Clinician Article
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.
PMID: 37385278
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Public HealthRelevance - 7/7
Newsworthiness - 6/7 -
Family Medicine (FM)/General Practice (GP)Relevance - 6/7
Newsworthiness - 6/7 -
General Internal Medicine-Primary Care(US)Relevance - 6/7
Newsworthiness - 6/7 -
Special Interest - Obesity -- PhysicianRelevance - 6/7
Newsworthiness - 5/7 -
Internal MedicineRelevance - 6/7
Newsworthiness - 4/7
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.
Clinical Comments
Family Medicine (FM)/General Practice (GP)
As a family physician, this trial is very interesting showing oral semaglutide changed body weight by 15% versus 2% for placebo. It's worth noting "the protocol allowed flexibility in the implementation of the lifestyle intervention." More participants permanently discontinued semaglutide because of adverse events. This is a very important issue to be clarified in further trials and case reports. More evidence is needed to make recommendations.
General Internal Medicine-Primary Care(US)
This is an important step forward in the obesity epidemic and many of the downstream effects and healthcare costs arising from it. The indirect costs stemming from obesity are massive. Until now, pharmacologic measures have been largely unsuccessful and plagued by side effects, poor efficacy, etc. Subcutaneous semaglutide is now becoming more widely available and acceptable as a treatment for obesity. Hopefully, the availability of an oral option will increase availability and decrease costs for many more patients.
Internal Medicine
The lack of an alternative weight loss drug as a comparator makes me less likely to prescribe based on this study, and with this dose, 80% had GI side effects.
Public Health
This is a relevant study that demonstrates the efficacy and safety of oral daily semaglutide, 50mg, for treating obesity in patients without T2DM. The results are consistent for both sex, across ethnicity, and across the burden of overweight. This study has great clinical relevance to address the health problems of the obesity epidemic.
Special Interest - Obesity -- Physician
The trial and this paper were funded by Nova Nordisk, a pharmaceutical company marketing semaglutide. However the intervention and control groups appear balanced and significant weight differences result. The daily dose of 50mg semaglutide equates to 350mg weekly, which is more than 100x higher than the currently licensed 2.4mg sc weekly dose, commonly used for weight loss. Most prefer oral medications. One can only wonder about the implications for semaglutide supply issues to the diabetic population.
Special Interest - Obesity -- Physician
The oral form of semaglutide may extend the use of the drug to patients who are unwilling to use the injectable form. The weight loss outcomes are impressive, but are balanced by the high proportion of patients with vomiting (24%) and other GI side effects.
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