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

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Presentation on theme: "Slide Source: www.obesityonline.org Obesity Treatment Pyramid Diet Physical Activity Lifestyle Modification Pharmacotherapy Surgery."— Presentation transcript:

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

2 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 )

3 Slide Source: Obesity and Dietary Therapy “Duct Tape”

4 Slide Source: Short-term Obesity Therapy Does Not Result in Long-term Weight Loss Change in Weight (kg) Wadden et al. Int J Obes 1989;13 (Suppl 2):39. 5-year Follow-up 1-year Follow-up End of Treatment Baseline Diet alone Behavior therapy Combined therapy

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6 Slide Source: No Active TreatmentActive Treatment Sustained Weight Loss Can Be Achieved with Behavior Modification Therapy 0 Years 246 Men Björvell and Rössner. Int J Obes Relat Metab Disord 1992;16:623. Weight Loss (kg) Women

7 Slide Source: Cardinal Behaviors of Successful Long-term Weight Management National Weight Control Registry Data Self-monitoring: – Diet: record food intake daily, limit certain foods or food quantity – Weight: check body weight >1 x/wk Low-calorie, low-fat diet: – Total energy intake: kcal/d – Energy intake from fat: 20%-25% Eat breakfast daily Regular physical activity: kcal/wk (eg, walk 4 miles/d) Klem et al. Am J Clin Nutr 1997;66:239. McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.

8 Slide Source: Principles of Pharmacotherapy in the Management of Obesity

9 Slide Source: Regulation of Food Intake Brain NPY AGRP galanin Orexin-A Dynorphin ECS/CB1 Stimulate α-MSH CRH/UCN GLP-I CART NE 5-HT Inibit Central Signals Glucose CCK, GLP-1, Apo-A-IV Vagal afferents Insulin Ghrelin Leptin Cortisol Peripheral signals Peripheral organs +   + Gastrointestinal tract Adipose tissue Food Intake Adrenal glands External factors Emotions, Drugs Food characteristics Lifestyle behaviors Environmental cues

10 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

11 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

12 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

13 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.

14 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

15 Slide Source: Effect of Continuous vs Intermittent Subutramine 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

16 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.

17 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 QOM Continuous Phentermine Continuous Dummy

18 Slide Source: Regulation of Food Intake Brain NPY AGRP galanin Orexin-A Dynorphin ECS/CB1 Stimulate α-MSH CRH/UCN GLP-I CART NE 5-HT Inibit Central Signals Glucose CCK, GLP-1, Apo-A-IV Vagal afferents Insulin Ghrelin Leptin Cortisol Peripheral signals Peripheral organs +   + Gastrointestinal tract Adipose tissue Food Intake Adrenal glands External factors Emotions, Drugs Food characteristics Lifestyle behaviors Environmental cues

19 Slide Source: Modified from Marx, Science 2003 February 7; 299: (in News) Gastrointestinal Peptides Hormones food intake regulation digestion and metabolism Anti-obesity potential Anti-diabetes potential Vagus nerve Ghrelin Insulin Amylin Glucagon Leptin PYY GLP-1 CCK

20 Slide Source: GLP-1 GLP-1: incretin hormone Exenatide (Byetta); incretin mimetic – Enhances insulin secretion – Suppresses elevated glucagon secretion – Reduces food intake and body weight – Slows gastric emptying – Increase in beta-cell mass Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001; 86: Drucker DJ. Mol Endocrinol 2003; 17: Nielsen LL, et al. Reg Pept 2004; 117:77-88

21 Neuroendocrinology of Food Intake Regulation Hindbrain as a Target for Peripheral Satiety Signals Modified from Marx, Science 2003 February 7; 299: (in News) Leptin Insulin PYY Ghrelin GI tract Spinal nerves Vagus CCK Hypothalamus ARC NTS/AP Area Postrema: part of dorsal vagal complex chemoreceptive (no BBB) site of neural integration bi-directional projections to the GI tract (via vagal afferents and efferents) bi-directional projections to the hypothalamus, amygdala and other regions Amylin other circulating gut peptides

