Initiation of SGLT2 Inhibitors Versus DPP-4 Inhibitors in Metformin Users and Risk of Incident Depression: A...

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.

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.

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.

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.