1 Mechanick JI, Garber AJ, Handelsman Y, Garvey WT. Endocr Pract. 2012;18: Depression. Cancer. Gallbladder Disease

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1 Percent Obese Overweight Extremely obese Note: Age-adjusted by the direct method to the year 2 US Bureau of the Census using age groups 2 39, 4 59, and 6 74 years. Pregnant females excluded. Overweight defined as 25 BMI < 3; obesity defines BMI 3; extreme obesity defines as BMI 4. Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey (NHANES) data. 1. It is the strong contention of AACE that the view of obesity as a behavioral decision is debunked by biomedical evidence. 2. obesity is a primary disease, and the full force of our medical knowledge should be brought to bear on the prevention and treatment of obesity as a primary disease entity. 3. obesity is an altered physiological and metabolic state, with genetic, environmental, and behavioral determinants, which results in increased morbidity and mortality. 1 Mechanick JI, Garber AJ, Handelsman Y, Garvey WT. Endocr Pract. 212;18:642. Equilibrium Weight Weight Loss Gene 1 Gene 2 Baseline weight 25 lbs Weight Gain Garvey WT, 213 Environment & Behavior Individuals with Disease Ghrelin Leptin, PYY, CCK, Amylin Resting energy expenditure Hunger Calorie-dense food preferences Increased Appetite Decreased Energy Out Increased Energy In Garvey WT, 214 RISK FACTOR DEFINING LEVEL I. Waist Circumference men >12 cm (4 in) women >88 cm (35 in) II. Triglycerides 15 mg/dl III. HDL Cholesterol men <4 mg/dl women <5 mg/dl IV. Blood Pressure 13/ 85 mm Hg V. Fasting Glucose 1 mg/dl Depression Obesity PCOS: Polycystic ovary syndrome; NAFLD: Non-alcoholic fatty liver disease Grundy SM et al, Circulation. 24;19: Daniel S, Soleymani T, Garvey WT. Curr Opin Endocrinol Diabetes Obes, 2: , 213 Cancer Gallbladder Disease Medical Complications of Obesity Other Complications NAFLD Dyslipidemia Prediabetic States Diabetes CVD Hypertension PCOS Cardiometabolic Disease BioMechanical Complications Sleep Apnea Osteoarthritis Stress Incontinence GERD Dismobility/ Disability 1

2 BMI and weight history Waist circumference Blood pressure Laboratory values Fasting blood glucose Lipid parameters (TG, HDL-c, LDL-c) Role of 2-hour OGTT and HbA1c In addition to: Family History, Past medical history, ROS, Medications, Smoking, etc OGTT, oral glucose tolerance test; TG, triglycerides; ROS, review of systems Incidence of Diabetes Per 1 Person-Years Waist Circumference (cm) Solid lines pertain to values between the race-specific 5th and 95th percentiles of waist circumference. Dotted lines are extrapolated values outside the race-specific ranges. Adjusted for age, sex, education, and income. Lutsey PL et al. Am J Epidemiol. 21;172(2): Chinese 12 Hispanic Black White 13 Locate upper hip bone and top of right iliac crest Place measuring tape around abdomen at level of iliac crest, keeping it parallel to the floor Ensure tape is snug but not compressing the skin Reduce energy intake by 5-1, kcal/d Reduce portion size, fat, and sugar Meal replacements (CWL) Exercise 15 min/wk (DPP) 175 min/wk (Look AHEAD) Record food intake, physical activity, and weight Accessed October 14, 213. Diabetes Prevention Program Research Group. N Engl J Med. 22;346:3933. Look AHEAD Research Group. Obesity. 26;14: CWL, commercial weight loss. Set realistic goals for weight loss/behavior change: 5% weight loss in 3 months and reassess When 5%-1% weight loss achieved, enter maintenance Close follow-up with patient: visits/phone Provide tips for weight loss from National Weight Control Registry If no weight loss in 3 months, modify plan to include pharmacotherapy Three most popular, with an evidence base to evaluate Weight Watchers: low cost (as little as $12/wk); 2 diet options, expanded from classic points program; can choose between Web-based and group setting Nutrisystem: provides food and telephone counseling, ~$28-$37/mo, shelf-stable dry or frozen foods with supplemental fruits and vegetables Jenny Craig: provides food and in-person or telephone counseling, ~$5-$65/mo, shelf-stable dry or frozen foods with supplemental fruits and vegetables Diabetes Prevention Program Research Group. N Engl J Med. 22;346:3933. Look AHEAD Research Group. Obesity. 26;14:

