Glucagon-Like Peptide-1 Receptor Agonists and Risk for Depression in Older Adults With Type 2 Diabetes

Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential antidepressant effects, population studies yield inconsistent results. 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). Target trial emulation study. U.S. National Medicare administrative data from January 2014 to December 2020. 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. 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. 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). 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). 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. National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.