Introduction and Objective: In the PIONEER PLUS randomized clinical trial (NCT04707469), once-daily oral semaglutide (SEMA) with investigational 25 mg and 50 mg doses demonstrated greater reductions in HbA1c and weight versus the approved 14 mg dose in people with type 2 diabetes (T2D) inadequately controlled on 1-3 oral glucose-lowering agents. This post hoc analysis compared changes in HbA1c and weight between the 25 mg and 14 mg groups among participants previously treated with metformin only. Methods: PIONEER PLUS enrolled adults (≥18 years) with T2D, baseline HbA1c 8.0-10.5% and BMI ≥25.0 kg/m2, randomized 1:1:1 to once-daily oral SEMA 14, 25 or 50 mg for 68 weeks. For this post hoc analysis, we included participants who were on metformin monotherapy prior to randomization and compared changes in HbA1c and weight from baseline to week 52 between the 25 mg and 14 mg groups. Between-group differences were tested using ANCOVA model. Results: Of 1,606 all participants in the trial, 262 (16.3%) on metformin monotherapy treated with 14mg or 25mg oral SEMA were included in this analysis (14 mg: n = 128; 25 mg: n = 134). Baseline characteristics were similar (Mean age: 56.9 and 56.5 yrs; Duration of diabetes: 7.9 vs. 8.2 yrs; Weight: 102.5 vs. 104.3 kg; HbA1c: 8.9% vs. 9.0%) for participants in 14mg and 25mg group respectively. At week 52, the 25 mg group had significantly greater weight change vs. 14mg (−7.9 kg vs.-4.5kg; Between-group difference: -3.4kg; p=0.0002); In terms of HbA1c, 25mg group had greater reduction but not statistically significant comparing to the 14mg group (-2.1% vs. -1.9%; Between-group difference: -0.19%, p=0.2454). Conclusion: In this post hoc analysis of PIONEER PLUS, among participants with T2D previously treated with metformin only, oral semaglutide 25 mg showed significantly greater weight reduction and a similar HbA1c reduction at week 52 compared with the approved 14 mg dose. Findings should be interpreted as exploratory. Disclosure L. Xie: None. C.K. R: None. A. Navas: Other - I receive a UNC pre-doctoral fellowship funded by Novo Nordisk.; Current; Novo Nordisk. C. Muhammad: Employee; Current; Novo Nordisk. Stock/Shareholder; Current; Novo Nordisk.
XIE et al. (2026) studied this question.