Tirzepatide lowers heart attack and cardiovascular event risk in adults with type 2 diabetes

By Tarun Sai LomteReviewed by Susha Cheriyedath, M.Sc.Aug 10 2026

Real-world data suggest tirzepatide may reduce major cardiovascular events beyond standard diabetes care, with the strongest signals seen for myocardial infarction and mortality.

Study: Tirzepatide and the risk of atherosclerotic cardiovascular events: population based cohort study. Image Credit: Dragana Gordic / Shutterstock

In a recent study published in The British Medical Journal, researchers assessed whether initiating tirzepatide alongside standard care was associated with a lower risk of major adverse cardiovascular events (MACE).

Tirzepatide is a dual incretin agonist of glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors. It can reduce body weight and blood glucose, but its cardiovascular effects are debated. While observational studies and randomized trials have found tirzepatide’s protective effects on hospitalization for heart failure and all-cause mortality, evidence on major cardiovascular events remains limited.

Randomized trials have increasingly shifted toward head-to-head comparisons of active agents rather than placebo-controlled designs. For example, tirzepatide was found to be non-inferior to dulaglutide with respect to MACE in the SURPASS-CVOT trial.

Such head-to-head designs can inform the choice between alternative agents, but they do not address the incremental benefit of adding tirzepatide to a contemporary background treatment.

About the study

In the present study, researchers estimated the magnitude of MACE reduction associated with the addition of tirzepatide to the standard of care. Specifically, tirzepatide was compared to a validated placebo proxy, an active comparator whose cardiovascular neutrality has been demonstrated in placebo-controlled outcomes trials, by emulating the SURPASS-CVOT trial design and eligibility criteria using healthcare claims data.

The team analyzed data from two administrative claims databases in the United States (US) from May 2022 to May 2025. The databases comprised longitudinal data on personal characteristics, diagnoses, dispensed drugs, and medical procedures. Consistent with SURPASS-CVOT, this study included patients aged ≥ 40 years with atherosclerotic cardiovascular disease and type 2 diabetes (T2D).

Specifically, patients with a body mass index ≥ 25 kg/m² and evidence of prior ischemic stroke, myocardial infarction (MI), or peripheral, coronary, or carotid artery disease, who initiated tirzepatide or sitagliptin (placebo proxy), were included. Individuals with pregnancy, active liver disease, advanced heart failure, end-stage kidney disease, conditions predisposing to adverse effects related to incretin, or recent use of GLP-1 receptor agonists were excluded.

Patients were followed up until the occurrence of an outcome, health-plan disenrollment, treatment discontinuation or switching, or for 1 year. Outcomes included MACE, defined as a composite of stroke, myocardial infarction (MI), and all-cause mortality, rather than cardiovascular mortality. Infection-related mortality was examined as a post hoc exploratory outcome.

The researchers also assessed an expanded composite of stroke, MI, unstable angina, and coronary revascularization. Safety outcomes were gastrointestinal (GI) adverse events and infections requiring hospitalization.

In addition, abdominal hernia and lumbar radiculopathy were assessed as negative control outcomes. The team estimated propensity scores and applied overlap weighting. Weighted Kaplan-Meier survival methods were used to estimate event-free survival. Cox proportional hazards models were used to estimate hazard ratios (HRs). Absolute risk and risk difference at one year were calculated from weighted survival curves.

Findings

The study included 52,971 individuals, of whom 17,618 initiated sitagliptin, and 35,353 initiated tirzepatide. Following overlap weighting, each group included 7,442 individuals with balanced characteristics. Women accounted for 50.8% of the weighted cohort, which had an average age of approximately 70 years. Statin use was documented in 85% of patients, insulin use in 18%, and sodium-glucose cotransporter 2 inhibitor use in 21% in each group.

At one year, the weighted MACE risk was 2.9% with tirzepatide and 4.4% with sitagliptin, with a risk difference of −1.4% and HR of 0.68. HRs of individual components were 0.91 for stroke, 0.67 for MI, and 0.55 for all-cause mortality. When mortality was excluded, the combined outcome of MI or stroke also favored tirzepatide.

The MACE association was driven primarily by lower hazards of MI and all-cause mortality, with infection-related deaths contributing to the mortality difference. 

The tirzepatide group showed lower infection-related mortality, while the expanded composite modestly favored tirzepatide as well. It was associated with a markedly lower risk of infections requiring hospitalization.

Results were broadly consistent across sensitivity analyses and patient subgroups.

Conclusions

In summary, the addition of tirzepatide to the standard of care was associated with a lower MACE risk than the addition of sitagliptin, with a 32% lower hazard of MACE. The HR of stroke did not differ meaningfully between the two groups. The tirzepatide group showed lower rates of infections requiring hospitalization and infection-related mortality, with no differences in GI adverse events.

No associations were observed with negative control outcomes. However, the authors cautioned that the mortality findings may be particularly susceptible to residual confounding, including differences between patients prescribed sitagliptin and tirzepatide.

The study’s limitations include the short follow-up duration, with a median on-treatment follow-up of less than six months, reliance on a placebo proxy with a different mode of administration (oral vs. subcutaneous), possible treatment or outcome misclassification in claims data, limited generalizability beyond insured US patients with established atherosclerotic cardiovascular disease, and potential residual confounding.

Overall, the study highlights how trial-anchored evidence can help inform timely clinical and regulatory decision-making.