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.