Tirzepatide Linked to Lower 1-Year MACE Risk in T2D

Key Takeaways

• In US adults with type 2 diabetes and established atherosclerotic cardiovascular disease, tirzepatide initiation was associated with a lower 1-year risk of major adverse cardiovascular events than sitagliptin.
• The absolute 1-year major adverse cardiovascular event risk was 2.9% with tirzepatide and 4.4% with sitagliptin.
• The association appeared to be driven mainly by lower myocardial infarction and all-cause mortality, while stroke did not differ meaningfully.
• Lower infection-related mortality and fewer infections requiring hospitalization were observed with no difference in gastrointestinal adverse events, although the authors cautioned that mortality findings may be susceptible to residual confounding and that on-treatment follow-up was short.

Adults with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) often need additional glucose-lowering therapy despite persistent cardiovascular risk. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist, has had uncertain effects on major cardiovascular events in routine care. Investigators therefore used a cardiovascularly neutral comparator to estimate the incremental association of adding tirzepatide to standard care.

In a BMJ population-based cohort study of tirzepatide and atherosclerotic cardiovascular events, investigators emulated SURPASS-CVOT with US administrative claims data collected from May 2022 to May 2025. Eligible patients were aged 40 years or older with T2D and ASCVD who initiated tirzepatide or sitagliptin, including those with prior ischemic stroke, myocardial infarction (MI), or peripheral, coronary, or carotid artery disease.

Patients also had a body mass index of at least 25 kg/m2, and major exclusions included pregnancy, active liver disease, advanced heart failure, end-stage kidney disease, conditions predisposing to incretin-related adverse effects, and recent glucagon-like peptide 1 receptor agonist use. Follow-up continued until an outcome, disenrollment, treatment discontinuation or switching, or 1 year. The primary endpoint was major adverse cardiovascular events (MACE) composed of stroke, MI, and all-cause mortality, and investigators also assessed an expanded composite, infection-related mortality, gastrointestinal (GI) adverse events, infections requiring hospitalization, and negative control outcomes in a cohort of 52,971 people using propensity scores, overlap weighting, weighted Kaplan-Meier methods, and Cox models.

At 1 year, the weighted risk of MACE was 2.9% with tirzepatide and 4.4% with sitagliptin, for an absolute risk difference of -1.4%.

The hazard ratio for MACE was 0.68, and component hazard ratios were 0.67 for MI and 0.55 for all-cause mortality. Those findings suggested that the overall association was concentrated in MI and mortality.

Stroke did not differ meaningfully between groups, with a hazard ratio of 0.91. The combined MI-or-stroke outcome and the expanded composite also favored tirzepatide, while infection-related mortality and infections requiring hospitalization were lower, GI adverse events did not differ, negative control outcomes were not associated, and sensitivity and subgroup analyses were broadly consistent.

The authors said the mortality findings may be particularly susceptible to residual confounding, including differences between patients prescribed sitagliptin and tirzepatide, and author-cited safety and follow-up details from the cohort comparison noted a median on-treatment follow-up of less than six months despite the 1-year analytic horizon. Claims-based analyses can also be affected by treatment or outcome misclassification, and the placebo-proxy comparator differed from tirzepatide in route of administration. Generalizability was described as limited beyond insured US patients with established ASCVD, and the study reports observational associations rather than causal effects.

The BMJ cohort linked tirzepatide initiation with lower 1-year MACE risk than sitagliptin in insured US adults with T2D and established ASCVD. The pattern was concentrated in MI and all-cause mortality rather than stroke. Short follow-up and potential residual confounding shape how those findings are interpreted.

Clinician Questions

Which patients with type 2 diabetes do these tirzepatide cardiovascular findings apply to?

These findings apply to insured US adults aged 40 years or older with T2D, established ASCVD, and body mass index of at least 25 kg/m2 who initiated tirzepatide or sitagliptin. Established ASCVD included prior ischemic stroke, MI, or peripheral, coronary, or carotid artery disease, and the authors described generalizability as limited beyond insured US patients with established ASCVD.

How was MACE defined in the tirzepatide versus sitagliptin cardiovascular comparison?

In this cohort of adults with T2D and established ASCVD, MACE was defined as a composite of stroke, MI, and all-cause mortality rather than cardiovascular mortality. Investigators also examined an expanded composite and assessed infection-related mortality separately as a post hoc exploratory outcome.

Why is the mortality signal with tirzepatide interpreted cautiously in adults with type 2 diabetes and ASCVD?

The authors said mortality findings in the tirzepatide versus sitagliptin comparison may be particularly susceptible to residual confounding, including differences between patients prescribed the 2 drugs. Median on-treatment follow-up was less than six months, which narrows how firmly mortality patterns can be interpreted over the 1-year analytic horizon.