What is it about?

This was the first large phase 3 clinical study to test how effective oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist (GLP-1RA), would be for controlling high blood glucose in patients with type 2 diabetes who were currently managing their disease with just lifestyle changes. Over 26 weeks, oral semaglutide 14 mg (the maximum dose studied) reduced HbA1c (a marker of elevated blood glucose) by 1.4% from a baseline value of 8%, compared to a 0.3% reduction with placebo. Oral semaglutide 14 mg enabled 77% of patients to achieve a diabetes target HbA1c of <7%. Furthermore, patients who were taking oral semaglutide 14 mg also lost body weight (2.3 kg more than with placebo). There were no unexpected safety concerns with oral semaglutide. Some patients did experience mild to moderate gastrointestinal effects, such as nausea, that faded with time, and this is consistent with the known tolerability profile of GLP-1RAs.

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Why is it important?

Oral semaglutide is an innovative treatment for type 2 diabetes. Semaglutide belongs to a group of drugs called GLP-1RAs, which are considered a highly effective treatment class. Although GLP-1RAs have been available since 2005, this is the first time a GLP-1RA has been made into a tablet instead of being given by an injection. As such, this treatment increases the oral treatment options for patients with type 2 diabetes who need more effective control of their blood glucose while supporting weight loss.


Glucagon-like peptide receptor agonists (GLP-1RAs) are very effective treatments for managing high blood glucose and promoting weight loss in patients with type 2 diabetes. However, the availability of GLP-1RAs as injectable therapies have perhaps limited their use and earlier consideration in care. It was therefore with a mix of excitement and disbelief that I heard of the plans to try and administer semaglutide, a peptide-based GLP-1RA, in an oral formulation. The digestive tract typically degrades peptides, and I was unsure whether this could be overcome by including combining semaglutide in a tablet with a compound designed to help its absorption through the stomach. If such an approach were shown to be effective, it would represent a significant breakthrough and open up the benefits of GLP-1RA therapy to a wider group of patients. I was therefore honored to be the lead investigator on the first phase 3 trial with oral semaglutide, PIONEER 1, which showed that oral semaglutide was very effective for controlling blood glucose and promoting loss of body weight in patients with type 2 diabetes currently managed by diet and exercise. In addition, the trial confirmed that the safety profile was as expected for a GLP-1RA. I have watched with interest as other trials from the oral semaglutide phase 3 PIONEER program have reported their results and not only reinforced the effectiveness and safety of this agent across a range of patients being treated with different background medications but demonstrated greater efficacy than many other currently available treatment options. This has, indeed, been a ‘pioneering’ journey that marks a significant milestone for diabetes care.

vanita aroda
Harvard University

Read the Original

This page is a summary of: PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes, Diabetes Care, June 2019, American Diabetes Association,
DOI: 10.2337/dc19-0749.
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