3 All Participants Weight change (kg) Metformin Lifestyle Cumulative incidence (%) (n=182) Metformin (n=173) Lifestyle (n=179) Risk reduction 31% by metformin 58% by lifestyle Years from Randomization N= Years from randomization The DPP Research Group. N Engl J Med. 22;346:3933. The DPP Research Group. N Engl J Med. 22;346:3933. Incidence Rate per 1 Person-years Change in Weight From Baseline (kg) Reduction in initial weight (%) Look AHEAD Trial (N=5145) Diabetes support and education Intensive lifestyle intervention Retention at 4 years: ILI = 94.1% DSE = 93.1% Years -1.1% P<.1.7% Adapted from Hamman RF, et al. Diabetes Care. 26;29: ILI, intensive lifestyle intervention; DSE, diabetes support and education. Look AHEAD Research Group. Arch Intern Med. 21;17: Look AHEAD Trial (N=5145) At 1 year DSE ILI Weight loss (%) HbA1c (%) FPG (mg/dl) % on diabetes medications Systolic BP (mm Hg).8.8 Diastolic BP (mm Hg) LDL-C (mg/dl) HDL-C (mg/dl) TG (mg/dl) P.1, P=.1 vs customary support. BP, blood pressure; CV, cardiovascular; DSE, diabetes support and education; ILI, intensive lifestyle intervention; T2DM, type 2 diabetes mellitus. Look AHEAD Research Group. Diabetes Care. 27;3: Look AHEAD Research Group. Arch Intern Med. 21;17: It is difficult for patients to maintain their weight loss over time. weight loss (kg) -1 CHO/Pro/Fat -3 65/15/2% 55/25/2% -5 45/15/4% 35/25/4% months Sacks FS. et al. NEJM 29;36(9)

4 Adjunct to a lifestyle intervention program - includes reduced calorie diet Addition of a medication achieves greater weight loss than lifestyle intervention alone. Presence of obesity-related complications and need for more aggressive weight loss therapy. Helps sustain weight loss. Obesity requires long-term treatment and follow-up. ASBP, AACE and AHA/ACC/TOS Obesity Guidelines all advise use of medications for patients who have sufficient health risk Indications and Dose Indication: weight loss in patients with BMI 3 kg/m 2 or BMI 27 kg/m 2 with weightrelated comorbid condition(s) 12 mg po tid with meals Diet should not contain > 3% fat OTC preparation: Alli 6 mg tid and Warnings Pregnancy Chronic malabsorption Cholestasis Warnings Oxalate stones Take L-thyroxine or cyclosporine 3 hours apart from orlistat Risk of hypoglycemia with diabetes meds US FDA. Drugs@FDA. Patient monitoring Monitor glucose in patients who have hyperglycemia and/or diabetes Take multivitamin containing fat soluble vitamins Adverse events include oily spotting, flatus, fecal urgency, fecal incontinence Metamucil has been shown to reduce bowel effects Weight Change (kg) -3-9 Completers Data + lifestyle (n=564) Orlistat + lifestyle (n=85) Torgerson JS, et al. Diabetes Care. 24;27: Week.1 kg.9 kg P<.1 vs placebo Indications and Dose Indication: weight loss and Warnings in patients with BMI 3 kg/m 2 or BMI 27 Pregnancy kg/m 2 with weightrelated comorbid Coadministration with Warnings condition(s) other serotonergic or 1 mg po bid, schedule antidopaminergic pending (IV) agents Valvular heart disease Discontinue if 5% Cognitive impairment weight loss is not achieved in Psychiatric disorders (euphoria, suicidal 12 weeks thoughts, depression) Priapism Risk of hypoglycemia with diabetes meds Laboratory monitoring Monitor glucose in patients who have hyperglycemia and/or diabetes Adjust non-glucosedependent antihyperglycemic medications as needed US FDA. Drugs@FDA. Accessed August 7, 214. Smith SR et al. NEJM. 21;363: Endpoint Lorcaserin P value Waist circumference <.1 (cm) SBP/DBP (mm Hg) 1.4/ 1.1.8/.6.4/.1 Cholesterol (% Δ) Total LDL HDL Safety HR (beats/min) 2. Intention-to-Treat Beck depression Analysis II with LOCF Imputation 1.1 HOMA-IR, homeostasis model assessment of insulin resistance Smith SR et al. NEJM. 21;363: Triglycerides (%) <.1 HOMA-IR <

