Medical Management of Obesity

Educational Objectives

The goal of this program is to improve medical management of obesity. After hearing and assimilating this program, the clinician will be better able to:

1. Explain the physiology and pathophysiology of weight regulation.
2. Identify effective medical treatment strategies for obesity.
3. Recognize contraindications to use of medications for weight management.

Summary

Approach to weight management: as with other chronic diseases, treatment of obesity must be lifelong and typically relies on combination therapy; use “people first” language when talking to patients; create a weight history to identify onset of weight gain and periods of increases in weight; try to correlate weight gain with specific medications or diseases; puberty, pregnancy, and menopause are vulnerable times for women; identify lifetime maximum weight and previous successful strategies, and compare current weight to the maximum

Physiology and pathophysiology of weight regulation: governed by interactions among 3 major organ systems (the brain [“command center”]; the gastrointestinal [GI] system and adipose tissue [sensing organs]); hormone patterns signal the brain as to, eg, when food is eaten, caloric intake; through leptin, adipose tissue stores signal adequate or inadequate status; GI system — nutrient absorption triggers secretion of gut hormones; satiety factors — eg, glucagon-like peptide 1 (GLP-1), peptide YY, cholecystokinin; provide feedback by binding to receptors in the hypothalamus; convey fullness and satisfaction; after fullness is achieved, hormone levels begin to gradually fall; the stomach produces the hormone ghrelin; the ghrelin level rises over time, signaling hunger; time zero — point at which food is eaten; the levels of secretion of fullness hormones and degree of suppression of ghrelin are proportional to caloric intake; consuming less than a normal, full meal results in decreased secretion of satiety hormones and decreased suppression of ghrelin; failure to achieve full satisfaction stimulates food-seeking behavior

Medications for weight loss: bind to cells in the hypothalamus and potentiate the fullness signal; satiety is achieved with fewer calories; the hunger hormone is dampened between meals; effectiveness plateaus when patients are 6% to 10% below their initial weights

Criteria for pharmacologic weight management: body mass index (BMI) ≥27 with weight-related comorbidity, especially hypertension (HTN), dyslipidemia, or diabetes mellitus, or BMI >30 (no comorbidities required); medications approved by the Food and Drug Administration (FDA) include tetrahydrolipstatin, phentermine plus topiramate (Qsymia), bupropion plus naltrexone, and liraglutide; phentermine alone is inexpensive but off-label

Phentermine plus topiramate: in randomized controlled trials (RCTs), achieved ≈10.5% weight loss at ≈2 yr (differed from placebo by 7%-8%);short-term side effects include increases in heart rate, blood pressure (rarely), and anxiety; some patients have more energy and better concentration; use of phentermine alone is approved by the FDA for ≈3 mo; phentermine plus topiramate can be continued long term; a centrally acting adrenergic agent; boosts secretion of norepinephrine (NE); although there have been concerns about worsening of HTN and tachyarrhythmias, data show stable or reduced blood pressure with long-term use; phentermine is an amphetamine derivative but is nonaddictive and does not cause withdrawal syndrome (can be discontinued without tapering); the speaker typically starts with half of a 37.5-mg generic tablet and titrates up, as tolerated; if not tolerated, use an 8-mg phentermine dose (Lomaira)

Topiramate: can be used alone (off-label) for patients with contraindications to phentermine; nuisance side effects include cognitive and memory effects and paresthesias; contraindicated for patients with history of kidney stones; category X for pregnancy (has a known association with birth defects); the speaker starts with 25 mg of generic topiramate, twice daily (a morning dose with phentermine, the second dose with dinner); titrate up to 100 mg twice daily (therapeutic dose for weight management); if dysesthesias occur with 100 mg, revert to 75 mg twice daily; this approach is followed after stabilization on phentermine (preferred over a fixed combination dose)

Cardiovascular (CV) safety: cohort study — compared phentermine alone, generic phentermine plus topiramate, and a fixed combination dose; although confidence intervals (CIs) were broad, the data indicate that risks for major adverse CV events (MACE), myocardial infarction (MI), death from MI, and stroke were lower among current users of the drugs than in a reference population

Long-term safety of phentermine or phentermine-topiramate: study from the Patient-Centered Research Institute (PCORI) — followed ≈14,000 adults with ≥1 prescription for phentermine for ≈2 yr; among responders to phentermine, long-term use was associated with a loss of ≈7% of excess weight; no serious CV events or deaths were observed with use of the drugs for ≤2 yr; authors concluded that limiting phentermine use to 3 mo (the on-label duration) does not align with current concepts of pharmacologic management of obesity; FDA Adverse Event Reporting System — a database analysis found no safety signals for coagulopathy, pulmonary HTN, or other CV events; data support longer-term use in selected populations without existing heart disease (HD)

Naltrexone plus bupropion (Contrave): average weight loss with ≥2 yr of use is less than that with phentermine-topiramate (4%-5% vs 6%-10%); a MACE outcomes trial (Nissen et al, 2016) found that, compared with the placebo group, the MACE rate was lower with naltrexone-bupropion at ≤2 yr but converged thereafter (suggesting noninferiority); however, the FDA stopped the study at 1 yr because of possible influence on the results by a premature press release; nausea is the most common adverse effect; bupropion is a centrally acting adrenergic agent (may affect blood pressure and cause insomnia); the speaker uses generic bupropion, starting at 150 mg daily, then increasing to twice daily; for naltrexone, the initial dose is one-quarter of a 50-mg tablet (then titrated up every 2 wk)

