Association Between Glucagon-Like Peptide-1 Receptor Agonists and Risk of Depression in U.S. Older Adults with Type 2 Diabetes

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising treatments for T2D due to their cardiorenal and weight loss benefits. Previous studies suggested that GLP-1RAs might have potential antidepressant effects. However, population studies examining the association between GLP-1RAs and depression risk are limited and yield mixed results.

Objectives: We conducted this population-based cohort study to assess the association between GLP-1RA use and risk of depression in older adults with T2D.

Methods: The Medicare beneficiaries (≥66 years old) with T2D newly prescribed either GLP-1RAs, sodium-glucose cotransporter 2 inhibitors (SGLT2i) or dipeptidyl peptidase 4 inhibitors (DPP4i) were identified from 2016-2020 national Medicare Claims data. The patients were excluded if they had a diagnosis of type 1 diabetes or depression or ESRD, or had treatment of antidepressants in the previous 1 year. The primary outcome was incident depression defined as ≥ 1 diagnosis code based on the Chronic Conditions Warehouse (CCW) algorithm. To minimize potential confounding at baseline, we employed a 1:1 propensity score (PS) matching approach. PS was calculated based on a set of baseline covariates, including age, sex, comorbidities, and medication. Additionally, we utilized a Cox proportional hazards regression to estimate the hazard ratio (HR) with 95% confidence intervals (CI) for depression. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc).

Results: After 1:1 PS matching, 14,420 and 13,738 pairs were included in GLP-1RA vs. SGLT2i cohort and GLP-1RA vs. DPP4i cohort, respectively. The baseline covariates between two groups after 1:1 PS matching were well-balanced (SMD < 0.1). We employed the Kaplan-Meier plots to show the cumulative incidence of incident depression over time between matched groups. The incidence rates were 76.25 and 70.03 per 1,000 person-years for the GLP-1RA group and SGLT2i group in the GLP-1RA vs. SGLT2i cohort. GLP-1RAs were not significantly associated with an increased risk of incident depression compared to SGLT2i (HR, 1.08; 95%CI, 0.98-1.20). In the GLP-1RA vs. DPP4i cohort, GLP-1RAs were significantly associated with a decreased risk of incident depression compared to DPP4i (HR, 0.85; 95%CI, 0.77-0.94). There was no evidence of interaction among subgroups in the association between GLP-1RAs and risk of depression.

Conclusions: In this population-based cohort study, we observed a significantly lower risk of depression associated with GLP-1RA compared to DPP4i, while there was no significant difference between GLP-1RAs and SGLT2i.