05/06/2019 1 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 1 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 2 05/06/2019 2 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. • 3 Should we treat obesity with drugs? 4 05/06/2019 3 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. 5 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. 6 05/06/2019 4 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. 7 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. 8 05/06/2019 5 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 9 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. 10 05/06/2019 6 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 11 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 12 05/06/2019 7 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. 13 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 14 05/06/2019 8 Dual Benefits 15 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 16 05/06/2019 9 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. 17 Prescribing weight loss medication Step 4. Use shared decision making • To