Obesity Pharmacotherapy: Options and Applications in Clinical Practice

Scott Kahan, MD, MPH Pharmacotherapy • Few providers prescribe pharmacotherapy. • Few patients use pharmacotherapy. • Pharmacotherapy can be extremely effective but also misused, overused, or underused. • Patients respond differently to each medication. • Combining therapeutic options significantly improves weight loss and other outcomes. • Pharmacotherapy can be effective for weight maintenance, not just weight loss. Few Eligible Patients Use Obesity Pharmacotherapy

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Use of pharmacotherapy for weight loss within 0 >27‐<30 >30‐<35 >35‐<40 >40 Overall Body mass index at index (kg m2)

Zhang S, et al. Obesity Science & Practice.2016;2:104-114. FDA-approved Pharmacotherapy Options for the Treatment of Obesity

• and other noradrenergic agents • • Phentermine/ ER • • SR/ SR • Liraglutide 3.0mg

ER = extended release; SR = sustained release. Phentermine

• Sympathomimetic amine, NE release • Blunts • Approved in 1959 for short-term use, schedule IV • Dosing: 8 to 37.5 mg qAM; use lowest effective dose • Contraindications: pregnancy, nursing, MAOIs, glaucoma, abuse history, hyperthyroidism • Relative contraindications: uncontrolled hypertension, tachycardia, history of CAD, CHF, stroke, arrhythmia • Warnings: primary pulmonary hypertension, valvular heart disease, tolerance, risk of abuse, concomitant use with alcohol

CAD = coronary artery disease; CHF = congestive heart failure; HTN = hypertension; MAOIs = monoamine oxidase inhibitors; NE = norepinephrine. Phentermine [package insert]. Cranford, NJ: Alpex Pharma SA; 2011; Munro JF, et al. Br Med J. 1968;1(5588):352‐354. Orlistat

• Lipase inhibitor, decreases fat absorption • Approved 1999; long-term use • Not scheduled • 120 mg TID with meals (Rx) or 60 mg TID (OTC) • Use MVI with fat-soluble vitamins at bedtime • Contraindications: pregnancy, chronic malabsorption syndrome, cholestasis • Possible gastrointestinal adverse events MVI = multi‐vitamin; OTC = over‐the‐counter. Orlistat [package insert]. South San Francisco, CA: Genentech; 2012; Orlistat [package insert]. Moon Township, PA: GlaxoSmithKline; 2011. Lorcaserin

• Selective 5-HT2C receptor agonist • Increases satiety • Approved in 2012 for long-term use; schedule IV • Single dose: 10 mg BID • Contraindications: pregnancy • Warnings: co-administration with serotonergic or antidopaminergic agents, valvular heart disease, psychiatric disorders (euphoria, suicidal thoughts, depression), priapism • Discontinue if less than 5% weight loss after 12 weeks of use

BELVIQ [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; 2012. Lorcaserin: Outcomes by Responder Status

LOR = lorcaserin; PBO = placebo. Smith SR, et al. Obesity. 2014;22:2137‐2146. Reprinted with permission. Phentermine/Topiramate ER

• Phentermine: sympathomimetic amine; blunts appetite • Topiramate: 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

GABA = gamma-aminobutyric acid. Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012. Naltrexone SR/Bupropion SR

• Naltrexone: opioid receptor antagonist; blocks autoinhibition of POMC neurons and amplifies the effect of bupropion • Bupropion: dopamine/noradrenaline reuptake inhibitor • Not a controlled substance • Standard dose: 32/360 mg (2 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

POMC = pro-opiomelanocortin. Contrave (naltrexone SR/bupropion SR) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf;. Liraglutide 3.0 mg

• Glucagon-like peptide 1 (GLP-1) receptor agonist • Multiple actions; effect on weight is primarily via POMC neurons • Liraglutide 1.8 mg FDA-approved in 2010 for T2DM • Liraglutide 3.0 mg FDA-approved for primary indication of obesity in December 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 T2DM = type 2 mellitus; REMs = Risk Evaluation and Mitigation Strategies; SC = subcutaneous. Saxenda (liraglutide 3.0 mg) prescribing information. http://novo-pi.nnittest.com/saxenda.pdf. Weight Loss in Patients Completing 1 Year of Treatment

