Tirzepatide may be associated with a lower 1-year weighted risk of major adverse cardiovascular events compared with sitagliptin among patients with type 2 diabetes and established atherosclerotic cardiovascular disease.
In a population-based cohort study, investigators analyzed de-identified administrative claims data from Optum Clinformatics and Merative MarketScan from May 2022 to May 2025. They included 52,971 patients aged 40 years or older who initiated tirzepatide (n = 35,353) or sitagliptin (n = 17,618), an active cardiovascular-neutral comparator serving as a placebo proxy.
The study emulated eligibility criteria from SURPASS-CVOT. Eligible patients had a documented previous myocardial infarction; ischemic stroke; or coronary, carotid, or peripheral arterial disease.
The primary outcome was major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or all-cause mortality. Follow-up began the day following treatment initiation and continued until the occurrence of MACE, health plan disenrollment, treatment discontinuation or switching, or 1 year. The primary analysis used an on-treatment approach as a per-protocol analogue.
The investigators estimated propensity scores using all baseline covariates and applied overlap weighting to highlight patients with the greatest clinical equipoise between treatment groups. Before weighting, patients initiating tirzepatide were younger, had higher body mass index, and had fewer comorbidities compared with those initiating sitagliptin. Following weighting, measured baseline characteristics were balanced, and the overlap-weighted population included approximately 7,442 patients per group.
At 1 year, weighted MACE risk was about 3% with tirzepatide vs. 4% with sitagliptin, with a study estimated number needed to treat of 70. The risk of myocardial infarction or stroke was approximately 2% with tirzepatide and 3% with sitagliptin. The risks of myocardial infarction and all-cause mortality were lower with tirzepatide, whereas the risk of ischemic stroke was similar between the groups.
“[O]ur approach provides a direct comparison with standard of care and quantifies absolute risk differences and [number needed to treat]—measures that are directly interpretable for clinical decision-making,” wrote lead study author Nils Krüger, of the Division of Pharmacoepidemiology and Pharmacoeconomics in the Department of Medicine at Brigham and Women’s Hospital and Harvard Medical School, and colleagues.
The investigators cautioned that mortality findings may be affected by residual confounding, noting that previous benchmarking analyses identified this concern when glucagon-like peptide-1 receptor agonists were compared with dipeptidyl peptidase-4 inhibitors.
Tirzepatide was also associated with fewer infection-related hospital admissions compared with sitagliptin. Infection-related mortality was lower in a post hoc analysis, while gastrointestinal adverse events did not differ meaningfully between the groups. The investigators proposed that infection-related pathways could contribute to the observed mortality association.
Negative-control outcomes of lumbar radiculopathy and abdominal hernia showed no association between treatments, supporting the robustness of confounding adjustment.
The study was limited by its relatively short follow-up and reliance on sitagliptin as a proxy for placebo. Although outcomes were estimated through 1 year, mean on-treatment follow-up was 182 days, and median follow-up was less than half a year in both groups. The investigators cited possible residual confounding and treatment or outcome misclassification in claims data; dosing and timing of treatment escalation were not observed. The findings may not generalize to uninsured patients, non-US health care systems, or patients without established atherosclerotic cardiovascular disease.
The study was funded by the National Institutes of Health (NIH) and the German Heart Foundation. Krüger reported support from the German Heart Foundation for the submitted work. Shirley V. Wang reported institutional grants or contracts to Brigham and Women’s Hospital from the US Food and Drug Administration and the NIH; as well as consulting fees from Cytel, Exponent, and MITRE for unrelated work. Sebastian Schneeweiss reported institutional grants or contracts to the Brigham and Women’s Hospital from the US Food and Drug Administration, the NIH, Boehringer Ingelheim, Takeda, and UCB, along with consulting fees from Aetion for unrelated work.
Source: The BMJ
