CLINICAL DILEMMAS IN OBESITY MANAGEMENT Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine Declaration of full disclosure: No conflict of interest

Case 1 50 year old woman, in good health, no history of cigarettes, in for check up. BMI 29. Should you tell her she is overweight? What further assessment and treatment should you begin?

CLASSIFICATION OF OVERWEIGHT AND OBESITY BY BMI Obesity Class BMI (kg/m2) 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

BMI AND MORTALITY: Overall Combined NHANES I, II, and III data set BMI 25-59 y 60-69 y ≥70 y <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

An Office-Based Approach Make the diagnosis (and communicate it) Assess readiness for change Prescribe diet and exercise Consider medications and surgery

HEALTH PROFESSIONAL ADVICE AND WEIGHT LOSS 12,835 adults, BMI over 30 kg/m2, check-up in last year Random-digit, population-based sample, 50 states 42% told by health professional to lose weight Those told to lose weight more likely to report trying to lose weight: OR 2.79 (95% CI 2.53-3.08)

INTENTIONAL WEIGHT LOSS AND DEATH Prospective CDC cohort study, 6391 adults, followed for 9 years Those reporting intentional weight loss had 24% reduction in mortality Those reporting unintentional weight loss had 31% higher mortality Those reporting attempted but unsuccessful weight loss also had 20% reduction in mortality Gregg, Ann Int Med 2003

METABOLIC SYNDROME Fulfill 3 or more criteria: Waist: men > 102 cm ( > 40 in); women > 88 cm ( > 35 in) HDL: men < 40; women < 50 Triglycerides: ≥150 mg/dl BP: ≥130/85 (or use of medications) Fasting glucose: ≥110 mg/dl ICD-9: 277.7 NCEP, JAMA 2001

GOALS OF MANAGEMENT Be as fit as possible at current weight Prevent further weight gain If successful at 1 and 2, begin weight loss

Case 2 50 year old woman, in good health, in for check up. BMI 32 with metabolic syndrome. She says, “ I have to lose weight, and I am planning on doing that. I am about to try the South Beach diet.”

DIET THERAPY 48 RCT’S Average weight loss 8% over 3-12 months

VLCD’s vs LCD’s: Meta-analysis of 29 U.S. Studies Weight loss studies with > two year f/u 13 VLCDs, 14 LCDs Mostly observational studies (few RCT’s) Weight loss (as % of initial weight): 1y 2y 3y 4y 5y LCDs 7.2 4.2 3.5 2.8 2.0 VLCDs 16.1 9.7 7.8 7.0 6.2 Anderson, Am J Clin Nutr, 2001

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 Wt Loss (kg) 3.9 6.6 4.6 4.9 Dansinger, JAMA 2005

COMPARISON OF ATKINS, ORNISH, WEIGHT WATCHERS, AND ZONE 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 Weight loss associated with adherence, but not diet type CRP and insulin reductions associated with weight loss, but not diet Dansinger, JAMA, 2005

DIET APPROACHES Diets low cal (low fat, low carbohydrate), meal replacement Commercial programs Weight Watchers™, Jenny Craig™, TOPS™, Overeaters Anonymous™, Nutrisystem.com,™ Shapedown,™ The Solution™ Internet programs (by RDs) Fitday.com, Dietwatch.com, Cyberdiet.com, eDiets.com, Shapeup.org

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

FITNESS AND OBESITY Nurses Health Study Total death (RR) normal overweight Active 1.00 1.91 Not active 1.55 2.42 116,564 women, 24 year observational study Hu FB, NEJM 2004

SUCCESSFUL WEIGHT LOSS MAINTENANCE 3000 subjects in National Weight Control Registry: 30-lb weight loss for 1-year Average weight loss 30kg (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 Wing and Hill, Ann Rev Nutr, 2001

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 and Hill, Ann Rev Nutr, 2001

Case 3 46 year old woman, in good health, in for check up. BMI 42 with diabetes. In 1996 she lost 20 pounds on phen-fen. She wants a new weight loss drug and a referral for weight loss surgery.

