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The Efficacy of Pharmaceutical and Surgical Approaches to weight loss

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.

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The Efficacy of Pharmaceutical and Surgical Approaches to weight loss

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  1. 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

  2. Principles of Pharmacotherapy in the Management of Obesity

  3. Drugs Approved by FDA for Treating Obesity

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

  5. Drugs Approved by FDA for Treating Obesity

  6. Orlistat Prevents Fat Digestion and Absorption 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.

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

  8. Effect of Long-term Orlistat Therapy on Body Weight -4.1 kg Placebo Change in Weight (kg) -6.9 kg Orlistat P<0.001 vs placebo 0 52 104 156 208 Weeks Torgenson et al. Diabetes Care 2004;27:155

  9. Meta-analysis of RCTs Evaluating Effect of Orlistat Therapy on Weight Loss at 1-Year *All subjects had type 2 diabetes WMD=weighted mean difference -10 -5 0 5 10 FavoursTreatment FavoursControl Padwal et al. Int J Obes 2003;27:1437

  10. Placebo Orlistat Independent Effect of Orlistat on Plasma LDL-Cholesterol Change inPlasmaLDL-CholesterolConcentration(mmol/L) * * * * 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:A873.

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

  12. Gastrointestinal Side Effects of Orlistat Therapy Values are percentage of subjects. Sjostrom et al. Lancet 1998;352:167.

  13. Case Report of Effect of Orlistat on Blood Cyclosporin A Concentration Orlistat Start Switch to Neoral Blood Cyclosporin AConcentration (ng/mL) 0 100 200 300 400 Time (d) Le Beller et al. Transplantation 2000;70:1541.

  14. 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

  15. 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

  16. 60 mg tid 120 mg tid Orlistat 60mg + Diet: Significantly More Effective Than Placebo + Diet 0 Placebo -1 -2 -3 -4 -5 % change from baseline -6 -7 -8 -9 -10 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Treatment week 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 +/-- SE Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

  17. 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

  18. Undesired GI Effects Result from Meals with More than 15-20 Grams of Fat * * * * * Significantly different 60 mg compared 120 mg (p<0.05) Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

  19. Multi-Vitamin Supplement Recommended with Orlistat Therapy Rate of 2 Consecutive Below-Normal Vitamin Levels in 6 Months of Treatment * 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 Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

  20. Undesired GI Effects Result from Meals with More than 15-20 Grams of Fat * * * * * Significantly different 60 mg compared 120 mg (p<0.05) Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

  21. Multi-Vitamin Supplement Recommended with Orlistat Therapy Rate of 2 Consecutive Below-Normal Vitamin Levels in 6 Months of Treatment * 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 Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006

  22. Even Small Weight Losses Have Positive Impact on Risk Factors ~5% Weight Loss 5%-10% Weight Loss 1 1 HbA1c Blood pressure 2 2 Total cholesterol 3 3 HDL cholesterol 3 3 Triglycerides -- 4 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):211S-216S. 4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:264-270.

  23. Sibutramine Blocks Neuronal Monoamine (Serotonin, Norepinephrine, Dopamine) Reuptake X S S = Monoamine = Sibutramine

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

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

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

  27. -10 -5 0 5 10 FavoursTreatment FavoursControl Meta-analysis of RCTs Evaluating Effect of Sibutramine Therapy on Weight Loss at 1-Year • All subjects had hypertension • WMD=weighted mean difference Padwal et al. Int J Obes 2003;27:1437

  28. Adverse Effects of Sibutramine Therapy Meridia™ Package Insert, 2001.

  29. Blood Pressure and Pulse Rate After 1 Year Sibutramine Therapy in Patients with Controlled Hypertension *P<0.05 vs placebo. McMahon et al. Arch Intern Med 2000;160:2185.

  30. Additive Effects of Behavior and Diet Therapy with Pharmacotherapy for Obesity Medication alone Medication and behaviormodification * Weight Change (%) * Medication, behaviormodification and meal replacements 0 2 4 6 8 10 12 Time (months) *P<0.05 vs medication alone. Wadden et al. Arch Intern Med 2001;161:218.

  31. Bariatric Surgery In the Management of Obesity

  32. Obese Patients Have Unrealistic Weight Loss Goals Foster et al. J Consult Clin Psychol 1997;65:79.

  33. Surgery Pharmacotherapy Lifestyle Modification Diet Physical Activity Obesity Treatment Pyramid

  34. Guide for Selecting Obesity Treatment BMI Category (kg/m2) The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084

  35. 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)

  36. 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)

  37. What are The Operative Results? • 30-35% weight loss in 12-18 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

  38. 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

  39. 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

  40. Obesity-Related ResourcesProfessional 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) www.naaso.org www.aafp.org www.acsm.org www.diabetes.org www.eatright.org www.gastro.org www.americanheart.org www.obesity.org www.asbs.org

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