The Efficacy of Pharmaceutical and Surgical Approaches to

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

Principles of Pharmacotherapy in the Management of Obesity Slide Source: www. obesityonline. org

Drugs Approved by FDA for Treating Obesity Trade Names DEA Schedule Approved Use Year Approved Orlistat Xenical None Long-term 1999 Sibutramine Meridia IV Long-term 1997 Diethylpropion Tenulate IV Short-term 1973 Phentermine Adipex, lonamin IV Short-term 1973 Phendimetrazine Bontril, Prelu-2 III Short-term 1961 Benzphetamine Didrex III Short-term 1960 Generic Name Slide Source: www. obesityonline. org

Effect of Continuous and Intermittent Phentermine Therapy on Body Weight Loss (lbs) Continuous Dummy Continuous Phentermine Alternate Phentermine and Dummy 0 4 8 12 16 20 24 Time (weeks) Munro JF et al. Brit Med J 1: 352, 1968 28 32 36 Slide Source: www. obesityonline. org

Drugs Approved by FDA for Treating Obesity Trade Names DEA Schedule Approved Use Year Approved Orlistat Xenical None Long-term 1999 Sibutramine Meridia IV Long-term 1997 Diethylpropion Tenulate IV Short-term 1973 Phentermine Adipex, lonamin IV Short-term 1973 Phendimetrazine Bontril, Prelu-2 III Short-term 1961 Benzphetamine Didrex III Short-term 1960 Generic Name Slide Source: www. obesityonline. org

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

Fecal Fat Excretion (% intake) Effect of Orlistat Dose on Fecal Fat Excretion 0 200 400 600 800 1000 1200 Orlistat Daily Dose (mg) Zhi et al. Clin Pharmacol Ther 1994; 56: 82. Slide Source: www. obesityonline. org

Change in Weight (kg) Effect of Long-term Orlistat Therapy on Body Weight -4. 1 kg Placebo -6. 9 kg Orlistat P<0. 001 vs placebo 0 52 104 Weeks Torgenson et al. Diabetes Care 2004; 27: 155 156 208 Slide Source: www. obesityonline. org

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) *All subjects had type 2 diabetes WMD=weighted mean difference Padwal et al. Int J Obes 2003; 27: 1437 -10 -5 0 Favours Treatment 5 Favours Control 10 Slide Source: www. obesityonline. org

Independent Effect of Orlistat on Plasma LDL-Cholesterol Change in Plasma LDLCholesterol Concentration (mmol/L) * * * Placebo * Orlistat 0 -5 5 – 10 10 – 15 >15 Weight Loss Category (%initial body weight) *P < 0. 01 vs placebo. Data pooled from 5 trials (N = 1773). Segal et al. FASEB J. 1999; 13: A 873. Slide Source: www. obesityonline. org

Orlistat Inhibits Dietary Cholesterol Absorption Cholesterol Absorbed (% ingested) * Baseline Orlistat *P<0. 05 vs baseline. Mittendorfer et al. Obes Res 2001; 9: 599. Slide Source: www. obesityonline. org

Gastrointestinal Side Effects of Orlistat Therapy Year 1 Placebo Fatty/oily stool Increased defecation Liquid stools Fecal urgency Flatulence Flatus with discharge Fecal incontinence Oily evacuation Low plasma vitamin conc: Vitamin A Vitamin D Vitamin E Year 2 Orlistat Placebo Orlistat 5 7 10 3 3 0 0 1 31 20 13 10 7 7 7 6 1 2 5 2 2 0 0 0 8 2 8 3 3 1 2 5 0. 6 0. 9 0. 3 5. 1 4. 6 0. 8 0 0 3. 1 1. 6 Values are percentage of subjects. Sjostrom et al. Lancet 1998; 352: 167. Slide Source: www. obesityonline. org

Case Report of Effect of Orlistat on Blood Cyclosporin A Concentration Orlistat Start Blood Cyclosporin A Concentration (ng/m. L) Switch to Neoral 0 100 Le Beller et al. Transplantation 2000; 70: 1541. 200 Time (d) 300 400 Slide Source: www. obesityonline. org

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

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

Orlistat 60 mg + Diet: Significantly More Effective Than Placebo + Diet 0 Placebo 60 mg tid 120 mg tid % change from baseline -1 -2 -3 -4 -5 -6 -7 -8 -9 -10 0 4 8 12 16 20 24 28 32 36 Treatment week 40 44 48 52 Significant relative weight change from baseline at 6 months for 60 mg vs. placebo and 120 mg vs. placebo, P<0. 001 - ITT population, observed data; mean +/-- SESlide Source: FDA Advisory Committee Review of orlistat 60 mg OTC, Jan 23, 2006 www. obesityonline. org

