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.
Method: This randomized, 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 9 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.
Results: 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).
Data are observed (ie. as-measured) mean absolute values of BMI (A), waist circumference (B), HbA1c (C), systolic and diastolic blood pressure (D; error bars are SE), geometric mean values of high-sensitivity C-reactive protein (E; y-axis is on a logarithmic scale, error bars are SE calculated on a logarithmic scale and back transformed to a linear scale), and observed proportions of participants by glycaemic status at baseline and, in people with baseline prediabetes, at week 68 (F) from the in-trial observation period, all for the full-analysis set.
(A–E) Numbers below the graphs are the number of participants contributing to the mean and geometric mean. (F) Proportions might not total 100 because of rounding. Corresponding data for the on-treatment observation period are shown in the Appendix (pg28).
HbA1c=glycated haemoglobin. ✱Baseline glycaemic status in all participants with normoglycaemia and prediabetes. Presence of type 2 diabetes at screening was an exclusion criterion. However, 5 participants (n = 2, oral semaglutide 50 mg; n = 3, placebo) developed an HbA1c of 6.5% or more between screening and baseline; these participants are not shown in the figure. †Week 68 glycaemic status in participants with baseline prediabetes.
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 8.5–18.7; p < 0.0001), 10% (220 [69%] vs 35 [12%]; OR 14.7, 9.6–22.6), 15% (170 [54%] vs 17 [6%]; OR 17.9, 10.4–30.7), and 20% (107 [34%] vs 8 [3%]; OR 18.5, 8.8–38.9) 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.