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1 1:55-2:4pm Medical Management of Obesity: Lifestyle, Medicine, and Surgery SPEAKER Osama Hamdy, MD, PhD, FACE Disclosures The following relationships exist related to this presentation: Osama Hamdy, MD, PhD, FACE: Advisory board member for AstraZeneca. Consultant for Merck, Inc., and Abbott Nutrition. Contracted research for National Dairy Counsel, and Novo- Nordisk. Ownership interest in healthimation, Inc. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Learning Objectives 1. Indications for pharmacological treatment of obesity 2. Mechanism of action of the four newly approved anti obesity medications 3. Short and long term efficacy of anti obesity medications on body weight 4. Impact of anti obesity medications on A1C, lipid profile and blood pressure 5. Side events and contraindications of anti obesity medications Classical Obesity Guidelines Intensive lifestyle intervention using a multidisciplinary approach (3 6 months) Medications approved for long term use for patients who do not succeed on their own, with: BMI 3 Kg/m 2 or BMI 27 Kg/m 2 with comorbidity Bariatric surgery is indicated for patients who do not succeed on their own, with: BMI 4 Kg/m 2 or BMI 35 Kg/m 2 with co morbidity

2 Strategies for optimal weight loss Aim for 5-1% weight loss and a maintenance of ~7% for long-term Lifestyle Intervention for Weight Management Proper Medical Nutrition Therapy (MNT) Caloric level & Dietary Composition Meal Replacements Proper Exercise Type Duration Frequency Behavioral Modification SMART Goals Cognitive support Medications Diabetes Medications Weight loss medications Patient adherence and compliance for long-term success Models of Successful Weight Management Look AHEAD Study Dietary Intake: kcal/day < 25 lb kcal/day > 25 lb Dietary Intake: 15 kcal/day for women 18 kcal/day for men Why WAIT Program Structured dietary intervention & modified macronutrient composition Relatively higher protein, LGI & higher fibers Provide structure menus Calorie replacements Food records Calorie intake (~5 less) Carbs to 4 45% Calorie Replacements: (2 liquid meal + one snack bar) Transition at week 2 Menu plans provided Physical Activity: Gradual increases Goal of 175 min/wk 1, steps Calorie Replacements: (2 liquid meal + 2 snacks food) Transition at week 6 Menu plans provided Physical Activity: Gradual increases Goal of 3 min/wk average Balanced exercise (more resistance exercises) Natural food (dinner menus and snacks) and Calorie Replacement Glycemic index Protein intake to 3% Fiber MUFA Medication Changes: PCP Medication Change: Endocrinologist Saturated fat and sodium Wadden TA et al. Obesity. 29;17: Hamdy O et al. Curr Diab Rep. 28;8:

3 Balanced Exercise Model Percentage Weight Reduction in Patients with Diabetes in the Real World Clinical Practice over 5 years (Joslin Why WAIT Program). Duration in Months 3M 6M 9M 12M 15M 18M 21M 24M 27M 3M 33M 36M 39M 42M 45M 48M 51M 54M 57M 6M % 6. Flexibility Stretching Yoga Aerobic Walking Swimming Biking Dancing Strength Resistance tubing Weight lifting Yoga Weight Loss (%) % Stopped insulin 5-6% Reduction in Medications 6.4% 9.% Strength exercise is particularly important during weight reduction 16. p<.1 (group 1 vs. group 2) Total Group n=129 Group 1 n=61 (Participants maintained <7% weight loss at 1 year) Group 2 n=68 (Participants maintained > 7% weight loss at 1 year) Hamdy O et al. BMJ Open Diabetes Res Care. 217 Jan 4;5(1):e259 Do we need to use pharmacotherapy for weight loss? It may help jump start weight loss and increase motivation Anti Obesity Medications It may help in improving adherence to dietary intervention It may improve chances of achieving target weight loss It may help in maintaining weight loss for long term But remember, obesity is a chronic disease that may require drug intervention (1 drugs for HTN, 4 drugs for DM)

4 Phentermine and Orlistat Agents Action Notes Phentermine Central noradrenergic agent Approved, month prescription limit Schedule II IV Orlistat Pancreatic lipase inhibitor Blocks ~ 3% of fat absorption Approved, 1999 Available OTC in smaller dose of 6 mg Orlistat In Practice Approved by FDA, 1999 Approved in adolescents Dosing: Rx: 12 mg TID with each meal OTC: 6 mg TID with each meal Advise patients: Nutritionally balanced, reducedcalorie diet; approximately 3% of calories from fat Take a multivitamin containing fat soluble vitamins at bedtime (A,D,E,K) Contraindications and Warnings Contraindications: Pregnancy, chronic malabsorption syndrome, cholestasis Warnings: Decrease cyclosporine exposure, rare cases of severe liver injury, increased levels of urinary oxalate GI AEs: Oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation and fecal incontinence Kushner RF. Expert Opin Pharmacother. 28;9: Orlistat [prescribing information]. San Francisco, CA: Genentech; Orlistat [package insert]. Moon Township, PA. GlaxoSmithKline, 211. Centrally Acting Medications