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23 Slide Source: Safety and Tolerability Exenatide Open-Label Extensions Exenatide generally well tolerated Adverse events – Nausea (30-40%) – Diarrhea (7%) – Vomiting (9%) – Feeling jittery (5%) – Dizziness (3%) – Headache (3%)

24 Amylin Binding Sites in the Brain Amylin: A Neuroendocrine Hormone Amylin Receptor Identified C C NN RAMP 1 or 3 CTR Dorsale Raphe Nucleus AccumbensArea Postrema Beaumont K, et al. Mol Pharm 1993; 44: Adapted from Muff R, et al. Endocrinology1999; 140:

25 Effects of Pramlintide in Type 2 Diabetes Week 4Week 13Week 26 Pooled 120 µg BID Pramlintide Intent to Treat Populations Week 4Week 13Week 26 Week 4Week 13Week Data on file, Amylin Pharmaceuticals, Inc. Placebo + Insulin (N=284; Baseline A1C 9.3%) 120 µg Pramlintide BID Dose + Insulin (N=292; Baseline A1C 9.1%) Placebo + Insulin 120 µg Pramlintide Change in Insulin Use (%) Change in A1C (%) Change in Weight (lb)

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27 Slide Source: Energy Balance Feeding Behavior Gastric emptying GI motility Hepatic glucose output Lipogenesis Hepatic Lipogenesis Adipose Tissue Metabolism Glucose Homeostasis Glucose uptake Glucose, lipid oxidation Lipolysis Lipogenesis Ghrelin, PYY Limbic forebrain Motivation for palatable food Hypothalamus Hunger/satiety Endocannabinoid System (CB-1) as a Potential Target of Action for Modulation of Energy Homeostasis and Obesity 27

28 Slide Source: The ECS is Overactivated in: 28  Animal models of genetic obesity  Animal models of diet-induced obesity  Human obesity

29 Slide Source: Endocannabinoids Stimulate Food Intake in Mice Hao S et al. Eur J Pharmacology. 2000; 392: Anandamide mg/kg Vehicle *P<0.05; **P<0.01 vs vehicle Day Food intake ( grams/day ) * * * ** 29

30 Slide Source: Engeli S, et al. Diabetes 2005; 54:2838–2843. * P<0.05 vs lean women The ECS is Upregulated in Human Obesity 30

31 Slide Source: >30.0 BMI (kg/m 2 ) >30.0 Caucasians African Americans P<0.05* P<0.01* P<0.05* BMI (kg/m 2 ) Percent of subjects with FAAH 385 A/A genotype by BMI category % of subjects with FAAH 385 A/A * vs normal BMI A Mutation in the Enzyme That Degrades Endocannabinoids is Associated with Increased BMI Sipe JC et al. Int J Obes Relat Metab Disord.2005;29:

32 Slide Source: CB 1 Blockade Produces a Dose-Related Reduction in Food Intake in Mice Wiley JL et al. Br J Pharmacol. 2005;145: Rimonabant Dose (mg/kg -1 ) Food intake (g) 32

33 Slide Source: Adipose tissue metabolism – EC stimulation with CB 1 agonist increases adipose tissue LPL expression while CB 1 blockade inhibits this effect – CB 1 stimulation reduces while blockade increases adiponectin synthesis – CB 1 blockade reverses the histological changes in adipose tissue produced by diet-induced obesity – EC stimulation reduces the expression of AMP kinase in visceral fat Supporting Evidence: 33 Cota D et al. J Clin Invest. 2003;112:423. Matias I, et al. XV ICRS Symposium June 24-27, 2005; Clearwater, Fla. Jbilo O, et al. FASEB J. 2005;19:

34 Slide Source: The Peripheral ECS in Adipose Tissue Adipose tissue of obese mice fed a high fat diet (HFD) plus rimonabant resembles that of lean mice fed a standard diet (STD) Jbilo O, et al. FASEB J. 2005;19: Standard Diet High Fat Diet High Fat Diet + Rimonabant

35 Slide Source: ECS Stimulation, Centrally and Peripherally, Favors Metabolic Processes that Lead to: 35  Weight Gain  Lipogenesis  Insulin Resistance  Dyslipidemia  Impaired Glucose Homeostasis

