Risk of depression with GLP-1 receptor agonists use in overweight or obese adults with type 2 diabetes

Aims: The association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and depression remains uncertain due to contradictory evidence. We compared the risk of incident depression between GLP-1 RAs and sodium-glucose cotransporter-2 inhibitors (SGLT2is) in overweight or obese adults with type 2 diabetes. Materials and Methods: We conducted a new-user, active-comparator cohort study using a deidentified electronic health record network from January 2016 to July 2024. After 1:1 propensity score matching, we compared 25 704 new GLP-1 RA users to 25 704 SGLT2i users with newly diagnosed type 2 diabetes and overweight/obesity, excluding those with prior mood disorders. The primary outcome was a composite of incident depression diagnosis or antidepressant initiation, assessed from 1 month to 1 year post-initiation using Cox models and time-varying analyses. Results: In 51 408 patients (mean age 56.8 years, 48.9% male), GLP-1 RA use was associated with higher depression incidence versus SGLT2i use (17.0% vs. 14.8%; hazard ratio 1.09, 95% CI 1.04–1.14; p < 0.001), with an absolute risk difference of 2.2%. The association was stronger in adults ≥65 years (HR 1.15) and plateaued after approximately 6 months. In secondary analysis, GLP-1 RA use was associated with a lower rate of all-cause mortality (HR 0.74, 95% CI 0.63–0.88). Conclusions: GLP-1 RA initiation was associated with a statistically significant increase in depression risk compared to SGLT2i use (9% relative increase, 2.2% absolute risk difference over 1 year), particularly during the subacute period and in older adults. This observed association must be balanced against substantial mortality benefits. Enhanced monitoring and shared decision-making are warranted.