Coronary artery disease -related outcomes associated with semaglutide and tirzepatide in type 2 diabetes mellitus and obesity: a systematic review and meta-analysis.

AIMS: Semaglutide and tirzepatide are widely used drugs in the treatment of metabolic diseases based on incretin-based therapy. However, evidence on coronary artery disease (CAD)-related outcomes has largely been derived from separate randomized trials with different control groups, and focused synthesis across CAD phenotypes remains limited. This study aimed to evaluate CAD-related outcomes reported in randomized controlled trials (RCTs) of semaglutide and tirzepatide in adults with type 2 diabetes (T2DM) and/or obesity.

DATA SYNTHESIS: We systematically searched PubMed, Embase, Scopus, Web of Science, CENTRAL, and ClinicalTrials.gov from database inception to September 26, 2025, for RCTs evaluating subcutaneous semaglutide or tirzepatide in T2DM and/or obesity. Separate pooled analyses were performed for semaglutide and tirzepatide using random-effects models. Prespecified outcomes included the broad CAD-related composite, acute coronary syndrome (ACS), myocardial infarction (MI), unstable angina (UA), chronic coronary syndrome (CCS), angina pectoris, and trial-reported CAD events, defined as CAD events explicitly reported in the original trials. Among the 45 included trials, semaglutide showed lower pooled estimates for the broad CAD-related composite (RR = 0.80, 95% CI [0.73-0.87]; p < 0.001), ACS (RR = 0.77, 95% CI [0.70-0.85]; p < 0.001), MI (RR = 0.70, 95% CI [0.62-0.80]; p < 0.001), UA (RR = 0.82, 95% CI [0.70-0.96]; p = 0.017), and angina pectoris (RR = 0.73, 95% CI [0.60-0.89]; p = 0.002) in the pooled analyses. For tirzepatide, pooled estimates were not statistically significant for most CAD-related outcomes, including the broad CAD-related composite (RR = 0.74, 95% CI [0.52-1.07]; p = 0.110). A lower pooled estimate was observed for trial-reported CAD events in tirzepatide trials, but this finding was based on fewer events and was interpreted as exploratory.

CONCLUSION

In semaglutide trials, treatment was associated with lower pooled risks across several CAD-related outcomes, particularly acute coronary phenotypes in adults with T2DM and/or obesity. Evidence for tirzepatide remained less precise because of fewer CAD-related events and limited CAD-specific outcome data. Further dedicated cardiovascular outcome trials, longer follow-up studies, and more standardized reporting of CAD-related outcomes are needed.