OBESITY 2008: DIET, EXERCISE, DRUGS, AND SURGERY Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine Declaration of full disclosure: No conflict of interest CLASSIFICATION OF OVERWEIGHT AND OBESITY BY BMI Obesity Class BMI (kg/m 2 ) Underweight <18.5 Normal 18.5 24.9 Overweight 25.0 29.9 Obesity I 30.0 34.9 II 35.0 39.9 Extreme Obesity III >40 For a 40 yo woman, which BMI is associated with the lowest allcause mortality? BMI AND MORTALITY: Overall Combined NHANES I, II, and III data set BMI 25-59 y 60-69 y 70 y 1. 18 2. 24 3. 28 4. 34 5. 38 <18.5 1.38 2.30 1.69 18.5-<25 1.00 1.00 1.00 25 to <30 0.83 0.95 0.91 30 to <35 1.20 1.13 1.03 35 1.83 1.63 1.17 Flegal, JAMA, 2005 1
Excess Deaths by Body Mass Index (NHANES) Excess Deaths Trends Over NHANES Surveys I, II, and II. Flegal, JAMA 2007. Flegal, JAMA 2007 40 yo woman, BMI 33. Which abnormality best predicts her 10 year mortality? METABOLIC SYNDROME Fulfill 3 or more criteria: 1. Waist circumference: 36 inches 2 Fasting blood sugar: 110 mg/dl 3 Systolic BP: 140 mm Hg 4. Triglycerides: 185 mg/dl 5. Exercise test: early stage 2 (fatigue) Waist: men > 102 cm ( > 40 in); women > 88 cm ( > 35 in) HDL: men < 40; women < 50 (or meds) Triglycerides: 150 mg/dl (or meds) BP: 130/85 (or meds) Fasting glucose: 100 mg/dl ICD-9: 277.7 NCEP, Circulation, 2003 2
CVD MORTALITY AND METABOLIC SYNDROME 19,173 men from the ACLS study CVD Mortality Normal weight Healthy 1.00 Metabolic Synd 2.06 Overweight Healthy 1.27 Metabolic Synd 1.80 Obese Healthy 2.70 Metabolic Synd 2.83 40 yo woman, BMI 36. Motivated to begin diet therapy. Which of the following is contraindicated: 1. Meal replacement, very low calorie diet 2 Atkins diet 3 Ornish diet 4. Zone diet 5. All are contraindicated 6. None are contraindicated Katzmarzyk, Diabetes Care, 2005 VLCD s s vs LCD s: Meta-analysis analysis of 6 RCTs Trials with direct comparisons Short-term: mean 12.7 weeks Long-term: mean 1.9 years Weight loss (as % of initial weight): short-term long-term LCDs 9.7 5.0 VLCDs 16.1 6.3 In the last year, I have prescribed (or referred a patient for) a very low calorie diet (VLCD) for weight loss. 1. Yes 2 No (p) (0.001) (0.2) Tsai and Wadden, Obesity, 2006 3
COMPARISON OF ATKINS, ORNISH, WEIGHT WATCHERS, AND ZONE 160 patients, randomly assigned Intention to treat at 1 year Atkins Ornish WW Zone Wt Loss (kg) 2.1 3.3 3.0 3.2 Completers (%) 53 50 65 65 Completers at 1 year Atkins Ornish WW Zone Wt Loss (kg) 3.9 6.6 4.6 4.9 COMPARISON OF ATKINS, ORNISH, WEIGHT WATCHERS, AND ZONE Weight loss associated with adherence, but not diet type Each group: 25% lost 5%, 10% lost 10% of initial weight Each diet reduced LDL/HDL by 10% No significant effects on BP or glucose CRP and insulin reductions associated with weight loss, but not diet Dansinger, JAMA 2005 Dansinger, JAMA, 2005 COMPARISON OF ATKINS, ZONE, ORNISH, AND LEARN 311 patients, randomly assigned Intention to treat at 1 year Atkins Zone LEARN Ornish Wt Loss (kg) 4.7 * 1.6 2.6 2.2 LDL-C (mg/dl) 0.8 0.0 0.6-3.8 HDL-C (mg/dl) 4.9* 2.2 2.8 0.0 Glucose (mg/dl) -1.8-1.6 0.5-0.8 SBP (mm Hg) -7.6* -3.3-3.1-1.9 DBP (mm Hg) -4.4* -2.1-2.2-0.7 40 yo woman, BMI 36. Motivated to begin diet therapy. Which of the following is contraindicated: 1. Meal replacement, very low calorie diet 2 Atkins diet 3 Ornish diet 4. Zone diet 5. All are contraindicated 6. None are contraindicated * p < 0.5 Gardner, JAMA 2007 4
