Pharmacotherapy.

Name: Pharmacotherapy.
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Description: Pharmacotherapy.

Pharmacotherapy

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

Applying Pharmacotherapy Trials to the Practice Setting – 6 Tips
Mean responses describe how patients fare on average. The weight loss curves describe the tempo of weight loss. The placebo response indicates the strength of the behavioral approach. Note units Treatment Month 1 2 3 4 5 6 7 8 9 10 11 12 –2 Note plateau Placebo response indicates behavioral program Mean Change in Weight (%) –4 –6 –8 Drug Placebo

Categorical responses indicate the chance an individual patient has of meeting key response levels, 5% and 10%. Significance levels and n’s are important. Chances of response 80 † † Placebo (n=87) 70 † Drug (n) † 60 1 mg (95) 50 5 mg (107) † 10 mg (99) Patients (%) 40 * † † 15 mg (98) 30 20 mg (96) 30 mg (101) 20 † note * 10 5% Responders 10% Responders *P < 0.01 vs placebo †P < vs placebo

6. There is no placebo effect in weight loss studies. The placebo represents the effect of the behavioral intervention. Study or Subcategory WMD (Random) 95% CI Author 1, 1998* -10 -5 10 5 Author 2, 1998 Author 3, 1999 Author 4, 2000 Author 5, 2000 Author 6, 2000 Author 7, 2000 Author 8, 2002 Author 9, 2002 Total (95% CI) Metanalyses use placebo-subtracted weight loss and demonstrate the effect of the medication independent of behavioral intervention.

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

Antiobesity Drugs Approved for Long-Term Use: How They Work
Sibutramine Orlistat 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 Slide 8

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

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.

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

Sibutramine Produces Dose-Related Weight Loss
Placebo (n = 84) Sibutramine, mg (n) –5 1 (92) * 5 (103) Approved dose range Mean Weight Change (lb) –10 * 10 (95) * –15 Slide 12 15 (94) * 20 (89) * 30 (96) –20 3 6 9 12 15 18 21 24 Week **10 and 15 mg are recommended doses Bray GA et al. Obes Res. 1999;7:189.

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

STORM: 77% (ITT) Achieved > 5% Weight Loss at Six Months
Weight Maintenance 230 Placebo 225 220 Body Weight (lb) 215 210 205 Slide 61 200 Sibutramine Weight loss during months 1–6 and sequential weight changes during months 7–24 for the sibutramine and placebo treatment groups in STORM During the weight loss phase (months 1–6), All patients received sibutramine 10 mg/day and an individualized 600 Kcal/day deficit program based on resting metabolic rate It was observed that patients who completed the open weight loss phase of the trial on sibutramine 10 mg lost approximately 26 lb. The unusual, almost linear nature of the weight loss during this phase may be attributable to the individualized treatment of diet and exercise for each patient Only patients on a very low calorie diet (VLCD) have previously demonstrated a greater weight loss than patients in this phase of STORM In almost half the patients (46%), weight loss was at least 10% 82% of all patients achieved at least 5% weight reduction Looking only at those who completed the 6-month period, over half (54%) achieved the 10% target, and 93% exceeded 5% 195 2 4 6 8 10 12 14 16 18 20 22 24 Month *Same diet, exercise for sibutramine, placebo; P  0.001, sibutramine vs placebo for weight maintenance James WPT et al. Lancet. 2000;356:2119.

STORM: Sibutramine Promotes Weight Loss Maintenance*
Weight Maintenance 230 Placebo 225 220 Body Weight (lb) 215 210 205 Slide 61 200 Sibutramine Weight loss during months 1–6 and sequential weight changes during months 7–24 for the sibutramine and placebo treatment groups in STORM During the weight loss phase (months 1–6), All patients received sibutramine 10 mg/day and an individualized 600 Kcal/day deficit program based on resting metabolic rate It was observed that patients who completed the open weight loss phase of the trial on sibutramine 10 mg lost approximately 26 lb. The unusual, almost linear nature of the weight loss during this phase may be attributable to the individualized treatment of diet and exercise for each patient Only patients on a very low calorie diet (VLCD) have previously demonstrated a greater weight loss than patients in this phase of STORM In almost half the patients (46%), weight loss was at least 10% 82% of all patients achieved at least 5% weight reduction Looking only at those who completed the 6-month period, over half (54%) achieved the 10% target, and 93% exceeded 5% 195 2 4 6 8 10 12 14 16 18 20 22 24 Month *Same diet, exercise for sibutramine, placebo; P  0.001, sibutramine vs placebo for weight maintenance James WPT et al. Lancet. 2000;356:2119.

