Initiation of SGLT2 Inhibitors Versus DPP‐4 Inhibitors in Metformin Users and Risk of Incident Depression: A Nationwide, Claims‐Based Active‐Comparator New‐User Study

AIMS: To examine the association between initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors and risk of incident depression compared with dipeptidyl peptidase-4 (DPP-4) inhibitors among adults with newly diagnosed Type 2 diabetes receiving metformin. MATERIALS AND METHODS: We conducted a nationwide active-comparator new-user cohort study with a 90-day adherent-survivor landmark design, using the Korean National Health Insurance Service database linked with national health check-up and mortality data (2014-2022). Adults with newly diagnosed Type 2 diabetes receiving metformin who newly initiated SGLT2 inhibitors or DPP-4 inhibitors as add-on therapy were identified. This study was designed as a 90-day adherent-survivor landmark analysis. Propensity score matching was performed in a 1:1 ratio, yielding 10 013 matched pairs. The primary outcome was incident depression, defined as ≥ 2 outpatient or inpatient claims with ICD-10 codes F32-F33. The secondary outcome was suicide mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs) under intention-to-treat and as-treated approaches. RESULTS: Among 38 297 eligible participants, 300 depression events occurred among SGLT2 inhibitor users and 391 among DPP-4 inhibitor users in the matched cohort. Initiation of SGLT2 inhibitors was associated with a lower risk of depression compared with DPP-4 inhibitors (HR 0.85, 95% CI 0.73-0.99). Similar findings were observed in as-treated analyses (HR 0.80, 95% CI 0.65-0.98). Associations were generally consistent across clinically relevant subgroups and appeared more pronounced among older adults, females and individuals with greater comorbidity burden. Suicide mortality was infrequent in both groups. CONCLUSIONS: Among 90-day adherent survivors with Type 2 diabetes receiving metformin, initiation of SGLT2 inhibitors as add-on therapy was associated with a lower risk of incident depression compared with DPP-4 inhibitors.