5 Newly FDA Approved Weigh Loss Medications Agents Action Approval, Dose 1. Lorcaserin 5 HT 2C serotonin agonist Little affinity for other serotonergic receptors Approved in mg twice daily 2. Phentermine/ Topiramate ER 3. Naltrexone HCl/bupropion HCl Sympathomimetic Anticonvulsant (GABA receptor modulation, carbonic anhydrase inhibition, glutamate antagonism) Opioid antagonist Neuronal reuptake inhibitor of dopamine and norepinephrine Approved in /23, 7.5/46, 11.25/69, 15/92 once Approved in 214 Escalating dose from 8/9 mg to 32/36 mg over 4 weeks 4. Liraglutide GLP 1 analog Central suppression of appetite Approved in mg SC once BLOOM Study: Weight Change Over Two Years (Lorcaserin 1 mg Bid) 12 Year 1 Year 2 Lorcaserin >5% weight loss (year 1) 47.5% on lorcaserin 2.3% on placebo (P<.1) Body Weight (Kg) % on lorcaserin 45.1% on placebo completed year 1 Out of them >5% was maintained (year 2) 67.9% on lorcaserin 5.3% on placebo (P<.1) 92 9 yr 1 and 2 (N=684) Lorcaserin in yr 1, placebo in yr 2 (N=275) Lorcaserin in yr 1 and 2 (N=564) Average 1-year weight loss is 5.8 kg 2.2 Kg (p<.1) Populations are ITT (LOCF). Bars indicate standard errors Study Week Smith SR, et al. NEJM. 21;363:

6 Effect of Lorcaserin in Patients with T2DM: BLOOM DM Study Change in HbA1C Decreasing Use in Diabetes Medications Effect of Lorcaserin on Blood Pressure, Lipids in Obese Adults After 1 Year Baseline Mean A1C (%) LS Mean A1C (%) P<.1 vs placebo P=.87 vs placebo Lorcaserin Lorcaserin 1 mg BID 1 mg QD (n=248) (n=251) (n=93) Patients Decreasing Use of Antidiabetic Agents (%) (n=248) 11.7 Lorcaserin 1 mg BID (n=251) 17.1 Lorcaserin 1 mg QD (n=95) 23.4 Change (mm Hg) P<.5 (Intention-to-Treat Analysis with LOCF Imputation) Lorcaserin 1 mg BID Adapted from: O Neil PM, et al. Obesity. 212;2: Adapted from: Smith SR, et al. NEJM. 21;363: Lorcaserin: Adverse Events Reported by 5% or More in Any Group Lorcaserin: Pros and Cons Adverse Event N (%) Headache Dizziness Lorcaserin (N=3195) (N=3185) 537 (16.8) 321 (1.1) 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) Generally good tolerability Fewer side events Average weight loss at 1 year 5.8 Kg (55% adherence for 1 year) Label carries warnings about valvular heart disease (no evidence of risk from echo studies, but sample size too small to exclude the possibility) Label advises use with extreme caution in patients taking SSRIs, SNRIs, MAOIs, other serotonergic drugs Not studied in patients taking antidepressants (use with caution) In patients without diabetes mellitus Lorcaserin hydrochloride [package insert]. Woodcliff Lake, NJ: Eisai Inc.;

