Medication Management in Obesity: A Look at Pediatrics and Adult Treatments

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Medication Management in Obesity: A Look at Pediatrics and Adult Treatments

Obesity is an ever-increasing global health concern and a major modifiable risk factor for the development of comorbid conditions such as cardiovascular disease, osteoarthritis, and some forms of cancer. The utilization of pharmacological and lifestyle interventions for the promotion of weight loss in this population can provide sustained reduction of adipose tissue and increase patient quality of life. Guidelines for pharmacological management of obesity in adults highlight the importance of lifestyle management, such as improving nutritional quality of meals and increasing physical activity, as a foundation for managing obesity. However, physiological changes that developed concurrently with weight gain over time can often counteract implemented lifestyle modifications and lead to unsustainable weight loss. Pharmacotherapy is recommended when treatment goals are not, or unable to be met, with changes in lifestyle alone. Several weight loss medications are US Food and Drug Administration (FDA) approved for weight management in adult patients with a body mass index (BMI) of ≥30 kg/m² or adults with a BMI of ≥27 kg/m² with weight-related comorbidities such as hypertension, dyslipidemia, and type 2 diabetes mellitus^1-4.

A 2024 recommendation statement from the United States Preventative Services Task Force (USPSTF) highlighted investigative areas for behavioral and pharmacological interventions in children and adolescents with high BMI (≥95^th percentile for age and sex). A total of 58 randomized control trials (RCTs) were included in analysis (N= 10,143). Of the trials included, 50 RCTs examined the use of behavioral interventions in achieving target weight loss goals and improvement in overall quality of life. Pooled analyses showed a statistically significant increase in global quality of life (mean difference [MD] 1.9; 95% confidence interval [CI] 0.2 to 3.5) in 11 RCTs (n= 1,922) but only showed an association within the reduction of BMI and other weight-related outcomes (MD between groups -0.7 kg/m²; 95% CI -1 to -0.3) in 28 RCTs (n= 4,494; I²= 86.8%) after 6 to 12 months of behavioral intervention. In behavioral interventions with ≥26 contact hours, the mean difference in change in quality of life measurements were 3.8 points (95% CI 3.6 to 4.1) with most study scales ranging from 0 to 100. When combined with physical activity sessions, behavioral interventions with ≥26 contact hours showed larger effects on reduction in BMI (-1.4 kg/m²; 95% CI -2.2 to -0.6) in 11 RCTs (n= 1,087; I²= 87.8%) and weight loss (-2.6 kg; 95% CI -3.8 to -1.3 kg) in 10 RCTs (n= 907; I²= 58.2%) than interventions <26 hours (p= 0.004). Evidence of improvement in cardiometabolic risk factors were evaluated in 16 RCTs, with pooled analyses showing behavioral interventions with ≥26 contact hours, in conjunction with physical activities, improves systolic (SBP) (MD in SBP -3.6 mmHg; 95% CI -5.7 to -1.5 mmHg; 8 RCTs [n=773]; I²= 47.3%) and diastolic (DBP) blood pressure (MD in DBP -3 mmHg; 95% CI -5.7 to -1.5 mmHg; 8 RCTs [n=774]; I²= 49.3%) and fasting plasma glucose level (MD -1.9 mg/dL; 95% CI -2.7 to -1.2 mg/dL; 4 RCTs [n= 367]; I²= 0%) after 6 to 12 months. No behavioral intervention studies with <26 contact hours were associated with improvement in SBP. Trials rarely reported on depression, social adjustment, or long-term benefits of behavioral intervention on these health outcomes⁵.

From these findings, children and adolescents ages 6 years or older are recommended to receive intensive behavioral interventions focused on providing patient and family support; providing education on healthy eating habits, safe exercise routines, and behavioral change techniques such as goal setting and self-management for both children and parents. With a Grade B recommendation, the USPSTF recommends ≥26 contact hours with patients to reach their goal weight loss and improve overall quality of life^5,6.

