Facts and Fads: Weighing in on Obesity Management Michelle L. Hilaire, PharmD, CDE, BCPS, FCCP Colorado Pharmacists Society 2016 Winter CE and Ski Seminar January 9 th - 13 th

Conflict of Interest  I have no conflicts of interest to disclose.

Objectives  Describe the prevalence of overweight and obese patients in the U.S.;  Discuss recommendations included in the recent obesity management guidelines;  Compare and contrast the mechanism, safety, efficacy and clinical usefulness of chronic prescription weight management products;  Evaluate potential risks and benefits of over-the-counter weight-loss supplements.

Introduction  Obesity is a disease and a major public health epidemic  Weight loss has many benefits: – Risk factor improvement – Prevention of disease – Reduced blood pressure – Improvement in feeling and function  Although more is usually better, even modest weight loss can result in significant improvement of health Iantorno M, Campia U, Di Daniele N, et. al. Obesity, inflammation and endothelial dysfunction. J Biol Regul Homeost Agents. April-June 2014; 28(2): Apovian CM, Argonne LJ, Bessesen DH, et.al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. February 2015; 100(2):

Body Mass Index (BMI) Classifications from the Centers for Disease Control and Prevention Website Centers for Disease Control and Prevention.(2015). Obesity. Retrieved March 29, 2015 from BMI (kg/m 2 )Weight Status Below 18.5Underweight 18.5 – 24.9Normal or Healthy Weight 25.0 – 29.9Overweight 30.0 and AboveObese

Prevalence and Economic Burden (U.S.)  Percentage of adults (≥ 20ys) classified as obese is 37.7% (~78 million people) – If we include overweight criteria, it increases to 69%  Estimated annual medical cost of obesity in the U.S. was $147 billion in 2008  Medical costs for obese individuals are $1,429 higher than medical costs for individuals of normal weight  Approximately 17% of children/adolescents aged 2-19 years old are obese – Obesity has declined in children aged 2-5 years old, from 13.9% in to 8.9% in Ogden CL, Carroll MD, Fryar CD, Flegal KM. Prevalence of obesity among adults and youth: United States, 2011–2014. NCHS data brief, no 219. Hyattsville, MD: National Center for Health Statistics Centers for Disease Control and Prevention. (2015). Obesity. Retrieved October 1, 2015 from

Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2014 ¶ Prevalence estimates reflect BRFSS methodological changes started in These estimates should not be compared to prevalence estimates before

Risk Factors-Obesity  National Heart, Lung, and Blood Institute guidelines recommend looking at two other predictors for assessing someone’s likelihood of developing obesity-associated diseases: – Waist circumference (abdominal fat is a predictor of risk for obesity- related diseases) – Other risk factors for diseases and conditions associated with obesity  High blood pressure  Physical inactivity Centers for Disease Control and Prevention. (2015). Obesity. Retrieved October 1, 2015 from

Risk Factors (continued)  Being obese increases your risks for many different disease states including: – Cancer – Type 2 diabetes – Osteoarthritis – Depression – Hypertension – Obstructive sleep apnea – Cardiovascular disease – Hyperlipidemia – Non-alcoholic fatty liver disease Apovian CM, Argonne LJ, Bessesen DH, et.al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. February 2015; 100(2):

Obesity Variability Among Ethnic Groups (U.S.) Ogden CL, Carroll MD, Fryar CD, Flegal KM. Prevalence of obesity among adults and youth: United States, 2011–2014. NCHS data brief, no 219. Hyattsville, MD: National Center for Health Statistics

Obesity Among Age Groups (U.S.) 40.2% 37.0% 32.3% Ogden CL, Carroll MD, Fryar CD, Flegal KM. Prevalence of obesity among adults and youth: United States, 2011–2014. NCHS data brief, no 219. Hyattsville, MD: National Center for Health Statistics

Causes of Obesity  Multifactorial – Medications* – Lifestyle (Diet and Exercise)* – Environmental and socioeconomic causes – Gut microbes – Genetic factors – Syndromes Apovian CM, Argonne LJ, Bessesen DH, et.al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. February 2015; 100(2): Carthage P, Moran MB, Shanahan F. Gut microbiota and obesity: role in aetiology and potential therapeutic target. Best Practice & Research Clinical Gastroenterology. 2014; 28:

Medications That Can Cause Weight Gain  Antidiabetics  Antidepressants  Antipsychotics  Antiepileptics  Oral contraception  Antiretrovirals  Corticosteroids  Antihistamines with greater CNS activity Apovian CM, Argonne LJ, Bessesen DH, et.al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. February 2015; 100(2):

Lifestyle Interventions Increased Physical Activity Weight Loss Weight Maintenance Cardio and Resistance Training Behavioral Therapy Diet Portion Sizes and Meal Composition Limit Calories kcal/day: Men kcal/day: Women This is the first line treatment for weight loss Goal is a 5-10% weight loss, but even a 3-5% weight loss produces clinically meaningful health benefits in patients with cardiovascular risk factors Jensen MD, Ryan DH, Apovian CM, et al AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;125(25 suppl 2): S102-S138.

