Pharmacotherapy of Obesity: Practical Application for Clinical Care

Transcription

1 Pharmacotherapy of Obesity: Practical Application for Clinical Care Caroline M. Apovian, MD, FACN, FACP, DABOM Professor of Medicine and Pediatrics Boston University School of Medicine Director, Nutrition & Weight Management Center Section of Endocrinology, Diabetes, and Nutrition Boston Medical Center Boston, Massachusetts Scott Kahan, MD, MPH, FTOS, DABOM Medical Director, Strategies to Overcome and Prevent (STOP) Obesity Alliance George Washington University Washington, DC Kimberly A. Gudzune, MD, MPH Assistant Professor Johns Hopkins University School of Medicine Baltimore, Maryland

2 Disclosures Dr Apovian: Consultant: Merck; Nutrisystem; Zafgen; sanofi-aventis; Orexigen; EnteroMedics; Scientific Intake; Gelesis; Ferring; Takeda; Novo Nordisk Research funding: Aspire Bariatrics; GI Dynamics; Pfizer; Gelesis; Orexigen; MetaProteomics; Takeda; MYOS Corporation; The Dr. Robert C. and Veronica Atkins Foundation Stockholder: Science Smart, LLC Dr Kahan: Consultant: Novo Nordisk; Takeda; Orexigen; Eisai Dr Gudzune: Has no relevant financial relationships to disclose 2

3 Learning Objectives Identify obesity as a disease, not a behavioral problem, and consider the implications of that paradigm shift on attitudes toward treating the condition Identify indications that lifestyle interventions have not been sufficient to result in weight loss Describe the pharmacology of, and indications for, the use of the currently available medications for chronic weight management Describe ongoing management of people using anti-obesity medications, including means to gauge both therapeutic efficacy or the need to consider bariatric surgery 3

4 Program Case Study Introduction The Disease of Obesity Obesity Etiology Caroline M. Apovian, MD, FACN, FACP, DABOM Clinical Overview of Anti-Obesity Medications for Weight Management Scott Kahan, MD, MPH, FTOS, DABOM Barriers to the use of Pharmacotherapy When to Consider Bariatric Surgery Kimberly Gudzune, MD, MPH 4

5 Public Health Crisis: 69% of American Adults are Overweight or Obese The average American is now 23 pounds overweight. ~ Dr. Thomas R. Frieden, director of the U.S. Centers for Disease Control and Prevention 5 Ogden CL, et al. JAMA. 2014;312(2):

6 U.S. Adult Overweight/Obesity by BMI BMI: < >35 >40 Underweight Normal Overweight Obesity I Obesity II Obesity III U.S. Adult Population 31% 34% 20.6% 8.1% 6.4% 35.1% Obese Ogden CL, et al. JAMA. 2014;312(2): % Overweight and Obese More than two-thirds 6 6

7 Extreme or Massive Obesity is Rapidly Expanding as a Subgroup BMI Increase by Category, 2001 to 2010 >10-fold increase Category BMI kg/m 2 Underweight < 18.5 Normal weight Overweight Obese 30 Grade Grade Grade 3 40 (severe, extreme, or morbid obesity) Grade 4 50 Sturn R, et al. Int J Obes (Lond). 2013;37(6): Grade Poirier P, et al. Circulation 2009;120:86-95.

8 Case: 52-year-old female CC: I can t lose weight. Family history: type 2 diabetes and CAD Tried multiple diets; lifestyle interventions are not currently achieving weight loss goals. Current medications Multivitamin, calcium, vitamin B12, vitamin D Vital statistics and laboratory results for this visit Height: 5 7 Weight: 190 lb BMI: 29 kg/m 2 (overweight) Blood pressure: 145/95 mm Hg Fasting blood glucose: 97 mg/dl HbA1C: 5.9 Vitals and labs: patient is hypertensive and dyslipidemic, but no dysglycemia 8

