Tirzepatide Demonstrates Cardioprotective Effects in T2D With ASCVD

Tirzepatide initiation in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) resulted in a lower risk of major adverse cardiovascular events (MACEs) compared to placebo proxy, according to recent data.^1,2

Although previous trials have shown tirzepatide’s protective effects on all-cause mortality and hospital admission for heart failure, evidence for MACEs is more limited. Tirzepatide has currently only proven its noninferiority to dulaglutide in the SURPASS-CVOT trial, while dulaglutide displayed modest cardiovascular event reductions in the placebo-controlled REWIND trial.²

“Clinical trials are increasingly comparing active ingredients with one another,” Nils Krüger, MD, MPH, instructor in medicine in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School and lead author on the study, said in a statement. “Database studies that are benchmarked against the results of traditional clinical trials can fill this gap without actually withholding potentially beneficial therapies such as GLP-1 agonists from study participants.”¹

Krüger and colleagues collected deidentified data from 2 national US administrative claims databases, Optum Clinformatics and Merative MarketScan, including detailed longitudinal data on medical diagnoses, procedures, and outpatient drug dispensations for millions of patients across the US. Patients aged ≥40 years with T2D and established ASCVD were included – these patients were also required to have a BMI ≥25 and documented evidence of previous myocardial infarction, ischemic stroke, or coronary, peripheral, or carotid artery disease confirmed through diagnostic codes or revascularization procedures.²

Index date was defined as the first outpatient dispensing of tirzepatide or sitagliptin, precluding a 183-day washout, that met eligibility criteria. Sitagliptin was selected as the neutral placebo proxy for the study based on several previous trials demonstrating its lack of impact on cardiovascular outcomes. Krüger and colleagues began follow-up on the day after cohort entry and continued until the earliest occurrence of MACE, disenrollment from the health plan, treatment discontinuation or switching, or 1 year.²

The study’s primary endpoint of MACE was a composite of myocardial infarction, stroke, and all-cause mortality – this endpoint was assessed as a composite with and without mortality, as well as individually. Krüger and colleagues used validated outcome algorithms based on inpatient diagnostic codes, which showed a positive predictive value of 94% for myocardial infarction and 95% for ischemic stroke. An expanded composite including myocardial infarction, stroke, coronary revascularization, and unstable angina was also utilized.²

A total of 52,971 patients were included in the analysis, of whom 35,353 began tirzepatide and 17,618 initiated sitagliptin. Patients in the tirzepatide arm were younger, had higher BMI, and had fewer comorbidities than those in the sitagliptin arm, prior to propensity score weighting. During a pooled mean on-treatment follow-up of 182 days, weighted risk of MACE was 2.9% (95% CI, 2.5% to 3.4%) for patients receiving tirzepatide and 4.4% (95% CI, 3.8% to 4.9%) with sitagliptin, resulting in a risk difference of -1.4% (95% CI, -2.1% to -0.7%). Cumulative incidence curves diverged within the first 3 months after treatment initiation, continuing to separate throughout the observation period.²

With mortality excluded from the composite endpoint, effect estimates for myocardial infarction and stroke remained similar (HR, 0.74; 95% CI, 0.61 to 0.91). Among individual components of MACE, myocardial infarction had a hazard ratio of 0.67 (95% CI, 0.52 to 0.87), ischemic stroke had 0.91 (95%, 0.64 to 1.28), and all-cause mortality had 0.55 (95% CI, 0.42 to 0.72). The expanded composite endpoint also favored tirzepatide, with a hazard ratio of 0.92 (95% CI, 0.85 to 0.99).²

Ultimately, despite the clarity of these data, Krüger and colleagues noted multiple limitations to the study. Among these were the relatively short follow-up period of 1 year and the reliance on sitagliptin as a proxy given its different administration compared to tirzepatide. Additionally, further confounding from unmeasured factors could partially explain the reduced risk of all-cause mortality and rapid-onset cardiovascular benefits.²

“While non-definitive, these findings add to the growing and consistent evidence base from both randomized and trial benchmarked observational studies that the cardiovascular effects of incretin-based treatments may emerge earlier than expected and independently of weight loss,” Krüger and colleagues wrote. “From a patient perspective, framing the protective effects in absolute terms such as the difference in event risk if tirzepatide is added to treatment versus maintaining standard background treatment may help communicate the tangible magnitude of benefit and support shared decision making.”²

References

1. Technical University of Munich. Obesity drug significantly reduces the risk of infections and serious cardiovascular events. Eurekalert! August 6, 2026. Accessed August 7, 2026. https://www.eurekalert.org/news-releases/1139120

2. Krüger N, Schneeweiss S, Wang SV. Tirzepatide and the risk of atherosclerotic cardiovascular events: Population based cohort study. BMJ. 2026;394. doi:10.1136/bmj-2026-100011