SURPASS-CVOT emulation sees tirzepatide reduce MACE vs dulaglutide in T2D

While results from the SURPASS-CVOT trial are not yet in, observational insurance claims data reveal that tirzepatide reduces major adverse cardiovascular events (MACE) vs dulaglutide in adults with type 2 diabetes (T2D), as shown in a target trial emulation presented at ADA 2025.

“We hypothesized that new initiators of tirzepatide would have a lower incidence of MACE vs new initiators of dulaglutide,” said Dr John Ostrominski, a fellow in cardiovascular (CV) medicine and obesity medicine at the Brigham and Women’s Hospital, Boston, Massachusetts, US.

Over a median follow-up of 5 months, the incidence rate (IR) of all-cause death, nonfatal MI, or nonfatal stroke (‘modified’ MACE) was 31.3 per 1,000 person-years (PY) in individuals started on tirzepatide vs 39.4 per 1,000 PY in those started on dulaglutide (rate difference, −8.1 per 1,000 PY, 95 percent confidence interval [CI], −15.4 to −0.8; p=0.03). As such, initiation of tirzepatide was associated with a 20-percent reduction in modified MACE vs dulaglutide (hazard ratio [HR], 0.80, 95 percent CI, 0.65–0.99).

Individuals included in the cohort (n=18,466) were adults with T2D and atherosclerotic CV disease (ASCVD) identified from a large US commercial database based on meeting the eligibility criteria of SURPASS-CVOT. [ADA 2025, abstract 223-OR]

“Findings from this target trial emulation suggest that among adults with T2D and established ASCVD, tirzepatide may reduce the risk of MACE vs dulaglutide,” said Ostrominski. “These findings may inform clinical, regulatory, and coverage decisions for this population.”

Driven by all-cause mortality

Of the three components of the primary outcome of modified MACE, a reduction in all-cause mortality drove the overall observed CV benefit with tirzepatide vs dulaglutide. Compared with an IR of 18.6 per 1,000 PY in dulaglutide users, deaths occurred at a rate of 12 per 1,000 PY in tirzepatide users (rate difference, −6.6 per 1,000 PY, 95 percent CI, −11.4 to −1.7; p<0.01), with an associated 40-percent risk reduction (HR, 0.60, 95 percent CI, 0.43–0.83).

For nonfatal MI and nonfatal stroke, trends towards lower IRs with tirzepatide vs dulaglutide were observed (p=0.5 and p=0.9, respectively).

“The apparent potential benefit of tirzepatide vs dulaglutide among new initiators in this population was driven almost entirely by all-cause mortality,” said Ostrominski.

It should be noted that the definition of MACE in SURPASS-CVOT comprises CV death, MI, and stroke. [Am Heart J 2024:267:1-11] All-cause death was used instead in the MACE definition in the current population-based study because the individuals’ mode of death could not be retrieved from claims data.

“Although we didn't have the mode of death, we could evaluate specific types of hospitalizations,” explained Ostrominski.

Ostrominski and colleagues also tried to minimize residual confounding by performing propensity score matching before assessing the clinical outcomes, resulting in equal-sized groups of 9,233 new initiators for each drug (mean age 69 years, 49.3 percent male, mean baseline glycated haemoglobin 7.64 percent overall). Consequently, balance between groups was achieved for 125 covariates.

“Incremental” benefits?

The ongoing SURPASS-CVOT trial (n=13,299) being emulated is a randomized, double-blind, active-controlled CV outcomes trial (CVOT) comparing tirzepatide with dulaglutide for CV safety and efficacy.

Besides acting as a glucagon-like peptide-1 (GLP-1) receptor agonist, which dulaglutide represents, tirzepatide is a dual agonist with additional glucose-dependent insulinotropic polypeptide (GIP) receptor agonism.

SURPASS-CVOT is therefore assessing the “open question about what the incremental benefits of GIP agonism might be beyond targeting GLP-1 receptors,” as Ostrominski described.