placebo represents the effect of the behavioral intervention. WMD (Random) 95% CI Author 9, 2002 Author 5, 2000 Author 4, 2000 Author 3, 1999 Author 2, 1998 Author 1, 1998* Author 7, 2000 Author 8, 2002 Total (95% CI) Author 6, 2000 Study or Subcategory Metanalyses use placebo-subtracted weight loss and demonstrate the effect of the medication independent of behavioral intervention.

6 Principles of Obesity Medication Use Lifestyle interventions are the foundation of medicating for obesity The behavioral approach should be implemented with knowledge of the medication’s mechanism of action –Orlistat with 30% fat diet –Sibutramine with meal plan that takes advantage of its satiety promotion Obesity medications do not cure obesity, just as antihypertensives do not cure hypertension Not all patients respond to a weight loss medication. –If the drug’s use is not associated with weight loss within four weeks, it should be stopped Medications work as long as they are used –Weight gain occurs on stopping medications, although there is some evidence in support of efficacy of intermittent medication

7 Obesity Pharmacotherapy Outline How to apply drug trial data to clinical practice Principles of obesity medication use in clinical practice Medications approved for long-term use –sibutramine (Meridia) –orlistat (Xenical) Medications approved for short term use –phentermine –others rarely used: mazindol, diethylpropion Medications for use in special patients –the depressed obese patient – bupropion (Wellbutrin) and venlafaxine (Effexor) –type 2 diabetes – metformin, pramlintide (Symlin), exendin-4 (Exenatide) –patients with neuropsychiatric problems - topiramate (Topamax) and zonisamide (Zonegran) Medications in development

8 Antiobesity Drugs Approved for Long-Term Use: How They Work SibutramineOrlistat FDA approved 1997 Induces feeling of satiety – Less preoccupation, feeling satisfied with less food – Greater control of food intake – Need to monitor BP early in program Once daily with or without food FDA approved 1999 Reduces absorption of ~30% dietary fat – Fat in diet passes undigested – Facilitates weight loss – GI side effects 3 times daily with meals and a vitamin supplement recommended

9 Ryan DH et al. Obes Res. 1995;3(suppl 4):553S. S = sibutramine  = norepinephrine = serotonin Norepinephrine Serotonin S S S S S S S S S S S S S S S Reuptake Mechanisms of Action Sibutramine’s Active Metabolites Block Serotonin and Norepinephrine Reuptake

10 Other SNRIs Venlafaxine (Effexor) –Widely used in depression –Similar side effect profile to sibutramine, small blood pressure increases –Produces some weight loss Rudolph RL, Derivan AT. J Clin Psychopharmacol. 1996;16(suppl 2):54S.

11 Sibutramine Key Facts Multiple large clinical trials demonstrating: −Dose-related weight loss occurs for 6 months −Amount of weight loss related to intensity of behavioral approach −Efficacy in weight loss maintenance demonstrated ≥ 2 years −Weight loss produces benefits in lipids, body composition and is associated with mean blood pressure decrease −Trials in patients with hypertension and diabetes Favorable side effect profile: −No abuse potential −No valvuloplasty, no PPH Cautions −Blood pressure should be monitored −Should not use with MAOIs, erythromycin, ketoconazole

12 Sibutramine Produces Dose- Related Weight Loss **10 and 15 mg are recommended doses Placebo (n = 84) Sibutramine, mg (n) 1 (92) Week Mean Weight Change (lb) 5 (103) 10 (95) 15 (94) 20 (89) 30 (96) * * * * * 0 –5 –10 –15 – Bray GA et al. Obes Res. 1999;7:189. Approved dose range

13 The Amount of Weight Loss with Sibutramine Is Related to the Intensity of the Behavioral Intervention* Wadden TA et al. Arch Intern Med 2001;161: Sibutramine + Group Sessions Sibutramine + Group Sessions + Meal Replacements * Weight loss at 6 months

14 STORM: 77% (ITT) Achieved > 5% Weight Loss at Six Months James WPT et al. Lancet. 2000;356:2119. *Same diet, exercise for sibutramine, placebo; P  0.001, sibutramine vs placebo for weight maintenance Month Body Weight (lb) Placebo Sibutramine Weight Loss Weight Maintenance

15 STORM: Sibutramine Promotes Weight Loss Maintenance* Month Body Weight (lb) Placebo Sibutramine Weight Loss Weight Maintenance *Same diet, exercise for sibutramine, placebo; P  0.001, sibutramine vs placebo for weight maintenance James WPT et al. Lancet. 2000;356:2119.

16 Following VLCD, Sibutramine Promotes Additional Weight Loss and Weight Loss Maintenance Sibutramine Placebo = very low calorie diet (VLCD) P < for months 1 to 12, sibutramine vs placebo Mean Weight (lb) Treatment Month – Adapted with permission from Apfelbaum M et al. Am J Med. 1999;106:179.

