GLP-1 Receptor Agonist Therapy in Children and Adolescents with Obesity: A Network Meta-Analysis of Differential Cardiometabolic Efficacy and Safety Profiles.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used in adolescents with overweight or obesity, but their comparative effects on cardiometabolic outcomes across different agents remain uncertain. We aimed to compare the efficacy and safety of different GLP-1RAs on key cardiometabolic parameters in adolescents with overweight or obesity, with or without type 2 diabetes. We searched PubMed, Embase, Web of Science, the Cochrane Library, and ClinicalTrials.gov from inception to May 1, 2026. Randomised clinical trials comparing GLP-1RAs with placebo or another active agent in eligible adolescents were included. Two reviewers independently extracted data and assessed risk of bias following PRISMA guidelines for network meta-analysis. We used a Bayesian random-effects model for data synthesis. 17 RCTs with 1230 participants were included. Semaglutide 2.4mg SC was associated with the largest reductions in body weight (mean difference -18.00kg; 95% credible interval -24.34 to -11.69, high confidence), BMI (-5.9kg/m^2, -10.5 to -1.3, high confidence), and waist circumference (-12.2cm, -21.67 to -2.67). For glycaemic control, dulaglutide 1.5mg SC showed the largest reduction in HbA1c (-1.50%, -1.84 to -1.15, high confidence), and lixisenatide 20 ug SC showed the largest reduction in fasting plasma glucose (-3.98mmol/L, -7.46 to -0.60); however, these rankings derive from networks with sparse head-to-head evidence and wide credible intervals for indirect comparisons. Exenatide 20 ug SC was associated with a reduction in systolic blood pressure (-6.64mmHg, -13.22 to -0.17) based on limited indirect evidence from early-phase trials. No agent improved lipid profiles in a statistically significant manner. In this network meta-analysis of adolescents with overweight or obesity, GLP-1RAs showed differential cardiometabolic profiles. Semaglutide 2.4mg produced the largest point estimates for weight-related outcomes, dulaglutide 1.5mg and lixisenatide 20 ug for glycaemic endpoints, and exenatide 20 ug for systolic blood pressure. These findings are hypothesis-generating: most active-treatment comparisons were indirect, many nodes were informed by single trials, and SUCRA rankings should not be interpreted as evidence of definitive clinical superiority.