SYSTEMATIC REVIEW article
Front. Cardiovasc. Med.
Sec. Cardiovascular Metabolism
Effects of subcutaneous or oral semaglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials
Provisionally accepted
- Chongqing Sixth People's Hospital, Chongqing, China
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Abstract 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.
Keywords: Cardiovascular disease1, major adverse cardiovascular events2, Semaglutide3, Type 2 Diabetes Mellitus4, Meta-analysis5
Received: 23 Oct 2025; Accepted: 28 Nov 2025.
Copyright: © 2025 Tan, Yin and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yangguang Yin
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