Update on Obesity Pharmacotherapy

Educational Objectives

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

1. Cite American Academy of Pediatrics guidelines regarding use of pharmacotherapy in pediatric patients with obesity.
2. List common side effects associated with glucagon-like peptide-1 agonists.
3. Select appropriate medications for obesity in adolescents.

Summary

Obesity: pediatric obesity is a complex chronic disease influenced by genetics, environment, and biology; the focus of the treatment is on preventing life-limiting complications over time; the American Academy of Pediatrics (AAP) suggests lifestyle modification, pharmacotherapy, and surgery, based on the severity of the disease; lifestyle modification can result in a 5- to 20-lb weight loss, while surgery may be appropriate for patients requiring 80- to 100-lb weight loss for metabolic health and disease prevention; pharmacotherapy offers benefits to young people with obesity, especially in class II and III categories at primary and subspecialty care level

Recommendations: the AAP recommends pediatricians and health care clinicians to offer medications approved by the US Food and Drug Administration (FDA) to adolescents (≥12 yr of age) with obesity (may offer for children between 8 and 11 yr of age); the approach should be based on the severity of the disease (not age); pediatricians can consider off-label products and access the appropriate medication for their patients; pharmacotherapy should be an adjunct to the best available lifestyle treatment, even if not comprehensive; consider multimodal care; should be based on patients age, signs, and symptoms; consider cost and availability; need more education for clinicians and patients to effectively implement the treatment plan; the goal is risk reduction and prevention of life-limiting complications, with appropriate start and stop times in collaboration with the family; pediatric obesity should be treated as a chronic disease, with quarterly visits and laboratory workups twice a year

Glucagon-like peptide-1 (GLP-1) agonists: stimulate postprandial insulin secretion, reduce glucagon secretion, and delay gastric emptying, which reduces hunger and food intake and increases satiety; the most effective agents for obesity; weigh the adverse effects (AEs) against the disease burden; gastrointestinal (GI) effects are most significant; these include nausea, vomiting, and diarrhea (within the first 12 wk) and can be mitigated with nutritional guidance and slow titration; children experience less fatigue, headache, mood changes, and pancreatitis than adults

Considerations: access is a challenge; these medications are expensive and often not covered by insurance; they are the most effective agents for patients with severe obesity, particularly for patients with insulin resistance phenotypes; the FDA approved daily preparations for type 2 DM and obesity and weekly preparations (semaglutide [Wegovy]) for young people with obesity (≥12 yr of age); in obesity trials, checking waterfall plots is important because of the heterogeneity in responses; the goal is to determine which agents patients tolerate and how to get the patients on those agents; a trial studied liraglutide in younger children and found a much greater weight change vs placebo; a trial of once-weekly semaglutide in adolescents with body mass index (BMI) >95th percentile (followed over 68 wk) observed a 16% change in BMI in 73% of patients, indicating less heterogeneity; 62% of adolescents in the semaglutide group experienced GI adverse effects vs 42% in the placebo group; mitigating GI effects in children — mostly caused by delayed gastric emptying; eat smaller meals; nutritional recommendations can help patients prevent these issues

Tips: many programs recommend increasing protein intake (60 g/day) for young children through consultation with a nutritionist or a one-page handout to prevent muscle loss; stress related to social media is a common issue; GLP-1 agonists are more effective when they remain in circulation longer; there are dual agonists (tirzepatide [eg, Mounjaro, Zepbound]) and triple agonists; tirzepatide can be used in adults (no pediatric indication) and is more effective and has fewer AEs; the efficacy of these agents is approaching bariatric surgery efficacy; while surgery can be a great option for young children with severe obesity and comorbidities, access can be challenging

Phentermine: approved by the FDA for obesity in 1961; effective as a monotherapy in ≈40% of children; it increases catecholamine release in the hypothalamus; it is a very low-dose stimulant agent; it is available in various dosing requirements, so the dose can be modified as needed; it is affordable and accessible and can help manage fatigue, a common issue in young people with obesity

