Phase 3 trial finds once-daily oral semaglutide 50 mg produced 15.1% weight loss

A once-daily pill containing 50 mg of semaglutide helped adults with overweight or obesity lose an average of 15.1% of their body weight over 68 weeks, compared with 2.4% for placebo, in a phase 3 trial published in The Lancet ^[1]. The trial, called OASIS 1, assigned 667 people without type 2 diabetes at 50 outpatient clinics in nine countries across Asia, Europe, and North America ^[1].

Participants were randomly allocated 1:1 to oral semaglutide 50 mg or a visually matching placebo, taken once a day for 68 weeks, plus a lifestyle intervention in both groups ^[1]. To enroll, adults needed a body mass index of at least 30 kg/m2, or at least 27 kg/m2 with weight-related complications and other conditions, and could not have type 2 diabetes ^[1]. Screening ran from Sept 13 to Nov 22, 2021, and the trial is listed as complete ^[1].

What the trial measured

The estimated mean change in body weight from the start of the trial to week 68 was -15.1% (standard error 0.5) with oral semaglutide 50 mg and -2.4% (0.5) with placebo, an estimated treatment difference of -12.7 percentage points (95% CI -14.2 to -11.3; p<0.0001) ^[1]. The analysis counted all participants regardless of whether they stopped treatment or used other weight-lowering therapies ^[1]. The authors described the weight decrease as "superior and clinically meaningful" compared with placebo ^[1].

More participants on the drug reached common weight-loss thresholds at week 68: at least 5%, 269 of 317 (85%) versus 76 of 295 (26%); at least 10%, 220 (69%) versus 35 (12%); at least 15%, 170 (54%) versus 17 (6%); and at least 20%, 107 (34%) versus 8 (3%) ^[1]. In other words, about 15% of the participants counted in the drug group did not reach a 5% reduction, while about a third lost 20% or more ^[1].

Side effects and funding

Adverse events were reported by 307 of 334 participants (92%) taking oral semaglutide 50 mg and 285 of 333 (86%) taking placebo. Gastrointestinal adverse events, mostly mild to moderate, were reported by 268 participants (80%) on the drug and 154 (46%) on placebo ^[1]. Safety was assessed only in participants who received at least one dose of trial medication ^[1]. Rates of serious adverse events, discontinuation because of side effects, and specific symptoms such as nausea or vomiting have not been reported. The trial was funded by Novo Nordisk, and several authors disclosed consulting fees, research grants, or employment with the company ^[1].

Why it matters for patients

Injectable GLP-1 medicines have dominated this category, and an effective daily pill would change the practical experience of treatment for people who prefer not to inject. It also matters that this was a 50 mg oral dose. Whether that dose will be filed for US approval, when it might reach pharmacies, and what it would cost have not been reported ^[1]. The 50 mg pill tested here is not described in the trial as an approved product.

The results apply to a specific group: adults with overweight or obesity and without type 2 diabetes, followed for 68 weeks ^[1]. Weight loss in people with type 2 diabetes, results beyond 68 weeks, cardiovascular outcomes, and what happened to participants' weight after treatment stopped are not reported ^[1].

Tolerability is the other practical issue. While most gastrointestinal side effects were mild to moderate, 8 in 10 participants on the drug reported at least one, compared with about 5 in 10 on placebo ^[1]. Average results also hide wide variation: the trial shows a substantial share of participants lost 20% or more, and a smaller share lost less than 5% ^[1].

What happens next

The trial is registered with ClinicalTrials.gov as NCT05035095 and is now complete ^[1]. No regulatory submission, launch date, price, or further study of the 50 mg dose for weight management is described in the published findings ^[1]. Novo Nordisk funded the research ^[1].