Higher-dose oral glucagon-like peptide-1 (GLP-1) receptor agonist therapy may offer additional metabolic benefits in type 2 diabetes mellitus (T2DM). Findings presented at the ADA Scientific Sessions 2026 evaluated glycemic and weight outcomes with oral semaglutide 25 mg versus the approved 14 mg dose among participants previously treated with metformin alone in the PIONEER PLUS trial.

PIONEER PLUS was a randomized clinical trial enrolling adults with T2DM, baseline glycated hemoglobin (HbA1c) between 8.0% and 10.5%, and body mass index (BMI) of at least 25 kg/m². Participants were randomized 1:1:1 to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. This post hoc analysis included participants receiving metformin monotherapy before randomization and compared changes in HbA1c and body weight from baseline to week 52 between the 25 mg and 14 mg groups.

Findings

• Among 1606 trial participants, 262 individuals receiving metformin monotherapy were included in the analysis, comprising 128 treated with oral semaglutide 14 mg and 134 treated with 25 mg.
• Baseline characteristics were generally similar between groups, including age, diabetes duration, body weight, and HbA1c.
• At week 52, body weight reduction was greater with oral semaglutide 25 mg compared with 14 mg (−7.9 kg vs −4.5 kg), corresponding to a between-group difference of −3.4 kg (P=0.0002).
• HbA1c reduction was numerically greater with the 25 mg dose than with 14 mg (−2.1% vs −1.9%), although the between-group difference was not statistically significant (−0.19%; P=0.2454).

This exploratory post hoc analysis suggested that oral semaglutide 25 mg produced greater weight reduction than the approved 14 mg dose in adults with T2DM previously treated with metformin alone. HbA1c reductions were generally similar between doses, and findings should be interpreted cautiously given the subgroup exploratory design.