Effects of subcutaneous or oral semaglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials.

BACKGROUND

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, reduce cardiovascular risk in type 2 diabetes mellitus (T2DM), but the consistency between oral and subcutaneous formulations remains unclear.

METHODS

This meta-analysis was registered prospectively in PROSPERO (CRD 420251147337). A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using fixed-/random-effects models, with sensitivity, subgroup, and GRADE assessments.

RESULTS

Four RCTs (n = 19,663) showed semaglutide significantly reduced primary outcome risk (HR 0.83; 95% CI 0.76-0.91), nonfatal myocardial infarction (HR 0.79; 0.67-0.92), and revascularization (HR 0.71; 0.61-0.83), with a modest decrease in heart failure hospitalization (HR 0.85; 0.72-1.00). No significant effects were seen for cardiovascular death, all-cause death, nonfatal stroke, or unstable angina hospitalization. Subgroup analyses confirmed no efficacy differences between formulations. Evidence quality was "moderate" for cardiovascular death, all-cause death, nonfatal stroke, unstable angina hospitalization, and "high" for the remainder.

CONCLUSIONS

Semaglutide lowers cardiovascular risk in T2DM, primarily improving major adverse cardiovascular events, nonfatal myocardial infarction, and revascularization, with oral and subcutaneous forms demonstrating consistent efficacy.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251147337, PROSPERO CRD420251147337.