Glucagon‐Like Peptide‐1 Receptor Agonists and Risk of Mental Health Disorders in Type 2 Diabetes: Active Comparator, New User Cohort Study

AIMS: We evaluated the risk of mental health disorders among glucagon-like peptide-1 receptor agonist (GLP1RA) users compared with users of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors. MATERIALS AND METHODS: We conducted a nationwide, active-comparator new-user cohort study using the Korean claims database from 2012 to 2022. Patients aged ≥ 18 years who initiated GLP1RAs, SGLT2 inhibitors, or DPP4 inhibitors for type 2 diabetes were included. We compared the hazard ratios (HRs) and 95% confidence intervals (CIs) for depression, anxiety, sleep disorders, and suicide using the Cox proportional hazards models after propensity score matching. RESULTS: The 18 825 GLP1RA users were matched with 623 750 SGLT2 inhibitor users, and 5762 GLP1RA users with 874 902 inhibitor users. Compared with DPP4 inhibitors, GLP1RAs were not associated with increased risks of depression (HR 1.00 [95% CI, 0.83-1.20]), anxiety (0.92 [0.77-1.08]), or sleep disorder (1.14 [0.97-1.33]). In contrast, compared with SGLT2 inhibitors, GLP1RA use was associated with higher risks of depression (1.20 [1.09-1.31]) and anxiety (1.09 [1.00-1.19]). Suicidality events were rare and not observed among GLP1RA users. CONCLUSIONS: Initiation of GLP1RAs was not associated with increased risk of mental health disorders compared with DPP4 inhibitors. Differences in the risk of depression and anxiety were observed compared with SGLT2 inhibitors. These findings suggest that psychiatric safety signals may vary by active comparator and provide real-world evidence on the psychiatric safety of GLP-1-based therapies. Further studies incorporating detailed clinical data and high-risk subgroups are needed to clarify underlying mechanisms.