A new real-world evidence study suggests that the incretin-based medicines tirzepatide and semaglutide have comparable cardiovascular (CV) benefits for patients with type 2 diabetes (T2D) and elevated CV risk.¹ While clinical trials have shown benefits for both drugs, the lack of direct head-to-head comparisons has left uncertainty regarding the optimal treatment choice in clinical practice.

To address this evidence gap, investigators conducted five cohort studies using data from United States insurance programmes between 2018 and 2025. The study first emulated two major cardiovascular outcome trials, SUSTAIN-6 (semaglutide) and SURPASS-CVOT (tirzepatide), to benchmark and validate their design and analytical framework.

Following this validation, the effectiveness of each drug was assessed in expanded populations more reflective of routine clinical practice. Finally, a direct head-to-head comparison of tirzepatide versus semaglutide was performed. Propensity score matching was used to balance baseline confounders across the cohorts. The primary composite endpoint was myocardial infarction (MI), stroke, or all-cause mortality.

In the expanded population analyses, semaglutide was associated with a lower risk of the composite outcome of MI or stroke compared with sitagliptin (hazard ratio [HR]: 0.82; 95% CI, 0.74 to 0.91). Tirzepatide showed a non-significant trend towards a lower risk of the composite outcome of MI, stroke, or mortality compared with dulaglutide (HR: 0.87; 95% CI, 0.75 to 1.01).

In the direct head-to-head comparison, there was no significant difference between tirzepatide and semaglutide for the primary composite endpoint of MI, stroke, or all-cause mortality (HR: 1.06; 95% CI, 0.95 to 1.18).

This large-scale, real-world analysis suggests that tirzepatide and semaglutide confer similar degrees of cardiovascular protection in patients with T2D at high CV risk. While randomised trials like SURMOUNT-5 have shown tirzepatide to be superior for weight loss, these new data indicate this may not translate to superior cardiovascular outcomes.² The study authors concluded, "These findings support a comparable cardiovascular benefit of tirzepatide and semaglutide in clinical practice and demonstrate how rigorously designed real-world evidence can complement randomized clinical trials."¹

References

1. Krüger N, Schneeweiss S, Desai RJ, et al. Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice. Nat Med (2025). https://doi.org/10.1038/s41591-025-04102-x

2. SURMOUNT-5 Investigators. A trial of tirzepatide versus semaglutide for weight management. N Engl J Med 2025. https://doi.org/10.1056/NEJMoa2416394

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