Type 2 diabetes mellitus (T2DM) affects over 537 million adults worldwide. When oral antidiabetic drugs (OADs) fail, escalation to injectable therapy is required, yet no systematic review has simultaneously compared once-weekly semaglutide against basal insulin and other GLP-1 receptor agonists - specifically exenatide ER, insulin glargine, dulaglutide, and liraglutide - in insulin-naïve patients uncontrolled on OADs. This review aimed to evaluate the efficacy and safety of once-weekly semaglutide versus injectable antidiabetic therapies - specifically basal insulin (insulin glargine) and three GLP-1 receptor agonists (exenatide ER, dulaglutide, and liraglutide) - in adults with T2DM inadequately controlled on OADs, through pairwise meta-analyses of randomized controlled trials (RCTs). Five databases were searched from inception to April 2026. Eligible studies were phase 2b-4 RCTs of at least 12 weeks comparing once-weekly semaglutide against injectable therapy in insulin-naïve adults with T2DM. Two reviewers performed selection, extraction, and Cochrane Risk of Bias version 2 (RoB 2) assessment; both are co-authors with prior trial familiarity, constituting a registered protocol deviation. Random-effects pairwise meta-analyses were performed, and certainty was assessed using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Four Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) RCTs were included (n = 3,680 total; 2,705 analyzable for the primary comparison). Semaglutide 1.0 mg reduced HbA1c versus all comparators (mean difference (MD) -0.64%, 95% confidence interval (CI) -0.80 to -0.47; low certainty) and body weight (MD -4.38 kg, 95% CI -5.76 to -3.01; low certainty). Against GLP-1 RAs specifically, body weight reduction was homogeneous (MD -3.72 kg, 95% CI -4.17 to -3.28; I² = 0%; moderate certainty). Systolic BP was reduced (MD -2.32 mmHg; moderate certainty). HbA1c less than 7.0% was achieved more frequently with semaglutide (relative risk (RR) 1.60; low certainty). Hypoglycemia risk was lower versus insulin glargine (RR 0.53; moderate certainty). Gastrointestinal (GI) adverse events and treatment discontinuation were higher with semaglutide versus insulin (both low certainty). Moderate-certainty evidence supports greater body weight reduction with semaglutide versus other GLP-1 RAs and lower hypoglycemia risk versus basal insulin. Low-certainty evidence suggests HbA1c benefits versus all comparators. Certainty is limited by heterogeneity, open-label design across all included trials, and exclusive industry sponsorship by the manufacturer of semaglutide. Future independent trials are needed.
