Background:
Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential antidepressant effects, population studies yield inconsistent results.
Objective:
To compare the risk for depression in older adults with type 2 diabetes (T2D) initiating treatment with GLP-1RAs versus sodium–glucose cotransporter-2 inhibitors (SGLT2is) or dipeptidyl peptidase-4 inhibitors (DPP4is).
Design:
Target trial emulation study.
Setting:
U.S. National Medicare administrative data from January 2014 to December 2020.
Patients:
Adults aged 66 years or older with T2D initiating treatment with a GLP-1RA were matched 1:1 on propensity score with those initiating treatment with either an SGLT2i or a DPP4i.
Measurements:
The primary end point was incident depression. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) with 95% CI within matched groups.
Results:
A total of 14 665 matched pairs of older adults were included in the cohort for GLP-1RAs versus SGLT2is; the rate difference of depression between GLP-1RA users and SGLT2i users was 3.48 (95% CI, −0.81 to 7.78) per 1000 person-years, with an HR of 1.07 (CI, 0.98 to 1.18). In the cohort for GLP-1RAs versus DPP4is (13 711 matched pairs), the rate difference was −5.78 (CI, −10.49 to −1.07) per 1000 person-years, with an HR of 0.90 (CI, 0.82 to 0.98).
Limitation:
Unmeasured confounders (such as hemoglobin A1c levels and body mass index), outcome misclassification, and limited generalizability to all GLP-1RA users (for example, younger populations or those without T2D receiving the drug for obesity treatment).
Conclusion:
Among older adults with T2D, the incidence of depression was relatively low. Use of GLP-1RAs was associated with a modestly lower risk for depression compared with use of DPP4is, but not SGLT2is.
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