Oral Semaglutide 25 mg Produces 13.6% Weight Loss in People with Obesity (OASIS 4 Trial)

What the researchers found

At 64 weeks, oral semaglutide 25 mg produced a mean body weight reduction of 13.6% versus 2.2% for placebo (estimated difference: -11.4 percentage points; 95% CI: -13.9 to -9.0; P < 0.001). Participants on semaglutide were significantly more likely to achieve weight loss thresholds of 5%, 10%, 15%, and 20% or more (P < 0.001 for all comparisons).

Physical function quality of life (IWQOL-Lite-CT score) also improved significantly with oral semaglutide versus placebo (P < 0.001). Gastrointestinal adverse events were the most common side effects, occurring in 74.0% of semaglutide patients versus 42.2% of placebo patients.

Why it matters

Injectable semaglutide (Wegovy) is already a blockbuster weight loss drug, but many patients prefer pills to injections. This trial shows a 25 mg oral dose — lower than the 50 mg also being studied — can produce clinically significant weight loss of nearly 14%. This dose could offer a middle ground: more weight loss than the current 14 mg oral dose (approved for diabetes as Rybelsus) while being more practical than injections for patients who prefer oral medication.

How the study worked

OASIS 4 was a 71-week, double-blind, randomized, placebo-controlled trial conducted at 22 sites across four countries. 307 participants without diabetes who had a BMI ≥30 (or ≥27 with at least one obesity-related complication) were randomized 2:1 to oral semaglutide 25 mg or placebo once daily, alongside lifestyle interventions. Coprimary endpoints at week 64 were percent change in body weight and achieving ≥5% weight loss.

What this study cannot tell us

The sample size (307 participants) is modest for a phase 3 weight loss trial. People with diabetes were excluded, limiting generalizability. The 74% gastrointestinal adverse event rate is high, though described as predominantly transient. The trial was funded by Novo Nordisk, the manufacturer. No head-to-head comparison with injectable semaglutide was performed in this trial.

How to read the evidence

This is a well-designed, double-blind, randomized, placebo-controlled phase 3 trial published in the New England Journal of Medicine — the highest tier of clinical evidence. The modest sample size (307) is the main limitation, but results are highly statistically significant.

When this study was published

Published in 2025 in the New England Journal of Medicine. This is a landmark trial in the OASIS program and represents the most current data on oral semaglutide 25 mg for obesity.

The bigger picture

The OASIS trial program is systematically testing oral semaglutide at higher doses than currently approved. While injectable semaglutide 2.4 mg (Wegovy) produces about 15% weight loss, oral semaglutide 25 mg achieves 13.6% — closing the gap between pill and injection. This matters enormously for market access, patient preference, and global obesity treatment, especially in populations where self-injection is a barrier to treatment.

Questions still open

• How does 25 mg oral semaglutide compare directly to 2.4 mg injectable semaglutide in a head-to-head trial?
• What is the long-term weight maintenance profile after stopping oral semaglutide 25 mg?
• Would the 50 mg oral dose from OASIS 1 justify the additional pill burden given the GI side effect profile?

Common questions

Read the original research

Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity.

The New England journal of medicine, 393(11), 1077-1087

Citation

Wharton, Sean; Lingvay, Ildiko; Bogdanski, Pawel; Duque do Vale, Ruben; Jacob, Stephan; Karlsson, Tobias; Shaji, Chaithra; Rubino, Domenica; Garvey, W Timothy. (2025). Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity.. The New England journal of medicine, 393(11), 1077-1087. https://doi.org/10.1056/NEJMoa2500969