Slide Source: The Efficacy of Pharmaceutical and Surgical Approaches to weight loss Valentine J. Burroughs, MD MBA Chief Medical Officer North General Hospital, New York, New York University of Medicine and Dentistry of New Jersey Newark, New Jersey March 31, 2007

Slide Source: Principles of Pharmacotherapy in the Management of Obesity

Slide Source: Drugs Approved by FDA for Treating Obesity Generic Name Trade Names DEA Schedule Approved Use Year Approved OrlistatXenicalNoneLong-term1999 SibutramineMeridiaIVLong-term1997 DiethylpropionTenulateIVShort-term1973 Phentermine Adipex, lonamin IVShort-term1973 Phendimetrazine Bontril, Prelu-2 IIIShort-term1961 BenzphetamineDidrexIIIShort-term1960

Slide Source: Effect of Continuous and Intermittent Phentermine Therapy on Body Weight 0 Time (weeks) Munro JF et al. Brit Med J 1:352, 1968 Weight Loss (lbs) Alternate Phentermine and Dummy Continuous Phentermine Continuous Dummy

Slide Source: Drugs Approved by FDA for Treating Obesity Generic Name Trade Names DEA Schedule Approved Use Year Approved OrlistatXenicalNoneLong-term1999 SibutramineMeridiaIVLong-term1997 DiethylpropionTenulateIVShort-term1973 Phentermine Adipex, lonamin IVShort-term1973 Phendimetrazine Bontril, Prelu-2 IIIShort-term1961 BenzphetamineDidrexIIIShort-term1960

Slide Source: Orlistat Prevents Fat Digestion and Absorption by Binding to Gastrointestinal Lipases TG=triglyceride; MG=monoglyceride; FA=fatty acid. Mucosal Cell Intestinal Lumen Orlistat TG LIPASE LIPASE LIPASE Bile Acids Micelle MG FA

Slide Source: Effect of Orlistat Dose on Fecal Fat Excretion Zhi et al. Clin Pharmacol Ther 1994;56:82. Fecal Fat Excretion (% intake) Orlistat Daily Dose (mg)

Slide Source: Effect of Long-term Orlistat Therapy on Body Weight 0 Weeks 52 Torgenson et al. Diabetes Care 2004;27:155 Change in Weight (kg) P<0.001 vs placebo -4.1 kg -6.9 kg Placebo Orlistat

Slide Source: Meta-analysis of RCTs Evaluating Effect of Orlistat Therapy on Weight Loss at 1-Year Study or Sub-category WMD (random) 95% CI Hollander 1998* Sjostrom 1998 Davidson 1999 Finer 2000 Heuptman 2000 Lindgarde 2000 Rossner 2000 Bakris 2002 Broom 2002 Kelley 2002* Miles 2002* Total (95% CI) Padwal et al. Int J Obes 2003;27:1437 *All subjects had type 2 diabetes WMD=weighted mean difference Favours Treatment Favours Control

Slide Source: Independent Effect of Orlistat on Plasma LDL-Cholesterol Weight Loss Category (%initial body weight) Change in Plasma LDL- Cholesterol Concentration (mmol/L) Segal et al. FASEB J. 1999;13:A873. *P < 0.01 vs placebo. Data pooled from 5 trials (N = 1773) – 1010 – 15>15 Placebo Orlistat * * * *

Slide Source: Orlistat Inhibits Dietary Cholesterol Absorption Cholesterol Absorbed (% ingested) *P<0.05 vs baseline. Mittendorfer et al. Obes Res 2001;9:599. BaselineOrlistat *

Slide Source: Gastrointestinal Side Effects of Orlistat Therapy Year 1Year 2 PlaceboOrlistatPlaceboOrlistat Fatty/oily stool Increased defecation Liquid stools Fecal urgency Flatulence 3723 Flatus with discharge 0701 Fecal incontinence 0702 Oily evacuation 1605 Low plasma vitamin conc: Vitamin A Vitamin D Vitamin E Sjostrom et al. Lancet 1998;352:167. Values are percentage of subjects.