“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

SIBUTRAMINE ALONE AND WITH LIFESTYLE MODIFICATION Figure 2. Mean ({+/-}SE) Weight Loss in the Four Groups, as Determined by an Intention-to-Treat Analysis (Panel A) and a Last-Observation-Carried-Forward Analysis (Panel B). Subjects who received combined therapy lost significantly more weight at all times than subjects in the other three groups. Subjects treated with lifestyle modification alone and those treated with sibutramine plus brief therapy lost significantly more weight at week 18 than those who received sibutramine alone, with no other significant differences at any other time. Panel B shows that a last-observation-carried-forward analysis yielded the same statistical conclusions. Wadden, T. A. et al. N Engl J Med 2005;353:2111-2120

OFF-LABEL USE Sertraline – SSRI More selective 5-HT uptake inhibitor In Phase III trials now Buproprion – NA re-uptake inhibitor RCT of 327 obese pts, 24 weeks; Wt. loss: 2% placebo vs. 5% in 300/400 mg Topiramate – CA inhibitor RCT in 385 obese pts; dose-ranging; 24 wks Wt loss: -2.6% placebo vs. -5 to -6% w/drug Topiramate: weak carbonic anhydrase inhibitor; modulates the GABA receptors – approved as an anti-epileptic drug; Unclear mechanism that contributes to weight loss effects.

OTHER DRUGS OFF-LABEL Amantadine Other SSRIs (fuvoxamine, venlafaxine, citalopram, others) H2 blockers (cimetidine) 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 Zonisamide – antiepileptic Wt loss: -5.9 kg with drug vs. 0.9 kg with placebo Topiramate: weak carbonic anhydrase inhibitor; modulates the GABA receptors – approved as an anti-epileptic drug; Unclear mechanism that contributes to weight loss effects.

RIMONABANT (Acomplia™) 1,507 severely obese people, Europe, 2-years (2005) rimonabant 7.3 kg loss placebo 2.5 kg loss 3,040 obese people, US, 2-years (2004) rimonabant 7.6 kg loss placebo 2.3 kg loss

Change From Baseline, kg Year 1 Body Weight Placebo 5 mg of Rimonabant 20 mg of Rimonabant Change From Baseline, kg 12 24 36 52 Weeks

Change From Baseline, kg Year 2 Body Weight Placebo/Placebo 20 mg rimonabant/Placebo 20 mg rimonabant/20 mg Change From Baseline, kg 52 60 68 76 84 92 104 Weeks

RIMONABANT (Acomplia™) Side Effects Nausea: 13.7% with drug vs. 5.5% on placebo Dizziness: double with drug Diarrhea: double with drug Depression: 2.8% vs. 1.6% Drop outs: 19% with drug vs. 13% with placebo

PRINCIPLES OF DRUG THERAPY NIH: BMI > 30 kg/m2 or 27 kg/m2 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

Wouldn’t It Be Easier Just To Have Surgery?

National Trends in Annual Numbers of Bariatric Procedures, 1998-2003 Data based on nationwide inpatient sample Projection based on preliminary data from 12 states for 2003 No. of Procedures 1998 1999 2000 2001 2002 2003 Year Error bars indicate 95% confidence intervals

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 et al JAMA 2005;294:1909

Types of Surgery Restrictive Malabsorptive Horizontal Gastroplasties Vertical Banded Gastroplasty (VGB) Silastic Ring Vertical Gastroplasty (SRVG) Adjustable Gastric Banding Malabsorptive Jejunoileal Bypass (JIB) Biliopancreatic Diversion (BPD) Duodenal Switch Long Limb Gastric Bypass Restrictive with Malabsorptive Component Roux-en-Y Gastric Bypass (RYGPB)

Restrictive Procedures Adjustable Gastric Banding VBG Adjustable Gastric Banding Roux-en-Y GB

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 of Comorbidities

BARIATRIC SURGERY META-ANALYSIS 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

Mortality Rate After Bariatric Surgery Flum, D. R. et al. JAMA 2005;294:1903-1908. .

Survival After Bariatric Surgery by Age Group Flum, D. R. et al. JAMA 2005;294:1903-1908.

LACK OF METABOLIC EFFECTS OF LIPOSUCTION 15 women, before and after liposuction (8 with normal glucose tolerance, 7 with diabetes) Weight loss: 9.1 kg (NLs) and 10.5kg (DM) No change in insulin sensitivity of muscle, liver, or adipose tissue No change in C-reactive protein, IL-6, TNF alpha or adiponectin No change BP, glucose, insulin, lipids Klein, NEJM 2004

The Magic Formula