Background: Cardiovascular benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been established in randomized trials among patients with type 2 diabetes; however, evidence about whether benefits translate comparably across individual agents in routine clinical practice remains limited.

Objectives: To compare GLP-1 RA initiation versus DPP-4 inhibitor initiation on the risk of cardiovascular events and all-cause death.

Methods: Using the DeSC nationwide claims database in Japan (April 2014–March 2025), we applied an active comparator new-user design among adults with type 2 diabetes actively treated with ≥1 antidiabetic medication and without contraindications. The primary outcome was a composite of hospitalization for myocardial infarction, stroke, or heart failure, and all-cause death. Propensity score overlap weights and inverse probability of censoring weights were applied to address confounding and differential censoring, respectively. Cumulative risks at 24 months were estimated via pooled logistic regression, with RRs, RDs, and 95% CIs obtained using robust variance.

Results: A total of 114,282 patients (12,787 GLP-1 RA initiators, 101,495 DPP-4 inhibitors initiators) were included in the analysis. Mean age was 69.0 and 73.6 years, and 47.6% and 48.0% were female, in GLP-1 RA and DPP-4 inhibitor initiators, respectively. The weighted 24-month risk of the composite outcome was 15.5% (95% CI: 14.7–16.3) in GLP-1 RA initiators and 17.8% (95% CI: 17.4–18.3) in DPP-4 inhibitor initiators (reference), corresponding to RD of -2.3 percentage points (95% CI: -3.2, -1.5) and RR of 0.87 (95% CI: 0.82, 0.92).

Conclusions: In this nationwide cohort study in Japan, GLP-1 RA initiation was associated with a lower 24-month risk of cardiovascular events and all-cause death compared with DPP-4 inhibitor initiation. Agent-specific comparisons of liraglutide, dulaglutide, and semaglutide against DPP-4 inhibitors using a consistent design will also be presented.