We know being overweight and obese is not healthy How do we know who can or should use weight loss products?

Obesity Guidelines, Recommendations and Position Statements GuidelineYear Released Endocrine Society 1 * 2015 National Institute for Health and Care Excellence (NICE) American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) 3 * 2014 American Society of Bariatric Physicians American Heart Association/American College of Cardiology/The Obesity Society (AHA/ACC/TOS) 5 * 2013 *Discussing in presentation 1 Apovian CM, Argonne LJ, Bessesen DH, et.al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. February 2015; 100(2): Stegenga H, Haines A, Jones K, Wilding J. Identification, assessment, and management of overweight and obesity: summary of updated NICE guidance. BMJ 2014; 349: g Garvey WT, Garber AJ, Mechanick JI, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the 2014 advanced framework for a new diagnosis of obesity as a chronic disease. Endocr Pract. 2014;20: Seger JC, Horn DB, Westman EC, Primack C, Schmidt SL, Ravasia D, McCarthy W, Ferguson U, Sabowitz BN, Scinta W, Bays HE. Obesity Algorithm, presented by the Obesity Medicine Association, Jensen MD, Ryan DH, Apovian CM, et al AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;125(25 suppl 2): S102-S138.

Obesity Management GuidelineEmphasis Endocrine SocietyCauses of obesity Weight-centric approach to obesity management Medications that can promote weight loss Medications that can contribute to weight gain AACE/ACEStaged approach to diagnosis, evaluation and intervention Weight loss as key to reversing or controlling weight associated comorbidities AHA/ACC/TOSHealth risks with obesity Weight loss benefits Changes in diet and lifestyle Appropriateness of bariatric surgery Apovian CM, Argonne LJ, Bessesen DH, et.al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. February 2015; 100(2): Garvey WT, Garber AJ, Mechanick JI, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the 2014 advanced framework for a new diagnosis of obesity as a chronic disease. Endocr Pract. 2014;20: Jensen MD, Ryan DH, Apovian CM, et al AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;125(25 suppl 2): S102-S138.

AHA/ACC/TOS-2013 and Endocrine Society  Incorporated only Level 1 evidence into guidelines  Relies on BMI to define obesity  Criteria to identify patients to lose weight are BMI and Waist Circumference BMI (kg/m 2 )Classification Normal Weight Overweight Class I Obesity Class II Obesity ≥ 40Class III Obesity Waist Circumference Cut-off (cm) Male>102 Female>88

AACE/ACE-2014 DiagnosisAnthropometric component BMI (kg/m 2 ) Clinical componentPrevention/Treatm ent Normal< 25Primary Overweight No obesity related complicationsSecondary Obesity≥ 30No obesity related complications Obesity Stage 1 ≥ 25Presence of 1 or more mild-to- moderate obesity related complications Tertiary Obesity Stage 2 ≥ 25Presence of 1 or more severe obesity related complications Utilized varying levels of evidence plus expert opinion Looks at anthropometric and clinical components Emphasis on impact of weight gain on individual patient health

Medication Management GuidelinePharmacotherapy Endocrine Society-BMI ≥ 30 -BMI ≥ associated comorbid condition (HTN, T2D,OSA,DLD) -Adjunct to behavioral therapy American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) -For secondary prevention/treatment-optional -For tertiary prevention/treatment-included -BMI≥ 27 American Heart Association/American College of Cardiology/The Obesity Society (AHA/ACC/TOS) -BMI ≥ 30 -BMI ≥ associated comorbid condition (HTN, T2D,prediabetes,DLD,elevated waist circumference) -Adjunct to lifestyle interventions

Overview of Treatment Options  Nutrition/Dietary modifications  Behavioral therapy  Physical activity  Identify/Treat conditions causing weight gain  Identify possible medications increasing body weight  Bariatric surgery  Pharmacotherapy

