The assessment of non-inferiority 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.

Objectives:  The aim of the study was to determine whether oral semaglutide is non-inferior to the subcutaneous, 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 type 2 diabetes were analyzed. Following PRISMA and Cochrane guidelines (PROSPERO CRD420251017953), data were extracted on efficacy, safety, and clinical outcomes. Non-inferiority was assessed using predefined margins; post hoc superiority analyses examined secondary endpoints. Evidence certainty was evaluated using GRADE.

Results:  Both formulations of semaglutide significantly reduced HbA1c: oral by -1.16 percentage points (95% CI, -1.22--1.09) and subcutaneous by -1.40 percentage points (95% CI, -1.47--1.33). Oral semaglutide met the non-inferiority margin at 50% of the subcutaneous effect. Subcutaneous semaglutide was superior for weight loss (-2.19 kg; 95% CI, -3.57--0.81; P <0.01), BMI reduction (-0.88 kg/m2; 95% CI, -1.55--0.21; P <0.05), and triglyceride lowering (-0.09 mmol/L; 95% CI, -0.14--0.04; P <0.001).

Conclusions:  Both forms of semaglutide effectively improve glycemic control in type 2 diabetes. Oral semaglutide is non-inferior in lowering HbA1c, while subcutaneous semaglutide is superior in weight, BMI, and triglyceride reductions. Given similar safety profiles and modest differences in other outcomes, treatment selection should be guided by clinical goals and patient preferences.