Obesity Pharmacotherapy: Options and Applications in Clinical Practice. Scott Kahan, MD, MPH

Obesity Pharmacotherapy: Options and Applications in Clinical Practice Scott Kahan, MD, MPH

Obesity 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 Use of pharmacotherapy for weight loss within 12 months after the index date, % 2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 1.3 0.9 0.6 0.7 0.2 >27 <30 >30 <35 >35 <40 >40 Overall Body mass index at index (kg m 2 ) Zhang S, et al. Obesity Science & Practice.2016;2:104-114.

FDA-approved Pharmacotherapy Options for the Treatment of Obesity Phentermine and other noradrenergic agents Orlistat Phentermine/topiramate ER Lorcaserin Naltrexone SR/bupropion SR Liraglutide 3.0mg ER = extended release; SR = sustained release.

Phentermine Sympathomimetic amine, NE release Blunts appetite 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, drug 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 diabetes 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 10 % Weight Loss 5 0 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/ topiramate ER Naltrexone/ bupropion SR Liraglutide 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 Dry mouth Agitation Constipation CVD, CHF, arrhythmias Uncontrolled hypertension MAOI use Hyperthyroidism Glaucoma Pregnancy Primary pulmonary hypertension Discontinuation (CNS): Phentermine 17% Placebo 3% Orlistat GI complaints Chronic malabsorption Gallbladder disease May increase cyclosporine exposure; Liver failure Multivitamin administration 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% 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?! Permission required to reprint SUCRA = surface under the cumulative ranking curve. Khera R, et al. JAMA. 2016; 315:2424 2434.

Choosing Between Options Permission required to reprint 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 Elevated seizure risk History of recurrent kidney stones History of glaucoma Uncontrolled hypertension Coronary artery disease Moderate-to-severe renal impairment Moderate-to-severe hepatic impairment SSRI use Naltrexone/bupropion Avoid/Caution Phentermine/topiramate, orlistat Phentermine/topiramate Naltrexone/bupropion, phentermine Phentermine Do not exceed half-dose: phentermine/topiramate, naltrexone/bupropion Caution: liraglutide, lorcaserin Do not exceed half-dose: phentermine/topiramate Do not exceed one-quarter dose: naltrexone/bupropion Caution: liraglutide, lorcaserin Caution: lorcaserin SSRI = selective serotonin reuptake inhibitor.

Dual Benefits If Patient has Obesity and Smoking Depression Migraines Diabetes Chronic constipation Elevated LDL Consider (But not Explicitly Approved) Naltrexone/bupropion Naltrexone/bupropion Phentermine/topiramate ER Liraglutide 3.0 mg Orlistat 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 Permission required to reprint Adapted from Wadden, et al. N Eng J Med. 2005;353:2111 2120.

Emerging Therapeutic Options: Setmelanotide Permission required to reprint

Emerging Therapeutic Options: Setmelanotide Setmelanotide a melanocortin 4 receptor agonist Investigator initiated, open label study Two patients with proopiomelanocortin 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.