High Investigational Doses of Oral Semaglutide Safe and Efficacious for Inadequately Uncontrolled Diabetes

Based on data from the PIONEER clinical trial program, semaglutide is approved at once-daily oral doses of 7 mg or 14 mg for the treatment of type 2 diabetes (T2D) in adults. Data from the latest study in the program, the PIONEER PLUS trial, suggests higher doses are safe and efficacious for adults with T2D who need additional glycemic control.

Vanita R. Aroda, MD, director of Diabetes Clinical Research at Brigham and Women’s Hospital, and colleagues report in The Lancet that glycemic control and weight loss with oral semaglutide 25 mg and 50 mg were superior to results with 14 mg. These higher doses might facilitate individually tailored treatment intensification.


PIONEER PLUS was conducted at 177 sites in 14 countries. Adults were eligible if they had glycated hemoglobin (HbA1c) of 8.0% to 10.5%, had body mass index ≥25 kg/m2, and were on stable daily oral doses of one to three glucose-lowering drugs.

Between January 15 and September 22, 2021, 1,606 people were randomly assigned to oral semaglutide 14 mg (n=536), 25 mg (n=535) or 50 mg (n=535). Treatment was initiated at 3 mg, then escalated on a prespecified schedule according to dose group. Participants continued their existing glucose-lowering medications except for dipeptidyl peptidase-4 inhibitors.

After 68 weeks of treatment, participants were followed for five weeks. The last study visit of the last participant occurred on March 6, 2023.

Primary Endpoint

From baseline to week 52, HbA1c improved in all groups but was superior with once-daily 25 mg or 50 mg:

  • 14 mg: mean change, −1.5 percentage points
  • 25 mg: −1.8 percentage points (estimated treatment difference [ETD] vs. 14 mg, −0.27 percentage points; P=0.0006)
  • 50 mg: −2.0 percentage points (ETD vs. 14 mg, −0.53 percentage points; P<0.0001)

Confirmatory Efficacy Endpoint

Weight loss between baseline and week 52 was observed in all groups but was greatest with the higher semaglutide doses:

  • 14 mg: −4.4 kg
  • 25 mg: −6.7 kg (ETD vs. 14 mg, −2.32 kg; P<0.0001)
  • 50 mg: −8.0 kg (ETD vs. 14 mg, −3.63 kg; P<0.0001)

Secondary Efficacy Outcomes

Compared with participants assigned to semaglutide 14 mg, those on the higher doses were:

  • Significantly more likely to reach an HbA1c target of <7.0% or ≤6.5%
  • More than twice as likely to have weight loss ≥10% from baseline
  • Less likely to need rescue medication

HbA1c reductions and weight loss were largely sustained to week 68.


There were no new safety concerns with the 25-mg and 50-mg semaglutide doses. All three doses were well tolerated, although some adverse events were slightly more common with the higher doses:

  • Adverse events (AEs) leading to premature treatment discontinuation—10% of participants in the 14-mg group, 12% of the 25-mg group, and 13% of the 50-mg group; these were principally gastrointestinal events of mild or moderate severity and short duration that occurred during the dose-escalation phase
  • Level 1–3 hypoglycemic episodes—13% of the 14-mg group, 14% of the 25-mg group, and 17% of the 50-mg dose group; 4% in each group were considered clinically relevant, and one episode in the 50-mg group was severe
  • AEs of special focus (e.g., diabetic retinopathy, pancreatitis, and acute gallbladder disease)—Rates were similar across groups; no thyroid cancers were reported
  • Serious AEs—Rates were similar across treatment groups

There were ten deaths during the trial, judged by the investigators as unlikely to be treatment-related.

Potential Opportunities to Improve Care

The American Diabetes Association’s 2023 guidelines for pharmacologic glycemic treatment recommend individualized selection of glucose-lowering medications based on the patient’s glycemic and weight loss targets. The most recent consensus report of the ADA and the European Association for the Study of Diabetes for managing hyperglycemia sharpens the focus on weight management as a key treatment target.

Accordingly, the results of PIONEER PLUS suggest dose escalation of semaglutide and other glucagon-like peptide-1 receptor agonists could be a valuable strategy to improve outcomes for people with type 2 diabetes.

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