EXERCISE FOR OBESITY Meta-analysis analysis of 43 RCTs: : 3476 participants Exercise vs no Rx small weight losses Exercise plus diet vs diet alone -1.1 kg Increased intensity of exercise -1.5 kg Exercise without weight loss -BP, -TG, -FBS Shaw, Cochrane, 2006 FITNESS AND MORTALITY Aerobics Center Longitudinal Study 25,714 men, 44 years old, 14 year observational study CV death (RR) normal overweight obese Fit 1.0 1.5 1.6 Not fit 3.1 4.5 5.0 Total death (RR) normal overweight obese Fit 1.0 1.1 1.1 Not fit 2.2 2.5 3.1 Wei, JAMA 1999 CVD MORTALITY AND METABOLIC SYNDROME 19,173 men from the ACLS study CVD Mortality Fitness adjusted RR Normal weight Healthy 1.00 1.00 Metabolic Syn 2.06 1.60 Overweight Healthy 1.27 1.00 Metabolic Syn 1.80 1.19 Obese Healthy 2.70 1.59 Metabolic Syn 2.83 1.43 PEDOMETERS INCREASE PHYSICAL ACTIVITY Meta-analysis analysis of 26 Studies: 2767 participants RCTS (8): Pedometer users increased 2491 steps Observational studies (18) Pedometer users increased 2183 steps Overall: 26.9% increase in steps Goal (10,000 steps per day) important predictor) BMI decreased 0.38; BP decreased 3.8 mmhg Katzmarzyk, Diabetes Care, 2005 Bravata, JAMA 2007 5
40 yo woman, BMI 33. Which abnormality best predicts 10 year all cause mortality? 1. Waist circumference: 36 inches 2 Fasting blood sugar: 110 3 Systolic BP: 140 4. Triglycerides: 185 5. Exercise test: early stage 2 (fatigue) 40 yo woman, BMI 36. Much to your surprise (and satisfaction), she has lost 35 pounds. In order to maintain her new weight, her lifelong daily calorie intake should be: 1. 2000 kcals 2 1800 kcals 3 1600 kcals 4. 1400 kcals 5. 1200 kcals SUCCESSFUL WEIGHT LOSS MAINTENANCE 3000 subjects in National Weight Control Registry: 30-lb weight loss for 1-year Average weight loss 33 kg (10 BMI units less), average weight maintenance 5.5 years 45 years old, 80% women, 97% Caucasian 46% overweight as child, 46% one parent obese, 27% both parents SUCCESSFUL WEIGHT LOSS MAINTENANCE High levels of physical activity Women 2545 kcal/week, men 3293 kcal/week (1-hour moderate intensity per day Only 9% report no physical activity Diet low in fat, high in carbohydrate 1381 kcal day, 24% fat, 19% protein, 56% CHO 4.87 meals or snacks/day Fast food 0.74/week Regular self-monitoring of weight 44% weigh once per day; 31% once per week Wing, Am J Clin Nutr, 2005 Wing, Am J Clin Nutr, 2005 6
40 yo woman, BMI 36. Much to your surprise, she has lost 35 pounds. In order to maintain her new weight, her lifelong daily calorie intake should be: 1. 2000 kcals 2 1800 kcals 3 1600 kcals 4. 1400 kcals 5. 1200 kcals GOALS OF MANAGEMENT Be as fit as possible at current weight Prevent further weight gain If successful at 1 and 2, begin weight loss BEHAVIOR THERAPY Key elements Goal setting Self-monitoring Stimulus control Cognitive skills BEHAVIOR THERAPY Meta-Analysis of 36 Studies Behavioral vs placebo -2.5 kg more weight lost Behavior plus diet and exercise Better in 5 of 6 studies -4.9 kg more weight lost Fabricatore, J Am Diet Assoc, 2007 Shaw, Cochrane Database, 2005 7
In the last year, I have prescribed a medication for weight loss. The medication I most commonly prescribe for weight loss is: 1. Yes 2 No 1. Phentermine 2. Sibutramine 3. Orlistat 4. Topiramate 5. Exenatide 6. Other LONG TERM PHARMACOTHERAPY OF OBESITY Review of all RCT s more than 36 weeks published since 1960 Weight loss in excess of placebo: % of initial kg s Phen-fen 11.0% 9.6 kg Phentermine 8.1% 7.9 kg Sibutramine 5.0% 4.3 kg Orlistat 3.4% 3.4 kg Dexfenfluramine 3.0% 2.5 Kg Fluoxetine -0.4% -0.4 kg Diethyproprion -1.5% -1.5 kg Glazer, Arch Int Med 2001 OFF-LABEL USE Buproprion NA re-uptake inhibitor RCT of 327 obese pts, 24 weeks; Wt. loss: 2% placebo vs. 5% in 300/400 mg Metformin Wt loss: -2 kg with drug vs. -0 kg with placebo vs. -4 kg with lifestyle in DPP Exenatide (Byetta) - Wt loss: -4-5 kg in open label study at 80+ weeks 8
