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Donna H. Ryan, MD Professor Emerita Pennington Biomedical Research Center Baton Rouge, LA, USA

The Role of Pharmacology in Weight Management: Putting Medications in Perspective for Chronic Weight Management

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Disclosures

• Consulting fee: Amgen, Gila Therapeutics, IFA Celtic, Novo Nordisk, Bausch Health, Real Appeal, Sanofi, Quintiles Novella, Paul Hastings, Simmons and Simmons, ReDesign Health, KVK Tech • Speakers bureau: Novo Nordisk, Bausch Health • Equity: Gila Therapeutics, Scientific Intake, Epitomee, ReDesign Health

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Objectives At the end of the session, attendees will be able to • identify when to start a weight loss medication, • identify how to choose the right one for the right patient, • identify when to combine approaches for better results and • discuss future prospects in obesity pharmacotherapy. •

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Should we treat obesity with drugs?

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Should we treat obesity with drugs?

No! not by themselves Yes! when patients need help • Drugs don’t work on their own. • For patients who struggle to lose They work through biology to enough weight to get health reinforce the patient’s intention to benefits, drugs can help them adhere to a dietary plan. Better better adhere to the dietary plan adherence = more weight loss. to lose more weight. Drugs also Drugs also sustain lost weight as sustain weight loss as long as they long as they are taken. are taken.

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Rationale for Medications in Obesity Management

• Food intake is biologically determined. • Weight loss is opposed and regain promoted by physiology of reduced obese state. • Medications work through biology of appetite regulation to help patients adhere to diet plans. • Medications help patients lose more weight than lifestyle alone, and thus achieve more health benefits. • Continuing medications sustains reduced body weight.

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Modest Weight Loss Has Benefits— Greater Weight Loss Is Associated With Greater Benefits • Progression from prediabetes to diabetes1 −3.0% • Measures of glycemia1 • Triglycerides and HDL cholesterol1 For all of these, • Systolic and diastolic blood pressure1 −5.0% more is better! • Hepatic steatosis (measured by MRS)2 More weight • Measures of feeling and function loss = more – Symptoms of urinary stress incontinence1 −10.0% – Measures of sexual function3 improvement. – Quality of life measures (IWQOL)4 • NASH activity score (measured by biopsy)1 −15.0% • Apnea-hypopnea index1 • Reduction in CV events, mortality, remission of T2DM5,6

• 1. Cefalu WT, et al. Diabetes Care. 2015;38:1567-1582; 2. Lazo M, et al. Diabetes Care. 2010;33:2156-2163. • 3. Wing R, et al. Diabetes Care. 2013;36:2937-2944; 4. Kolotkin RL, et al. Obes Res. 2001;9:564-571. • 5. Sjostrom L, et al. JAMA. 2012;307:56-65; 6. Sjostrom L, et al. JAMA. 2014;311:2297-2304.

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Why have medications gotten a bad rap? Older medications were not safe. • They weren’t studied properly! Short-term studies, few patients. We thought we could produce weight loss and the patient would be cured.

The science of obesity was not understood. • We thought patients just needed to be told to eat less and exercise more and try harder.

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Apovian CM, Aronne LJ, Bessesen DH et al. Pharmacologic Management of obesity: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015;100(2):342–362. .

Guidance on medications which produce weight loss or are weight neutral Bariatric Surgery But… within the context of foundational treatment with diet, physical activity and behavior Pharmacotherapy modification

And… recognizing that some patients benefit from bariatric Behavioral Modification to surgery. Change Diet, Physical Activity

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Current Medications and How They Work http://www.accessdata.fda.gov/scripts/cder/drugsatfda/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Scheduled Agent Action Approval Drug • Sympathomimetic amine; norepinephrine release and Phentermine Approved 1959 • YES to lesser extent releases other monoamines • Pancreatic lipase inhibitor; Blocks absorption of 30%of Approved 1999 Orlistat • NO ingested dietary fat OTC Approved 2006 • 5-HT serotonin agonist 2C Approved 2012 • YES Lorcaserin • Little affinity for other serotonergic receptors • Sympathomimetic Phentermine/ • Anticonvulsant (GABA receptor modulator carbonic Approved 2012 • YES Topiramate ER anhydrase inhibitor, glutamate antagonist) Naltrexone SR/ • Opioid receptor antagonist Approved 2014 • NO Bupropion SR • Dopamine/norepinephrine reuptake inhibitor

Liraglutide 3.0 mg • GLP-1 receptor agonist Approved 2014 • NO

OTC: over the counter; ER: extended release; GABA: gamma-aminobutyric acid; SR: sustained release.

