Tirzepatide Cuts MACE Risk in Diabetes With Heart Disease

Adding tirzepatide (Mounjaro; Eli Lilly and Company) to standard care lowered the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease, according to a population-based cohort study published in The BMJ. For pharmacists counseling patients on incretin-based therapy, the finding offers an absolute, real-world estimate of what initiating tirzepatide on top of background treatment may achieve—one case of MACE prevented for every 70 patients treated over 1 year.¹

“Our findings suggest that tirzepatide may be especially attractive when lowering glucose, reducing weight, and addressing residual atherosclerotic cardiovascular risk are simultaneous priorities,” Nils Krüger, MD, MPH, a physician data scientist at Harvard Medical School and Brigham and Women’s Hospital and lead study author, told Pharmacy Times.

Why an Anchor to Standard Care Was Needed

Randomized trials and observational studies have shown tirzepatide to be non-inferior to another glucagon-like peptide-1 (GLP-1) receptor agonist, dulaglutide (Trulicity; Eli Lilly and Company), for MACE, which is a composite of myocardial infarction, stroke, and all-cause mortality. But evidence on the incremental benefit of adding tirzepatide to standard care has been more limited, leaving uncertainty for regulators and clinicians. To address this, researchers emulated the design and eligibility criteria of the SURPASS-CVOT trial (NCT04255433) using health care claims data, comparing tirzepatide against sitagliptin (Januvia; Merck), a dipeptidyl peptidase-4 (DPP-4) inhibitor selected as a cardiovascular-neutral placebo proxy based on prior studies showing no effect on cardiovascular outcomes.^1-5

What the Study Found

The analysis drew on 2 US claims databases (Optum Clinformatics and Merative MarketScan) covering May 2022 to May 2025, including 52,971 individuals (median age 69.8 years; 50.8% female) with T2D, a body mass index of at least 25, and established heart disease. Of these, 35,353 initiated tirzepatide and 17,618 initiated sitagliptin; propensity score overlap weighting balanced baseline differences between groups.¹

At 1 year, the weighted risk of MACE was 2.9% (95% CI, 2.5% to 3.4%) with tirzepatide versus 4.4% (95% CI, 3.8% to 4.9%) with sitagliptin, corresponding to a risk difference of −1.4% (95% CI, -2.1% to -0.7%) and a hazard ratio (HR) of 0.68 (95% CI, 0.58-0.80), corresponding to a 32% relative reduction and a number needed to treat (NNT) of 70. Among individual components, tirzepatide was associated with a lower hazard for myocardial infarction (HR, 0.67; 95% CI, 0.52-0.87; NNT, 130), whereas ischemic stroke showed no meaningful difference (HR, 0.91; 95% CI, 0.64-1.28). All-cause mortality was also lower (HR, 0.55; 95% CI, 0.42-0.72; NNT, 122). Cumulative incidence curves diverged within the first 3 months.¹

An Unexpected Infection Signal

Beyond the cardiovascular endpoints, tirzepatide was linked to markedly lower rates of infections requiring hospital admission (HR, 0.64; 95% CI, 0.55-0.75; NNT, 48) and infection-related mortality (HR, 0.40; 95% CI, 0.26-0.61; NNT, 200). The authors suggest part of the survival benefit may reflect mechanisms beyond atherosclerosis, given obesity's role as a risk factor for serious infections, though they note that this hypothesis requires further substantiation.¹

“This is a highly interesting and relevant finding,” Krüger highlighted. “The consistency of our findings across a randomized active-comparator trial and a placebo-like comparison from clinical practice makes it unlikely that the finding is explained solely by residual confounding.”

How to Weigh the Evidence

This is an observational study, and the authors are candid about its limits: the design cannot fully rule out residual confounding, follow-up was relatively short (median on-treatment follow-up was under half a year), and sitagliptin differs from tirzepatide in administration (oral versus subcutaneous). The findings may not generalize to uninsured patients, non-US systems, or populations without established cardiovascular disease. Importantly, the team previously benchmarked its design, data, and analytics against a randomized trial before drawing causal conclusions.¹

Krüger and his fellow authors caution that while the study offers a transparent estimate of what initiating tirzepatide might achieve in routine care, it does not establish a mortality indication or define the optimal sequence for cardiometabolic therapy. Cardiovascular efficacy cannot benefit a population if cost, authorization barriers, supply, and discontinuation prevent sustained treatment, a set of access considerations directly relevant to pharmacy practice.^1,6

“Tirzepatide should be considered a complementary component of comprehensive cardiovascular risk reduction rather than a replacement for established therapies,” Krüger cautioned.

For pharmacists, the practical takeaway is a defensible absolute framing to bring into shared decision-making conversations—paired with realistic attention to whether a patient can start and stay on therapy.¹

REFERENCES

1. Krüger N, Schneeweiss S, Wang SV. Tirzepatide and the risk of atherosclerotic cardiovascular events: a population-based cohort study. BMJ. 2026;394:e100011. doi:10.1136/ bmj-2026-100011

2. Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes. N Engl J Med. 2025;393(24):2409-2420. doi:10.1056/NEJMoa2505928

3. Aminorroaya A, Camargos AP, Oikonomou EK, Khera R. Cardiovascular efficacy of tirzepatide in patients with type 2 diabetes mellitus: an individual participant data meta-analysis of 8 randomized clinical trials. JACC. 2025;85(12):415. doi:10.1016/S0735-1097(25)00899-X

4. A study of tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes (SURPASS-CVOT). ClinicalTrials.gov Identifier: NCT04255433. Last Updated July 8, 2026. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT04255433

5. Green JB, Bethel A, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-242. doi:10.1056/NEJMoa1501352

6. Eyadiel LS, Modarressi T. Bridging the gap: pragmatic strategies to overcome barriers in the implementation of cardiometabolic care. J Cardiac Fail. 2026;2(2):147-156. doi:10.1016/j.yjcafi.2025.08.015