News & Perspective

Enabling oral administration of therapeutic peptide: results from the PIONEER-1 trial

2 years ago, OP Editor

Oral delivery of therapeutic peptides has always been a challenging topic because protein will denature in the gastrointestinal tract, making it difficult to deliver the drug to the targeted site. Recently, a breakthrough has been made by Dr. Aroda and her PIONEER-1 trial research team, who demonstrated a significant reduction in hemoglobin A1c (HbA1c) with the use of the glucagon-like peptide 1 (GLP-1) receptor agonist, semaglutide, in a tablet formulation, when compared against placebo.1 The results were presented at the American Diabetes Association (ADA) 78th Scientific Sessions.1

Semaglutide is a GLP-1 receptor agonist that received the U.S. Food and Drug Administration (FDA) approval towards the end of 2017, given as an injection adjunct to diet and exercise for the treatment of type 2 diabetes in adult patients.2

The PIONEER-1 trial was led by Dr. Vanita Aroda, Associate Director of Diabetes Clinical Research at the Brigham and Women’s Hospital, Boston, Massachusetts, US, who have tested the efficacy of semaglutide given as an oral tablet, and the results were very encouraging.1

PIONEER-1 was a phase 3a, randomized, double-blinded, placebo-controlled trial, which recruited 703 patients with type 2 diabetes, who have not received any drug treatment after their disease became uncontrollable with diet and exercise alone.1 The patients were randomly assigned to receive 3mg, 7mg, or 14mg oral semaglutide (n=175 for each treatment arm), or placebo (n=178) once-daily for 26 weeks.1 Patients were being told to continue diet and exercise, but no other medications were allowed.1 The HbA1c and body weight changes from baseline were calculated at the end of the 26 weeks treatment.1

The results showed that the oral semaglutide had a statistically significant HbA1c lowering effect across all three dosage levels, with the highest dose producing an average of 1.5% reduction in HbA1c after 26 weeks.1 The 14mg group also reduced body weight by an average of 4.1kg, which was statistically significant as compared to placebo.1 The rate of adverse events (AEs) was similar in the semaglutide groups and the placebo group (58%, 53%, and 57% for the 3mg, 7mg, and 14mg semaglutide group vs. 56% for the placebo group), with mild to moderate nausea being the most common AEs in patients receiving semaglutide.1

“This is the first phase 3 study showing that we have an oral GLP-1 in development that is… glucose lowering and looks like it has positive effects on weight loss in typical patients with type 2 diabetes. It also has safety and tolerability similar to what we already know of this class of drugs [injectable GLP-1 receptor agonists],” said Dr. Aroda during the presentation at the ADA 2018 Scientific Sessions.3

She also said the weight loss effect had not reached a plateau at the point of data cutoff, suggesting that the weight loss effect of semaglutide may not be fully reflected in this trial.3

However, even with the 1.5% HbA1c reduction that is considered as clinically significant, Dr. Sree Nair, Professor of Medicine at Mayo Clinic School of Medicine, Rochester, Minnesota, US, called for cautions when trying to interpret the results, as it will be important to look at other evidence from the active-controlled trials before reaching a conclusion.3

To better assess the clinical values of oral semaglutide, head-to-head comparisons with existing antihyperglycemic drugs have been conducted in the PIONEER-2 (vs. empagliflozin),4 PIONEER-4 (vs. liraglutide vs. placebo),5 and PIONEER-7 (vs. sitagliptin) trials.6 A cardiovascular outcome trial for oral semaglutide (PIONEER-6) is also close to its completion date in September 2018.7 By the time all the evidence are available, a full picture on the benefits with the use of oral semaglutide should become more apparent.



  1. Aroda VR, Rosenstock J, Terauchi Y, et al. Effect and Safety of Oral Semaglutide Monotherapy in Type 2 Diabetes—PIONEER 1 Trial. ADA 78th Scientific Sessions. June 22-26, 2018. Orlando, Florida, U.S. Abstract 2-LB.
  2. FDA Approves Semaglutide for Type 2 Diabetes. Medscape. 2017 (Accessed August 24, 2018, at
  3. PIONEER: First Phase 3 Data on Oral Semaglutide in Diabetes. Medscape. 2018 (Accessed August 24, 2018, at
  4. Efficacy and Safety of Oral Semaglutide Versus Empagliflozin in Subjects With Type 2 Diabetes Mellitus (PIONEER 2). (Accessed Aug 27, 2018, at
  5. Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus (PIONEER 4). (Accessed Aug 27, 2018, at
  6. Efficacy and Safety of Oral Semaglutide Using a Flexible Dose Adjustment Based on Clinical Evaluation Versus Sitagliptin in Subjects With Type 2 Diabetes Mellitus. (PIONEER 7). (Accessed Aug 27, 2018, at
  7. A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes (PIONEER 6). (Accessed August 24, 2018, at


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