Adults with type 2 diabetes mellitus (T2DM) and established atherosclerotic cardiovascular disease (ASCVD) require glucose-lowering therapies that address both glycemic control and cardiovascular risk, yet comparative real-world outcome data across newer injectable agents remain limited. A target trial emulation published in Diabetes Care evaluated cardiovascular outcomes with tirzepatide compared with dulaglutide or semaglutide in commercially insured adults with T2DM and ASCVD.

Two parallel emulations included adults who initiated subcutaneous tirzepatide, dulaglutide, or semaglutide between June 2022 and December 2024. After one-to-one propensity score matching, the analysis included 9,233 tirzepatide-dulaglutide pairs and 25,266 tirzepatide-semaglutide pairs. The primary endpoint was modified major adverse cardiovascular events (MACE), defined as nonfatal myocardial infarction, nonfatal stroke, and all-cause death.

Among tirzepatide and dulaglutide initiators, modified MACE rates were lower with tirzepatide (31.3 vs 39.4 per 1,000 person-years; HR 0.80; 95% CI 0.65-0.99). Lower all-cause mortality was also observed with tirzepatide (HR 0.60; 95% CI 0.43-0.83). In contrast, modified MACE rates were similar between tirzepatide and semaglutide initiators (23.7 vs 23.2 per 1,000 person-years; HR 1.03; 95% CI 0.90-1.17). Post hoc analyses also showed lower pneumonia-related hospitalization rates with tirzepatide vs dulaglutide.

Overall, tirzepatide was associated with lower modified MACE risk than dulaglutide in routine care, while cardiovascular outcomes were comparable with semaglutide.