Semaglutide 25 mg Oral Versus Semaglutide 2.4 mg Injectable: An Indirect Treatment Comparison of Weight Loss Outcomes

AIMS: Semaglutide, a GLP-1 receptor agonist, has demonstrated significant weight loss benefits for patients with overweight or obesity in both oral and subcutaneous (s.c.) formulations. Given comparable systemic exposure between formulations, an indirect treatment comparison (ITC) was conducted to confirm comparable efficacy. MATERIALS AND METHODS: A naïve Bucher ITC was conducted using data from two well-matched randomized controlled trials: OASIS 4 (once-daily oral semaglutide 25 mg vs. placebo) and STEP 1 (once-weekly s.c. semaglutide 2.4 mg vs. placebo). Both studies enrolled adults with obesity or overweight with ≥ 1 weight-related complication and implemented similar lifestyle changes alongside semaglutide/placebo. The ITC compared percentage change in body weight, the proportion of participants achieving ≥ 5%, ≥ 10%, ≥ 15%, ≥ 20% weight loss, changes in cardiometabolic parameters, and quality of life (IWQoL-Lite-CT PF). Safety outcomes were descriptively compared. RESULTS: Oral and s.c. semaglutide delivered comparable efficacy across all outcomes assessed. While small numerical advantages favoured oral or s.c. semaglutide on some endpoints, the differences and associated uncertainty supported therapeutic equivalence. For percentage weight change, s.c. semaglutide showed a small numerical advantage (estimated treatment difference [ETD]: 1.01%-points (95% confidence intervals [CI]: -1.61, 3.63) under treatment regimen; 0.55%-points (95% CI: -2.25, 3.35) under efficacy), but well below the FDA's 5% threshold for clinical relevance. Safety profiles were broadly comparable. CONCLUSIONS: This ITC suggests that oral semaglutide 25 mg and s.c. semaglutide 2.4 mg offer comparable efficacy for weight management in adults with obesity.