Slide Source: Case Report of Effect of Orlistat on Blood Cyclosporin A Concentration Blood Cyclosporin A Concentration (ng/mL) Le Beller et al. Transplantation 2000;70:1541. Time (d) Orlistat Start Switch to Neoral

Slide Source: FDA Approved Orlistat 60mg for Non-Prescription Use on February 7, 2007 Trade name: allī For weight loss In overweight adults With reduced-calorie, low-fat diet One capsule with each meal containing fat

Slide Source: The OTC Orlistat Product Will Provide Both Medication and Behavioral Support Behavioral Support: Welcome Guide Companion Guide QuickFact Cards Healthy Eating Guide Calorie and Fat Counter Daily Journal Online 12-month Support Program Compliance shuttle

Slide Source: Orlistat 60mg + Diet: Significantly More Effective Than Placebo + Diet % change from baseline Placebo 60 mg tid 120 mg tid Treatment week Significant relative weight change from baseline at 6 months for 60 mg vs. placebo and 120 mg vs. placebo, P< ITT population, observed data; mean +/-- SE Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

Slide Source: Orlistat 60 mg vs. 120 mg Fewer GI events with 60 mg dose Significantly lower chance of GI events in first four weeks of treatment One third fewer GI events within first week Lower withdrawal rate due to GI events Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

Slide Source: Undesired GI Effects Result from Meals with More than Grams of Fat 6 Months Placebo60 mg tid120 mg tid Adverse event N=634 N=623N=632 Fecal urgency7.9%18.8%23.4% Oily spotting1.1%17.7%21.7% Flatus with discharge1.9%17.3%19.9% Fatty/Oily stool2.7%17.2%21.7% Oily evacuation0.6%11.6%13.4% Increased defecation2.7%7.1%8.2% Fecal incontinence0.8%4.7%7.8% * Significantly different 60 mg compared 120 mg (p<0.05) * * * * Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

Slide Source: Multi-Vitamin Supplement Recommended with Orlistat Therapy *Significant difference between 60-mg and 120-mg doses; Fisher’s Exact Test at p<0.05 This analysis includes all U.S. Studies (NM14336, NM14161, and NM14185) conducted by Roche of orlistat 60 and 120 mg that did not require routine vitamin supplementation Placebo (%)60 mg tid (%)120 mg tid (%) Vitamin A3/580 (0.5)1/203 (0.5)15/962 (1.6) Vitamin D13/558 (2.3)2/209 (1.0)*50/954 (5.2) Vitamin E2/565 (0.4)7/196 (3.6)29/944 (3.1) Beta-carotene2/576 (0.3)3/207 (1.4)40/977 (4.1) Rate of 2 Consecutive Below-Normal Vitamin Levels in 6 Months of Treatment Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

Slide Source: Undesired GI Effects Result from Meals with More than Grams of Fat 6 Months Placebo60 mg tid120 mg tid Adverse event N=634 N=623N=632 Fecal urgency7.9%18.8%23.4% Oily spotting1.1%17.7%21.7% Flatus with discharge1.9%17.3%19.9% Fatty/Oily stool2.7%17.2%21.7% Oily evacuation0.6%11.6%13.4% Increased defecation2.7%7.1%8.2% Fecal incontinence0.8%4.7%7.8% * Significantly different 60 mg compared 120 mg (p<0.05) * * * * Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

Slide Source: Multi-Vitamin Supplement Recommended with Orlistat Therapy *Significant difference between 60-mg and 120-mg doses; Fisher’s Exact Test at p<0.05 This analysis includes all U.S. Studies (NM14336, NM14161, and NM14185) conducted by Roche of orlistat 60 and 120 mg that did not require routine vitamin supplementation Placebo (%)60 mg tid (%)120 mg tid (%) Vitamin A3/580 (0.5)1/203 (0.5)15/962 (1.6) Vitamin D13/558 (2.3)2/209 (1.0)*50/954 (5.2) Vitamin E2/565 (0.4)7/196 (3.6)29/944 (3.1) Beta-carotene2/576 (0.3)3/207 (1.4)40/977 (4.1) Rate of 2 Consecutive Below-Normal Vitamin Levels in 6 Months of Treatment Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

Slide Source: Even Small Weight Losses Have Positive Impact on Risk Factors HbA1c HDL cholesterol Blood pressure Triglycerides Total cholesterol 5%-10% Weight Loss ~5% Weight Loss 1. Wing RR et al. Arch Intern Med. 1987;147: Mertens IL, Van Gaal LF. Obes Res. 2000;8: Blackburn G. Obes Res. 1995;3(Suppl 2):211S-216S. 4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:

Slide Source: Sibutramine Blocks Neuronal Monoamine (Serotonin, Norepinephrine, Dopamine) Reuptake = Monoamine S S = Sibutramine

Slide Source: Effect of Continuous vs Intermittent Sibutramine Therapy on Body Weight Body Weight Change (kg) Wirth and Krause. JAMA 2001;286:1331. Sibutramine dose=15 mg/d. Time (wk) Placebo Intermittent sibutramine Continuous sibutramine Run-in period