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Agent 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 Hyperthyroidism Placebo – 3% Constipation 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 serotonergic Valvular heart disease Lorcaserin – 8.6% Fatigue drugs 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 – 24% Headache Chronic opioid use Glaucoma Placebo – 12% Insomnia MAOI use, Pregnancy Hepatotoxicity Liraglutide 3.0 Nausea Personal/family history of Thyroid c-cell tumors (rodents) Discontinuation: GI complaints medullary thyroid carcinoma or Acute pancreatitis Liraglutide – 9.8% MEN2 Gallbladder disease Placebo – 4.3% History of pancreatitis Hypoglycemia, Tachycardia Pregnancy Renal impairment, Suicidal behavior

All data from product labels

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Prescribing weight loss medication – Step 1. Do no harm.

• Follow the label • BMI >30 or >27 with comorbidity • Determine lack of success with prior weight loss efforts • Use contraindications and warnings to exclude certain medications • Examples: • Do not prescribe for cosmetic reasons • Do not prescribe phentermine in patients with history of CVD • Chronic malabsorption syndrome – do not prescribe orlistat • History of pancreatitis – use liraglutide 3.0 mg with caution • History of seizures, patients on opiates – do not prescribe naltrexone/bupropion

All information from product labels

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What Can Be Expected from Lifestyle Change? F from the 2013 ACC/AHA/TOS Obesity Guidelines on Lifestyle Intervention • Gold standard: trained interventionist; face to face counseling; 14 sessions in 6 months with follow-up for 1 year; comprehensive (diet, physical activity and behavioral therapy); reliably produces mean 8 kg weight loss at 1 year. • No difference in individual or group approaches. • Telephone interventions generally equal to face-to-face. • Internet or email interventions produce less weight loss. • Commercial counseling programs (with or without packaged foods) and (in person or telephone counseling) can be effective – Jenny Craig, Nutrisystem, Weight Watchers. Approximately 1 in 5 patients will achieve >5% loss with self-help approaches; most patients (~70%) will achieve >5%with intensive programmatic approaches to lifestyle counseling. Jensen MD, Ryan DH, Donato KA, et al. Guidelines (2013) for managing overweight and obesity in adults. Obesity 2014;22(S2):S1-S410.

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Prescribing weight loss medication Step 2. Consider added benefits of medications Dual benefits may be appropriate for selected patients. • For patients with obesity and type 2 diabetes, consider medication with glycemic effect, ie. Liraglutide 3.0 mg • For patients that would benefit from lowering their LDL levels, orlistat may be appropriate to lower dietary fat intake • For patients who are trying to quit smoking or who have depression, bupropion has indications for smoking cessation and depression

All information from product labels LDL, low-density lipoprotein

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Dual Benefits

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Prescribing weight loss medication Step 3. Identify medications that drive weight gain and switch to weight-neutral meds or those associated with weight loss.

All information from product labels LDL, low-density lipoprotein

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Weight Effects of Common Medications1 Alternatives Weight Gain Medication (Weight Reducing Associated With Use in Parentheses) (Metformin, acarbose, Insulin, sulfonylureas, TZDs, mitiglinide, miglitol, pramlintide, Diabetes medications sitagliptin?a exenatide, liraglutide, SGLT-2 inhibitors) Hypertension ACE inhibitors?, calcium channel blockers?, α-Blocker?, β-blocker? medications angiotensin-2 RAs

Amytriptyline, doxepin, imipramine, Antidepressants and nortriptyline, trimipramine, mirtazapine, (Bupropion), nefazodone, fluoxetine (short mood stabilizers fluoxetine?, sertraline?, paroxetine, term, sertraline, <1 year) fluvoxamine

Oral contraceptives Depot progesterone Barrier methods, IUDs

? represents uncertain/under investigation.