36 Slide Source: RIO: Rimonabant In Overweight/Obesity CB-1 Blockade in Human Studies (>6600 patients enrolled) Pi-Sunyer FX.Obes Res. 2004;12(suppl):08-OR, A

37 Slide Source: RIO-Europe and RIO-Lipids: Weight Change at 1 Year Completers ITT (LOCF) Placebo Rimonabant 20 mg Placebo Rimonabant 20 mg ITT LOCF Weight change (kg ) Weeks Van Gaal et al. The Lancet 2005; 365: Despres J-P, et al. N Engl J Med. 2005;353:

38 Slide Source: Placebo Rimonabant 20 mg Rimonabant 20 mg/PLB RIO-NA: Weight Change over 2-Years in Re-randomized Patients Weight (kg) Change from Baseline over 2 Years (Mean +/- SEM) ITT (LOCF) -7.4 kg ± kg ± kg ± LOCF Weeks Weight change (Kg) Pi-Sunyer FX et al. JAMA 2006;295:

39 Slide Source: RIO-NA: HDL-C and TG over 2 Years* HDL-cholesterolTriglycerides ITT, LOCF Change in Triglycerides (%) Weeks Placebo Rimonabant 20 mg Rimonabant 5 mg Weeks Change in HDL-cholesterol (%) % p< % ns +7.8% LOCF % p< % +4.0% ns LOCF *Patients on same treatment for 2 years Pi-Sunyer FX et al. JAMA 2006;295:

40 Slide Source: Change in HDL-C (%) Week P<0.001 P= RIO-Lipids: Percent Change in HDL-C and TG Levels at 1 Year Despres J-P, et al. N Engl J Med. 2005;353: Rimonabant 20 mg Rimonabant 5 mg Placebo Placebo: 11. 8% R5 mg: 14.2% (ns v. placebo) R20 mg: 19.1% (p< v. placebo) ITT, LOCF Completers Placebo: 0.0. % R5 mg: 1.2% R20 mg:-12.6% (p < v. placebo) Week Change in TG (%) P<

41 Slide Source: End Point Placebo Rimonabant 5 mg Rimonabant 20 mg P-value PLB vs 20 mg Weight loss (kg)- 1.4± ± ±0.3<0.001 Decrease in waist circumference (cm) - 1.9± ± ±0.3<0.001 % of patients with weight loss ≥ 10% <0.001 % of patients with weight loss ≥ 5% <0.001 RIO-DIABETES Results: Weight Changes Scheen A. Late Breaking Clinical Trials. ADA Scientific Session 2005.

42 Slide Source: RIO-NA: Overall Safety Year %9.4 %7.2 % Subjects discontinued due to adverse event Rimonabant Placebo 4.5 %3.8 %3.5 % Subjects with any serious adverse event 85.5 %83.4 %82.0 % Subjects with any adverse event 44.9 %49.0 % 49.1 % Overall discontinuations 20 mg n = mg n = 1214 n = 607 Rimonabant Pi-Sunyer FX et al. JAMA 2006;295:

43 Slide Source: RIO-NA: Adverse Events Leading To Drug Discontinuation in Year 1 Placebo Rimonabant (N=607) (%) 5 mg ( N=1214) (%) 20 mg (N=1219) (%) Psychiatric disorders Depressed mood disorders Anxiety Irritability Insomnia0.2< Nervous system disorders Headache Dizziness Gastrointestinal disorders Nausea According to MedDRA, in any rimonabant groups : in main SOCs (>=1% ) and in at least 6 patients (0.5%). One patient may report several events Pi-Sunyer FX et al. JAMA 2006;295:

44 Slide Source: RIO-NA: Main Adverse Events Leading to Drug Discontinuation in Year 2* 2 (0.6)1 (0.3)0 (0) Anxiety 4 (1.2)4 (1.3)3 (1.0) Depressed mood disorders 7 (2.1)6 (2.0)4 (1.3) Psychiatric disorders 20 mg (N=333) N (%) 5 mg (N=300) N (%) (N=298) N (%) RimonabantPlacebo *Patients receiving the same treatment for 2 years Pi-Sunyer FX et al. JAMA 2006;295:

45 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 severe obesity

46 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.

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