Association of antidiabetic medications with depression risk and All-Cause mortality in type 2 Diabetes: A TriNetX-Based cohort study.

Objective: Individuals with type 2 diabetes face elevated risks of depression and all-cause mortality. This study aimed to compare the associations of different glucose-lowering drugs-metformin, GLP-1 receptor agonists (GLP-1 RA), DPP-4 inhibitors (DPP-4i), and SGLT-2 inhibitors (SGLT-2i)-with these risks.

Methods: Using TriNetX, we conducted a retrospective cohort study of 359,787 patients with type 2 diabetes receiving monotherapy with the aforementioned drugs. Propensity score matching balanced baseline characteristics, and Cox proportional hazards models were used to estimate hazard ratios (HRs) for incident depression and all-cause mortality. Additional subgroup analyses were performed stratified by sex and age.

Results: We assessed the association between glucose-lowering therapies and the risk of depression and all-cause mortality over 1-, 3-, and 5-year follow-up periods. Compared to metformin, GLP-1 RA users were associated with a higher risk of depression (HR 1.54-1.84) and a modestly elevated risk of all-cause mortality at 1 and 3 years (HR 1.19 and 1.21, respectively), though this association was not observed at 5 years. Relative to SGLT-2 inhibitors (SGLT-2i), GLP-1 RA users demonstrated a higher risk of depression (HR 1.33-1.59) and all-cause mortality (HR 1.24-1.35). SGLT-2i use was associated with a lower risk of depression (HR 0.62-0.70) and all-cause mortality (HR 0.54-0.65) compared to DPP-4 inhibitors (DPP-4i). Notably, DPP-4i users exhibited the highest risk of both depression and all-cause mortality relative to metformin (HR 1.53-1.74 and HR 1.56-1.57, respectively).

Conclusions: SGLT-2i was associated with significant reductions in depression and mortality risks, highlighting its potential advantages for type 2 diabetes management. 1 Background.