5 Lorcaserin Lorcaserin 1 mg BID 1 mg QD Baseline (n=248) (n=251) (n=93) Mean HbA1c (%) LS Mean HbA1c (%) Change in HbA1c BLOOM-DM Study -1 Patients Increasing Use of Antidiabetic Agents (%) Change in Diabetes Medications Lorcaserin Lorcaserin (n=248) 1 mg BID 1 mg QD (n=251) (n=95) P<.1 vs placebo. P=.87 vs placebo. BLOOM-DM, Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus. O Neil PM, et al. Obesity. 212;2: N (%) Lorcaserin (N=3195) (N=3185) Headache 537 (16.8) 321 (1.1) Dizziness 27 (8.5) 122 (3.8) Nausea 264 (8.3) 17 (5.3) Constipation 186 (5.8) 125 (3.9) Fatigue 229 (7.2) 114 (3.6) Dry mouth 169 (5.3) 74 (2.3) US FDA CDER Lorcaserin NDA May 2, 214. Indications and Dose Indication: weight loss in patients with BMI 3 kg/m 2 or BMI 27 kg/m 2 with weightrelated comorbid condition(s) Treatment dose daily: phentermine 7.5 mg/ topiramate ER 46 mg Maximum dose daily: phentermine 15 mg/ topiramate ER 92 mg and Warnings Pregnancy, glaucoma, hyperthyroidism, MAOIs Warnings Fetal toxicity Increased heart rate Suicide and mood and sleep disorders Acute myopia and glaucoma Cognitive impairment Metabolic acidosis Creatinine elevations Hypoglycemia with diabetes medications Laboratory Monitoring At baseline and periodically throughout - Bicarbonate - Potassium - Glucose MAOIs = monoamine oxidase inhibitors. US FDA. Drugs@FDA. Accessed August 7, 214. Doses are lower than Phentermine as single agent (3 mg) Topiramate for epilepsy or migraine prophylaxis (2 mg) Dosing (phentermine/topiramate ER): 3.75/23 mg q AM initiation dose X 2 weeks 7.5/46 mg treatment dose; If <3% weight loss after 12 weeks 15/92 mg full dose If <5% weight loss after 12 weeks, discontinue. US FDA. Drugs@FDA. Accessed August 7, 214. LS mean weight loss (kg) LOCF Weeks: n: PHEN/TPM CR 7.5/ n: PHEN/TPM CR 15/ n: PHEN/TPM CR 7.5/46 PHEN/TPM CR 15/92 Garvey WT et al. Am J Clin Nutr. 212;95(2): Variable Changes from baseline to week 56 in secondary endpoints Garvey WT et al. Am J Clin Nutr. 212;95(2): Phentermine Topiramate ER 7.5/46 mg P value Waist (cm) <.1 Systolic BP (mm Hg) Diastolic BP (mm Hg) Triglycerides (%) <.1 LDL C (%) HDL C (%) <.1 CRP (mg/l) <.1 Adiponectin (µg/ml) <.1 5

6 Cumulative Incidence Rate of Type 2 Diabetes PHEN/TPM ER 7.54/46 1 PHEN/TPM ER 15/ Weeks Garvey WT et al. Diabetes Care. 214;37: Percentage of Subjects Achieving HbA1c Goals HbA1c 7.% HbA1c 6.5% ( 53 mmol/mol) ( 48 mmol/mol) (n=55) PHEN/TPM ER 15/92 (n=75) P,.5 vs. placebo Garvey WT et al, Diabetes Care, epub Sept 23, Change in Dose/Number of Diabetes Meds Subjects (%) Decreased No. of Increased No. of Antidiabetic Medications Antidiabetic Medications 29.1 Adverse Event (%) (N=3749) PHEN/TP M ER Low PHEN/TP M ER Mid PHEN/TP M ER Top Paresthesia Dry mouth Constipation Dysgeusia Insomnia US FDA CDER Phentermine/TopiramateER (NDA) 2258 May 2, 214. Indications and Dose Indication: weight loss in patients with BMI 3 kg/m 2 or BMI 27 kg/m 2 with weight-related comorbid condition(s) Treatment dose is 8 mg naltrexone/9 mg bupropion given as 2 pills bid Begin with 1 pill each AM and escalate dose over 4 weeks to 2 pills bid Discontinue if 5% weight loss is not achieved in 12 weeks and Warnings Pregnancy Uncontrolled HTN Seizure Disorder Chronic opioid use MAOIs Warnings Angle closure glaucoma Suicidal behavior/ideation Increase BP and HR Seizures Risk of hypoglycemia with diabetes meds US FDA. Drugs@FDA. Laboratory monitoring Monitor glucose in patients who have hyperglycemia and/or diabetes Adjust non-glucosedependent antihyperglycemic medications as needed NOTE: high fat meal increases blood levels Weight Change From Baseline (%) P<.1 compared with placebo Greenway F et al. Lancet. 21;376(9741): % -5.6%.1% MITT, LOCF analysis Naltrexone SR 16 mg/bupropion SR 36 mg Naltrexone SR 32 mg/bupropion SR 36 mg Variable Waist (cm).2.5 <.1 Systolic BP (mm Hg) Diastolic BP (mm Hg) Pulse Rate (bpm).4-1. <.5 Triglycerides (%) <.1 LDL C (%) HDL C (%) 8..8 <.1 CRP (%) <.76 Fasting Changes insulin (%) from baseline to week in secondary.6 endpoints <.7 Greenway FL et al, Lancet 376:595, 21. Naltrexone/ Bupropion ER 32/36 mg P value 6