9 Q: What would you recommend for this patient? BMI 29 with prediabetes and probably HTN Family history positive for CAD and DM A. Dietary and exercise lifestyle recommendations B. Medication including off-label use of metformin C. On-label use of Belviq (lorcaserin), Contrave (Bupropion/naltrexone), Qsymia (phentermine/topiramate), or Saxenda (liraglutide) D. Off-label use of GLP-1 or SGLT-2 inhibitor 9

10 Designation of Obesity as a Disease Medical Associations and Societies 1 American Association of Clinical Endocrinologists American Academy of Family Physicians American College of Cardiology American College of Surgeons American Medical Association American Society for Reproductive Medicine American Urological Association The Endocrine Society The Obesity Society The Society for Cardiovascular Angiography and Interventions Obesity is a disease: leading obesity groups agree June World / National Health Organizations 1,2 World Health Organization Food and Drug Administration National Institutes of Health 1. ASMBS, TOS, ASBP, AACE Joint Statement. Obesity is a disease: leading obesity groups agree. June 19, Accessed September 11, American Medical Association. AMA Resolution No. 420 (A-13). June 19,

11 Obesity: A Major Contributor to Disease Psychological 1 Depression Poor self-image Poor quality of life Eating disorder Neurologic 1 Stroke Intracranial hypertension Dementia Pulmonary 1 Obstructive sleep apnea Hypoventilation syndrome Asthma Pulmonary hypertension Dyspnea Musculoskeletal 1 Low back pain Osteoarthritis Restrictive mobility Genitourinary 1,2 PCOS Abnormal menses Infertility Urinary incontinence Low testosterone Dermatologic 1 Venous stasis Cellulitis Gastrointestinal 1 Nonalcoholic fatty liver disease Gall bladder disease GERD Hernia Metabolic 1 Type 2 diabetes Gout Insulin resistance Metabolic syndrome Cancer 3 Esophagus Stomach Colorectal Liver Gallbladder Pancreas Breast Cardiovascular 1 Atherosclerosis Hypertension Dyslipidemia CHF Corpus uteri Ovary Kidney Meningioma Thyroid Multiple myeloma CHF=congestive heart failure; GERD=gastroesophageal reflux disease; PCOS=polycystic ovarian syndrome. 1. Catenacci VA, et al. Clin Chest Med. 2009;30(3): Wang C, et al. Diabetes Care. 2011;34(7): Lauby-Secretan B, et al. N Engl J Med. 2016;375(8):

12 How Obesity Causes Disease 12

13 Ectopic Fat Deposits Associated with Metabolic Disorders Systemic effects Increased metabolic risk factors Local effects Increased risk for vascular diseases Pancreatic fat Intramuscular fat Fatty liver Visceral fat Perivascular fat Epi/pericardial fat Myocardial steatosis Renal sinus fat -cell dysfunction, insulin resistance, impaired glucose metabolism, inflammation, lipotoxicity Systemic and intramuscular insulin resistance, mitochondrial dysfunction, impaired lipid and glucose metabolism Hepatic insulin resistance, oxidative stress, inflammation, lipogenic transcription factors, VLDL-TG Inflammation, macrophage infiltration, insulin resistance, altered release of adipokines, altered FFA metabolites, RAS activation, oxidative stress Inflammation, TNF-, IL-6, leptin, MCP-1, cell adhesion molecules, calcification, decreased diastolic function, coagulation defects Hypertension, vascular resistance, glumerosclerosis, proteinuria, intra-renal pressure Metabolic syndrome Cardiovascular disease, type 2 diabetes FFA = free fatty acid; IL = interleukin; MCP-1 = monocyte chemoattractant protein 1; RAS = renin angiotensin system; TG = triglyceride; TNF- = tumor necrosis factor ; VLDL = very low density lipoprotein; Gustafson B, et al. Atherosclerosis. 2015;241(1):