So is there a Magic Little Pill?  MAGIC may not be the right word – There are newer products that can be used as an adjunct to lifestyle modification-NOT A SUBSTITUTION

Obesity Medications  Most obesity products target appetite mechanisms  Potential target mechanisms: – Central inhibition of dietary intake – Increased energy expenditure – Peripheral impairment of dietary absorption Apovian CM, Argonne LJ, Bessesen DH, et.al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. February 2015; 100(2):

New FDA-Approved Weight Loss Options Generic NameBrand NameApproval Date LorcaserinBelviq ® June 2012 (C-IV) Phentermine & Topiramate ER Qsymia ® July 2012 (C-IV) Naltrexone SR & Bupropion SR Contrave XR ® September 2014 LiraglutideSaxenda ® December 2014 Arena. Belqiq (lorcaserin) tablets. Prescribing Information. Revised August Vivus. Qsymia (phentermine and topiramate) capsules. Prescribing Information. Revised October Orexigen. Contrave (naltrexone and bupropion) tablets. Prescribing Information. Revised September NovoNordisc. Saxenda (liraglutide) injection. Prescribing Information. Revised January 2015.

Common Indication  All approved as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of: – 30 or greater – 27 or greater in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus or dyslipidemia

Comparison of Products AgentMechanism of ActionExpected Weight Loss Clinical Effects LorcaserinSerotonergic (5-HT 2c ) receptor agonist 5-6%-Appetite and food intake Phentermine & Topiramate ER Sympathomimetic amine/anticonvulsant 5-11%-Appetite and food intake -Potential metabolic effects Naltrexone SR & Bupropion SR Opioid/DA and NE reuptake inhibitor 5-6%-Appetite and food intake LiraglutideGLP-1 receptor agonist4-8%-Delayed Gastric Emptying; Increased Satiety Apovian CM, Argonne LJ, Bessesen DH, et.al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. February 2015; 100(2): Arena. Belqiq (lorcaserin) tablets. Prescribing Information. Revised August Vivus. Qsymia (phentermine and topiramate) capsules. Prescribing Information. Revised October Orexigen. Contrave (naltrexone and bupropion) tablets. Prescribing Information. Revised September NovoNordisc. Saxenda (liraglutide) injection. Prescribing Information. Revised January 2015.

Dosing AgentStrengths AvailableDirections Lorcaserin10mg1 tablet twice daily Phentermine & Topiramate ER 3.75mg/23mg, 7.5mg/46mg, 11.25mg/69mg,15mg/92m g 1 capsule orally in the morning: 3.75mg/23mg x 14 days, 7.5mg/46mg. At 12 weeks, can increase to 11.25mg/69mg x 14 days, then max of 15mg/92mg daily Naltrexone SR & Bupropion SR 8mg/90mg1 tablet daily in AM x 7 days, 1 tablet BID x 7 days, 2 tablets in AM, 1 tablet PM x 7 days, 2 tablets BID Liraglutide0.6mg, 1.2mg, 1.8mg, 2.4mg, 3mg Inject subcutaneously, initiate 0.6mg daily for one week and then titrate up at weekly intervals to max of 3mg Arena. Belqiq (lorcaserin) tablets. Prescribing Information. Revised August Vivus. Qsymia (phentermine and topiramate) capsules. Prescribing Information. Revised October Orexigen. Contrave (naltrexone and bupropion) tablets. Prescribing Information. Revised September NovoNordisc. Saxenda (liraglutide) injection. Prescribing Information. Revised January 2015.

Treatment Decisions AgentFollow Up (guideline) Time to assess treatment (PI) Discontinue (Guidelines) Discontinue (PI) LorcaserinMonthly x 3 months, then every 3 months 12 weeks< 5% baseline weight loss or safety/tolerability issues at any time May try alternate therapy < 5% baseline weight loss Phentermine & Topiramate ER 12 weeksIf at 12 weeks-< 3% of 7.5/46mg dose or if 5% not achieved on max dose of 15/92mg Naltrexone SR & Bupropion SR 12 weeks< 5% baseline weight loss Liraglutide16 weeks< 4% baseline weight loss Apovian CM, Argonne LJ, Bessesen DH, et.al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. February 2015; 100(2): Arena. Belqiq (lorcaserin) tablets. Prescribing Information. Revised August Vivus. Qsymia (phentermine and topiramate) capsules. Prescribing Information. Revised October Orexigen. Contrave (naltrexone and bupropion) tablets. Prescribing Information. Revised September NovoNordisc. Saxenda (liraglutide) injection. Prescribing Information. Revised January 2015.