RIMONABANT Meta-analysis of 4 studies Rimonobant plus diet vs diet alone, for 1 year or more Rimonabant 20-4.9 kg loss (5%) Improved waist circ, BP, HDL, TG Attrition 40%: GI, psychiatric, neuro Rimonobant 5 mg -1.3 kg loss RIMONABANT June 2007 FDA advisory committee recommends that rimonabant not be sold in the US pending further study of depression and suicidality. Sanofi withdraws bid to sell rimonabant in US Curioni, Cochrane, 2006 RIMONABANT AND CAD: The STRADIVARIUS Trial 839 patients, randomly assigned, 18 months f/u Rimonabant Placebo p Weight (kg) -4.3-0.5.001 PAV % +0.25 +0.51.22 TAV mm 3-2.2 +0.88.03 Psych effects 43.4 28.4.001 PRINCIPLES OF DRUG THERAPY NIH: BMI > 30 kg/m 2 or 27 kg/m 2 with co-morbidity (but in practice almost never) Motivated to begin structured exercise and low calorie diet Begin medications at completion of one month successful diet and exercise Continue medications only if additional weight loss achieved in first month with meds Nissen, JAMA 2008 9
Wouldn t It Be Easier Just To Have Surgery? In the last year, I have referred a patient for weight loss surgery. 1. Yes 2 No 57 yo woman, BMI 42 with diabetes, hypertension, and creatinine 1.4 asks about bariatric surgery. Her risk of mortality 30 days post-op is 1. 1 in 200 2. 1 in 100 3. 1 in 50 4. 1 in 25 5. 1 in 10 Who s Getting Surgery? Approved by most payers; cost effective Recent review indicates more surgeries done in: women those with private insurance those living in wealthier zip codes Santry HP JAMA 2005 10
Restrictive Types of Surgery Horizontal Gastroplasties Vertical Banded Gastroplasty (VGB) Silastic Ring Vertical Gastroplasty (SRVG) Adjustable Lap-Band Malabsorptive Jejunoileal Bypass (JIB) Biliopancreatic Diversion (BPD) Duodenal Switch Long Limb Gastric Bypass BANDING VS. CONVENTIONAL THERAPY FOR DIABETES RCT of 60 patients. 55 completed 2 year follow-up Banding Conventional p Remission 22 (73%) 4 (13%).001 Weight Loss 20.7% 1.7%.001 HbA1 6.00 7.21.001 Restrictive with Malabsorptive Component Roux-en-Y Gastric Bypass (RYGPB) Dixon, JAMA 2008 BARIATRIC SURGERY META-ANALYSIS Review of bariatric surgery (136 studies), 1990-2003, 22,092 patients weight loss (kgs) BMI decrease % excess weight loss Total -39.71-14.20-61.23 Gastric Banding -28.64-10.43-47.45 Gastric Bypass -43.48-16.70-61.56 Gastroplasty -39.82-14.20-68.17 Biliopancreatic diversion or duodenal switch -46.39-17.99-70.12 Buchwald, JAMA, 2004 % Resolution Comorbidity 100 90 80 70 60 50 40 30 20 10 0 Resolution of Comorbidities Bariatric Surgery A Systematic Review and Meta-analysis Buchwald H. et al. JAMA. 2004; 292(14):1724-37 Diabetes Hyperlipidemia HTN Sleep apnea Band VBG GBP D Switch 11
BARIATRIC SURGERY META-ANALYSIS Mortality Rate After Bariatric Surgery Review of bariatric surgery (136 studies), 22,092 patients Operative Mortality Gastric Banding 0.1% Gastric Bypass 0.5% Gastroplasty 0.1% Biliopancreatic diversion or duodenal switch 1.1% Buchwald, JAMA, 2004 Flum, JAMA 2005. 57 yo woman, BMI 42 with diabetes, hypertension, and creatinine 1.4 asks about bariatric surgery. Her risk of mortality 30 days post-op is 1. 1 in 200 2. 1 in 100 3. 1 in 50 4. 1 in 25 5. 1 in 10 Bariatric Surgery and Mortality Swedish Obese Subjects Study 4047 subjects, surgery vs. matched control. 10.9 years f/u Max weight loss % Final weight loss % Control 2 Gastric bypass 32 25 Vertical banded Gastroplasty 25 16 Banding 20 14 Sjostrom, NEJM, 2007 12
Bariatric Surgery and Mortality Swedish Obese Subjects Study Bariatric Surgery and Mortality Retrospective Cohort, Utah Surgical Practice Deaths HR Rate MI deaths Cancer deaths Control 129 0.063 25 47 Surgery 101 0.76 0.050 13 29 (p = 0.04) NNT 77 over 11 years (approx 850 per year) 9949 patients with surgery and 9628 who applied for drivers license, 7.1 years follow-up Deaths HR Rate CV deaths Cancer deaths Control 321 0.0057 104 73 Surgery 213 0.60 0.0037 55 31 (p = 0.001) NNT 513 over 7 years (approx 3600 per year) Sjostrom, NEJM, 2007 Adams, NEJM, 2007 The Magic Formula 13