17 Three Sibutramine Studies 1 Bray GA et al. Obes Res. 1999;7: Apfelbaum M et al. Am J Med. 1999;106: James WPT et al. Lancet 2000;356: P  vs placebo Percent Achieving Meaningful Weight Loss 6 months treatment 1 12 months treatment 2 24 months treatment 3

18 Weight Loss with Sibutramine Is Associated with Improvements in Lipids (STORM Data) Weight loss = months 1–6; Weight maintenance = months 7–24; *P < 0.001; † P = 0.002; ‡ P = 0.005; § P = vs placebo Sibutramine Placebo Triglycerides –25 –20 –15 –10 – Month Assessed % Change * † * –25 –20 –15 –10 – Sibutramine Placebo VLDL-Cholesterol Month Assessed % Change §‡ * Sibutramine Placebo HDL-Cholesterol % Change Month Assessed * * Adapted with permission from James WPT et al. Lancet. 2000;356:2119.

19 Weight Loss with Sibutramine Is Associated with Improvement in Waist Circumference (STORM data) NB: Same diet and exercise for both sibutramine and placebo Sibutramine Waist Circumference (in.) Month Placebo James WPT et al. Lancet. 2000;356:2119.

20 Sibutramine and Blood Pressure Labeling instructions: Warning. Blood pressure and pulse. MERIDIA SUBSTANTIALLY INCREASES BLOOD PRESSURE IN SOME PATIENTS. REGULAR MONITORING OF BLOOD PRESSURE IS REQUIRED WHEN PRESCRIBING MERIDIA. In placebo- controlled obesity studies, MERIDIA 5 to 20 mg once daily was associated with mean increases in systolic and diastolic blood pressure of approximately 1 to 3 mg relative to placebo…

21 * +2.6 * +3.8 * Dose Related Effects of Sibutramine on Systolic Blood Pressure (SBP) Change in SBP (mmHg) Sibutramine 20 mg n=1126 Sibutramine 30 mg n=128 Sibutramine 15 mg n=1924 Sibutramine 10 mg n=1318 Placebo n= * p < 0.05 compared to placebo -0.1 Data on file, Abbott Laboratories.

22 Sibutramine (n=1,898) Control (n=1,521) Patients (%) No> 0 – 40 increase SBP or DBP increase (mmHg) Maximum BP Changes vs. Baseline Adapted from Sharma AM et al. NAASO Post hoc analysis of 21 randomized placebo controlled trials of ≥ 12 weeks duration 3419 overweight and obese patients with normal or controlled blood pressure Sibutramine mg n=1898; placebo n= 1521

23 STORM: Change in Vital Signs James WPT et al. Lancet. 2000;356:2119. Baseline to 24 Months in Sibutramine Treatment Group Mean Change SibutraminePlacebo BP, mm HG Systolic Diastolic Pulse rate (bpm) In STORM most subjects reached 20 mg per study design

24 Blood Pressure is Lowered with Weight Loss Using Sibutramine Adapted from Sharma AM, Int J Obes Relat Metab Disord 2001;25 (Suppl 4): S20-S23. Although weight loss with sibutramine was not associated with equivalent BP reductions as placebo, a greater proportion of sibutramine treated patients achieved weight loss. Change in SBP (mmHg) 78%47% 22%53%6%23% % of treatment group

25 The Reality of Sibutramine’s BP Effects Mean BP changes in recommended dose range is ~ 1 mm Hg increase A few, < 5%, have unacceptable blood pressure increases while on sibutramine Significant weight loss, > 5%, is associated with mean BP decrease on sibutramine BP effects of sibutramine are blocked by beta blockers 1 BP effects of sibutramine are blocked by exercise program 2 In addition to peripheral effects, sibutramine may have central “clonidine-like” sympatholytic effects 1 1.Birkenfeld AL et al. Circulation 2002;106: Berube-Parent S et al. IJO 2001;25:

26 Tips for Managing Patients on Sibutramine Start at 10 mg once daily Prescribe a sensible diet – –Meal replacements for two meals and two snacks + one sensible meal per day –Portion controlled diet with at least three meals per day Follow –up: –4 pounds weight loss in first 4 weeks helps predict success –Monitor blood pressure. Use clinical judgement about continuing Increase dose to increase weight loss, provided BP is well controlled. Decrease dose or discontinue for BP concerns Stay within recommended dose range of 5 to 15 mg Encourage long term use

27 Antiobesity Drugs Approved for Long-Term Use: How They Work SibutramineOrlistat FDA approved 1997 Induces feeling of satiety – Less preoccupation, feeling satisfied with less food – Greater control of food intake – Need to monitor BP early in program Once daily with or without food FDA approved 1999 Reduces absorption of ~30% dietary fat – Fat in diet passes undigested – Facilitates weight loss – GI side effects 3 times daily with meals and a vitamin supplement recommended

