A large clinical trial found that a daily semaglutide pill produced significant weight loss and health benefits comparable to injectable versions, setting the stage for possible FDA approval later this year.
A daily pill containing semaglutide, the active ingredient in Ozempic, helped adults with overweight or obesity lose substantially more weight than placebo over 64 weeks, according to results published today in The New England Journal of Medicine. The phase 3 study, OASIS-4, positions an oral version of Ozempic as a potential needle-free option for chronic weight management, pending U.S. regulatory review.
Conducted at 22 sites in four countries, OASIS-4 randomly assigned 307 adults without diabetes in a 2:1 ratio to receive oral semaglutide 25 mg (n=205) or placebo (n=102), alongside lifestyle counseling. The trial included a 12-week dose escalation and a seven-week off-treatment follow-up, spanning 71 weeks in total with 64 weeks on therapy. Participants had a body-mass index of at least 30, or at least 27 with at least one weight-related complication.
The investigators report two complementary estimates of effect. Under the “trial product estimand,” which reflects outcomes if all participants adhered to treatment as intended, people taking the semaglutide pill lost an average of 16.6% of their baseline body weight at week 64, compared with 2.7% on placebo. More than a third (34.4%) in the oral semaglutide group achieved at least 20% weight loss, versus 2.9% with placebo. Using the more pragmatic “treatment policy estimand,” which counts outcomes regardless of perfect adherence, mean weight loss was 13.6% with the pill versus 2.2% with placebo, and 29.7% versus 3.3% achieved at least 20% weight loss.
Across analyses, participants on the pill were significantly more likely to hit 5%, 10%, 15%, and 20% weight-loss thresholds than those on placebo (all P<0.001). Physical function, measured by the IWQOL-Lite-CT instrument, also improved meaningfully with the pill, as did several cardiovascular risk factors.
Industry Perspective
“The oral semaglutide 25 mg data show compelling efficacy for an oral weight management medication with 16.6% weight loss and a safety and tolerability profile consistent with injectable Wegovy,” said Martin Holst Lange, chief scientific officer and executive vice president of Research & Development at Novo Nordisk. “Currently, less than 2% of individuals with obesity in the US receive obesity medication and Wegovy in a pill may also address patient preference for oral treatment. Pending FDA approval, ample supply will be available to meet the expected US demand as we hope to set a new treatment benchmark for oral weight loss medications for people with overweight or obesity.”
Although Ozempic is the brand used for semaglutide in type 2 diabetes and Wegovy is the brand for chronic weight management, the company and outside experts have frequently compared efficacy across the various semaglutide formulations. In OASIS-4, Novo Nordisk notes that oral results were comparable in magnitude to those reported previously for the injectable formulation.
Gastrointestinal side effects—well known for the GLP-1 class—were the most frequent adverse events and were typically mild to moderate and transient. Nausea occurred in 46.6% of those on the pill versus 18.6% on placebo; vomiting occurred in 30.9% versus 5.9%, respectively. Adverse events leading to discontinuation occurred in 6.9% on the pill and 5.9% on placebo. Serious adverse events were reported in 3.9% and 8.8%, respectively. Investigators said the overall tolerability profile aligns with that seen for injectable semaglutide across extensive post-marketing experience.
Clinical Implications
“The OASIS 4 trial results further underscore the significant impact that semaglutide can have in achieving sustainable weight loss and broader health benefits,” said Sean Wharton, MD, the study’s lead author and medical director of the Wharton Medical Clinic. “Oral semaglutide 25 mg builds on the proven efficacy and established safety and tolerability profile of semaglutide and represents a significant advancement in obesity treatment. People with overweight or obesity have individual preferences, and with oral semaglutide as a potential new treatment option, more of those who are not on treatment today may consider starting GLP-1 treatment.”
Novo Nordisk submitted a New Drug Application to the U.S. Food and Drug Administration in February 2025 for the once-daily oral semaglutide 25 mg as a therapy for chronic weight management—the first oral GLP-1 to be filed for this indication in the United States. The company says the FDA review is expected to conclude by the end of this year. If approved, production of the pill for weight management will be fully U.S.-based, with manufacturing already underway.
Experts caution that OASIS-4 excluded people with diabetes, so the findings may not generalize to all patients who might use semaglutide. The study’s on-treatment duration was 64 weeks; longer follow-up will help clarify weight-loss maintenance and long-term cardiometabolic outcomes after dose stabilization or discontinuation.
Reference: “Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity” by Sean Wharton, Ildiko Lingvay, Pawel Bogdanski, Ruben Duque do Vale, Stephan Jacob, Tobias Karlsson, Chaithra Shaji, Domenica Rubino and W. Timothy Garvey, 17 September 2025, New England Journal of Medicine.
DOI: 10.1056/NEJMoa2500969
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