7 Adverse Event (%) (N=573) Naltrexone/Bupropion 32/36 mg Nausea Headache Constipation Dizziness Vomiting Dry mouth Hot flush Indications and Dose Indication: weight loss in patients with BMI 3 kg/m 2 or BMI 27 kg/m 2 with weight-related comorbid condition(s) Treatment dose for obesity is 3 mg daily at any time of day without regard to timing of meals. Initiate at.6 mg/day for 1 week; increase dose at weekly intervals until 3 mg. Not for use in combination with insulin or another GLP-1 RA and Warnings Pregnancy Personal or family history of MTC or MEN 2 Risk of thyroid C- cell tumors Acute pancreatitis Acute gallbladder disease Increased HR monitor Renal impairment Hypersensitivity Suicidal behavior and ideation Hypoglycemia Monitoring In pts with diabetes taking an insulin secretagogue, considering reducing dose of secretagogue, and monitor blood glucose. Liraglutide should not be used with insulin. Evaluate change in body weight; if 4% reduction of baseline body weight has not occurred at 16 weeks, consider discontinuing medication. Monitor heart rate at regular intervals. Greenway FL et al, Lancet 376:595, 21. US FDA. Drugs@FDA. S Liraglutide :: Change in Body Weight (%) Run-in n = 27 n = ± 21. kg Treatment period n = 181 n = 168 n = 156 n = 144 n = 153 n = Time (weeks) Mean ± SD weight at run-in (week -12): 15.9 ± 22.1 kg F = follow-up period; S = screening period. Wadden TA et al. Int J Obes (Lond). 213;37(11): F Liraglutide 3. mg Efficacy of Liraglutide 3 mg for Weight Loss on Glycemic Control Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial Lira 1.8 mg Lira 3. mg HbA1c -.3% -1.1% -1.3% Fasting Glucose OGTT increment % with HbA1c < 7% 27% 67% 69% % with HbA1c 6.5% 15% 46% 57% Change in diabetes medications Decrease 6% 8% 13% No Change 67% 82% 82% Increase 27% 9% 5% Davies MJ et al, JAMA. 215;314(7): % weight loss from baseline after 1 year All data placebo-subtracted, maximal dose, ITT-LOCF, 1 year, unless otherwise indicated Phentermine/ Topiramate Liraglutide 3 mg Naltrexone/ Bupropion Lorcaserin Orlistat Phentermine Change in Weight (%) -1-3 Control Banding Vertical-banded gastroplasty Gastric bypass Years No. patients Control Banding Gastroplasty Bypass Garvey WT. Endocr Pract. 213;19(5): Sep 6:1 31. Wadden TA et al. Int J Obes (Lond). 213;37(11): Sjostrom L, et al. N Engl J Med. 27;357(8): Massachusetts Medical Society.. 7

8 A Guide to Selecting Treatment Percentage without Diabetes Sjostrom L, et al. JAMA. 214;311: Diabetes Duration at Baseline < 1 year 1-3 years 4 years Follow-up Time (years) BMI Category Treatment Diet, physical activity, and behavior Pharmacotherapy Appropriate NHLBI Guidelines No Surgery No No Yes Yes Yes Yes With comorbidities Yes Yes Yes No LAGB only With comorbidities Bariatric surgeries require lifestyle medical follow-up. ⱡ FDA approved gastric band surgery for patients with BMI 3 and one weight related medical condition (February 211). LAGB, laparoscopic adjustable gastric banding Pi-Sunyer FX, et al. Available at Yes Medications are an adjunct to lifestyle intervention program that includes nutritional, behavioral, and physical activity components Most medications suppress appetite and enhance the patient s ability to comply with a reduced-calorie diet Provide significantly greater weight loss over that achieved by lifestyle intervention alone If patient does not lose 5% or greater weight loss after 12 weeks on the maximal dose of the medication, discontinue and try another medication Help to sustain weight loss and prevent weight regain over time Patients that will benefit most are those with obesity-related complications (ie, weight loss used therapeutically to treat obesity-related complications) Obesity is a life-long disease and will require chronic therapy 8