Slide Source: Weight Loss Initial Responders to Sibutramine Can Maintain Long-term Weight Loss James et al. Lancet 2000:356:2119. Randomization at 6 months in those with >5% weight loss. Body Weight (lb.) Month Placebo Sibutramine mg/d Weight Maintenance

Slide Source: Use of Sibutramine within a Health Maintenance Organization Enhances Weight Loss 0 Weeks Porter et al. Am J Manag Care 2004;10:369 Weight Change (kg) 2652 No drug therapy Sibutramine therapy

Slide Source: Meta-analysis of RCTs Evaluating Effect of Sibutramine Therapy on Weight Loss at 1-Year Study or Sub-category WMD (random) 95% CI McMahon 2000 Smith 2001 McMahon 2002 * Total (95% CI) Padwal et al. Int J Obes 2003;27:1437 All subjects had hypertension WMD=weighted mean difference -10 Favours Treatment Favours Control

Slide Source: Adverse Effects of Sibutramine Therapy Subjects (%) Adverse Effect Placebo Sibutramine Headache Dry mouth Constipation Insomnia Dizziness Hypertension Tachycardia Palpitation Meridia™ Package Insert, 2001.

Slide Source: Blood Pressure and Pulse Rate After 1 Year Sibutramine Therapy in Patients with Controlled Hypertension PlaceboSibutramine Systolic BP change (mm Hg) Diastolic BP change (mm Hg) * Pulse rate change (beats/min) * Withdrawal due to hypertension (% subjects) McMahon et al. Arch Intern Med 2000;160:2185. *P<0.05 vs placebo.

Slide Source: Additive Effects of Behavior and Diet Therapy with Pharmacotherapy for Obesity Weight Change (%) Wadden et al. Arch Intern Med 2001;161:218. *P<0.05 vs medication alone. Time (months) Medication alone Medication and behavior modification Medication, behavior modification and meal replacements * *

Slide Source: Bariatric Surgery In the Management of Obesity

Slide Source: Obese Patients Have Unrealistic Weight Loss Goals OutcomeWeight (lbs)% Reduction Initial2180 Dream13538 Happy15031 Acceptable16325 Disappointed18017 Foster et al. J Consult Clin Psychol 1997;65:79.

Slide Source: Obesity Treatment Pyramid Diet Physical Activity Lifestyle Modification Pharmacotherapy Surgery

Slide Source: Guide for Selecting Obesity Treatment The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No Treatment >40 Diet, Exercise, Behavior Tx Pharmaco- therapy With co- morbidities +++ Surgery With co- morbidities + BMI Category (kg/m 2 )

Slide Source: What Operations are Performed? Restrictive Surgeries-limit amount of food held by a surgically created smaller gastric pouch and slow gastric emptying 1.) Vertical Banded Gastroplasty (VBG) 2.) Laparoscopic Adjustable Silicone Gastric banding (LASGB)

Slide Source: What Operations are Performed? Restrictive Malabsorbtive-gastric restriction combined with selective malabsorbtion 1.) Roux-en-Y Gastric Bypass (RYGB) The most commonly performed proc. 2.) Biliopancreatic Diversion (BPD) or Biliopancreatic Diversion with Duodenal Switch (BPDDS)

Slide Source: What are The Operative Results? 30-35% weight loss in months Roux-en-Y Gastric bypass the most widely accepted and best results Higher volume centers and surgeons have best results. Still risk and complications 10 year weight loss maintenance best with surgery

Slide Source: Treatment of the Metabolic Syndrome in Overweight or Obese Patients Weight loss induced by diet and increased physical activity is the cornerstone of therapy Weight loss induced by drug therapy can also improve specific features of the metabolic syndrome Bariatric surgery is the most effective weight loss therapy for extremely obese subjects and improves all features of the metabolic syndrome

Slide Source: Conclusions Obesity is a chronic disease Modest weight loss (5% -10% of body weight) can have considerable medical benefits Lifestyle change (diet and physical activity) is the cornerstone of therapy Pharmacotherapy can be useful in properly selected patients Bariatric surgery is the most effective therapy for obesity

Slide Source: Obesity-Related Resources Professional Associations North American Association for the Study of Obesity (NAASO) American Academy of Family Physicians (AAFP) American College of Sports Medicine (ACSM) American Diabetes Association (ADA) American Dietetic Association (ADA) American Gastroenterological Association (AGA) American Heart Association (AOA) American Obesity Association (AOA) American Society for Bariatric Surgery (ASBS)