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

Undesired GI Effects Result from Meals with More than 15 -20 Grams of Fat 6 Months Placebo 60 mg tid 120 mg tid Adverse event N=634 N=632 Fecal urgency 7. 9% Oily spotting 1. 1% N=623 * 18. 8% * 17. 7% Flatus with discharge 1. 9% 19. 9% Fatty/Oily stool 2. 7% 17. 3% * 17. 2% Oily evacuation 0. 6% 11. 6% 13. 4% Increased defecation 2. 7% 8. 2% Fecal incontinence 0. 8% 7. 1% * 4. 7% 23. 4% 21. 7% 7. 8% * Significantly different 60 mg compared 120 mg (p<0. 05) Source: FDA Advisory Committee Review of orlistat 60 mg OTC, Jan 23, 2006 Slide Source: www. obesityonline. org

Multi-Vitamin Supplement Recommended with Orlistat Therapy Rate of 2 Consecutive Below-Normal Vitamin Levels in 6 Months of Treatment Placebo (%) 60 mg tid (%) 120 mg tid (%) Vitamin A 3/580 (0. 5) 1/203 (0. 5) 15/962 (1. 6) Vitamin D 13/558 (2. 3) 2/209 (1. 0)* 50/954 (5. 2) Vitamin E 2/565 (0. 4) 7/196 (3. 6) 29/944 (3. 1) Beta-carotene 2/576 (0. 3) 3/207 (1. 4) 40/977 (4. 1) * Significant difference between 60 -mg and 120 -mg doses; Fisher’s Exact Test at p<0. 05 This analysis includes all U. S. Studies (NM 14336, NM 14161, and NM 14185) conducted by Roche of orlistat 60 and 120 mg that did not require routine vitamin supplementation Source: FDA Advisory Committee Review of orlistat 60 mg OTC, Jan 23, 2006 Slide Source: www. obesityonline. org

Undesired GI Effects Result from Meals with More than 15 -20 Grams of Fat 6 Months Placebo 60 mg tid 120 mg tid Adverse event N=634 N=632 Fecal urgency 7. 9% Oily spotting 1. 1% N=623 * 18. 8% * 17. 7% Flatus with discharge 1. 9% 19. 9% Fatty/Oily stool 2. 7% 17. 3% * 17. 2% Oily evacuation 0. 6% 11. 6% 13. 4% Increased defecation 2. 7% 8. 2% Fecal incontinence 0. 8% 7. 1% * 4. 7% 23. 4% 21. 7% 7. 8% * Significantly different 60 mg compared 120 mg (p<0. 05) Source: FDA Advisory Committee Review of orlistat 60 mg OTC, Jan 23, 2006 Slide Source: www. obesityonline. org

Multi-Vitamin Supplement Recommended with Orlistat Therapy Rate of 2 Consecutive Below-Normal Vitamin Levels in 6 Months of Treatment Placebo (%) 60 mg tid (%) 120 mg tid (%) Vitamin A 3/580 (0. 5) 1/203 (0. 5) 15/962 (1. 6) Vitamin D 13/558 (2. 3) 2/209 (1. 0)* 50/954 (5. 2) Vitamin E 2/565 (0. 4) 7/196 (3. 6) 29/944 (3. 1) Beta-carotene 2/576 (0. 3) 3/207 (1. 4) 40/977 (4. 1) * Significant difference between 60 -mg and 120 -mg doses; Fisher’s Exact Test at p<0. 05 This analysis includes all U. S. Studies (NM 14336, NM 14161, and NM 14185) conducted by Roche of orlistat 60 and 120 mg that did not require routine vitamin supplementation Source: FDA Advisory Committee Review of orlistat 60 mg OTC, Jan 23, 2006 Slide Source: www. obesityonline. org

Even Small Weight Losses Have Positive Impact on Risk Factors ~5% Weight Loss 5%-10% Weight Loss 1 1 Blood pressure 2 2 Total cholesterol 3 3 Hb. A 1 c HDL cholesterol Triglycerides -- 1. Wing RR et al. Arch Intern Med. 1987; 147: 1749 -1753. 2. Mertens IL, Van Gaal LF. Obes Res. 2000; 8: 270 -278. 3. Blackburn G. Obes Res. 1995; 3(Suppl 2): 211 S-216 S. 4. Ditschunheit HH et al. Eur J Clin Nutr. 2002; 56: 264 -270. 4 Slide Source: www. obesityonline. org

Sibutramine Blocks Neuronal Monoamine (Serotonin, Norepinephrine, Dopamine) Reuptake X S = Monoamine S = Sibutramine Slide Source: www. obesityonline. org

