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Obesity update Internal Medicine Review Columbia University August 12, 2010 Judith Korner, MD, PhD Assistant Professor, Department of Medicine College of Physicians & Surgeons Director, Weight Control Center Columbia University Medical Center Obesity Trends* Among U.S. Adults BRFSS, 1991, 1996, 2004 (*BMI 30, or about 30 lbs overweight for 5’4” person) 1991 1996 2004 No Data <10% 10%–14% 15%–19% 20%–24% ≥25% Medical Complications of Obesity Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Gall bladder disease Idiopathic intracranial hypertension Stroke Cataracts Coronary heart disease Diabetes Dyslipidemia Hypertension GERD Severe pancreatitis Gynecologic abnormalities Cancer abnormal menses infertility polycystic ovarian syndrome breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Osteoarthritis Skin Gout Phlebitis venous stasis Age-Adjusted Relative Risk Relationship Between BMI and Risk of Type 2 Diabetes 93.2 100 Men Women 75 54.0 50 42.1 40.3 27.6 21.3 25 1.0 2.9 1.0 4.3 1.0 5.0 1.5 <23 23 23.9 24 24.9 8.1 2.2 15.8 25 26.9 27 28.9 4.4 6.7 11.6 0 <22 29 30.9 31 32.9 33 34.9 35+ Body Mass index (kg/m2) Chan J et al. Diabetes Care 1994;17:961. Colditz G et al. Ann Intern Med 1995;122:481. Slide Source: www.obesityonline.org Relationship Between Weight Gain in Adulthood and Risk of Type 2 Diabetes Mellitus 6 Men Relative Risk 5 Women 4 3 2 1 0 -10 -5 0 5 10 15 20 Weight Change (kg) Willett et al. N Engl J Med 1999;341:427. Slide Source: www.obesityonline.org Relationship Between BMI and Cardiovascular Disease Mortality Relative Risk of Death 3.0 Men 2.6 Women 2.2 1.8 1.4 1.0 Lean Overweight Obese 0.6 <18.5 18.5 – 20.4 20.5 – 21.9 22.0 – 23.4 23.5 – 24.9 25.0 – 26.4 26.5 – 27.9 28.0 – 29.9 30.0 – 31.9 32.0 – 34.9 35.0 >40.0 – 39.9 Body Mass index Calle et al. N Engl J Med 1999;341:1097. Slide Source: www.obesityonline.org Relationship Between BMI and Comorbidities is Positive, Even in the “Normal” Range Men Women 6 6 5 5 4 4 3 3 2 2 1 1 0 0 <21 22 Type 2 diabetes Cholelithiasis Hypertension Coronary heart disease 23 24 25 26 27 28 29 Body Mass Index (kg/m2) Willett WC, et al. N Engl J Med. 1999;341:427-434. 30 <21 22 23 24 25 26 27 28 Body Mass Index (kg/m2) 29 30 Physical Exam •Vitals (use appropriate size BP cuff ) •Height, Weight, Calculate BMI (kg/m2) wt (lb) x 703 ht (in2) Overweight ≥ 25 Obese ≥ 30 •Measure waist circumference (>35 inches for women; >40 inches for men) •Skin changes: acanthosis nigricans, pigmented striae How to Measure Waist Circumference ● Place a measuring tape, held parallel to the floor, around the patient’s abdomen at the level of the iliac crest ● The tape should fit snugly around the waist without compressing the skin ● Take the measurement at the end of a normal expiration A waist circumference of ≥40 inches in men or ≥35 inches in women is diagnostic of abdominal obesity and suggests the presence of other cardiometabolic risk factors. Adapted from Grundy SM, et al. Circulation. 2005;112:2735-2752. 9 Laboratory Tests •Biochemistry Profile •Thyroid Profile •Lipid Profile •Fasting Insulin and Glucose Consider insulin resistance if insulin > 10U/ml or glucose is >95 mg/dl •EKG •If clinical suspicion of Cushing’s - 24 hr UFC •If clinical suspicion of PCOS - androgen profile •If clinical suspicion of sleep apnea - sleep study Initiating a Discussion about Weight What’s in a Name? Patients’ Preferred Terms for Describing Obesity • “Imagine you are visiting your doctor for a check up. The nurse has measured your weight and found that you are at least 50 pounds over your recommended weight.” • “Please indicate how desirable or undesirable you would find each of the following terms if your doctor used it to describe your weight.” Wadden Obesity Res 11, 2003 Wadden, Obes Res 11:1140 Initiating a Discussion • “Ms. Jones, could we talk for a moment about your weight?” • “Tell me your thoughts about your weight at this time. I know how hard you’ve worked in the past to control it. What are your goals now?” as opposed to • The “call-it-what-it-is” approach which fails