1. Apovian CM et al. J Clin Endocrinol Metab. 2015;100:342-362.

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Prescribing weight loss medication Step 4. Use shared decision making • To engage the patient in the decision about taking a medication; patients need to know what to expect • To determine the dietary strategy to match the medication’s mechanism of action • Example: Orlistat requires a low-fat approach • To negotiate the most intensive lifestyle changes that the patient will agree to undertake • Medications don’t work on their own

All information from product labels LDL, low-density lipoprotein

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Combining Therapies Produces Greater Weight Loss

Wadden TA, et al. N Eng J Med. 2005;353(20):2111-20.

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Prescribing weight loss medication Step 5. Remember heterogeneity of treatment effects

All drugs have stopping rules • No medication works in every patient

• We generally want to see 4-5% weight loss in All signs point to yes, or 12-16 weeks maybe no • If a patient has not responded, stop the drug and try another

All information from product labels LDL, low-density lipoprotein

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When individual weight loss is displayed, it looks like this:

McCullough PA, et al. Poster AANP 2013.

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Medications approved for weight management – Dosing and Response Evaluation Agent Dosing Response Evaluation Phentermine 8 mg; 15 mg; 30 mg Only approved for short term use Orlistat 120 mg orally with each meal Not addressed in label 10 mg orally twice daily or Lorcaserin Stop if <5% loss at 12 weeks 20 mg orally daily Orally in am; At 12 weeks, opon to ↑ to 11.25 mg/69 mg Phentermine/ 3.75 mg/23 mg × 14 days; × 14 days, then 15 mg/96 mg; Topiramate ER Then, 7.5/46 mg ×14 days. Stop if <5% loss at 12 weeks on top dose Orally; Wk 1 -1 tab (8 mg/90 mg) in am ; Naltrexone SR/ Wk 2 - 1 in am 1 in pm; Stop if <5% loss at 12 weeks Bupropion SR Wk 3 - 2 in am 1 in pm; Wk 4 - 2 in am 2 in pm. Inject subcutaneously (any time of day); Wk 1 - 0.6 mg; Liraglutide 3 mg Stop if <4% weight loss at 16 weeks increase dose by 0.6 mg weekly until dose is 3.0 mg (Wk 5)

All data from product labels

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Prescribing weight loss medications Step 6. Use for the long term • Orlistat, lorcaserin, phentermine/topiramate, naltrexone/bupropion and liraglutide all have an indication for “chronic weight management.” • These medications can be used indefinitely, just like our drugs for hypertension, diabetes and dyslipidemia. • Encourage patients to use the medications for the long term.

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How long should we treat with medications? Liraglutide 3.0 mg: 3 Year observation

le Roux CW, et al. Lancet. 2017;389(10077):1399-1409.

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Let’s look at individual medications

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Phentermine: FDA-Approved for Obesity Management: Short-Term Use

• Sympathomimetic agent; Scheduled drug (II or IV) • Common adverse events1: insomnia, elevated heart rate, dry mouth, taste alterations, dizziness, tremors, headache, diarrhea, constipation, vomiting, gastrointestinal distress, anxiety, restlessness

ENDO Pharmacotherapy Guidelines2: “In patients with uncontrolled hypertension or a history of heart disease, we recommend against using sympathomimetic agents phentermine and diethylpropion. 1 (strong rec, moderately high quality evidence)

1. Yanovski SZ, Yanovski JA. JAMA. 2014;311:74-86 2. Apovian CM, Aronne LJ, Bessesen DH et al. Pharmacologic Management of obesity: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015;100(2):342–362.

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Randomized comparison of weight loss at 28 weeks with lifestyle intervention and placebo, phentermine 7.5 mg or phentermine 15 mg Aronne LJ, et al. Obesity 2013. 21, 1-9. 0 Placebo -2 -1.71 Phentermine 7.5 -4 mg -6 Phentermine 15

Weight Loss (%) -5.45 -6.06 mg -8

Data shown are LS mean and all comparisons are statistically significant. Treatment arms not shown are topiramate 46 mg and 92 mg and phentermine/topiramate ER 7.5/ 46 mg and 15/92 mg.