28 Lipase Mucosal Cell TG FA MG Micelle Bile Acids Intestinal Lumen Orlistat Orlistat Prevents Fat Digestion by Binding to Gastrointestinal Lipases Lipase TG=triglyceride; MG=monoglyceride; FA=fatty acid

29 Orlistat: Key Facts Multiple large clinical trials demonstrating −Weight loss occurs for 6 months −Efficacy in weight loss maintenance demonstrated ≥ 4 years −Weight loss produces benefits in glycemic control, lipids, waist circumference, BP −Trials in persons with diabetes and hypertension −Independent action on LDL cholesterol Favorable side effect profile −No abuse potential −No valvulopathy, no PPH Cautions −Vitamin supplement required for long term use −May interfere with cyclosporin absorption Likely to be available over the counter in 2006

30 % of Patients > 5%> 10% % of Weight Lost Placebo + diet Orlistat + diet Meta-analysis of data derived from 4 clinical trials Xenical ® [package insert]. Nutley, NJ: Roche Laboratories, Orlistat: 2-Year Efficacy

31 Effect of Long-Term Treatment With Orlistat (The XENDOS Study) p < vs placebo Torgerson JS et al, Diabetes Care 2004; 27(1): Completers Data

32 Independent Effect of Orlistat on Plasma LDL-Cholesterol Segal et al. FASEB J 1999;13:A873. Data pooled from 5 trials (N=1773) 0 – 5 5 – – 15> 15 Change in Plasma LDL-Cholesterol Concentration (mmol/L) Weight Loss Category (% initial body weight) * * * * Orlistat Placebo *P < 0.01 vs placebo

33 Orlistat: Effect on Lipids and Waist Circumference HDL-CTG Waist Circumference Xenical ® [package insert]. Nutley, NJ: Roche Laboratories, Orlistat 120 mg TIDPlacebo Change (in) % Change

34 Orlistat: Effect on Blood Pressure in At-Risk Patients Orlistat + diet Placebo + diet Systolic (ISH, SBP  140 mm Hg) Diastolic (DBP  90 mm Hg) Data on File (Ref ). mm Hg P = 0.032P = NS mm Hg

35 Orlistat: Safety Sjöström L et al. Lancet. 1998;352:167. There is concern about fat-soluble vitamin absorption Adverse Events (AEs) at 1 Year

36 Tips for Managing Patients on Orlistat Discuss potential bowel effects and mechanism with patient Start at 120 mg before each meal Prescribe a moderate fat diet – –Caution patients about high fat meal or snack Metamucil has been shown to reduce bowel effects For long term use, prescribe a multivitamin Orlistat can interfere with cyclosporin absorption Encourage long term use.

37 Obesity Pharmacotherapy Outline How to apply drug trial data to clinical practice Principles of obesity medication use in clinical practice Medications approved for long-term use –sibutramine (Meridia) –orlistat (Xenical) Medications approved for short term use –phentermine –others rarely used: mazindol, diethylpropion Medications for use in special patients –the depressed obese patient – bupropion (Wellbutrin) and venlafaxine (Effexor) –type 2 diabetes – metformin, pramlintide (Symlin), exendin-4 (Exenatide) –patients with neuropsychiatric problems - topiramate (Topamax) and zonisamide (Zonegran) Medications in development

38 Drugs Approved by FDA for Short Term Use in Treating Obesity Diethylpropion (1959) Tenuate IV Phentermine (1959) Adipex-P, Ionamin IV Benzphetamine* (1960) Didrex III Phendimetrazine (1959) BontrilIII Methamphetamine Desoxyn II Mazindol* (1973) MazanorIV Generic Name Trade Names DEA Schedule Physicians’ Desk reference 59th Edition, *not listed in PDR, but available

39 FDA Approved Drugs for Short Term Use Use of schedule II or III drugs for weight management is not recommended. These agents are sympathomimetic as reflected by the side effect profile (restlessness, insomnia, increase in pulse, increase in blood pressure and others). Intermittent use is the only means to abide by prescribing guidelines. The medications promote appetite reduction. They should be used with an energy deficit diet. Weight loss with these medications averages 5 - 7% above placebo.