14 Pathogenesis of the Metabolic Syndrome Trait Complex Central Adiposity Secreted Adipocyte Factors: Adiponectin Leptin Resistin Free fatty acids PAI-1 IL-6 TNFα Angiotensinogen CETP Metabolic Consequences Dyslipidemia Increased large VLDL Increased small LDL Decreased large HDL Endothelial Dysfunction Vascular reactivity Dysfibrinolysis Inflammation Foam cell proliferation Insulin Resistance Glucose intolerance CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; IL-6 = interleukin 6; LDL = lowdensity lipoprotein; PAI-1 = plasminogen activator inhibitor 1; TNF- = tumor necrosis factor ; VLDL = verylow-density lipoprotein. WT Garvey,

15 Insulin Sensitivity ( mol/min per kg lean mass) Association Between Visceral Fat and Insulin Resistance BMI <25 kg/m 2 BMI 25 kg/m % Visceral Abdominal Fat CT scans courtesy of Wilfred Y. Fujimoto, MD. Carey DG, et al. Diabetes.1996;45(5):

16 Annual Prevalence of Obesity-Related Comorbidities, Three most prevalent and expensive annually Li Q, et et al. al. J Med J Med Econ. Econ. 2015;4:1-9. Sep 4:

17 Possible Causes of Poor Weight Loss Maintenance Adherence One explanation for the poor long-term outcome of weight-loss diets relates to behavior: Motivation to adhere to restrictive regimens typically diminishes with time Hypothalamic Injury Weight loss elicits biological adaptations that promote weight regain: Specifically, a decline in energy expenditure (adaptive thermogenesis) and an increase in hunger Ebbling CB, et al. JAMA. 2012;307(24):

18 Biological Adaptation How long do these biological adaptations persist w/ calorie restriction? Evidence suggests often indefinitely 1 Biological pressure to restore bodyweight to the highest-sustained lifetime level gets stronger as weight loss increases. 2 Then is a patient ever truly recovered from obesity? Few individuals ever fully recover from obesity 1,2 Individuals with obesity who lose weight are essentially in remission and biologically very different than their counterparts 1,2,3 1. Ochner CN., et al. Physiol Behav 2013;120: Rosenbaum M, et al. Int J Obes (London). 2010;34 (suppl 1) S47 S Ochner CN, et al. Lancet. 2015;3(4):

19 Obesity Associated with Hypothalamic Injury in Rodents and Humans Rodent models of obesity, induced by consuming high-fat diet (HFD), are characterized by inflammation both in peripheral tissues and hypothalamic areas critical for energy homeostasis Unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain Both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding Evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI Findings suggest obesity is associated with neuronal injury in a brain area crucial for body weight control in both humans and rodent models Thaler JP, et al. J Clin Invest. 2012;122(1):

20 Hypothalamus is a Regulation Center of Appetite and Energy Expenditure Integrates peripheral and CNS signals that collectively modulate feeding behavior and energy balance 1-3 A primary regulation center is the arcuate nucleus (ARC) 1 ARC of the Hypothalamus CNS, central nervous system ARC, arcuate nucleus Primarily based on data from animal studies. 1. Yu JH et al. Diabetes Metab J. 2012;36: Morton GJ et al. Nature. 2006; 443: Cone RD. Nat Neurosci. 2005; 8: NetterImages. Accessed October 2,

21 Hypothalamic Injury Diminishes Signaling to Cortex and NTS*, Leading to Greater Weight Gain AGRP: agouti-related peptide; α-msh: α-melanocyte-stimulating hormone; GHSR: growth hormone secretagogue receptor; INSR: insulin receptor; LepR: leptin receptor; MC4R: melanocortin-4 receptor; NPY: neuropeptide Y; POMC: proopiomelanocortin; PYY: peptide YY; Y1R; neuropeptide Y1 receptor; Y2R: neuropeptide Y2 receptor. Apovian CM, et al. J Clin Endocrinol Metab. 2015;100(2): *NTS: nucleus tractus solitarius 21

22 The Fat Trap 2009, 50 obese men and women Men 233 lbs/average; women 200 lbs/average Extreme low-calorie diet Optifast shakes + 2 cups of low-starch vegetables Total kcal/d for eight weeks Reported feeling more hungry and preoccupied with food than before the weight loss 30-lb LOSS 11-lb GAIN 10 week weightloss program Sumithran P, et al. N Engl J Med. 2011;365(17): Body continues to fight against weight loss long after dieting has stopped 22 22