15 Medication Placebo

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5 % Weight Loss

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Torgerson JS, et al. Diabetes Care. 2004;27(1):155–161; Smith SR, et al. N Engl J Med. 2010;363:245–256; Fidler MC, et al. J Clin Endocrinol Metab. 2011;96:3067-3077; O'Neil PM, et al. Obesity (Silver Spring). 2012;20:1426–1436; Allison DB, et al. Obesity (Silver Spring). 2012;20(2):330–342; Gadde KM, et al. Lancet. 2011;377:1341–1352; Garvey WT, et al. Am J Clin Nutr. 2012;95:297–308; Greenway FL, et al. Lancet. 2010;376:595–605; Apovian CM, et al. Obesity (Silver Spring). 2013;21:935-943; Wadden TA, et al. Obesity (Silver Spring). 2011;19:110–120; Hollander P, et al. Diabetes Care. 2013;36:4022–4029; Wadden TA, et al. Int J Obes (Lond). 2013;37:1443-1451; Pi-Sunyer X, et al. N Enlg J Med. 2015;373:11-22. Phentermine/Topiramate CR: Long-term Outcomes - 2 Years

Garvey WT, et al. Am J Clin Nutr. 2012;95:297‐308. Reprinted with permission. Liraglutide 3.0 mg: Long-term Outcomes - 3 Years

le Roux C, et al. Poster presented at: TOS 2015; November 2‐7, 2015; Los Angeles, CA. Poster T‐P‐LB‐3843. Orlistat: Long-term Outcomes - 4 Years • Cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat • risk reduction: 37.3% (P = 0.0032) • Mean weight was significantly greater with orlistat (5.8 vs. 3.0 kg with placebo; P < 0.001)

Torgerson JS, et al. Diabetes Care. 2004;27:155‐161. Lorcaserin: Long-term Benefits Require Long-term Use

• Among pts in the lorcaserin group who had weight loss of >5% or more at year 1, the loss was maintained in a greater proportion of pts who continued to receive lorcaserin in year 2 than in those who reassigned to placebo (67.9% vs 50.3%, P<.001). • Mean body weight among pts who received lorcaserin in both years was lower than that among pts who received placebo in both years and lower than that among pts who received lorcaserin in year 1 and placebo in year 2.

Smith SR, et al. N Eng J Med. 2010;363:245-256. Liraglutide 3.0 mg for Weight Maintenance

Wadden TA, et al. Int J Obes (Lond). 2013;37:1443‐1451. Reprinted with permission. Improvements in Risk Factors and Comorbidities

Orlistat Lorcaserin Phentermine/ Naltrexone/ Liraglutide topiramate ER bupropion SR 3.0 mg WC     BP     LDL      HDL     TG      A1C      HR  ‐  Diabetes     

BP = blood pressure; HDL = high-density lipoprotein; HR = heart rate; LDL = low-density lipoprotein; TG = triglycerides; WC = waste circumference. Adipex-P (phentermine) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/088023s037lbl.pdf; Xenical (orlistat) prescribing information. http://www.gene.com/download/pdf/xenical_prescribing.pdf; Qsymia (phentermine/topiramate ER) prescribing information. https://qsymia.com/pdf/prescribing-information.pdf; Belviq (lorcaserin) prescribing information. www.belviq.com/documents/Belviq_Prescribing_information.pdf; Contrave (naltrexone SR/bupropion SR) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf; Saxenda (liraglutide 3.0 mg) prescribing information. http://novo-pi.nnittest.com/saxenda.pdf. Drug Common AE Contraindication Safety Consideration Tolerability Phentermine Insomnia CVD, CHF, arrhythmias Primary pulmonary hypertension Discontinuation (CNS): Dry mouth Uncontrolled hypertension Phentermine – 17% Agitation MAOI use Placebo – 3% Constipation Hyperthyroidism Glaucoma Pregnancy Orlistat GI complaints Chronic malabsorption May increase cyclosporine exposure; Discontinuation: Gallbladder disease Liver failure Orlistat – 8.8% Multivitamin administration Placebo – 5%

Phentermine/ Dry mouth Glaucoma Teratogenicity Discontinuation: topiramate ER Paresthesias Hyperthyroidism Metabolic acidosis Top dose – 17% Headache MAOI use Glaucoma Low doses – 12% Insomnia Pregnancy Placebo – 8%