Topiramate: used to treat seizure disorders and migraine headaches; enhances γ-aminobutyric acid type A activity, antagonizing AMPA glutamate receptors, which inhibits carbonic anhydrase, leading to satiety enhancement and control of food cravings; inexpensive, accessible, and well-tolerated at lower doses; AEs include numbness and tingling in the hands and feet (usually resolves within 1 or 2 wk) and fatigue; typically given at nighttime to prevent cognitive disruption; it also makes juice and soda taste like metal

Phentermine-topiramate (PHEN-TPM; Qsymia): received FDA approval in 2022 for adolescents (≥12 yr of age); Kelly et al (2022) compared placebo vs a mid-dose PHEN-TPM vs a high-dose PHEN-TPM and found a significant weight loss over 56 wk (8% to 10% weight loss); heterogeneity in responses can be challenging

Lisdexamfetamine (Vyvanse): is a stimulant agent; it increases the release of dopamine and norepinephrine into the extra neuronal space impacting the arcuate nucleus to promote satisfaction, satiety, decrease appetite, and increase energy expenditure; it is FDA approved for binge eating disorder in adults; it can be effective for children with these phenotypes (as 25% of young children with obesity also experience eating disorder); it can be used in many patients with concurrent diagnoses with obesity, eg, attention-deficit/hyperactivity disorder

Metformin: activates AMP-activated protein kinase; it is an insulin sensitizer; it is most effective in children with insulin resistance; it can decrease insulin levels and improve pre-diabetes risk; it can improve acanthosis nigricans (especially for patients with cosmetic concerns); it can be considered in women with polycystic ovary syndrome (often combined with an estrogen preparation); it can also be used in patients with concurrent use of atypical antipsychotic agents

Others: orlistat — FDA approved for obesity; inexpensive and easy to use; be aware of the AEs (make use challenging); naltrexone and bupropion — approved by the FDA for obesity in adults; many obese patients have concurrent mental health conditions, including depression and anxiety; mood stabilizing medications tend to be weight-gain promoting or weight-neutral; naltrexone and bupropion are mood promoting and weight-neutral or even weight-loss promoting

Readings

Correll CU, Sikich L, Reeves G, et al. Metformin add-on vs antipsychotic switch vs antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial. World Psychiatry. 2020;19(1):p69–80. doi: 10.1002/wps.20714; Kelly AS, Auerbach P, Barrientos-Perez M, et al. A randomized, controlled trial of liraglutide for adolescents with obesity. New England Journal of Medicine. 2020;382(22;p2117–2128. doi: 10.1056/NEJMoa1916038; Kelly AS, Bensignor MO, Hsia DS, et al. Phentermine/topiramate for the treatment of adolescent obesity. NEJM Evidence. 2022;1(6). doi: 10.1056/EVIDoa2200014; Lewis KH, Sloan CE, Bessesen DH, et al. Effectiveness and safety of drugs for obesity. BMJ. 2024;384:pe072686. doi: 10.1136/bmj-2022-072686; Lin KW, McKenna KA. Breaking down the AAP guideline on childhood obesity. American Family Physician. 2023;108(4):p335–336; Mital S, Nguyen HV. Cost-effectiveness of antiobesity drugs for adolescents with severe obesity. JAMA Network Open. 2023;6(10):pe2336400. doi: 10.1001/jamanetworkopen.2023.36400; Novograd J, Mullally JA, Frishman WH. Tirzepatide for weight loss: Can medical therapy “outweigh” bariatric surgery? Cardiology in Review. 2023;31(5):p278–283. doi: 10.1097/CRD.0000000000000515; Weghuber D, Kelly AS, Arslanian S. Once-weekly semaglutide in adolescents with obesity. New England Journal of Medicine. 2023;388(12):p1146.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Vidmar has been an advisory board member for Rhythm Pharmaceuticals and Soleno Pharmaceuticals. Members of the planning committee reported nothing relevant to disclose. Dr. Vidmar's lecture includes information related to the off-label use of tirzepatide and triple agonists in weight management, and lisdexamfetamine and metformin in weight management in children.

Acknowledgements

Dr. Vidmar was recorded at the 45th Annual Las Vegas Seminars: Pediatric Update, held in Las Vegas, NV, December 13-15, 2024, and presented by the American Academy of Pediatrics, California Chapter 4. For information on future CME activities from this presenter, please visit aap.org. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

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FP731402

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