23 14% Weight Loss Produced Changes in 8 Hormones That Encourage Weight Regain Mean fasting and postprandial levels of some peripheral signals at baseline and 62 weeks 15% Weight Loss Reduced: Leptin - 65% Peptide YY Cholecystokinin Insulin Amylin Increased: Ghrelin Pancreatic polypeptide Gastric inhibitory polypeptide Measures of appetite 10-week, lifestyle-based weight loss intervention in healthy overweight and obese adults (n=34) led to sustained elevations in appetite stimulating hormone(s) and decreases in appetite suppressing hormones NET RESULT OF THESE HORMONAL CHANGES is WEIGHT GAIN! Sumithran P, et al. N Engl J Med. 2011;365(17):

24 (cholecystokinin) Sustained Changes in Peripheral Signals for Up to One Year Following Weight Loss Mean fasting and postprandial levels of some peripheral signals at baseline and 62 weeks Ghrelin, pg/ml Appetite Stimulating Hormone was Higher Week 62 Baseline Postprandial Time, min Peptide YY, pg/ml Appetite Suppressing Hormone was Lower Baseline Week Postprandial Time, min Amylin, pg/ml Appetite Suppressing Hormone was Lower Baseline Week Postprandial Time, min CCK, fmol/ml Appetite Suppressing Hormone was Lower Baseline Week Postprandial Time, min 10-week, lifestyle-based weight loss intervention in healthy overweight and obese adults (n=34) led to sustained elevations in appetite stimulating hormone(s) and decreases in appetite suppressing hormones Sumithran P, et al. N Engl J Med. 2011;365(17):

25 Sustained Changes in Peripheral Signals for Up to One Year Following Weight Loss Mean fasting and postprandial ratings of hunger and desire to eat at baseline and weeks 10 and 62 Hunger Desire to Eat Changes were accompanied by significant increases in appetite based on self-reported ratings (P<0.001) Sumithran P, et al. N Engl J Med. 2011;365(17):

26 Summary Obesity is an epidemic with massive obesity being the fastest growing subgroup Obesity was designated a disease by multiple medical organizations in 2013 Increased expression of some hormones, suppression of others, leads to inflammation and disease Neurological injury in the brain and hormonal changes account for weight regain, not lack of willpower 26

27 Program Case Study Introduction The Disease of Obesity Obesity Etiology Caroline M Apovian, MD, FACN, FACP, DABOM Clinical Overview of Anti-Obesity Medications for Weight Management Scott Kahan, MD, MPH, FTOS, DABOM Barriers to the use of Pharmacotherapy When to Consider Bariatric Surgery Kimberly Gudzune, MD, MPH 27

28 Q: When do you prescribe obesity pharmacotherapy in your practice? A. I prescribe obesity medications in all my patients B. I do not prescribe obesity medications in my practice C. I prescribe only in patients who have severe obesity D. I prescribe only in patients who have obesity comorbidities E. I am not sure what are appropriate guidelines for prescribing 28

29 % of Participants Intensive Behavioral Therapy for Obesity >0% 5% 10% 15% >0% 5% 10% 15% YEAR 1 YEAR 8 Look AHEAD Research Group. Obesity. 2014;22(1):

30 Pharmacotherapy Increases Magnitude and Likelihood of Weight Loss Wadden TA, et al. Obesity. 2011;19(1):

31 XENDOS BLOOM BLOSSOM BLOOM-DM EQUIP CONQUER SEQUEL* COR I COR-II COR-BMOD COR-D SCALE Maintain SCALE Obesity Astrup et al (2012) Patients with 5% WL Pharmacotherapy Increases Magnitude and Likelihood of Weight Loss PBO ORL LOR PHEN/TPM ER BN LIRA Pucci A, et al. Can J Cardiol. 2015;31(2): Astrup A, et al. Int J Obes (Lond). 2012;36(6):