Contraindications/Precautions AgentContraindications/Precautions LorcaserinPregnancy, use with caution with SSRI, SNRI. MAOI, triptans REMS program-certified pharmacies can distribute, negative pregnancy test needed monthly Phentermine & Topiramate ER Pregnancy, breastfeeding, glaucoma, hyperthyroidism, MAOI use within the last 14 days Naltrexone SR & Bupropion SR Pregnancy, uncontrolled hypertension, seizures, anorexia or bulimia, chronic opioid use, MAOI use within last 14 days LiraglutidePregnancy, personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2, pancreatitis Arena. Belqiq (lorcaserin) tablets. Prescribing Information. Revised August Vivus. Qsymia (phentermine and topiramate) capsules. Prescribing Information. Revised October Orexigen. Contrave (naltrexone and bupropion) tablets. Prescribing Information. Revised September NovoNordisc. Saxenda (liraglutide) injection. Prescribing Information. Revised January 2015.

Safety Concerns Agent LorcaserinSerotonin syndrome, valvular heart disease, congenital impairment, psychiatric disorders, suicidal ideation, priapism, hypoglycemia Phentermine & Topiramate ER Increased HR and BP, elevated creatinine, acute myopia, glaucoma, mood and sleep disorder Naltrexone SR & Bupropion SR Suicidal ideation, seizures, increases in BP and HR, hepatotoxicity LiraglutideHypoglycemia, Not sharing the pen, renal impairment Apovian CM, Argonne LJ, Bessesen DH, et.al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. February 2015; 100(2):

Considerations for Optimizing Pharmacotherapy  Patient response will be variable to different medications  Safety and tolerability characteristics should be considered for individual patients  Medications should be paired with lifestyle changes to maximize therapeutic efficacy  An unsatisfactory clinical response at weeks, consider an alternative – Weight plateau is not a sign of tolerance or lack of efficacy – Withdrawing medication leads to weight regain

Over the Counter Weight Loss Supplements  Orlistat (Alli ® ) – Rx product-Xenical ®  60mg three times a day with meals – Rx is double the dose  MOA-absorption of ingested dietary fat  Not to be used in pregnancy, chronic malabsorption syndrome, cholelithiasis, transplant patients  Reduced fat soluble vitamin absorption, GI side effects, monitor for liver injury  Modest weigh loss GlaxoSmithKline. Alli (orlistat) capsules. Accessed October 1, 2015www.mialli.com

Dietary Supplements  February 2015-National Institute of Health’s Office published a review of 19 common ingredients used in weight loss supplements Possible or modest effects on weight loss and/or body fat were CaffeineChitosanChromium Conjugated linoleic acid Ephedra*Green coffee been extract Green TeaPyruvateWhite kidney bean extract Accessed October 1, 2015 *has been banned

Future Targets of Therapy  New lipase inhibitors (Cetilistat)  phase 3  Melanocortin-4 receptor agonists (RM-493)  phase 2  Triple monoamine re-uptake inhibitors (tesofensine)  phase 2  Neuropeptide Y5 receptor antagonists (velneperit)  pre-clinical trials  Methionine amino peptidase 2 inhibitor (beloranib)  pre-clinical trials  Manipulation of gut microbiota  emerging area of research Carthage P, Moran MB, Shanahan F. Gut microbiota and obesity: role in aetiology and potential therapeutic target. Best Practice & Research Clinical Gastroenterology. 2014; 28: Fani L, Bak S, Delhanty P et al. The melanocortin-4 receptor as a target for obesity treatment: a systematic review of emerging pharmacological therapeutic options. International Journal of Obesity. May 2013; 38: George M, Rajaram M, Shanmugam E. New and emerging drug molecules against obesity. Journal of Cardiovascular Pharmacology and Therapeutics. 2014; 19(1):

Conclusions  Obesity is a complex disease with many complications and co- morbidities.  Any degree of weight loss is beneficial, however, clinically meaningful weight loss produces significant benefits for preventing cardiovascular disease and metabolic syndrome.  New obesity management agents provide a range of options to achieve and maintain weight goals and improve long term health outcomes  The pharmacist can have a role in the management of obesity including lifestyle interventions and behavioral therapy as well as pharmacologic options.  Pharmacists need to educate providers and patients on options for weight loss mediations-both prescription and over-the-counter.