INTRODUCTION: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefits in trials involving high-risk patients with type 2 diabetes (T2D), while dipeptidyl peptidase 4 inhibitors (DPP-4is) have not. However, DPP-4is are still commonly prescribed in patients with T2D and atherosclerotic cardiovascular disease (ASCVD). This study compared time to occurrence of cardiovascular events, health care resource utilization (HCRU), and medical costs in patients with T2D and ASCVD who initiated once-weekly semaglutide vs a DPP-4i. METHODS: Two separate observational cohort analyses were conducted using Optum's de-identified Clinformatics RESULTS: After weighting, the CDM analysis included 14,461 semaglutide users and 38,630 DPP-4i users and the Komodo Healthcare Map analysis included 48,303 semaglutide users and 109,179 DPP-4i users. In CDM, semaglutide users had significantly decreased risk of stroke (hazard ratio [HR], 0.54), myocardial infarction (HR 0.64), and their composite (HR 0.59) vs DPP-4is. Semaglutide users also had fewer ASCVD-related and all-cause hospitalizations and outpatient visits and lower ASCVD-related and all-cause hospitalization and total medical costs. Results from Komodo Health were generally consistent with those from CDM. CONCLUSION: Semaglutide users had significantly reduced risk of cardiovascular outcomes, HCRU, and medical costs compared with DPP-4is. This corroborates results from prior studies of once-weekly GLP-1 RAs and reinforces the important role of semaglutide treatment for patients with T2D and ASCVD. Graphical abstract available for this article.