Abstract 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.
Chang et al. (Mon,) studied this question.