Assessment of noninferiority of oral vs subcutaneous semaglutide: a systematic review and meta-analysis.

INTRODUCTION: This systematic review and meta‑analysis is the first to comprehensively compare oral and subcutaneous semaglutide for type 2 diabetes (T2D) management. OBJECTIVES: Our aim was to determine whether oral semaglutide is noninferior to the subcutaneous preparation, assess potential superiority, and provide evidence‑based guidance for clinical decisions. PATIENTS AND METHODS: We searched clinical trial registries and bibliographic databases through April 30, 2025. Twelve randomized controlled trials involving 6253 adults with T2D were analyzed. Following the PRISMA and Cochrane guidelines (PROSPERO, CRD420251017953), the data were extracted on efficacy, safety, and clinical outcomes. Noninferiority was assessed using predefined margins, and post hoc superiority analyses examined secondary end points. Evidence certainty was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation criteria. RESULTS: Both formulations of semaglutide significantly reduced the level of glycated hemoglobin (HbA1c), that is, oral by 1.16 percentage points (95% CI, -1.22 to -1.09) and subcutaneous by 1.4 percentage points (95% CI, -1.47 to -1.33). Oral semaglutide met the noninferiority margin at 50% of the subcutaneous effect. Subcutaneous semaglutide was superior for weight loss (2.19 kg; 95% CI, -3.57 to -0.81; P <0.002), body mass index (BMI) reduction (0.88 kg/m2; 95% CI, -1.55 to -0.21; P <0.011), and triglyceride level lowering (0.09 mmol/l; 95% CI, -0.14 to -0.04; P <0.001). CONCLUSIONS: Both forms of semaglutide effectively improve glycemic control in T2D. Oral semaglutide is noninferior to subcutanous semaglutide in lowering HbA1c level, while subcutaneous semaglutide is superior in weight, BMI, and triglyceride reduction. Given similar safety profiles and modest differences in other outcomes, treatment selection should be guided by clinical goals and patient preferences.