Following VLCD, Sibutramine Promotes Additional Weight Loss and Weight Loss Maintenance
233 229 224 220 217 Placebo Mean Weight (lb) 211 207 202 198 Sibutramine Slide 16 194 –1 1 2 3 4 5 6 7 8 9 10 11 12 Treatment Month P < for months 1 to 12, sibutramine vs placebo = very low calorie diet (VLCD) Adapted with permission from Apfelbaum M et al. Am J Med. 1999;106:179.

Three Sibutramine Studies
Percent Achieving Meaningful Weight Loss Slide 17 6 months treatment 1 12 months treatment 2 24 months treatment 3 1Bray GA et al. Obes Res. 1999;7:189. 2Apfelbaum M et al. Am J Med. 1999;106:179. 3James WPT et al. Lancet 2000;356: P  vs placebo 5% 10% Bray GA et al 20% 0% Apfelbaum M et al 55% 23% James P et al 49% 19% Statistically significantly more patients achieve 5% and 10% weight loss with sibutramine treatment compared with placebo (P>0.05)

Weight Loss with Sibutramine Is Associated with Improvements in Lipids (STORM Data)
Triglycerides 5 5 VLDL-Cholesterol Placebo Placebo –5 –5 –10 % Change % Change –10  ‡ † * *    –15 * –15    Sibutramine     Sibutramine   –20  –20  –25 –25 6 12 18 24 6 12 18 24 Month Assessed 25 HDL-Cholesterol Month Assessed * *   Sibutramine 20    15 Weight loss = months 1–6; Weight maintenance = months 7–24; *P < 0.001; †P = 0.002; ‡P = 0.005; §P = vs placebo % Change Placebo 10 5   Adapted with permission from James WPT et al. Lancet. 2000;356:2119. 6 12 18 24 Month Assessed

Weight Loss with Sibutramine Is Associated with Improvement in Waist Circumference (STORM data)
44 43 Placebo 42 Waist Circumference (in.) 41 40 Sibutramine Slide 65 39 38 2 4 6 8 10 12 14 16 18 20 22 24 Month NB: Same diet and exercise for both sibutramine and placebo James WPT et al. Lancet. 2000;356:2119.

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…

Dose Related Effects of Sibutramine on Systolic Blood Pressure (SBP)
10 mg n=1318 Sibutramine 15 mg n=1924 Sibutramine 20 mg n=1126 Sibutramine 30 mg n=128 Placebo n=1944 10 8 6 +3.8 * Change in SBP (mmHg) 4 +2.6 * 2 +1.0 * -0.1 -0.1 -1 * p < 0.05 compared to placebo Data on file, Abbott Laboratories.

Maximum BP Changes vs. Baseline
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 30 25 20 15 10 5 Control (n=1,521) Sibutramine (n=1,898) Patients (%) No > 0 – < 5 5 – < – < – < – < – < – < – < 40 > 40 increase SBP or DBP increase (mmHg) Adapted from Sharma AM et al. NAASO 2003.

STORM: Change in Vital Signs
Baseline to 24 Months in Sibutramine Treatment Group Mean Change Sibutramine Placebo BP, mm HG Systolic 0.1 - 4.7 Diastolic 2.3 - 1.6 Pulse rate (bpm) 4.1 - 1.9 Slide 66 In STORM most subjects reached 20 mg per study design James WPT et al. Lancet. 2000;356:2119.

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

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 blockers1 BP effects of sibutramine are blocked by exercise program2 In addition to peripheral effects, sibutramine may have central “clonidine-like” sympatholytic effects1 Birkenfeld AL et al. Circulation 2002;106: Berube-Parent S et al. IJO 2001;25:

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

Antiobesity Drugs Approved for Long-Term Use: How They Work
Sibutramine Orlistat 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 Slide 27

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

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

Orlistat: 2-Year Efficacy
60 Placebo + diet 51.6 50 Orlistat + diet 40 36.4 % of Patients 27.3 30 20 15.4 10 > 5% > 10% % of Weight Lost Meta-analysis of data derived from 4 clinical trials Xenical® [package insert]. Nutley, NJ: Roche Laboratories, 1999.

