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Can a Higher Dose of Semaglutide Improve Glucose Management?

Published: 8/30/21
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By Arvind Sommi

This international clinical trial is enrolling an estimated 1,224 participants who have been diagnosed with type 2 diabetes, age 18 or older. This study is investigating if higher doses of oral semaglutide (currently sold as Rybelsus) will lead to lower A1C levels. 

Clinical Trials Identifier: NCT04707469

Trial Name: Research Study to Compare Three Doses of Semaglutide Tablets Taken Once Daily in People with Type 2 Diabetes (PIONEER PLUS)

Diabetes Type: Adults with type 2 diabetes

What is this trial testing?

The PIONEER PLUS trial is comparing three different doses of oral semaglutide to test if higher doses could better improve the management of glucose levels in 1,224 people with type 2 diabetes who have previously tried other oral glucose-lowering medicines. 

Participants will be randomized into three treatment groups – 14 mg, 25 mg, and 50 mg. Every participant will start by taking a daily 3 mg oral dose, and they will gradually increase their daily dose every four weeks until they reach either 14 mg, 25 mg, or 50 mg (depending on which group they are in). Once they reach their final dose amount, they will continue at that dose until the end of the trial (68 weeks). 

The trial is primarily measuring participants’ change in A1C levels at one year. Researchers will also look at other metrics such as changes in body weight, fasting blood glucose levels, change in waist circumference, and complications. It does not appear that this trial will be looking at Time in Range or continuous glucose monitor (CGM) values.

Why is this trial new or important?

Semaglutide is a GLP-1 receptor agonist that can improve glucose management in adults with type 2 diabetes and it is available in three forms. It is available as a daily glucose-lowering oral pill (called Rybelsus) and as a weekly glucose-lowering injection (called Ozempic). Additionally it is available specifically for weight management as a weekly injection (called Wegovy).

Currently, the highest approved dose of oral semaglutide is 14 mg. Research from the 81st ADA Scientific Sessions showed that for the injection version of semaglutide, a higher dose led to greater improvements in A1C reduction and weight loss (this higher dose is currently under review by the FDA). This clinical trial could pave the way for the FDA approval of a higher dose of oral semaglutide if it is deemed safe and can lead to greater reductions in A1C. Having these options for the oral version of the drug would give healthcare professionals more options for the people with diabetes they see.

Trial length: 68 weeks

Trial location: 177 locations around the world including the US, Australia, India, Europe, and more. 

Are you interested?

You may be eligible for this study if you:

●      Are 18 or older

  • Were diagnosed with type 2 diabetes at least six months prior to the day of screening.
  • Have an A1C between 8.0% and 10.5% 
  • Have a BMI equal to or above 25 kg/m­2
  • Are taking any of the following treatment regimens for 90 days prior to the day of screening:
    • Metformin
    • Sulfonylureas (SU) 
    • An SGLT-2 inhibitor
    • A DPP-4 inhibitors
  • Are NOT on insulin

You can see a full list of eligibility and exclusion criteria here

For more information: Please contact the Novo Nordisk study team at +1-866-867-7178 for more information. You can also email

About the authors

Arvind Sommi joined the diaTribe Foundation in 2021 after graduating from the University of Florida with a degree in Biology . Sommi is an Editor for diaTribe Learn. Arvind Sommi... Read the full bio »

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