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Clinical Trial
. 2023 Aug 26;402(10403):705-719.
doi: 10.1016/S0140-6736(23)01185-6. Epub 2023 Jun 26.

Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial

Filip K Knop  1 , Vanita R Aroda  2 , Ruben D do Vale  3 , Thomas Holst-Hansen  3 , Peter N Laursen  3 , Julio Rosenstock  4 , Domenica M Rubino  5 , W Timothy Garvey  6 ; OASIS 1 Investigators
Affiliations
Clinical Trial

Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial

Filip K Knop et al. Lancet. .

Abstract

Background: We assessed the efficacy and safety of the oral glucagon-like peptide-1 analogue, semaglutide 50 mg, taken once per day versus placebo for the treatment of overweight or obesity in adults without type 2 diabetes.

Methods: This randomised, double-blind, placebo-controlled, phase 3, superiority trial enrolled adults with a BMI of at least 30 kg/m2, or at least 27 kg/m2 with bodyweight-related complications and comorbidities, without type 2 diabetes. The trial was done at 50 outpatient clinics in nine countries across Asia, Europe, and North America. Participants were randomly allocated (1:1) via an interactive web-response system to oral semaglutide escalated to 50 mg, or visually matching placebo, once per day for 68 weeks, plus lifestyle intervention. Group assignment was masked for participants, investigators, and those assessing outcomes. Coprimary endpoints were the percentage change in bodyweight and whether participants reached a bodyweight reduction of at least 5% at week 68 for oral semaglutide 50 mg versus placebo, assessed regardless of treatment discontinuation or use of other bodyweight-lowering therapies (an intention-to-treat analysis). Safety was assessed in participants who received at least one dose of trial drug. This trial, registered with ClinicalTrials.gov (NCT05035095), is now complete.

Findings: From Sept 13 to Nov 22, 2021, 709 participants were screened, of whom 667 were randomly assigned to oral semaglutide 50 mg (n=334) or placebo (n=333). The estimated mean bodyweight change from baseline to week 68 was -15·1% (SE 0·5) with oral semaglutide 50 mg versus -2·4% (0·5) with placebo (estimated treatment difference -12·7 percentage points, 95% CI -14·2 to -11·3; p<0·0001). More participants reached bodyweight reductions of at least 5% (269 [85%] of 317 vs 76 [26%] of 295; odds ratio [OR] 12·6, 95% CI 8·5 to 18·7; p<0·0001), 10% (220 [69%] vs 35 [12%]; OR 14·7, 9·6 to 22·6), 15% (170 [54%] vs 17 [6%]; OR 17·9, 10·4 to 30·7), and 20% (107 [34%] vs 8 [3%]; OR 18·5, 8·8 to 38·9) at week 68 with oral semaglutide 50 mg versus placebo. Adverse events were more frequent with oral semaglutide 50 mg (307 [92%] of 334) than with placebo (285 [86%] of 333). Gastrointestinal adverse events (mostly mild to moderate) were reported in 268 (80%) participants with oral semaglutide 50 mg and 154 (46%) with placebo.

Interpretation: In adults with overweight or obesity without type 2 diabetes, oral semaglutide 50 mg once per day led to a superior and clinically meaningful decrease in bodyweight compared with placebo.

Funding: Novo Nordisk.

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Conflict of interest statement

Declaration of interests FKK has consulted for 89bio, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pharmacosmos, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; received research grants from Chr Hansen, Novo Nordisk, and Zealand Pharma; received honoraria for lectures, presentations, and educational events from 89bio, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pharmacosmos, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; received support for attendance at scientific meetings from Bayer, Boehringer Ingelheim, and Novo Nordisk; has participated in data safety monitoring boards or advisory boards for 89bio, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; and has received study drugs for clinical trials from Boehringer Ingelheim, Chr Hansen, Eli Lilly, Novo Nordisk, and Sanofi. FKK is a minority shareholder in Antag Therapeutics, a co-owner of the weight loss clinic Medicinsk Vægttabsbehandling ApS, and holds a patent for GIP peptide analogues (assignee University of Copenhagen; patent EP3189072B1, European Patent Office). VRA has received medical writing support from Novo Nordisk; consultancy fees from Applied Therapeutics, Fractyl, Novo Nordisk, Pfizer, and Sanofi; research grant support (to institution) from Applied Therapeutics, Eli Lilly, Fractyl, Novo Nordisk, and Sanofi; and support for attendance at investigator meetings and scientific conferences for related presentations from Eli Lilly, Fractyl, and Novo Nordisk. VRA's spouse is an employee of Janssen. RDdV and TH-H are employees of, and shareholders in, Novo Nordisk. PNL is an employee of Novo Nordisk. JR has received grants or research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Merck, Oramed, Novartis, Novo Nordisk, Pfizer, and Sanofi; has served on scientific advisory boards and received honorarium or consulting fees from Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Terns Pharma, and Zealand Pharma; and has received honoraria for lectures from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi. DMR has received medical writing support from Novo Nordisk; has been a clinical investigator for AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; has received consulting fees from Boehringer Ingelheim, Kayentis, and Novo Nordisk; has acted as an unpaid consultant for Eli Lilly; has received honoraria as a speaker from Boehringer Ingelheim and Novo Nordisk; has received personal fees from the American Diabetes Association, the Endocrine Society, Medscape, PeerView, and Prime Therapeutics for the development of continuing medical education materials; has received support for attendance at scientific congresses by the American Diabetes Association, the Endocrine Society, Medscape, Novo Nordisk, PeerView, and Prime Therapeutics; has participated in scientific advisory boards for Boehringer Ingelheim and Novo Nordisk; and is a shareholder in Eli Lilly. WTG has received medical writing support from Novo Nordisk; has served as a site principal investigator for multicentred clinical trials sponsored by his university and funded by Eli Lilly, Epitomee, Neurovalens, Novo Nordisk, and Pfizer; has served as a consultant on advisory boards for Alnylam Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Fractyl Health, Inogen, Merck, Novo Nordisk, and Pfizer; and has served on the executive committee of the American Association of Clinical Endocrinology (term expired May, 2021).

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