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

Apr 9, 2025Diabetes research and clinical practice

Links between diabetes medicines, depression risk, and overall death rates in type 2 diabetes

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Abstract

Among 359,787 patients with type 2 diabetes, SGLT-2 inhibitors were associated with a lower risk of depression and all-cause mortality.

GLP-1 receptor agonist users had a higher risk of depression compared to metformin users, with hazard ratios ranging from 1.54 to 1.84.
GLP-1 receptor agonists were associated with a modestly increased risk of all-cause mortality at 1 and 3 years, with hazard ratios of 1.19 and 1.21, respectively.
SGLT-2 inhibitors were linked to a lower risk of depression and all-cause mortality compared to DPP-4 inhibitors, with hazard ratios of 0.62-0.70 and 0.54-0.65, respectively.
DPP-4 inhibitor users exhibited the highest risk for both depression and all-cause mortality compared to metformin, with hazard ratios of 1.53-1.74 and 1.56-1.57, respectively.

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AIMS: 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).

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

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

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