Lorcaserin Headache MAOI use Serotonin syndrome Discontinuation: Dizziness Use with caution with Valvular heart disease Lorcaserin – 8.6% Fatigue serotonergic Depression Placebo – 6.7% Dry mouth Pregnancy Priapism Naltrexone/ Nausea Seizure disorder Suicidality in adolescents Discontinuation: bupropion SR GI complaints Uncontrolled hypertension Elevated blood pressure, pulse Naltrexone/bupropion – Headache Chronic opioid use Glaucoma 24% Insomnia MAOI use Hepatotoxicity Placebo – 12% Pregnancy Liraglutide 3.0 Nausea Personal/family history of Thyroid c‐cell tumors (rodents) Discontinuation: GI complaints medullary thyroid carcinoma Acute pancreatitis Liraglutide – 9.8% or MEN2 Gallbladder disease Placebo – 4.3% History of pancreatitis Hypoglycemia Pregnancy Tachycardia Renal impairment Suicidal behavior

Adipex‐P (phentermine) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/088023s037lbl.pdf; Xenical (orlistat) prescribing information. http://www.gene.com/download/pdf/xenical_prescribing.pdf; Qsymia (phentermine/topiramate ER) prescribing information. https://qsymia.com/pdf/prescribing‐information.pdf; Belviq (lorcaserin) prescribing information. www.belviq.com/documents/Belviq_Prescribing_information.pdf; Contrave (naltrexone SR/bupropion SR) prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf; Saxenda (liraglutide 3.0 mg) prescribing information. http://novo‐pi.nnittest.com/saxenda.pdf What’s the “Best” Medication?!

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SUCRA = surface under the cumulative ranking curve. Khera R, et al. JAMA. 2016; 315:2424‐2434. Choosing Between Options

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Yancy WS, et al. Arch Int Med. 2010;170:136-145. Choosing Between Options Drug factors • Contraindications • Dual benefits • Studied populations

Patient factors • Patient preferences • Adverse events • Prior experiences • Access

Physician factors • Provider knowledge/comfort Contraindications and Cautions

Clinical Scenario Avoid/Caution Elevated seizure risk Naltrexone/bupropion History of recurrent kidney stones Phentermine/topiramate, orlistat History of glaucoma Phentermine/topiramate Uncontrolled hypertension Naltrexone/bupropion, phentermine Coronary artery disease Phentermine Do not exceed half-dose: phentermine/topiramate, Moderate-to-severe renal naltrexone/bupropion impairment Caution: liraglutide, lorcaserin Do not exceed half-dose: phentermine/topiramate Moderate-to-severe hepatic Do not exceed one-quarter dose: impairment naltrexone/bupropion Caution: liraglutide, lorcaserin SSRI use Caution: lorcaserin

SSRI = selective serotonin reuptake inhibitor. Dual Benefits

If Patient has Consider (But not Explicitly Obesity and… Approved)…

Smoking Naltrexone/bupropion

Depression Naltrexone/bupropion

Migraines Phentermine/topiramate ER

Diabetes Liraglutide 3.0 mg

Chronic constipation Orlistat

Elevated LDL Orlistat Patients with Extreme Obesity (BMI >45)

BMI = Body Mass Index; PHEN/TPM = phentermine/topiramate. Kahan S, et al. Poster presented at: TOS 2015; November 2‐7, 2015; Los Angeles, CA. Poster T‐P‐3143. Choosing Between Options Drug Factors • Contraindications • Dual benefits • Studied populations

Patient Factors • Patient preferences • Adverse events • Prior experiences • Access

Physician Factors • Provider knowledge/comfort Combination Therapy

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Adapted from Wadden, et al. N Eng J Med. 2005;353:2111‐2120. Emerging Therapeutic Options:

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• Setmelanotide ‐ a ‐4 receptor agonist • Investigator‐initiated, open‐label study • Two patients with deficiency treated with setmelanotide • Patients had a sustainable reduction in hunger and substantial weight loss • 51.0 kg after 42 weeks in Patient 1 • 20.5 kg after 12 weeks in Patient 2

Kuhnen P, et al. N Engl J Med. 2016;375:240-246. New and Emerging Medical Devices for the Treatment of Obesity

• Novel oral capsulated device ‐ Taken before meals ‐ Particles released and expand in stomach by absorbing water ‐ Designed to enhance satiety and delay gastric emptying

Astrup A, et al. Presented at: ENDO 2014, June 21‐24, 2014; Chicago, IL. Abstract SUN‐0897. Final Thoughts on Pharmacotherapy

• Treatment of obesity with pharmacotherapy as an adjunct to lifestyle modification is a valuable option for obesity treatment. • Several options are available and FDA approved. • Understand potential benefits and risks of agents when planning treatment. • Different patients respond to different medications. • If one option doesn’t work well, consider others.