Psychiatric Safety of GLP ‐1 and Dual GIP / GLP ‐1 Receptor Agonists in Adolescents With Obesity

ABSTRACT Background Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and dual GIP/GLP‐1 receptor agonists are increasingly used for adolescent obesity, but concerns persist regarding psychiatric adverse events, particularly suicidality. Methods This retrospective cohort study used deidentified electronic health records from the TriNetX Global Collaborative Network. Adolescents with overweight or obesity were included. New users of semaglutide, liraglutide, or tirzepatide were compared with those receiving lifestyle interventions. Cohorts were balanced using propensity score matching. The primary outcome was suicide‐related events (suicidal ideation or suicide attempt). Secondary outcomes included suicidal ideation, suicide attempt, anxiety, insomnia, depression, and eating disorders, assessed from 30 days to 1095 days after the index date. Results After propensity score matching, 9222 adolescents were included in each group. Incretin‐based therapy was associated with lower risks of suicide‐related events (HR, 0.74; 95% CI, 0.57–0.95), suicidal ideation (HR, 0.73; 95% CI, 0.56–0.96), and anxiety (HR, 0.92; 95% CI, 0.84–0.99) compared with lifestyle intervention. No significant differences were observed for suicide attempt, insomnia, depression, or eating disorders. Risk reductions were significant among female adolescents (HR, 0.61; 95% CI, 0.46–0.82) and those without Type 2 diabetes (HR, 0.63; 95% CI, 0.47–0.85), but not among males or those with Type 2 diabetes. Sensitivity analyses supported the primary findings. Conclusions Among adolescents with obesity, incretin‐based therapy was not associated with increased psychiatric risk and was associated with lower risks of suicide‐related events, suicidal ideation, and anxiety compared with lifestyle intervention. Although a lower risk was observed compared with lifestyle intervention, this finding should be interpreted cautiously given potential selection bias and the lack of a significant difference in the active‐comparator analysis with metformin.