Increased Doses of Oral Semaglutide Can Induce Pronounced Weight Loss, Improve Glycemic Control

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Data from a pair of trials presented at ADA 2023 suggests an upped dose of oral semaglutide could soon be on the horizon, with results supporting use in chronic weight management as well as type 2 diabetes.

New indications could be on the horizon for oral semaglutide based on data from OASIS-1 and PIONEER PLUS trials.

Presented at the 83rd Scientific Sessions of the American Diabetes Association (ADA 2023), results of the studies suggest increased dosages of oral semaglutide could prove useful as a treatment for chronic weight management as well as contribute to improved glycemic control.


OASIS-1 was a phase 3 trial launched with the intent of exploring whether an increased dose of oral semaglutide might provide meaningful body weight reductions. With this in mind, OASIS-1 was designed as a randomized, double-blind, placebo-controlled, superiority trial with a coprimary endpoints of the percentage change in bodyweight and whether participants achieved a bodyweight reduction of at least 5% at week 68 for oral semaglutide 50 mg compared with placebo.

Overall, the trial enrolled and randomized 667 patients to oral semaglutide 50 mg or placebo therapy. For the purpose of analysis, investigators assessed the coprimary efficacy endpoints in an intention-to-treat analysis and the safety analyses included only participants who received at least 1 dose during the trial.

Upon analysis, results suggested use of oral semaglutide was associated with an estimated mean change in body weight of -15.1% (SE, 0.5) from baseline to week 68 compared to -2.4%(SE, 0.5) with placebo therapy (estimated treatment difference [ETD], -12.7 percentage points; 95% Confidence interval [CI], -14.2 to -11.3; P < .0001). Further analysis indicated a greater proportion of patients receiving oral semaglutide achieved body weight reductions of at least 5% (85% vs 26%; Odds Ratio [OR], 12.6; 95% CI, 8.5 to 18.7; P < .0001), 10% (69% vs 12%; OR, 14.7; 95% CI, 9.6 to 22.6), 15% (54% vs 6%; OR, 17.9; 95% CI, 10.4 to 30.7), and 20% (34% vs 8%; OR, 18.5; 95% CI, 8.8 to 38.9) at week 68 relative to placebo therapy.

Investigators pointed out adverse events occurred more frequently in those with oral semaglutide (92%) than with placebo therapy (86%). Investigators also pointed out gastrointestinal events, which were mostly mild to moderate in severity, were reported among 80% of those receiving oral semaglutide 50 mg and 46% of those receiving placebo therapy.

“Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them,” said Filip K Knop MD, PhD, Gentofte Hospital, University of Copenhagen.3 “The weight loss also led to improvements in physical functioning, allowing participants to have an improved quality of life for everyday activities.”


A multicenter, placebo-controlled, phase 3b trial, PIONEER PLUS was launched with the intent of exploring the safety and efficacy of oral semaglutide 25 mg and 50 mg relative to oral semaglutide 14 mg among adults with type 2 diabetes. A global study conducted at 177 sites in 14 countries, the trial screened 2294 individuals and 1606 underwent randomization. For inclusion in the trial, patients needed to be 18-75 years of age with an HbA1c in the range of 8.0-10.5%, a BMI of at least 25.0 kg/m2, and receiving stable doses of 1 to 3 oral-glucose lowering agents.

The trial population had a mean age of 58.2 (SD, 10.8) years, 41.7% were female, and the mean HbA1c at baseline was 9.0% (SD, 0.8). Patients were randomized in a 1:1:1 ratio to oral semaglutide in 14 mg, 25 mg, or 50 mg doses. The primary outcome of interest was change in HbA1c from baseline to week 52, which investigators evaluated with a treatment policy estimand in an intention-to-treat population.

Upon analysis, results indicated the mean changes in HbA1c at week 52 were -1.5 (SE, 0.05) percentage points with oral semaglutide 14 mg, -1.8 percentage point s(SE, 0.06) with oral semaglutide 25 mg (ETD, -0.27; 95% CI, -0.42 to -0.12; P =.0006), and -2.0 percentage points (SE, 0.06) with oral semaglutide 50 mg (ETD, -0.53; 95% CI, -0.68 to -0.38; P < .0001). When assessing safety, investigators noted adverse events were reported by 76%, 79%, and 80% of those receiving the 14 mg, 25 mg, and 50 mg doses, respectively.

“This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed,” said Vanita R. Aroda, MD, of the Division of Endocrinology, Diabetes and Hypertension at Brigham and Women's Hospital, Boston, Massachusetts.3 “We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting.”


  1. Knop FK, Aroda VR, do Vale RD, et al. 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. The Lancet. Published online 2023. doi:10.1016/s0140-6736(23)01185-6
  2. Aroda VR, Aberle J, Bardtrum L, et al. Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (Pioneer Plus): A multicentre, randomised, phase 3b trial. The Lancet. Published online 2023. doi:10.1016/s0140-6736(23)01127-3
  3. Late breaking weight loss innovations: New drug therapies shown to offer positive outcomes for obesity and type 2 diabetes management. Late Breaking Weight Loss Innovations: New Drug Therapies Shown to Offer Positive Outcomes for Obesity and Type 2 Diabetes Management | ADA. June 25, 2023. Accessed June 26, 2023.