Background: Once-daily oral semaglutide is an effective type 2 diabetes treatment. We aimed to investigate a new formulation of oral semaglutide at higher investigational doses versus the approved 14 mg dose in adults with inadequately controlled type 2 diabetes.
Method: This global, multicentre, randomized, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled adults with type 2 diabetes, glycated haemoglobin (HbA1c) 8.0−10.5% (64–91 mmol/mol), a BMI of 25.0 kg⁄m2 or greater, receiving stable daily doses of 3– oral glucose-lowering drugs. Participants were randomly assigned (1:1:1), by means of an interactive web response system, to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Investigators, site personnel, trial participants, and trial sponsor staff were masked to dose assignment throughout the trial. The primary endpoint was change in HbA1c from baseline to week 52, evaluated with a treatment policy estimand in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of trial drug. This trial is registered with ClinicalTrials.gov, NCT04707469, and the European Clinical Trials register, EudraCT 2020-000299-39, and is complete.
Results: Between Jan 15 and Sept 29, 2021, of 2294 people screened, 1606 (n = 936 [58.3%] male; n = 670 [41.7%] female; mean [SD] age 58.2 [10.8] years) received oral semaglutide 14 mg (n = 536), 25 mg (n = 535), or 50 mg (n = 535). At baseline, mean (SD) HbA1c was 9.0% (0.8; 74.4 mmol/L [SD 8.3]) and mean bodyweight was 96.4 kg (21.6).
Mean changes (SE) in HbA1c at week 52 were −1.5 percentage points (SE 0.05) with oral semaglutide 14 mg, −1.8 percentage points (0.06) with 25 mg (estimated treatment difference [ETD] −0.27, 95% CI −0.42 to −0.12; p = 0.0006), and −2.0 percentage points (0.06) with 50 mg (ETD −0.53, −0.68 to −0.38; p < 0.0001).
Adverse events were reported by 404 (76%) participants in the oral semaglutide 14 mg group, 422 (79%) in the 25 mg group, and 428 (80%) in the 50 mg group. Gastrointestinal disorders, which were mostly mild to moderate, occurred more frequently with oral semaglutide 25 mg and 50 mg than with 14 mg. 10 deaths occurred during the trial; none were judged to be treatment related.
Interpretation: Oral semaglutide 25 mg and 50 mg were superior to 14 mg in reducing HbA1c and bodyweight in adults with inadequately controlled type 2 diabetes. No new safety concerns were identified.
Funding: Novo Nordisk.
…Bodyweight loss was observed in all groups from baseline to week 52 with the treatment policy estimand (mean change −4.4 kg [SE 0.3] for oral semaglutide 14 mg, −6.7 kg [0.3] for 25 mg, and −8.0 kg [0.3] for 50 mg; Figure 3).
Change in bodyweight was statistically-significantly greater for oral semaglutide 25 mg and 50 mg, respectively, versus 14 mg (ETD −2.32 kg [95% CI −3.11 to −1.53; p < 0.0001] for oral semaglutide 25 mg and −3.63 kg [−4.42 to −2.84; p < 0.0001] for oral semaglutide 50 mg). Bodyweight loss was also observed in all groups with the trial product estimand (Figure 3). The percentage change in bodyweight from baseline to weeks 52 and 68 is shown in Table 2 and the Appendix (pg11). A statistically-significantly greater proportion of participants in the oral semaglutide 25 mg and 50 mg groups compared with the 14 mg group had bodyweight reduction of 5% or more (206 [41%] of 503 for 14 mg, 288 [60%] of 480 for 25 mg, and 334 [67%] of 495 for 50 mg) and 10% or more (70 [14%] of 503 for 14 mg, 139 [29%] of 480 for 25 mg, and 184 [37%] of 495 for 50 mg) at week 52 for the treatment policy estimand. Results were similar with the trial product estimand.
Reductions in bodyweight were maintained through to week 68 (Appendix pg12). Reductions in waist circumference were statistically-significantly greater with oral semaglutide 25 mg and 50 mg versus 14 mg. Results for other supportive secondary endpoints at weeks 52 and 68 are shown in Table 2 and the Appendix (pg19–20). Changes in fasting lipids were generally similar between groups, although greater reductions in triglycerides (both estimands) and greater increases in high-density lipoprotein cholesterol (trial product estimand only) were seen with oral semaglutide 50 mg versus 14 mg (Appendix pg21–22).