32 Pharmacotherapy Increases Magnitude and Likelihood of Weight Loss le Roux C, et al. Poster presented at: TOS 2015; November 2-7, 2015; Los Angeles, CA. Poster T-P-LB

33 Pharmacotherapy Improves Weight Maintenance Wadden TA, et al. Intl J Obes (London). 2013;37(11):

34 Key Obesity Pharmacotherapy Guidelines Use pharmacotherapy as adjunct to diet, exercise, and behavioral counseling for individuals with BMI 30+; or 27+ with comorbidity who are unable to lose and successfully maintain weight who meet label indications Use medications to promote long-term weight loss maintenance Assess efficacy and safety monthly for the first 3 months, then every 3 months thereafter At 3 months, if loss is 5% or more, continue; if not, discontinue and seek alternative approaches Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab,

35 Outcomes by Responder Status Smith SR, et al. Obesity (Silver Spring). 2014;22(10):

36 Obesity Pharmacotherapy 5 FDA-approved medications for long-term use Orlistat (Xenical/Alli) Phentermine/topiramate ER (Qsymia) Lorcaserin (Belviq) Naltrexone/Bupropion SR (Contrave) Liraglutide 3.0 mg (Saxenda) Phentermine (Lomaira/Adipex) approved for short-term use 36

37 Phentermine Mechanism of action (MOA): Sympathomimetic amine, norepinephrine (NE) release Blunts appetite Approved in 1959 for short-term use, schedule IV Dosing: 8 mg to 37.5 mg qam; use lowest effective dose Contraindications: pregnancy, nursing, MAOIs, glaucoma, drug abuse history, hyperthyroidism Relative contraindications: uncontrolled hypertension, tachycardia, CAD, CHF, stroke, arrhythmia Warnings: primary pulmonary hypertension, valvular heart disease, tolerance, risk of abuse, alcohol use Phentermine [package insert]. Sellersville, PA: Teva Pharmaceuticals USA;

38 Orlistat MOA: Lipase inhibitor, decreases fat absorption Approved 1999; long-term use Not scheduled Dosing: 120 mg TID with meals (Rx) or 60 mg TID (OTC) Use multivitamin supplement (MVI) with fat-soluble vitamins at bedtime Contraindications: pregnancy, chronic malabsorption syndrome, cholestasis Possible gastrointestinal adverse events Xenical [package insert]. Nutley, NJ: Roche Laboratories, Inc.;

39 Lorcaserin MOA: Selective 5-HT2C receptor agonist; increases satiety Approved in 2012 for long-term use; schedule IV Single dose: 10 mg BID Discontinue if less than 5% weight loss after 12 weeks of use Contraindications: pregnancy Warnings: co-administration with serotonergic agents, valvular heart disease, psychiatric disorders (euphoria, suicidal thoughts, depression), priapism Belviq [package insert]. Woodcliff Lake, NJ: Eisai, Inc.;

40 Phentermine/ Topiramate Extended Release Phentermine MOA: sympathomimetic amine; blunts appetite Topiramate MOA: increases GABA activity, carbonic anhydrase inhibitor, and other actions; prolongs satiety Approved in 2012 for long-term use; schedule IV Recommended dose: 7.5/46 mg; max: 15/92 mg Discontinue if less than 3% weight loss after 12 weeks Contraindications: pregnancy, glaucoma, MAOIs, hyperthyroidism Qysmia. [package insert]. Mountain View, CA: Vivus;

41 Naltrexone/Bupropion Extended Release Bupropion MOA: dopamine/noradrenaline reuptake inhibitor Naltrexone MOA: opioid receptor antagonist Not a controlled substance Standard dose: 32/360 mg (2 tablets BID) Consider discontinuation if <5% weight loss after 16 weeks Black box warning for suicidal thoughts in adolescents Contraindications: pregnancy, uncontrolled hypertension, seizure disorders, chronic opioid use, MAOIs Contrave [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.;

