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

Initiating tirzepatide was associated with a lower one-year risk of major adverse cardiovascular events than sitagliptin in people with type 2 diabetes and established cardiovascular disease. This was a large population based cohort study using US claims data, with a design benchmarked against randomised trials. The apparent benefit also included fewer infections requiring hospital admission and lower all cause mortality.

Journal article — Population based cohort study. Population: Adults aged ≥40 with type 2 diabetes and established atherosclerotic cardiovascular disease, identified from two US claims databases.. Sample size: 52971 participants. Follow-up: Up to one year follow-up. Interventions: Tirzepatide.

At one year, the weighted risk of major adverse cardiovascular events was 2.9% (95% CI 2.5% to 3.4%) with tirzepatide versus 4.4% (95% CI 3.8% to 4.9%) with sitagliptin, giving a risk difference of -1.4% (95% CI -2.1% to -0.7%) and hazard ratio 0.68 (95% CI 0.58 to 0.80). Myocardial infarction showed a hazard ratio of 0.67 (95% CI 0.52 to 0.87), while ischaemic stroke showed no meaningful difference (hazard ratio 0.91, 95% CI 0.64 to 1.28). Infections requiring hospital admission were lower with tirzepatide (hazard ratio 0.64, 95% CI 0.55 to 0.75), as was infection related mortality (hazard ratio 0.40, 95% CI 0.26 to 0.61). All cause mortality was also lower (hazard ratio 0.55, 95% CI 0.42 to 0.72). Negative control outcomes showed no association.

For researchers studying tirzepatide, this paper provides real-world evidence from a large cohort, benchmarked against randomised trials, suggesting cardiovascular benefit beyond standard care. It supports the expectation of reduced major adverse cardiovascular events in clinical practice, but does not establish causation or provide evidence for mechanisms, dosing, or longer-term outcomes without confirmation in randomised trials.

Key findings

• One-year risk of major adverse cardiovascular events was 2.9% with tirzepatide versus 4.4% with sitagliptin, a hazard ratio of 0.68.
• Myocardial infarction hazard was lower with tirzepatide (hazard ratio 0.67, 95% CI 0.52 to 0.87; number needed to treat 130).
• Ischaemic stroke showed no meaningful difference between groups (hazard ratio 0.91, 95% CI 0.64 to 1.28).
• Infections requiring hospital admission were lower with tirzepatide (hazard ratio 0.64, 95% CI 0.55 to 0.75).
• All cause mortality was lower with tirzepatide (hazard ratio 0.55, 95% CI 0.42 to 0.72).
• Negative control outcomes showed no association, supporting the study's internal validity.

Limitations

• Observational design means residual confounding cannot be fully excluded despite negative control analyses.
• Outcomes were derived from claims data, which may be subject to misclassification.
• Follow-up was limited to one year, so longer-term effects are not assessed.
• The study population was restricted to US patients with type 2 diabetes and established cardiovascular disease, limiting generalisability.

The record

• Journal: BMJ (Clinical research ed.) 394: e100011
• Published: 2026-08-05
• PMID: 42556854 — DOI: 10.1136/bmj-2026-100011
• MeSH terms: Humans, Cardiovascular Diseases, Myocardial Infarction, Diabetes Mellitus, Type 2, Hypoglycemic Agents, Cohort Studies, Aged, Middle Aged, United States, Female, Male, Atherosclerosis, Stroke, Dipeptidyl-Peptidase IV Inhibitors, Propensity Score, Sitagliptin Phosphate, Tirzepatide
• Author countries: Germany, USA

Peptide profiles: Tirzepatide.

All indexed evidence: Tirzepatide trials & papers.

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