Tirzepatide Matches Dulaglutide for Cardiovascular Protection With Added Metabolic Benefits: NEJM
In a large randomized trial involving patients with type 2 diabetes and established atherosclerotic cardiovascular disease, tirzepatide was noninferior to dulaglutide in reducing major cardiovascular events. While both drugs are approved for diabetes treatment, only dulaglutide currently carries an indication for cardiovascular risk reduction. Tirzepatide additionally demonstrated superior metabolic outcomes, including greater reductions in body weight and HbA1c, compared with dulaglutide. The study was published in The New England Journal of Medicine by Stephan J. and colleagues.
The present trial was undertaken to assess whether tirzepatide is not inferior to dulaglutide, the established cardioprotective GLP-1 receptor agonist, in major adverse cardiovascular event reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease.
This was an active-comparator-controlled, double-blind, randomized noninferiority trial. Patients with type 2 diabetes and established atherosclerotic cardiovascular disease were randomly assigned in a 1:1 ratio to receive either weekly subcutaneous tirzepatide (titrated up to 15 mg) or dulaglutide 1.5 mg. The primary composite endpoint included death from cardiovascular causes, myocardial infarction, or stroke. Noninferiority was pre-specified with an upper margin of 1.05 for the 95.3% confidence interval of the hazard ratio, while superiority required the upper limit to be below 1.00.
In all, 13,299 patients were randomized, of whom 13,165 were included in the modified intention-to-treat analysis. This included 6,586 patients in the tirzepatide group and 6,579 in the dulaglutide group. The mean age was 64.1±8.8 years, 29.0% were women, the mean body mass index was 32.6±5.5, the mean HbA1c was 8.4±0.9%, and the mean duration of diabetes was 14.7±8.8 years, reflecting a population with long-standing, high-risk disease.
Key Findings
During the period of study, a major adjudicated cardiovascular event occurred in 801 patients (12.2%) receiving tirzepatide and 862 patients (13.1%) receiving dulaglutide.
This corresponded to a hazard ratio of 0.92 (95.3% CI, 0.83–1.01). Tirzepatide met the prespecified criterion for noninferiority (P=0.003), but did not achieve superiority over dulaglutide (P=0.09).
These findings indicate that tirzepatide provides cardiovascular outcomes comparable to a therapy with proven cardiovascular benefit.
Among patients with type 2 diabetes and established atherosclerotic cardiovascular disease, tirzepatide was non-inferior to dulaglutide concerning major cardiovascular events. These findings support the cardiovascular safety of tirzepatide and reaffirm its role as an effective treatment option that couples metabolic benefit with comparable cardiovascular outcomes.
Reference:
Nicholls, S. J., Pavo, I., Bhatt, D. L., Buse, J. B., Del Prato, S., Kahn, S. E., Lincoff, A. M., McGuire, D. K., Miller, D., Nauck, M. A., Nishiyama, H., Nissen, S. E., Sattar, N., Weerakkody, G., Wiese, R. J., Zinman, B., Zoungas, S., Basile, J., Davies, M. J., … D’Alessio, D. (2025). Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes. The New England Journal of Medicine, 393(24), 2409–2420. https://doi.org/10.1056/nejmoa2505928
