GLP‐1RA comparative effectiveness against dementia onset relative to other antidiabetic medications in a large, multi‐site cohort of patients with type 2 diabetes

To address gaps in current research, this study aims to compare the impact of exposure to glucagon-like peptide-1 receptor agonists (GLP-1RA) versus sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase 4 inhibitors (DPP4i), and sulfonylureas (SU) on reducing the risk of dementia, using a rigorous targeted learning causal inference approach. Using clinical and claims data from four diverse US health-care systems, we emulated three two-arm trials contrasting sustained treatment with GLP-1RA versus SGLT2i, DPP4i, and SU on dementia diagnosis. We included diabetes patients aged ≥ 60 years who initiated medication between 2014 and 2022. We estimated cumulative risk differences at 2.5 years. In Cohort 1, there was no evidence of differential dementia risk between sustained exposure to GLP1-RA versus SGLT2i (adjusted risk difference [aRD] -0.001, 95% confidence interval [CI] -0.004, 0.001). In Cohorts 2 and 3, GLP-1RA was associated with reduced risk of dementia diagnosis compared to DPP4i and SU, respectively (aRD -0.013, 95% CI -0.017, -0.009; aRD -0.016, 95% CI -0.018, -0.015). Rigorous causal inference analysis suggests that sustained exposure to GLP-1RA may modestly reduce risk of dementia, compared to DPP4i or SU exposure-but not compared to SGLT2i. We researched the comparative effects of diabetes medications on dementia. We studied a large, diverse observational cohort of patients with diabetes in the United States. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) may modestly reduce risk of dementia compared to dipeptidyl peptidase 4 inhibitor or sulfonylurea exposure. GLP-1RAs do not show evidence of dementia risk reduction compared to sodium-glucose cotransporter 2 inhibitors. Physicians may consider this when making prescription decisions with patients.