42 Liraglutide 3.0 mg MOA: Glucagon-like peptide 1 (GLP-1) receptor agonist Multiple actions; effect on weight is primarily via hypothalamus neurons Liraglutide 1.8 mg approved for T2DM in 2010 Liraglutide 3.0 mg approved for obesity in 2014 Not a controlled substance Dosing: weekly escalation by 0.6 mg SC Discontinue if <4% weight loss at 16 weeks REMs: medullary thyroid carcinoma, acute pancreatitis Saxenda [package insert]. Plainsboro, NJ: Novo Nordisk, Inc.;

43 Improvements in Risk Factors and Comorbidities Orlistat Lorcaserin Phentermine/ topiramate ER Naltrexone/ bupropion SR Liraglutide 3.0 mg WC BP LDL HDL TG A1C HR 0 Diabetes 43

44 Program Case Study Introduction The Disease of Obesity Obesity Etiology Caroline M Apovian, MD, FACN, FACP, DABOM Clinical Overview of Anti-Obesity Medications for Weight Management Scott Kahan, MD, MPH, FTOS, DABOM Barriers to the use of Pharmacotherapy When to Consider Bariatric Surgery Kimberly Gudzune, MD, MPH 44

45 Weight-Favorable Medications for Management of Other Conditions (1) Condition Promote Weight Gain Weight-Neutral Promote Weight Loss Diabetes mellitus Insulin* Sulfonylureas TZDs Metiglinides DPP-4 Inhibitors Metformin Pramlintide GLP-1 Agonists SGLT2 Inhibitors Acarbose Miglitol Cardiovascular disease β Blockers** α Blockers ACE Inhibitors ARBs CCBs -- *Weight gain differs by type of insulin regimen used. Basal insulin only typically has less weight gain than premixed or combination therapy. **If needed, certain agents may have less weight gain effects including carvedilol, nebivolol, and bisoprolol. Apovian C, et al. J Clin Endocrinol Metab. 2015;100(2):

46 Weight-Favorable Medications for Management of Other Conditions (2) Condition Contraception Promote Weight Gain Medroxyprogesterone injection Weight-Neutral Combination OCPs Barrier methods IUDs Allergies Antihistamines* Decongestants Steroid inhalers Chronic inflammatory disease (e.g., RA) *Most common with sedating anti-histamines. Corticosteroids NSAIDs -- Promote Weight Loss Apovian C, et al. J Clin Endocrinol Metab. 2015;100(2):

47 Weight-Favorable Medications for Management of Other Conditions (3) Condition Promote Weight Gain Weight-Neutral Promote Weight Loss Depression Paroxetine Fluvoxamine Amytriptyline Doxepin Imipramine Nortriptyline Trimipramine Mirtazapine Lithium Fluoxetine* Sertraline* Bupropion *Weight loss may occur with short-term use. Apovian C, et al. J Clin Endocrinol Metab. 2015;100(2):

48 Weight-Favorable Medications for Management of Other Conditions (4) Condition Promote Weight Gain Weight-Neutral Promote Weight Loss Serious mental illness Clozapine Risperidone Olanzapine Quetiapine Haloperidol Perphenazine Quetiapine Ziprasidone Aripiprazole -- Epilepsy Carbamazepine Gabapentin Valproate Lamotrigine Topiramate Zonisamide Apovian C, et al. J Clin Endocrinol Metab. 2015;100(2):

49 Q: What has prevented you from prescribing weight loss medications? A. I have concerns about the long-term safety of these medications B. The side effects and risks of these medications are too great C. D. E. Patients have been dissatisfied with the weight loss results with these medications Patients should have the will power to lose weight without medications Patients don t stick with taking the medications and just regain weight 49