to recognize the offensive, derogatory manner in which the terms fatness and obesity are used by the public. Wadden Obesity Res 11, 2003 Setting Realistic Goals Realistic Goals • Moderate weight loss: 5-10% reduction in body weight over 6-12 months • Weight loss of this magnitude significantly decreases the severity of obesity-associated risk factors NIH/NHLBI, Obes Res 1998 Forget about Barbie • Barbie’s projected human measurements: 39-18-33 • Average white woman: age 18-25: 38-32-41 age 36-45: 41-34-43 Goal Weight Loss Defined by Subjects •Dream •Happy •Acceptable •Disappointed % Reduction 38% 31% 25% 17% •Average goal weight reduction was 32% Cornerstone of Weight Loss Treatment • Behavior Therapy, Diet, Exercise Behavior Therapy • Self-monitoring includes recording dietary intake (food choices, amounts, times), exercise and changes in body weight. • Stimulus control - identify and change cues that are associated with eating too much and exercising too little. For example, limiting exposure to food or separating eating from other activities such as reading or watching television. • Reinforcement encourages attainment of difficult to achieve goals. Reinforcement may come from a social support network or getting nonfood rewards for reaching goals. • Stress management helps coping with stressful events by developing outlets besides eating for reducing stress. Evaluating setbacks and determining how to do better next time can break the chain of negative thinking and self-punishment when lapses occur. Diet • Whatever works, but is healthy. Don’t be afraid to try different approaches. – – – – Low glycemic diets may reduce appetite (Ludwig DS) Low calorie density foods enhance satiety with fewer calories (Rolls B) Less palatable foods reduce calorie intake Structure helps • Liquid meal replacements • Prepackaged food Long-Term Weight Loss: Non-Pharmacologic Treatment VLCD: ≤800 kcal/day BMOD: behavior + 1200kcal/day Combined: VLCD + behavior Wadden Annals of Int Med 119:688 1993 Weight Loss Treatment • Behavior Therapy, Diet, Exercise • Pharmacotherpy: BMI 30, or 27 and 2 co-morbidities Mechanisms of Action: Sibutramine and Active Metabolites Block Serotonin, Norepinephrine, and Dopamine Reuptake MAO S S REUPTAKE Serotonin S S Release MAO S S REUPTAKE Norepinephrine Release S S S = sibutramine = norepinephrine, = serotonin Adapted from Ryan et al. Obesity Res. 1995;3(suppl 4):553S-559S. Sibutramine: Efficacy Mean Weight Change in 1 Year Trial 0 -2 Placebo (n = 76) Mean -4 Weight Change -6 (%) * * -8 10 mg qd (n = 79) 15 mg qd (n = 93) -10 0 1 2 3 4 5 6 7 8 Treatment Month *P < 0.01 vs placebo. Bray et al, Obes Res 1996;4:263-270 9 10 11 12 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) Wadden, T. et al. N Engl J Med 2005;353:2111-2120 Proportion of patients who maintained 5% and 10% weight loss from baseline on sibutramine 5% Responders 6 12 18 24 10% Responders MONTH 6 12 James PT et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet 2000; 356: 2119–25 18 24 Sibutramine: Safety – Adverse events: Headaches, constipation, fatigue, dry mouth most common – Vital signs: Potentially clinically significant blood pressure increases (1/12) – Contraindicated in patients with uncontrolled hypertension, coronary heart disease, other vascular disease or co-administration with SSRIs or MAOIs. – Pulmonary hypertension and valvular heart disease, associated with fenfluramines, not reuptake inhibitors Orlistat Mechanism of Action 30% of fat not absorbed Weight Change Over 104 Weeks Weight Loss (%) Placebo Orlistat 0 Diet Hypocaloric Eucaloric -4.5% -5 -8.1%* -10 -13 0 15 30 *P < 0.05 (vs placebo). Sjöström L, et al. Lancet. 1998;352:167-172. 