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Orlistat 120 mg 3 times daily by prescription Orlistat 60 mg 3 times daily OTC

• Blocks absorption of 30% ingested fat (intestinal lipase inhibitor) • 120 mg TID with meals (Rx) or 60 mg TID (OTC) • Available world-wide • Generally safe; Contraindications: pregnancy, chronic malabsorption syndrome, cholestasis • Reinforces low fat diet, has efficacy in LDL lowering • No effect on appetite • Must counsel patients regarding gastrointestinal side effects and steatorrhea • Consider using with Metamucil, multivitamin at bedtime

Information from product label

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Liraglutide 3.0 mg:

• Liraglutide is GLP-1 receptor agonist, given by daily injection • Not scheduled • Tolerability issues: nausea – requires dose escalation from 0.6 mg • Safety issues: pancreatitis risk; gall bladder disease risk; contraindicated with history of MEN II or medullary thyroid cancer. • Has indication for diabetes at 1.8 mg dose, so has secondary benefit on glycemia

Information from product label

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Lorcaserin 10 mg or 20 mg tabs

• 5HT 2c receptor agonist, reduces food intake • 20 mg/day single dose available • Scheduled (DEA) in US; though no abuse potential • Well tolerated • No evidence of valvulopathy. • With other serotonergic or SSRIs, prescribe with ‘extreme caution’ because of serotonin syndrome risk

Information from product label

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Phentermine/ Topiramate ER recommended dose 7.5 mg/46 mg • Two common medications, at low dose • Acts centrally to reduce food intake • Scheduled (DEA) in US • Titrate to 7.5mg/46 mg • Produces greatest weight loss, on average • Tolerability issues: taste disturbance (carbonation), • Safety issues: teratogenicity (topiramate), glaucoma (topiramate) • Obtain negative pregnancy test before use and monthly in women of child- bearing potential

Information from product label

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Naltrexone SR/ Bupropion SR 32/360 mg tabs

• Two common medications; reduces food intake centrally & may affect craving • Not scheduled • Titrate to 32mg/360 mg • Tolerability issues: nausea – requires dose escalation from 8 mg/90mg • Safety issues: opioid antagonist (naltrexone), lowers seizure threshold and can unmask mania and increase suicidality risk (bupropion) • Has indication for smoking cessation and depression (bupropion)

Information from product label

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Remember…..

• There is no ideal medication. In the right patient, every medication can be a good medication. In the wrong patient, every medication can be a bad medication. • Medications don’t work in every patient. The medication profile must be matched to the patient profile. • They don’t work on their own! The intensity of the lifestyle intervention will determine total weight loss.

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What not to do!

• Medications containing thyroid hormones: If patient is not hypothyroid, they just suppress endogenous thyroid production. If give in excess, can cause tachycardia, arrythmias, heart failure, myopathy, osteoporosis, amenorrhea and infertility. • HCG: ineffective and potentially dangerous • Dinitrophenol: uncoupling, thermogenic agent causes cataracts, hyperthermia and death. • Ephedrine: used with caffeine for weight loss; causes stroke, heart attack and death. • Clenbuterol: used for asthma in horses; causes hyperthyroidism, heart problems and death. • Sibutramine and fenfluramine: although removed from market for heart disease risk and valvulopathy, can be found in supplements

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Objectives At the end of the session, attendees will be able to identify when to start a weight loss medication, identify how to choose the right one for the right patient, identify when to combine approaches for better results and • discuss future prospects in obesity pharmacotherapy. •

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Emerging Use of Combinations: What Some Obesity Specialists Do… • Guidelines1 do not endorse off label therapy or combining medications with indication weight management. • Obesity specialists do use medications off label and combine some medications with obesity indications and a literature is starting to emerge.2,3,4

1. Apovian CM, Aronne LJ, Bessesen DH et al. Pharmacologic Management of obesity: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015;100(2):342–362. 2. Wilding JPH. Combination therapy for obesity. Journal of Psychopharmacology. 31(11)1503-1508. 3. Mandel L, Shukla A, Litman E, et al. Poster LB 3770 - 1, Obesity Week 2018 4. Cadegiani1,FA, Diniz GC, Alves G. Cadegiani et al. BMC Obesity (2017) 4:9.

