Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as an important therapeutic option for type 2 diabetes mellitus (T2DM), available in both oral and subcutaneous formulations. While subcutaneous semaglutide has been available since 2017, oral semaglutide (approved in 2019) represents the first oral GLP-1 receptor agonist. This meta-analysis compared the efficacy and safety of oral versus subcutaneous semaglutide in patients with T2DM. We conducted a systematic literature search across PubMed, Embase, Cochrane Library, and Web of Science from inception to March 15, 2025. Four studies (one randomized controlled trial and three retrospective studies) with a total of 559 patients (257 receiving oral and 302 receiving subcutaneous semaglutide) met our inclusion criteria. The included studies were published from 2017 to 2024. All studies had a six-month follow-up duration. Outcomes included changes in HbA1c, body weight, and treatment discontinuation due to adverse effects. Pooled analysis indicated that subcutaneous semaglutide achieved significantly greater reductions in HbA1c compared to oral semaglutide (SMD: 0.21, 95% CI: 0.04 to 0.38) with low heterogeneity (I-square: 22%). For body weight reduction, subcutaneous semaglutide showed greater effectiveness, though the difference was not statistically significant (SMD: 0.12, 95% CI: -0.27 to 0.52) with high heterogeneity (I-square: 81%). Notably, patients receiving oral semaglutide had a significantly higher risk of treatment discontinuation due to side effects (RR: 1.79, 95% CI: 1.13 to 2.83) with no heterogeneity (I-square: 0%). While both formulations demonstrated clinical benefits, subcutaneous semaglutide appears to offer superior glycemic control with fewer treatment-limiting adverse effects. These findings likely reflect the differences in bioavailability and pharmacokinetics between the two formulations. However, the choice between formulations should consider individual patient factors, including treatment adherence, preference for injection versus oral administration, and specific comorbidities. Future studies should investigate whether modified dosing protocols could improve the tolerability of oral semaglutide while maintaining efficacy.