Pharmacotherapy interventions for children and adolescents evaluated by the USPSTF for weight loss benefit included orlistat, liraglutide, semaglutide, and phentermine/topiramate. In 8 RCTs, outcomes for medication treatment included quality of life, reduction of BMI, and potential harms^5,6. In a randomized control trial (N= 539) evaluating the efficacy of orlistat on reduction of BMI in adolescents aged 12 to 16 years, patients treated with orlistat saw a 0.6 kg/m² decrease in BMI from baseline when compared to an increase of 0.3 kg/m² in patients treated with placebo after 12 months (p= 0.001); compared to 15.7% of placebo group, 26.5% of patients receiving orlistat lost at least 5% of their baseline BMI (p= 0.005) with a respective 4.5% and 13.3% decrease of 10% of their baseline BMI⁷. A randomized control trial (N= 227) evaluated the efficacy of mid-dose phentermine/topiramate (7.5 mg/46 mg) or high-dose (15 mg/92 mg) compared to placebo on the reduction of BMI in patients aged 12 to <17 years for 52 weeks. Patients receiving both the mid-dose and high-dose regimens of phentermine/topiramate showed a significant reduction in BMI from baseline when compared to placebo (p<0.0001), but no significant difference in BMI reduction was seen between mid- and high-dose regimens⁸. A study evaluating daily injections of 3 mg liraglutide in patients aged 12 to <18 years (N= 251), BMI was reduced by 1.6 kg/m² more than placebo following 13 months of treatment; however, in the absence of treatment intervention after 6 months, weight loss was no longer statistically significant⁹. Weekly injections of 2.4 mg semaglutide were given over a 16-month period to patients aged 12 to <18 years (N= 201) and showed a 16.7 percentage point greater reduction in baseline BMI when compared to placebo (95% CI -20.3 to -13.2; p<0.001); following discontinuation, patients regained an average of 3.1% of their baseline weight¹⁰. Impact on cardiometabolic outcomes were seen with high-dose phentermine/topiramate on reduction in SBP (MD -4; 95% CI -7.7 to -0.5) and high-density lipoprotein levels (MD 8.8%; 95% CI 2.2 to 15.4), and reduction in low-density lipoprotein with semaglutide (MD -7.1%; 95% CI -11.9 to -1.8); no statistically significant improvements were seen with other medications. Gastrointestinal adverse effects (nausea, vomiting, diarrhea, gallstone, flatus with discharge, or fecal incontinence) were seen in more than 60% of patients taking liraglutide, semaglutide, or orlistat. In one study, liraglutide showed significantly higher rates of gastrointestinal adverse events when compared to placebo (65% vs. 36%; relative risk 3.2; 95% CI 1.91 to 5.36; p<0.001) ⁹. High-dose phentermine/topiramate was associated with higher rates of musculoskeletal and psychiatric adverse effects when compared to placebo (8.8% vs. 1.8% for both categories of adverse effects)⁸. Adverse effect profiles of studied weight loss drugs significantly impacted patient willingness to continue therapy and serious adverse effects were rare. Of note, long-term adverse effects were not evaluated beyond 1 month following study drug discontinuation or longer than 17 months with treatment⁵.

                  The USPSTF recommends the initiation of comprehensive and intensive behavioral therapy prior to the use of pharmacological interventions primarily due to the limited data regarding long-term health effects of medication use and potential harms. Further studies evaluating the benefit of weight loss medication in children and adolescents over long periods of time (>12 months) are necessary to determine the benefit and harm sustained with weight loss medication use in this patient population⁵.

FDA Approved Weight Loss Medications
Medication	Used in Adults	Used in Children ≥12 years
Orlistat	Yes	Yes
	o   Three oral daily doses o   Common adverse effects include steatorrhea, oily fecal spotting, and fecal urgency; commonly resolves following 4 weeks of therapy o   Cardiometabolic benefit: reduction of systolic blood pressure, hemoglobin A1c, and LDL-C
Phentermine	Yes	Not approved
	o   One or twice oral daily doses o   Common adverse effects include xerostomia, headache, insomnia, and constipation
Phentermine-topiramate	Yes	Yes
	o   One oral daily dose o   Common adverse effects include dysgeusia, paresthesia, and xerostomia
Liraglutide	Yes	Yes
	o   Once daily subcutaneous injection o   Common adverse effects include nausea, vomiting, diarrhea, constipation, and abdominal pain
Semaglutide	Yes	Yes
	o   Once weekly subcutaneous injection o   Common adverse effects include nausea, vomiting, diarrhea, constipation, and abdominal pain
Tirzepatide	Yes	Not approved
	o   Once weekly subcutaneous injection o   Common adverse effects include nausea, vomiting, diarrhea, constipation, and abdominal pain
Key Points
·      Limited study data is available for the safety and efficacy of weight loss medication in children less than 12 years ·      All pharmacological interventions are recommended to be used as an adjunct therapy to behavioral and lifestyle interventions for both adult and child patients

 

References:

1. Gudzune KA, Kushner RF. Medications for Obesity: A Review. Published online July 22, 2024. doi:10.1001/jama.2024.10816
2. Qi QYD, Cox A, McNeil S, Sumithran P. Obesity medications: A narrative review of current and emerging agents. Osteoarthr Cartil Open. 2024;6(2):100472. Published 2024 Apr 25. doi:10.1016/j.ocarto.2024.100472
3. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline [published correction appears in J Clin Endocrinol Metab. 2015 May;100(5):2135-6. doi: 10.1210/jc.2015-1782]. J Clin Endocrinol Metab. 2015;100(2):342-362. doi:10.1210/jc.2014-3415
4. Grunvald E, Shah R, Hernaez R, et al. AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity. Gastroenterology. 2022;163(5):1198-1225. doi:10.1053/j.gastro.2022.08.045
5. US Preventive Services Task Force. Interventions for High Body Mass Index in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. 2024;332(3):226–232. doi:10.1001/jama.2024.11146
6. Styne DM, Arslanian SA, Connor EL, et al. Pediatric Obesity-Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017;102(3):709-757. doi:10.1210/jc.2016-2573
7. Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J. Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial [published correction appears in JAMA. 2005 Sep 28;294(12):1491]. JAMA. 2005;293(23):2873-2883. doi:10.1001/jama.293.23.2873
8. Kelly AS, Bensignor MO, Hsia DS, et al. Phentermine/topiramate for the treatment of adolescent obesity. NEJM Evidence. 2022;1(6).
9. Kelly AS, Auerbach P, Barrientos-Perez M, et al. A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity. N Engl J Med. 2020;382(22):2117-2128. doi:10.1056/NEJMoa1916038
10. Weghuber D, Barrett T, Barrientos-Pérez M, et al. Once-Weekly Semaglutide in Adolescents with Obesity. N Engl J Med. 2022;387(24):2245-2257. doi:10.1056/NEJMoa2208601

 

 

 

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