GLP-1 receptor agonist therapy in children and adolescents with obesity: A network meta-analysis of differential cardiometabolic efficacy and safety profiles.
In adolescents with obesity, semaglutide appears to have the largest impact on weight loss, while exenatide may reduce systolic blood pressure, but the evidence is limited and indirect.
Where it sits
this study against the rest of the exenatide corpusSummary and findings
This network meta-analysis evaluated the efficacy and safety of GLP-1 receptor agonists in adolescents with obesity. Exenatide 20 µg SC was associated with a reduction in systolic blood pressure. The study included 17 RCTs with a total of 1230 participants.
Abstract
<h4>Importance</h4>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.<h4>Methods</h4>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.<h4>Results</h4>17 RCTs with 1230 participants were included. Semaglutide 2.4 mg SC was associated with the largest reductions in body weight (mean difference -18.00 kg; 95% credible interval -24.34 to -11.69, high confidence), BMI (-5.9 kg/m<sup>2</sup>, -10.5 to -1.3, high confidence), and waist circumference (-12.2 cm, -21.67 to -2.67). For glycaemic control, dulaglutide 1.5 mg 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 (-3.98 mmol/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 (-6.64 mmHg, -13.22 to -0.17) based on limited indirect evidence from early-phase trials. No agent improved lipid profiles in a statistically significant manner.<h4>Conclusion</h4>In this network meta-analysis of adolescents with overweight or obesity, GLP-1RAs showed differential cardiometabolic profiles. Semaglutide 2.4 mg produced the largest point estimates for weight-related outcomes, dulaglutide 1.5 mg 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.
Background
The study addresses the comparative effects of GLP-1 receptor agonists on cardiometabolic outcomes in adolescents with obesity, a population increasingly treated with these agents. Prior research has indicated varying efficacy among different GLP-1RAs, but direct comparisons have been limited. This meta-analysis aims to clarify these differences and provide insights into their relative effectiveness and safety profiles.
Methods
The study included a systematic search of multiple databases for randomized clinical trials comparing GLP-1RAs with placebo or other agents in adolescents. A total of 17 RCTs with 1230 participants were included, employing a Bayesian random-effects model for data synthesis. The primary outcomes measured included body weight, BMI, waist circumference, glycaemic control, and systolic blood pressure.
Results
The primary endpoint for body weight showed that semaglutide 2.4 mg SC was associated with a mean difference of -18.00 kg, 95% CI -24.34 to -11.69. Other significant findings included reductions in BMI and waist circumference with semaglutide, and notable reductions in HbA1c and fasting plasma glucose with dulaglutide and lixisenatide, respectively. Exenatide demonstrated a reduction in systolic blood pressure of -6.64 mmHg, 95% CI -13.22 to -0.17.
Interpretation
The findings suggest that while semaglutide shows the most substantial effects on weight-related outcomes, the clinical significance of the reductions in systolic blood pressure with exenatide is uncertain due to the limited evidence base. The indirect nature of many comparisons and the reliance on single trials for certain agents limit the robustness of conclusions drawn from this analysis. Practitioners should interpret these results cautiously, considering the potential for confounding factors.
Key findings
- Semaglutide 2.4 mg SC was associated with a mean difference of -18.00 kg in body weight, 95% CI -24.34 to -11.69.
- Semaglutide 2.4 mg SC was associated with a mean difference of -5.9 kg/m² in BMI, 95% CI -10.5 to -1.3.
- Semaglutide 2.4 mg SC was associated with a mean difference of -12.2 cm in waist circumference, 95% CI -21.67 to -2.67.
- Dulaglutide 1.5 mg SC showed a mean reduction in HbA1c of -1.50%, 95% CI -1.84 to -1.15.
- Lixisenatide 20 µg SC showed a mean reduction in fasting plasma glucose of -3.98 mmol/L, 95% CI -7.46 to -0.60.
- Exenatide 20 µg SC was associated with a reduction in systolic blood pressure of -6.64 mmHg, 95% CI -13.22 to -0.17.
Limitations
- Most active-treatment comparisons were indirect.
- Many nodes were informed by single trials.
- SUCRA rankings should not be interpreted as evidence of definitive clinical superiority.