Tirzepatide and the risk of atherosclerotic cardiovascular events: population based cohort study

Abstract Objective To estimate the magnitude of reduction in major adverse cardiovascular events (MACE) that would be observed in clinical practice from adding tirzepatide to standard of care treatment. Design Population based cohort study, using a design, data, and analytical approach previously benchmarked against randomised trials. Setting Two national US claims databases, May 2022 to May 2025. Participants 52 971 participants aged ≥40 years with type 2 diabetes and established atherosclerotic cardiovascular disease who initiated tirzepatide (n=35 353) or sitagliptin (n=17 618), a cardiovascular outcome neutral comparator serving as a placebo proxy. Baseline characteristics were well balanced between treatment groups after propensity score overlap weighting. Main outcome measures The main outcome, MACE, was a composite of myocardial infarction, stroke, and all cause mortality and its individual components. Follow-up started the day after treatment initiation and continued until occurrence of the outcome, disenrollment from the health plan, treatment discontinuation or switching, or one year. Safety outcomes included infections requiring hospital admission and infection related mortality. Two negative control outcomes, lumbar radiculopathy and abdominal hernia, were analysed to assess residual confounding. Results At one year, the weighted one year risk of MACE was 2.9% (95% confidence interval (CI) 2.5% to 3.4%) in the tirzepatide group and 4.4% (3.8% to 4.9%) in the sitagliptin group (risk difference -1.4%, 95% CI -2.1% to -0.7%; number needed to treat (NNT)=70), corresponding to a hazard ratio of 0.68 (95% CI 0.58 to 0.80). For individual MACE components, tirzepatide was associated with a lower hazard for myocardial infarction (hazard ratio 0.67, 0.52 to 0.87; NNT=130), whereas ischaemic stroke showed no meaningful difference (0.91, 0.64 to 1.28; NNT 2500). Infections requiring hospital admission were lower with tirzepatide (0.64, 0.55 to 0.75; NNT=48), as was infection related mortality (0.40, 0.26 to 0.61; NNT=200) and all cause mortality (0.55, 0.42 to 0.72; NNT=122). Negative control outcomes showed no association. Conclusions In this cohort study using an approach benchmarked against randomised trials, initiating tirzepatide reduced the risk of MACE compared with a placebo proxy among people with type 2 diabetes and established atherosclerotic cardiovascular disease. Reductions in infection related events suggest broader non-atherosclerotic biological mechanisms may contribute to the observed benefit. This study shows how trial-anchored evidence from clinical practice can estimate the expected cardiovascular benefit of initiating tirzepatide beyond standard background treatment and inform shared decision making. Trial registration ClinicalTrials.gov NCT07203677 .