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In practice, obesity specialists use medications on-label and off-label

Naltrexone Phentermine Lorcaserin Liraglutide Bupropion

Phentermine SGLT 2 Bupropion Metformin Topiramate inhibitors

Zonisimide Topiramate GLP 1 RAs

Note: Orlistat does not affect appetite and it is unusual to use it in combination for the purpose of additional weight loss.

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Emerging Pharmacotherapies

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Leptin

• Discovered in 1992 • Protein produced by fat that circulates through the body • Chief function: Signals the brain to the amount of body fat stores • Fall in leptin levels = increase in food intake, reduction in energy expenditure • Leptin levels vary exponentially with fat mass; individuals with excess fat have increased leptin levels. • Individuals with leptin deficiency have been identified, but the condition is very rare.

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3 Turkish cousins with a mutation in Leptin

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After 3 Months of Treatment with Leptin

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After 10 months of treatment

Hormone Leads to Dramatic Weight Loss for Three Cousins

Aug. 7 – How can three family members slim down to half their body weight without even trying? With the help of an appetite control hormone called leptin, new research suggests.

Only 10 months later, the cousins have lost nearly half their body weight.

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What about Leptin as a treatment for weight loss?

• It didn’t work! Even at very high doses, weight loss was only minor and there were injection site reactions. • Leptin, as Metreleptin, is approved for leptin deficiency and for congenital and acquired lipodystrophy

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Pramlintide/Metreleptin: Restoring responsiveness to Leptin

Phase 3 development

stopped because ofEvaluable toxicity. N = 93; Least square mean ± SE; *P<0.05, **P<0.01, ***P<0.001 vs Neutralizing antibodies.monotherapies. LOCF, last observation carried forward

. Ravussin E et al: Obesity 2009;17:1736–1743.

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Therapy Targeting MC4R and POMC Setmelanotide

Kuhnen P, et al. N Eng J Med. 2016;375:240-246.

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Semaglutide 2.4 mg once weekly by injection in Phase 3 study* 16.00% 14% 14.00% 11.55% 12.00% 10.00% 9.31% 8.88% 9.09% 8.00% 6.30% 6.00% 5.40% 3.70% 4.00% 2.00% 0.00% Semaglutide Semaglutide Semaglutide Semaglutide Semaglutide Semaglutide Semaglutide Liraglutide 3 0.05 mg 0.1 mg 0.2mg 0.3 mg 0.4 mg 0.3 mg FE 0.4 mg FE mg Phase 2 dose ranging study of dailySeries doses 1 of semaglutide vs. liraglutide 3 mg. For Phase 3, semaglutide 2.4 mg weekly will be used.

1. O’Neil PM, et al. Lancet. 2018;392:637-649. . 50 05/06/2019 24

Tirzepatide (dual GLP1/GIP RA) Phase 2 dose ranging study over 26 weeks

Weight loss in Kg 0 -2 -4 -6 -8 -10

Mean Mean WeightKg loss in -12 Tirzepatide 10 Tirzepatide 15 Dulaglutide 1.5 Tirzepatide 5 mg placebo mg mg mg Weight loss in Kg -4.8 -8.7 -11.3 -2.7 -0.4

Frias JP, et al. Lancet. 2018 Nov 17;392(10160):2180-2193.

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Conclusions

• Our first generation medications approved for chronic weight management can produce on average ~5% weight loss in addition to that achieved with lifestyle change alone. • The next generation of medications will achieve ~10% weight loss in addition to that achieved with lifestyle change alone. (5 years in the future) • We will keep improving and will be able to produce results similar to bariatric surgery in about 15-20 years. • We will be able to normalize body weight in all individuals in about 50 years, when we understand personalized and precision approaches.

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Key Messages

• Medications can drive weight gain; they can also help patients lose weight and keep it off. Don’t be afraid to prescribe. • Know the drug profiles - prescribe the right medication in the right patient. • Always negotiate the most intensive lifestyle recommendation with the patient that you can. • Evaluate response at ~12 weeks on drug; continue if weight loss is > ~5% and change if weight loss is not ~5%. • Encourage patients to continue medication to keep weight off.

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Thank you!

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