7 Lorcaserin: Label Information Agent Lorcaserin Safety Information Warnings Co administration with other serotonergic or antidopaminergic agents Valvular disease Contraindications Pregnancy (category X) Phentermine/Topiramate Company offers 15 days trial, $75 discount card and weight loss material Current Insurance coverage: Poor (priced ~$21 28/month) Powell AG et al. Clin Pharmacol Ther. 211;9:4 51. Belviq (lorcaserin) Prescribing Information. Woodcliff Lake, New Jersey: Eisai Inc.; 212. SEQUEL Study: Effect of Phentermine/Topiramate ER on Weight Loss in Obese Adults Over 2 Years: Year 1 Year 2 Effects of Phentermine/Topiramate ER in Patients with T2DM: 2 years of treatment 4 6 N (year1) = Study completer 1542 (62%) 9.3% N (year 2) = (27 D/C due to SE) 1.5% p<.1 vs. placebo PHEN/TPM ER 7.5/46 PHEN/TPM ER 15/92 16 PHEN/TPM ER, phentermine/topiramate combination therapy ITT, intent to treat Results are for the completer population; presented as least-squares mean (95% CI). LOCF, last observation carried forward Data are for the ITT/ LOCF population. LS mean weight loss (%) Weeks LOCF 1.8% 2 Baseline Mean A1C (%) LS Mean A1C (%) Change in A1C Phen/Top Phen/Top 7.5/46 mg 15/92 mg (n=55) (n=26) (n=64) Patients With Net Change in Diabetes Medications (%) Change in Diabetes Medications 7.1 (n=227) 1.9 Phen/Top 7.5/46 mg (n=153) Percent increase minus percent decrease. P=.13 for between-group differences. Phen/Top 15/92 mg (n=295) Adapted from Garvey WT, et al. Am J Clin Nutr. 212;95: Adapted from Garvey WT, et al. Am J Clin Nutr. 212;95:

8 Effect of Phentermine/Topiramate ER on Blood Pressure and Lipid Levels After 56 Weeks Change (mm Hg) All P values are vs. placebo. P<.5 Gadde KM, et al. Lancet. 211;377: SBP DBP Change (%) Phentermine 7.5 mg plus topiramate 46. mg TC LDL-C HDL-CTriglycerides Phentermine 15. mg plus topiramate 92. mg Data are presented from the intention-to-treat analysis with LOCF. Least-squares means ± 95% CI Phentermine/Topiramate ER: EQUIP and CONQUER Most Commonly Reported TEAEs Adverse Event (%) (N=3749) N=1561 PHEN/TPM ER 3.75g/23mg PHEN/TPM ER 75mg/46mg PHEN/TPM ER 15mg/92mg Paresthesia Dry mouth Constipation Upper respiratory tract infection Headache Dysgeusia Nasopharyngitis Insomnia Dizziness Sinusitis Nausea Back pain Fatigue Blurred vision Diarrhea Phentermine and topiramate extended release [package insert]. Mountain View, CA : Vivus; 212. Dosing of Phentermine/Topiramate ER Titrate: 3.75/23 mg for 2 weeks 7.5/46 mg (once in the AM) Option to escalate to highest dose with low weight loss response (<5% in 3 months) Titrate again to 11.25/69 mg for 2 weeks 15/92 mg (once in the AM) No sudden withdrawal (seizures may occur) Every other day for a week Doses are lower than single agents (phentermine for weight loss or topiramate for migraine prophylaxis) Phentermine as single agent (15 3 mg) Topiramate as migraine prophylaxis (<2 mg) Safety of Phentermine/Topiramate ER Contraindications: Pregnancy, Glaucoma, Hyperthyroidism, MAO inhibitors Warnings Fetal toxicity cleft palate Increased heart rate Suicide, mood and sleep disorders Acute myopia and glaucoma Cognitive impairment Metabolic acidosis Creatinine elevations Hypoglycemia with diabetes meds Voluntary REMS program in place; pregnancy testing for those of childbearing potential advised before and during use REMS, Risk Evaluation and Mitigation Strategy Phentermine and topiramate extended release [package insert]. Mountain View, CA : Vivus; 212.

9 Phentermine/Topiramate : Label Information Practical tips about Phentermine/Topiramate ER Agent Topiramate/ phentermine Safety Information Warnings Birth defects, cleft palate Contraindications FDA Pregnancy Category X Co administration with MAO inhibitors Dose titration required, most patients may continue the middle dose Discuss paresthesia, dysguesia, insomnia before start Obtain pregnancy test before prescribing and monthly Tell patients about the hazards of sudden withdrawal Rare serious side effects should be always considered Company offers 14 days of starting dose, $75 discount coupons and weigh loss material Insurance coverage: Poor (priced ~$2 23) MAO: monoamine oxidase. Qsymia (phentermine and topiramate extended release) Prescribing Information. Mountain View, CA: VIVUS, Inc.; 213. Phentermine/Topiramate ER: Pros and Cons The 2 medications have been in the market for long time Weight loss of % at 2 years (impressive) Improvement of CV risk factors (A1C, BP, Lipid profile) Label carries warnings about teratogenicity Complex dose titration More side events (paresthesia, insomnia, dysgeusia, constipation) Naltrexone/Buproprion