45 60 Week 75 90 104 Orlistat Safety • The most common side effects include abdominal discomfort, oily spotting, flatuence with discharge, fecal urgency and incontinence. • Absorption of fat-soluble vitamins and some medications (eg. cycolsporine) may be affected. Noradrenergic Agents • Schedule IV drugs have a low potential for abuse • Phentermine (Adipex-P, Fastin): 18.75-37.5 mg/day • Phentermine resin (Ionamin): 15-30 mg/day • Diethylpropion (Tenuate, Tenuate Dospan): 25 mg 3x/day or sustained release 75 mg/day • Phenylpropanolamine (Dexatrim, Acutrim): withdrawn from market due to association with hemorrhagic stroke Yanovski NEJM 346:591 2002 Noradrenergic Agents (cont’d) • Approved by the FDA for short-term use: ~ 3 months • Studies show between 2-10 kg weight loss over placebo • Side effects: insomnia, dry mouth, constipation, euphoria, palpitations, hypertension R. Steinbrook, NEJM 350, 2004 Other Options for Weight Loss • Metformin • Review patient’s medications and consider alternatives Diabetes Prevention Program Research Group Does lifestyle intervention or administration of metformin prevent or delay the development of diabetes? Eligibility Criteria •3234 nondiabetic persons •Elevated fasting glucose (95-125 mg/dl) and •Elevated glucose 2h after 75g glucose load (140-199 mg/dl) •BMI ≥ 24 (≥ 22 in Asians) NEJM 346:393 2002 Average Wt Loss Placebo: 0.1 kg Metformin: 2.1 kg Lifestyle: 5.6 kg 50% ≥7% at 24 wk 38% ≥ 7% at most recent visit Decrease in daily energy intake Placebo: 249 kcal Metformin: 296 kcal Lifestyle: 450 kcal Diabetes Prevention Program Research Group Cumulative Incidence of Diabetes (%) Placebo Metformin Lifestyle Year Reduction in Incidence Compared with Placebo Metformin: 31% LifeStyle: 58% Number needed to treat for 3 y to prevent 1 case of DM Metformin: 13.9 NEJM 346: 393 2002 Lifestyle: 6.9 Impact of Anti-Diabetic Therapies on Weight GAIN NEUTRAL Sulfonylurea Glinide TZDs Metformin Insulin DPP4-Inhibitor LOSS GLP-1 agonist Alpha-Glucosidase Pramlintide Inhibitor Nathan et al Diabetes Care 31:1-11, 2008 CNS Drug-Induced Weight Gain Drugs that May Promote Weight Gain Antidepressants – Paroxetine – Mirtazapine – MAOIs, TCAs Antiepileptic drugs – Valproate – Gabapentin Antipsychotics – Clozapine, olanzapine, risperidone, quetiapine Lithium Drugs that Cause Little or No Weight Gain or Weight Loss Antidepressants – Bupropion – Venlafaxine Antiepileptic drugs – Topiramate – Lamotrigine – Zonisamide Antipsychotics – Ziprasidone – Aripiprazole MAOIs = monoamine oxidase inhibitors; TCAs = tricyclic antidepressants. Different Long-Term Effects of SSRIs on Body Weight * 3 2 1 Paroxetine (n = 47) Sertraline (n = 48) Fluoxetine (n = 44) 30 †P = .015 †P < .001 0 % Incidence of >7% Weight Gain Mean % Change in Body Weight 4 -1 25 20 15 10 5 †P †P < .003 0 Analysis is for treatment responders *P < .001 compared to baseline, †P-values for comparison to paroxetine Fava M, et al. J Clin Psychiatry. 2000;61:863-7. < .016 Efficacy of topiramate for weight loss in obese individuals: randomized double-blind placebocontrolled multicenter trial Bray et al, Obesity Research, (2003) 11:722 Adverse Events with Topiramate • Events were dose related and reversible after treatment was stopped • Paresthesia • Psychomotor slowing • Difficulty concentrating • Fatigue • Somnolence A look into the future… Sibutramine: Efficacy Mean Weight Change in 1 Year Trial 0 -2 Placebo (n = 76) Mean -4 Weight Change -6 (%) -8 * * 10 mg qd (n = 79) 15 mg qd (n = 93) Why not ? -10 0 1 2 3 4 5 6 Treatment *P < 0.01 vs placebo. Data on file, Knoll Pharmaceutical Company. 7 8 Month 9 10 11 12 Model of a weight-regulating feedback system Hypothalamus Vagus Nerve Autonomic Nervous System External Factors food availability, palatability Gut and Liver Insulin Pancreas Leptin Adipose Tissue Adrenal Steroids Adrenal Cortex Aronne LJ. Adapted from Campfield LA, et al. Science. 1998;280: Meal Size Energy Balance and Adipose Stores Food Intake Energy Expenditure 1383-1387; and Porte D, et al. Diabetologia. 1998;41:863-881. Combination Therapies Topiramate + Phentermine Zonisamide + Buproprion Bupropion + Naltrexone Leptin + Pramlintide Behavioral Mechanisms: Is Extreme Ravenousness Required? 2 oz chocolate bar 20 oz cola Total = = = 260 kcal 252 kcal 512 kcal Weight gain: 1 lb/week Forbes GB, et al. Br J Nutr. 1986;56:1-9. Allison DB, et al. Am J Psychiatry. 1999;156:1686-96. Disparagement of obese individuals is “the last socially acceptable form of prejudice.” Stunkard and Sobal, 1995