Effect of Long-Term Treatment With Orlistat (The XENDOS Study)
Completers Data -4.1 kg -6.9 kg 52 104 156 208 -12 -9 -6 -3 Placebo + lifestyle (n=557) Orlistat + lifestyle (n=853) Week Weight change (kg) p < vs placebo Torgerson JS et al, Diabetes Care 2004; 27(1):

Independent Effect of Orlistat on Plasma LDL-Cholesterol
0 – 5 5 – 10 10 – 15 > 15 LDL-Cholesterol Concentration (mmol/L) Change in Plasma Weight Loss Category (% initial body weight) -0.3 0.0 -0.5 -0.4 -0.2 -0.1 -0.6 -0.8 -1.0 -0.9 -0.7 * Orlistat Placebo *P < 0.01 vs placebo Segal et al. FASEB J 1999;13:A873. Data pooled from 5 trials (N=1773)

Orlistat: Effect on Lipids and Waist Circumference
Orlistat 120 mg TID Placebo 15 12.8 13 -0.5 11 -1 9.3 9 Change (in) -1.5 % Change 7 -1.6 -2 5 2.9 -2.5 3 -2.6 1.34 -3 1 Waist Circumference HDL-C TG Xenical® [package insert]. Nutley, NJ: Roche Laboratories, 1999.

Orlistat: Effect on Blood Pressure in At-Risk Patients
Systolic (ISH, SBP  140 mm Hg) Diastolic (DBP  90 mm Hg) mm Hg mm Hg -1 -2 -2 -4 -3 Orlistat + diet -4 -6 Placebo + diet -5 -8 -6 -7 -10 -8 -12 P = 0.032 -9 P = NS Data on File (Ref ).

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

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.

Drugs Approved by FDA for Short Term Use in Treating Obesity
Generic Name Trade Names DEA Schedule Diethylpropion (1959) Tenuate IV Phentermine (1959) Adipex-P, Ionamin IV Benzphetamine* (1960) Didrex III Phendimetrazine (1959) Bontril III Methamphetamine Desoxyn II Mazindol* (1973) Mazanor IV Physicians’ Desk reference 59th Edition, 2005. *not listed in PDR, but available

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.

Weight Loss with Continuous and Intermittent Phentermine
5 Weight loss (lbs) 16 10 15 32 Time in Weeks Munro JF, et al. Br Med J 1968; 1:

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 2002:10:633. 2. PDR Edition 29, 2005. 3. Darga et al, AJCN, 1991.

Treatment with Bupropion
Placebo -5 SR 300 Weight loss (%) -10 SR 400 -15 10 20 30 40 50 Weeks of Treatment Anderson Obes Res 2002:10:633.

Fluoxetine 60 mg and Weight Loss*
N = 23 Placebo -2 -4 N = 16 Weight Loss (kg) -6 -8 N = 22 N = 14 -10 Fluoxetine -12 -14 -16 1 3 5 7 9 13 17 21 29 37 45 53 Week number Darga et al, AJCN, 1991.

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.

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

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.

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

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.

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

Zonisamide versus Placebo
-2 Placebo Zonisamide -4 Weight loss (kg) -6 -8 2 4 6 8 10 12 14 16 18 Week Gadde IJO 2002 (Abs).

Medications Noted in ACP 2005 Pharmacotherapy Guidelines
Data Source Weight Loss Period for Weight Change Mean Weight Change 95% CI Sibutramine 29 RCTs 52 weeks 4.45 kg ( kg) Orlistat 22 RCTs 2.75 kg ( kg) Phentermine 9 RCTs weeks 3.6 kg ( kg) Diethylpropion 13 RCTs 6 -52 weeks 3.0 kg ( kg) Bupropion 3 RCTs weeks 2.77 kg ( kg) Fluoxetine -- Range to +0.4 kg Annals Internal Medicine 2005;142:

Van Gaal et al. Lancet 2005;365:1389-97.

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:

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 2006. Look AHEAD, SOS are evaluating mortality benefit of weight loss. Obesity pharmacotherapy is gaining legitimacy.

Obesity Pharmacotherapy: What Does the Future Hold?
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.

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