Semaglutide vs. tirzepatide in non-diabetic obesity: Real-world cardiovascular outcomes

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Created On: 21/09/2026

Cardiovascular risk remains an important concern in people with overweight or obesity, particularly those suffering from established atherosclerotic cardiovascular disease (ASCVD).

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Key take away

In people with overweight or obesity, established ASCVD, and no diabetes, using semaglutide is linked with lower risks of major adverse cardiovascular events than tirzepatide.

Background

Cardiovascular risk remains an important concern in people with overweight or obesity, particularly those suffering from established atherosclerotic cardiovascular disease (ASCVD). Semaglutide and tirzepatide are increasingly used for weight management, but comparative real-world evidence on their cardiovascular outcomes in people without diabetes is limited. The study compared the potency of semaglutide vs. tirzepatide in reducing major adverse cardiovascular events (MACE) in this population.

Method

This retrospective, observational cohort study used data from the Komodo Research Database. It included patients aged ≥45 years with overweight or obesity, established ASCVD, and no diabetes who initiated semaglutide or tirzepatide between May 13, 2022, and January 31, 2025. Propensity score matching was employed to balance baseline characteristics between treatment groups. The key outcomes ascertained were:

Revised 3-point MACE (rMACE-3: Myocardial infarction [MI], stroke, and all-cause mortality)
Revised 5-point MACE (rMACE-5: MI, stroke, hospital admission for heart failure, coronary revascularization or all-cause mortality).

Time to first cardiovascular event was analysed using Cox proportional hazards models.

Result

After propensity score matching, 10,625 subjects were included in each group. Semaglutide (glucagon‐like peptide‐1 [GLP‐1] receptor agonist) use was associated with a significantly lower risk of both rMACE-3 and rMACE-5 vs. tirzepatide (Table 1).

In the secondary per-protocol analysis, which included patients censored after treatment discontinuation, semaglutide remained associated with a lower risk of rMACE-3 (HR 0.43) and rMACE-5 (HR 0.57) compared with tirzepatide.

Conclusion

Among patients with overweight or obesity and established ASCVD without diabetes, treatment with semaglutide was linked with an early and greater reduction in the risk of both 3-point and 5-point revised MACE compared to tirzepatide. These real-world observational data offer valuable clinical insights supporting the cardioprotective benefits of semaglutide in non-diabetic secondary prevention settings.