Body Weight Change (kg) Effect of Continuous vs Intermittent Sibutramine Therapy on Body Weight Placebo Intermittent sibutramine Continuous sibutramine Run-in period 0 4 8 12 Sibutramine dose=15 mg/d. 16 20 24 28 32 Time (wk) Wirth and Krause. JAMA 2001; 286: 1331. 36 40 44 48 Slide Source: www. obesityonline. org

Initial Responders to Sibutramine Can Maintain Long-term Weight Loss Weight Maintenance Placebo Body Weight (lb. ) Sibutramine 10 -20 mg/d 0 2 4 6 8 10 12 14 Month 16 18 20 22 24 Randomization at 6 months in those with >5% weight loss. James et al. Lancet 2000: 356: 2119. Slide Source: www. obesityonline. org

Weight Change (kg) Use of Sibutramine within a Health Maintenance Organization Enhances Weight Loss No drug therapy Sibutramine therapy 0 26 Weeks Porter et al. Am J Manag Care 2004; 10: 369 52 Slide Source: www. obesityonline. org

Meta-analysis of RCTs Evaluating Effect of Sibutramine Therapy on Weight Loss at 1 -Year Study or Sub-category WMD (random) 95% CI Mc. Mahon 2000 Smith 2001 Mc. Mahon 2002 * Total (95% CI) -10 • All subjects had hypertension WMD=weighted mean difference Padwal et al. Int J Obes 2003; 27: 1437 -5 0 Favours Treatment 5 Favours Control 10 Slide Source: www. obesityonline. org

Adverse Effects of Sibutramine Therapy Adverse Effect Subjects (%) Placebo Sibutramine Headache 18. 6 30. 3 Dry mouth 4. 2 17. 2 Constipation 6. 0 11. 5 Insomnia 4. 5 10. 7 Dizziness 3. 4 7. 0 Hypertension 0. 9 2. 1 Tachycardia 0. 6 2. 6 Palpitation 0. 8 2. 0 Meridia™ Package Insert, 2001. Slide Source: www. obesityonline. org

Blood Pressure and Pulse Rate After 1 Year Sibutramine Therapy in Patients with Controlled Hypertension Placebo Sibutramine Systolic BP change (mm Hg) +1. 5 +2. 7 Diastolic BP change (mm Hg) -1. 3 +2. 0 * 0 4. 9 * 1. 4 5. 3 Pulse rate change (beats/min) Withdrawal due to hypertension (% subjects) *P<0. 05 vs placebo. Mc. Mahon et al. Arch Intern Med 2000; 160: 2185. Slide Source: www. obesityonline. org

Additive Effects of Behavior and Diet Therapy with Pharmacotherapy for Obesity Weight Change (%) Medication alone Medication and behavior modification Medication, behavior modification and meal replacements 0 2 *P<0. 05 vs medication alone. 4 6 8 Time (months) Wadden et al. Arch Intern Med 2001; 161: 218. 10 * * 12 Slide Source: www. obesityonline. org

Bariatric Surgery In the Management of Obesity Slide Source: www. obesityonline. org

Obese Patients Have Unrealistic Weight Loss Goals Outcome Weight (lbs) % Reduction Initial 218 0 Dream 135 38 Happy 150 31 Acceptable 163 25 Disappointed 180 17 Foster et al. J Consult Clin Psychol 1997; 65: 79. Slide Source: www. obesityonline. org

Obesity Treatment Pyramid Surgery Pharmacotherapy Lifestyle Modification Diet Physical Activity Slide Source: www. obesityonline. org

Guide for Selecting Obesity Treatment BMI Category (kg/m 2) Treatment 25 -26. 9 27 -29. 9 30 -34. 9 35 -39. 9 >40 Diet, Exercise, Behavior Tx + + + With comorbidities + Pharmacotherapy Surgery The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No. 00 -4084 Slide Source: www. obesityonline. org

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: www. obesityonline. org

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: www. obesityonline. org

What are The Operative Results? l 30 -35% weight loss in 12 -18 months l Roux-en-Y Gastric bypass the most widely accepted and best results l Higher volume centers and surgeons have best results. Still risk and complications l 10 year weight loss maintenance best with surgery Slide Source: www. obesityonline. org

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: www. obesityonline. org

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

Obesity-Related Resources Professional Associations North American Association for the Study of Obesity (NAASO) www. naaso. org American Academy of Family Physicians (AAFP) www. aafp. org American College of Sports Medicine (ACSM) www. acsm. org American Diabetes Association (ADA) www. diabetes. org American Dietetic Association (ADA) www. eatright. org American Gastroenterological Association (AGA) www. gastro. org American Heart Association (AOA) www. americanheart. org American Obesity Association (AOA) www. obesity. org American Society for Bariatric Surgery (ASBS) www. asbs. org Slide Source: www. obesityonline. org