Liraglutide: weight loss at 3 yr is ≈6% (superior to placebo); reduces diabetes risk by ≈80% (better than with metformin, with greater weight loss); there are no MACE data for the 3-mg dose, but the 1.8-mg dose is associated with reduction of ≈13% in risk for nonfatal MI, stroke, and death from any cause; adverse effects include nausea, queasiness, and vomiting; contraindicated for patients with personal or family history of pancreatitis or medullary carcinoma of the thyroid; can be used by those with chronic kidney disease (no dose adjustment needed)

Tips for pharmacologic management: attempt lifestyle changes first and continue during treatment; all drugs are category X for pregnancy and lactation; weight loss with medications is variable; long-term treatment is necessary (the speaker discontinues only for adverse effects and pregnancy); avoid phentermine, phentermine-topiramate, and bupropion in patients who have active HD, heart failure, arrhythmias, or untreated HTN, or are taking monoamine oxidase inhibitors

Reasons for underutilization of weight management medications: safety records of previous medications — “fen-phen” is a combination of phentermine and fenfluramine; fenfluramine was associated with pulmonary HTN and valvular issues (not true of phentermine); perceived need for frequent follow-up — home monitoring of blood pressure, with office follow-up at 4 to 6 mo, generally is sufficient; concern about controlled substances — phentermine is a schedule IV drug, but potential for abuse and risk for dependence are low; other reasons — ignorance of guidelines supporting use of these medications; belief that medications are for short-term use only; variable responses; inconsistent coverage by health insurance

Questions and Answers

Bulk of food and satiety cues: foods eaten whole provide greater suppression of ghrelin than the same foods processed in a blender; the amount of hormone secreted is proportional to the number of calories, but type of food changes the pattern (liquid meals appear to provide less appetite suppression than solid meals)

Satiety with protein vs carbohydrate vs fat: protein likely produces the best state of fullness, followed by carbohydrates in the form of whole foods (not simple carbohydrates), then fat; the type of food alters the signaling receptor systems in the brain; ultra-processed foods rapidly alter central receptors, leading to a 500-kcal/day increase in caloric requirements to reach the same level of satiety

Role of metformin in the nondiabetic patient: found beneficial in the Diabetes Prevention Program Study (an average 2-kg weight loss at 4 yr); the speaker typically limits use to patients who have diabetes (type 1 or 2) and obesity to lower their insulin dose or allow discontinuation of a sulfonylurea; may inhibit weight gain associated with antipsychotic agents

Readings

Bray GA et al. The science of obesity management: an Endocrine Society Scientific Statement. Endocr Rev. 2018;39(2):79-132. doi:10.1210/er.2017-00253; Daneschvar HL et al. FDA-approved anti-obesity drugs in the United States. Am J Med. 2016 Aug;129(8):879.e1-6; Narayanaswami V, Dwoskin LP. Obesity: Current and potential pharmacotherapeutics and targets. Pharmacol Ther. 2017 Feb;170:116-147; Pilitsi E et al. Pharmacotherapy of obesity: Available medications and drugs under investigation. Metabolism. 2019 Mar;92:170-192; Cosentino G et al. Phentermine and topiramate for the management of obesity: a review. Drug Des Devel Ther. 2011;7:267-278; Lewis KH et al. Safety and effectiveness of longer-term phentermine use: Clinical outcomes from an electronic health record cohort. Obesity (Silver Spring). 2019 Apr;27(4):591-602; Greenway FL et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010 Aug 21;376(9741):595-605; Lin CH et al. An evaluation of liraglutide including its efficacy and safety for the treatment of obesity. Expert Opin Pharmacother. 2020 Feb;21(3):275-285; Hall KD et al. Ultra-processed diets cause excess calorie intake and weight gain: An inpatient randomized controlled trial of ad libitum food intake. Cell Metab. 2019 Jul 2;30(1):67-77.e3; Nissen SE et al. Effect of naltrexone-bupropion on major adverse cardiovascular events in overweight and obese patients with cardiovascular risk factors: a randomized clinical trial. JAMA. 2016;315(10):990-1004. doi:10.1001/jama.2016.1558; Purnell JQ. Definitions, Classification, and Epidemiology of Obesity. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; April 12, 2018; Ritchey ME et al. Cardiovascular safety during and after use of phentermine and topiramate. J Clin Endocrinol Metab. 2019;104(2):513-522. doi:10.1210/jc.2018-01010.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Purnell is on the advisory board for Novo Nordisk. In his lecture, Dr. Purnell presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Purnell was recorded online at the 28th Annual Internal Medicine Review, held April 8-9, 2021, and presented by Oregon Health & Science University School of Medicine, Continuing Professional Development. For information on future CME activities from the Oregon Health & Science University School of Medicine, please visit ohsu.edu/school-of-medicine/cpd. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

IM683201

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.