10 Naltrexone/Buproprion COR II: Change in Body Weight With NB (32/36 mg/day) Oral, sustained release Bupropion: dopamine and norepinephrine reuptake antagonist Naltrexone: opioid antagonist Complimentary stimulation of central melanocortin pathways Reduce appetite Increase energy expenditure Change in Body Weight, % Week 28 Completers 2.4% 7.8% mitt LOCF 1.9% 6.5% Week 56 Completers 1.2% 1.4% 8.2% mitt LOCF 6.4% Padwal R. Curr Opin Investig Drugs. 29;1: N= 1496 P <.1 vs placebo at all time points. Apovian CM et al. Obesity (Silver Spring). 213;21: Week 28 weeks completer 53.7% in the NB (~5% of noncomplters due to SE) in placebo Week (56) >5% at 1 year 5.5% in NB 17.1% in Effect of Naltrexone SR/Bupropion SR on A1C: COR Diabetes Trial Naltrexone HCl and Bupropion HCl Most Commonly Reported AEs p<.1 NB 32/36 mg (n=166) (n=321) Baseline Mean A1C (%) LS Mean A1C (%) Change in A1C Naltrexone HCl and Buproprion HCl Adverse Reaction 32 mg/36 mg N = 2545, % N = 1515, % Nausea Constipation Headache Vomiting Dizziness Insomnia Dry mouth Diarrhea Anxiety Hot flush Fatigue Tremor 4..7 Naltrexone HCl and bupropion HCl Extended Release tablets Initial US Approval [Package Insert]; Takeda Pharmaceutical International, Inc.;Deerfield, IL Naltrexone HCl and bupropion HCl Extended-Release tablets- Initial US Approval [Package Insert]; Takeda Pharmaceutical International, Inc.;Deerfield, IL

11 Naltrexone/Bupropion: Label Information Naltrexone/Bupropion SR: Pros and Cons Agent Naltrexone/ bupropion Safety Information Black box warning: Increased risk of suicidal thoughts and behaviors associated with antidepressant drugs The Light Study (CVD outcomes trial ongoing) Nausea most common AE, generally mild to moderate and transient The 2 medications have been in the market for long time Weight loss of 6.4% at 1 year Improvement in A1C (.6%) Relatively cheaper and non controlled Complex dose titration More side events (nausea, constipation) It is not a controlled substance Company offers weigh loss material Cost: For commercial insurance $55/month for 2 months then $45/month For cash $7/month for 2 months then $6/month Accessed July 1, Apovian CM et al. Obesity (Silver Spring). 213;21: Liraglutide, an Antidiabetic Drug, Produce Weight Loss Liraglutide Weight Loss (kg) Screening Randomization 1.2 mg/day 1.8 mg/day 2.4 mg/day 3. mg/day Orlistat Weeks From Randomization Astrup A et al. Lancet. 29;374(971):

12 SCALE: Phase 3 Diabetes Trial (Weight Loss With Liraglutide) Effect of Liraglutide on the Progression to Prediabetes and Diabetes P <.5; P <.1; P <.1. a Baseline weight 16 kg; FAS, fasting visit data only; lines are observed means (± SE); statistical analysis is ANCOVA. b Proportions are observed means, FAS LOCF; estimates are from a logistic regression model using FAS LOCF. Davies et al. ADA 214. Abstract 97 OR. Pi-Sunyer X et al. N Engl J Med 215; 373:11-22 Liraglutide: Most Commonly Reported AEs Adverse Events, % (n=98) Liraglutide 3. (n=93) Nausea Constipation Diarrhea Vomiting Psychiatric Dyspepsia Summary of efficacy and safety of new antiobesity drugs Locaserin Phentermine/ Topiramate ER Naltrexone SR/ Bupropion SR Liraglutide Dose 1 mg bid 15/92 mg qd 32/36 mg qd 3 mg SC qd >5% at 1 year 47.5% 7% 48% 63% >1% at 1 year 22.6% 48% 25% 33% Major SE Contraindication/ warning Headache, dizziness, fatigue, nausea, constipation, dry mouth Co administration with other serotonergic or antidopaminergic agents Valvular disease Paresthesia, dry mouth, constipation, headache dysgeusia, insomnia, Nasopharyngitis Pregnancy, Glaucoma, Hyperthyroidism, MAO inhibitors Nausea, constipation, headache, vomiting, dizziness, insomnia Risk of suicidal thoughts and behaviors associated with antidepressant drugs Nausea, diarrhea, and constipation Acute Pancreatitis, thyroid medullary carcinoma, gall bladder disorder Hamdy O, 216 Joslin Diabetes Center

13 Thank You