Semaglutide significantly lowers acute coronary syndrome and MI risk in T2DM/obesity; tirzepatide shows no significant benefit.

Patients with Type 2 Diabetes Mellitus (T2DM) and obesity face a substantially elevated risk of Coronary Artery Disease (CAD). While incretin-based therapies like semaglutide (a GLP-1R agonist) and tirzepatide (a GLP-1R/GIPR co-agonist) are effective for glycemic control and weight management, a comprehensive synthesis of their direct impact on various CAD phenotypes has been lacking. Previous evidence largely stemmed from separate randomized trials with diverse control groups, making direct comparisons and pooled analyses challenging.

This systematic review and meta-analysis included 45 randomized controlled trials (RCTs) evaluating subcutaneous semaglutide or tirzepatide in adults with T2DM and/or obesity. Researchers systematically searched PubMed, Embase, Scopus, Web of Science, CENTRAL, and ClinicalTrials.gov. Separate pooled analyses were conducted for each drug 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.

In pooled analyses of semaglutide trials, treatment was associated with significantly lower risks across several CAD-related outcomes. The broad CAD-related composite risk was reduced (RR = 0.80, 95% CI [0.73-0.87]; p < 0.001), as was ACS (RR = 0.77, 95% CI [0.70-0.85]; p < 0.001).

Semaglutide treatment was associated with a 30% lower risk of myocardial infarction (MI) (RR = 0.70, 95% CI [0.62-0.80]; p < 0.001). Furthermore, unstable angina (UA) risk decreased (RR = 0.82, 95% CI [0.70-0.96]; p = 0.017), and angina pectoris risk was also lower (RR = 0.73, 95% CI [0.60-0.89]; p = 0.002). In contrast, 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 for trial-reported CAD events was observed with tirzepatide, but this finding was based on fewer events and considered exploratory.