Tirzepatide Linked to Lower MACE Risk Than Sitagliptin

Key Takeaways

• In a large U.S. claims-based cohort using propensity score overlap weighting among adults aged 40 years or older with type 2 diabetes and established atherosclerotic cardiovascular disease, tirzepatide was associated with a lower 1-year risk of major adverse cardiovascular events than sitagliptin, 2.9% versus 4.4%.
• Tirzepatide was also associated with lower hazards of myocardial infarction and all-cause mortality than sitagliptin in the overlap-weighted analysis.
• Ischemic stroke risk did not differ meaningfully between the treatment groups.
• The expanded composite endpoint that included coronary revascularization and unstable angina was also associated with a lower hazard with tirzepatide.

Adults with type 2 diabetes and established atherosclerotic cardiovascular disease often need treatment intensification that addresses glycemia, weight, and cardiovascular risk together. In routine U.S. care, an open question has been whether tirzepatide initiation is associated with lower cardiovascular event risk beyond contemporary background treatment when compared with a comparator intended to provide a neutral cardiovascular reference. Krüger and colleagues examined that question in a real-world cohort of adults already living with both conditions.

In Krüger and colleagues’ analysis, investigators used Optum Clinformatics and Merative MarketScan claims data to study adults aged 40 years or older with type 2 diabetes and established atherosclerotic cardiovascular disease from May 2022 to May 2025. The study included 52,971 initiators overall—35,353 receiving tirzepatide and 17,618 receiving sitagliptin—and used propensity score overlap weighting to balance measured baseline characteristics between groups. The effective overlap-weighted population included approximately 7,442 patients per treatment group, representing patients for whom either treatment was a plausible clinical choice. Sitagliptin served as a cardiovascular-neutral proxy comparator because prior evidence showed no cardiovascular benefit or harm. Major adverse cardiovascular events (MACE) were defined as myocardial infarction, stroke, and all-cause mortality. Investigators also assessed a separate expanded composite outcome of myocardial infarction, stroke, coronary revascularization, and unstable angina. Mean on-treatment follow-up was 182 days, and the analysis tracked the primary cardiovascular composite and its individual components.

Because the comparison was observational and claims-based, the reported differences should be interpreted as associations rather than definitive causal effects. The relatively short follow-up and the use of sitagliptin as a neutral reference point, rather than as a head-to-head comparator against another incretin-based therapy, also limit how far the findings can be extended. The investigators also described lower infection-related mortality and fewer infection-related hospital admissions with tirzepatide. The all-cause mortality findings warrant particular caution because the authors noted that residual confounding may remain, including possible preferential prescribing of dipeptidyl peptidase-4 inhibitors such as sitagliptin to frailer patients or those with shorter anticipated life expectancy. Krüger and colleagues said further work is needed to better define cardiovascular benefit and to clarify how much of the mortality difference may reflect atherosclerotic versus nonatherosclerotic mechanisms, including fewer serious infections.

The overlap-weighted BMJ analysis linked tirzepatide with lower cardiovascular event risk than sitagliptin among adults with type 2 diabetes and established atherosclerotic cardiovascular disease. The clearest signal was in myocardial infarction and all-cause mortality, while ischemic stroke was unchanged. Within the limits of a claims-based comparison, tirzepatide was associated with fewer major cardiovascular events than sitagliptin in this high-risk population.

Clinician Questions

Which adults with type 2 diabetes were represented in the tirzepatide versus sitagliptin cardiovascular comparison?

The study included 52,971 adults aged 40 years or older with type 2 diabetes and established atherosclerotic cardiovascular disease identified in U.S. Optum Clinformatics and Merative MarketScan claims data between May 2022 and May 2025. Investigators used propensity score overlap weighting, resulting in an effective weighted population of approximately 7,442 patients per treatment group. The study reflects routine U.S. claims-based care in this population rather than people without established atherosclerotic cardiovascular disease or a randomized trial cohort.

Why was sitagliptin used as the comparator in the tirzepatide cardiovascular outcomes analysis?

Investigators used sitagliptin as a cardiovascular-neutral proxy comparator because prior randomized and observational evidence showed no effect on cardiovascular outcomes. This frames the analysis against a placebo-like neutral reference point rather than against another incretin-based therapy.

How was MACE defined in the tirzepatide real-world analysis?

Major adverse cardiovascular events consisted of myocardial infarction, stroke, and all-cause mortality. Investigators also evaluated a separate expanded composite of myocardial infarction, stroke, coronary revascularization, and unstable angina.

What questions remain after the reported cardiovascular signal with tirzepatide? Further studies are needed to better assess longer-term cardiovascular benefit and to separate atherosclerotic from nonatherosclerotic mechanisms underlying the observed survival difference. The magnitude of the all-cause mortality association also requires cautious interpretation because the authors noted possible residual confounding, including preferential prescribing of dipeptidyl peptidase-4 inhibitors such as sitagliptin to frailer patients or those with shorter anticipated life expectancy. Further work is needed to determine how much of the observed mortality difference may relate to fewer serious infections versus residual confounding or other mechanisms.