50 Prescribing Habits for Weight-Loss Medications Few patients with obesity prescribed a weight loss medication Range 1-2% in large cohorts of insured patients More likely to pursue nonprescription options 4-18% report using herbs, supplements or OTC meds OTC products have no association with clinically significant weight loss Safety data often unknown and reports of previous serious adverse effects Bolen SD, et al., Obesity 2010; 18: Samaranayake NR et al., Ann Epidemiol. 2012;22: Xia Y, et al. Obesity. 2015;23: Nicklas JM, et al. Am J Prev Med. 2012;42: Bertisch SM, et al. Obesity (Silver Spring). 2008;16(7): Bray GA. Obesity (Silver Spring). 2008;16(3):

51 Prescriber Perceptions of Pharmacotherapy 80% of providers in a 2016 NEJM poll voted against prescribing an FDA-approved medication Preferred maximizing lifestyle modification first Short-sighted to simply treat obesity with a prescription medication Past history may be influencing current perceptions Amphetamine diet pills, fenfluramine, sibutramine Prompt us to look carefully at the safety profile of anti-obesity drugs Inappropriate to generalize and think that any potential antiobesity drug is unacceptably harmful Yeh JS, et al. N Engl J Med. 2016;375(12): Halpern B, Halpern A. Expert Opin Drug Saf. 2015;14(2):

52 Prescriber Perceptions of Pharmacotherapy Weight bias and stigma may also play a role Majority of physicians report limited efficacy in weight management Many feel unprepared with respect to training, in addition to limited time and reimbursement for services Weight management considered unrewarding or futile Avoid discussing weight and weight loss entirely when trying to balance multiple priorities during the visit Kristeller JL, et al. Prev Med.1997;26(4): ; Foster GD, et al. Obes Res. 2003;11(10): ; Fogelman Y, et al. Int J Obes Relat Metab Disord. 2002;26(10): ; Kushner RF, et al. Prev Med. 1995;23: ; Gudzune KA, et al. Patient Educ Couns. 2012;89(1):

53 Barriers to Pharmacotherapy Lack of long-term data efficacy and safety data Clinicians want to wait for definitive long-term data for weight-loss pharmacotherapy Not economically feasible for manufacturers Delays potentially useful options for decades Other chronic diseases the longterm use of medications is well accepted why is obesity different? Long-term surveillance necessary with any chronic medication Apply stopping rules if no benefit at ~12 weeks Concern about adverse effects Benefits do not outweigh the possible side effects Weight loss achieved highly variable between individuals Some may have substantial benefit Side effects an issue for any medication Counseling about side effects and risks important component of medication discussion to guide selection Shared decision-making process with patient Yeh JS, et al. N Engl J Med. 2016;375(12): Halpern B, Halpern A. Expert Opin Drug Saf. 2015;14(2): Fujioka K. Obesity (Silver Spring). 2015;23(Suppl 1):S7-S11. 53

54 Barriers to Pharmacotherapy Patient Non-adherence Patients are more likely to achieve clinically significant weight loss if they use prescription meds Medication persistence tends to be low Medications can be costly & few have insurance coverage Costs drives non-adherence for many patients Insurance coverage improves adherence and weight loss Patient Dissatisfaction with Results Most patients do not value modest weight loss Many misperceive the amount of weight loss that they are likely to achieve with medications Counseling on weight loss that may be achieved along with other health benefits may help manage expectations Nicklas JM, et al. Am J Prev Med. 2012;42(5): ; Risser JA, et al. Obes Res. 2005;13(1):86-92.; Wee CC, et al. J Gen Intern Med. 2004;19(12): ; Bray GA. Obesity (Silver Spring). 2008;16(3):

55 When to Consider Bariatric Surgery Approved for use in patients with: BMI 40 kg/m 2 BMI 35 kg/m 2 + obesity-related condition such as CVD, OSA, uncontrolled T2DM or severe OA Surgery Mechanism Mean Weight Loss - 1 Year Mean Weight Loss - 3 Years Adjustable Gastric Banding Restriction 30.2 kg 34.8 kg Sleeve Gastrectomy Restriction 40.4 kg 37.2 kg Roux-en-Y Gastric Bypass Restriction + Malabsorption 43.5 kg 41.5 kg Biliopancreatic Diversion Malabsorption 51.9 kg 53.1 kg Mechanick JI, et al. Obesity (Silver Spring). 2009;17 Suppl 1:S1-S70.; Maggard MA, et al. Ann Intern Med. 2005;142(7): ; Carlin AM, et al. Ann Surg. 2013;257(5):

