Oral Semaglutide 25 mg Versus Orforglipron 36 mg in Obesity: A Population-Adjusted Indirect Treatment Comparison.

AIMS: This study aimed to indirectly compare the effects of oral semaglutide 25 mg versus orforglipron 36 mg on body weight loss, other cardiometabolic biomarkers, and tolerability in adults with overweight (body mass index [BMI] ≥ 27 kg/m and at least one obesity-related complication) or obesity (BMI ≥ 30 kg/m), without diabetes, using data from OASIS 4 and ATTAIN-1. MATERIALS AND METHODS: Individual patient data from OASIS 4 and aggregate data from ATTAIN-1 informed anchored indirect treatment comparisons (ITCs). Baseline differences in sex, body weight and normoglycaemic status were adjusted for using population-adjustment methods. Efficacy (percentage body weight change, categorical body weight loss thresholds, other cardiometabolic biomarkers) and tolerability outcomes (treatment discontinuation due to any adverse event [AE] and due to gastrointestinal [GI] AEs) were analysed. RESULTS: Population-adjusted analyses showed a significantly greater percentage change from baseline in body weight with oral semaglutide 25 mg than with orforglipron 36 mg, with mean differences (MDs) of -3.2%-points (95% confidence intervals [CIs]: -5.9, -0.4; treatment-regimen estimand) and -3.0%-points (95% CI: -5.8, -0.3; efficacy estimand). Discontinuation was higher with orforglipron (due to any AE: odds ratio [OR]: 4.1 [95% CI: 1.3, 13.0] and due to GI AEs: OR: 13.9 [95% CI: 2.0, 96.0]). CONCLUSIONS: In this ITC, oral semaglutide 25 mg was associated with greater body weight loss and fewer discontinuations due to any AEs and due to GI AEs compared with orforglipron 36 mg. These findings provide insight into the comparative effectiveness and tolerability in the absence of head-to-head clinical trials.