40 Time in Weeks Weight loss (lbs) Weight Loss with Continuous and Intermittent Phentermine Munro JF, et al. Br Med J 1968; 1:

41 Obesity Pharmacotherapy Outline How to apply drug trial data to clinical practice Principles of obesity medication use in clinical practice Medications approved for long-term use –sibutramine (Meridia) –orlistat (Xenical) Medications approved for short term use –phentermine –others rarely used: mazindol, diethylpropion Medications for use in special patients –the depressed obese patient – bupropion (Wellbutrin) and venlafaxine (Effexor) –type 2 diabetes – metformin, pramlintide (Symlin), exendin-4 (Exenatide) –patients with neuropsychiatric problems - topiramate (Topamax) and zonisamide (Zonegran) Medications in development

42 Medicating the Depressed Obese Patient Many antidepressants produce weight gain Antidepressants associated with weight loss: –Bupropion (Wellbutrin) 1 –Venlafaxine (Effexor) 2 Antidepressant associated with initial weight loss at higher doses, followed by weight regain: –Fluoxetine (Prozac) 3 1. Anderson Obes Res 2002:10: PDR Edition 29, Darga et al, AJCN, 1991.

43 Treatment with Bupropion Placebo SR 400 SR 300 Weeks of Treatment Weight loss (%) Anderson Obes Res 2002:10:633.

44 Week number Placebo Fluoxetine N = 16 N = 14 N = 23 N = 22 Weight Loss (kg) Fluoxetine 60 mg and Weight Loss* Darga et al, AJCN,

45 Medicating the Patient with Type 2 Diabetes Weight gain is associated with use of thioglitazones, sulfonylureas and insulin. Metformin is associated with small amounts of weight loss. Pramlintide is associated with weight loss.

46 Weight Change with Metformin in DPP Trial Months in study Metformin + Placebo DPP NEJM 2002.

47 Pramlintide Pramlintide injection approved by FDA 3/2005. Indication: as an adjunct treatment in patients with T1DM or T2DM who use mealtime insulin therapy and have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin. Synthetic analog of human amylin, designed to replace reduced amylin secretion that accompanies beta cell. Patients in clinical trials used less mealtime insulin and also had a reduction in body weight compared to patients taking insulin alone.

48 Exenatide Exenatide is an incretin mimetic Exenatide exhibits many of the same effects as the human incretin hormone GLP-1 –Improve blood sugar –Weight loss The FDA’s action date for exenatide is April 30, 2005

49 Medicating the Neuropsychiatric Patient Many antiepileptics and antipsychotics produce weight gain. Two agents are associated with weight loss, topiramate and zonisamide. These agents are not approved for weight loss and are associated with substantial tolerability and toxicity issues that make them unacceptable for weight management in primary care. When medicating for neuropsychiatric disorders, a favorable weigh profile should be taken into account in choosing a medication.

50 Weight Loss with Topiramate Bray et al Obes Res 2003 in press.

51 Zonisamide versus Placebo Placebo Zonisamide Week Weight loss (kg) Gadde IJO 2002 (Abs).

52 Medications Noted in ACP 2005 Pharmacotherapy Guidelines Data Source Weight Loss Period for Weight Change Mean Weight Change95% CI Sibutramine 29 RCTs52 weeks4.45 kg( kg) Orlistat 22 RCTs52 weeks2.75 kg( kg) Phentermine 9 RCTs weeks3.6 kg( kg) Diethylpropion 13 RCTs6 -52 weeks3.0 kg( kg) Bupropion 3 RCTs weeks2.77 kg( kg) Fluoxetine 9 RCTs52 weeks-- Range to +0.4 kg Annals Internal Medicine 2005;142:

53 Obesity Pharmacotherapy Outline How to apply drug trial data to clinical practice Principles of obesity medication use in clinical practice Medications approved for long-term use –sibutramine (Meridia) –orlistat (Xenical) Medications approved for short term use –phentermine –others rarely used: mazindol, diethylpropion Medications for use in special patients –the depressed obese patient – bupropion (Wellbutrin) and venlafaxine (Effexor) –type 2 diabetes – metformin, pramlintide (Symlin), exendin-4 (Exenatide) –patients with neuropsychiatric problems - topiramate (Topamax) and zonisamide (Zonegran) Medications in development

54 Van Gaal et al. Lancet 2005;365:

55 Rimonabant Weight Loss and Waist Change over 1 year Mean weight loss 4.8 kg greater than placebo Improvements in HDL, TG, Insulin and HOMA- IR greater than with weight loss alone Side effect profile favorable Van Gaal et al. Lancet 2005;365:

56 Obesity Pharmacotherapy: What Does the Future Hold? Epidemic of obesity and comorbidities is unabated. Understanding of biology underlying obesity continues to expand. New drugs are coming on market – rimonabant Look AHEAD, SOS are evaluating mortality benefit of weight loss. Obesity pharmacotherapy is gaining legitimacy.

57 Medicating for obesity will follow the paradigm of other chronic diseases (HTN, DM). Medications for obesity will not cure obesity. Weight loss of 5-10% will be seen with new medications. Lifestyle will remain a cornerstone of medicating. Obesity Pharmacotherapy: What Does the Future Hold?


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