56 Bariatric Surgery Pros & Cons Benefits Improved obesity-related comorbidities T2DM up to 77% resolve HTN up to 62% resolve OSA up to 84% resolve Improved quality of life Reduce mortality 40% in overall mortality 50% in CVD deaths Complications Risk of death from procedures low <5% Variable by procedure type GI symptoms 7-38% Nutrition/electrolyte imbalances 3-17% Reoperation 2-12% Weight regain 9-25% Buchwald H, et al. JAMA. 2004;292(14): ; Levy P, et al. Obes Surg. 2007;17(9): ; Sjostrom L, et al. N Engl J Med. 2004;351(26): ; Sjostrom L, et al. JAMA. 2012;307(1):56-65.; Chang SH, et al. JAMA Surg. 2014;149(3):

57 Summary Obesity was designated a disease by multiple medical organizations in 2013 Causes of poor long-term weight loss include both behavioral and physiologic factors Several obesity pharmacotherapy options are approved for use, including long-term use, and have strong data on efficacy and safety Examining patients current medication lists is critical to identify weight-gain promoting medications and discuss weight-favorable alternatives For patients who fail lifestyle modifications +/- weight loss medications, bariatric surgery should be considered 57

58 Q&A

59 Thank You

60 BACKUP SLIDES

61 Effects of Phentermine Plus Topiramate on Bodyweight Gadde KM et al. Lancet. 2011;377:

62 Effects of Sustained-Release Naltrexone/Bupropion on Bodyweight Greenway FL et al. Lancet. 2010; 376:

63 Weight Loss Observed with Liraglutide Pi-Sunyer X et al., N Engl J Med. 2015; 373:

64 Impact of Liraglutide on Plasma Glucose, and Prevalence of Prediabetes Pi-Sunyer X et al., N Engl J Med. 2015; 373:

65 Rate of T2DM Development Pi-Sunyer X et al., N Engl J Med. 2015; 373:

66 Drug Common AE Contraindication Safety Consideration Tolerability Phentermine Insomnia Dry mouth Agitation Constipation CVD, CHF, arrhythmias Uncontrolled hypertension MAOI use Hyperthyroidism Glaucoma Pregnancy Orlistat GI complaints Chronic malabsorption Gallbladder disease Primary pulmonary hypertension May increase cyclosporine exposure; Liver failure Multivitamin administration Discontinuation (CNS): Phentermine 17% Placebo 3% Discontinuation: Orlistat 8.8% Placebo 5% Phentermine/ topiramate ER Dry mouth Paresthesias Headache Insomnia Glaucoma Hyperthyroidism MAOI use Pregnancy Teratogenicity Metabolic acidosis Glaucoma Discontinuation: Top dose 17% Low doses 12% Placebo 8% Lorcaserin Headache Dizziness Fatigue Dry mouth MAOI use Use with caution with serotonergic drugs Pregnancy Serotonin syndrome Valvular heart disease Depression Priapism Discontinuation: Lorcaserin 8.6% Placebo 6.7% Naltrexone/ bupropion SR Nausea GI complaints Headache Insomnia Seizure disorder Uncontrolled hypertension Chronic opioid use MAOI use Pregnancy Suicidality in adolescents Elevated blood pressure, pulse Glaucoma Hepatotoxicity Discontinuation: Naltrexone/bupropion 24% Placebo 12% Liraglutide 3.0 Nausea GI complaints Personal/family history of medullary thyroid carcinoma or MEN2 History of pancreatitis Pregnancy Thyroid c-cell tumors (rodents) Acute pancreatitis Gallbladder disease Hypoglycemia Tachycardia Renal impairment Suicidal behavior Discontinuation: Liraglutide 9.8% Placebo 4.3% 66