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High-Dose Rybelsus Trial Results Show Greater A1C and Weight Reduction in Type 2 Diabetes

Published: 3/27/23 4:06 pm
By Susannah Chen

Woman Taking RybelsusNovo Nordisk’s PIONEER PLUS trial has delivered promising A1C and weight loss results for patients with type 2 diabetes taking the oral semaglutide Rybelsus at significantly higher doses. 

Novo Nordisk has released initial results for PIONEER PLUS, a clinical trial testing Rybelsus at high doses. The results show significant reductions in both A1C levels and weight in patients with type 2 diabetes, marking the greatest amount of weight loss ever seen to date from an oral glucose lowering agent. 

Novo Nordisk said that results from the phase 3 trial testing its once-daily oral semaglutide Rybelsus at experimental doses of 25 mg and 50 mg for 68 weeks outperformed a 14 mg dose, which has been the maximum approved dose of Rybelsus thus far. Rybelsus – a semaglutide like the increasingly popular medication Ozempic, only taken by mouth rather than by injection – is prescribed for people with type 2, along with diet and exercise to help control blood sugar.

Based on these study results, which reveal an average A1C reduction of roughly 2 percentage points and an average weight reduction of 10% with the highest Rybelsus dose, Novo Nordisk plans to file for regulatory approvals of the 25 mg and 50 mg doses in the US and the EU later this year, the company said in a March 24 release. 

The PIONEER PLUS trial had an estimated enrollment of 1,244 type 2 diabetes participants requiring “treatment intensification” who used Rybelsus in addition to one and three other oral diabetes medications. All participants were started on the lowest starting dose of 3 mg and were later randomly assigned a final dose of 25 mg, 50 mg, or 14 mg. 

Trial results showed a statistically significant and superior reduction in A1C at week 52 with both the 25 mg and 50 mg doses compared to the 14 mg dose, which was used as control in place of a placebo (a drug with no therapy benefits). 

For patients with average baseline A1C levels of 9%, those who received the 25 mg and 50 mg doses of Rybelsus saw reductions of 1.9 percentage points and 2.2 percentage points, respectively; these figures came in above the 1.4 percentage point reduction for the approved Rybelsus dose. 

Patients treated with the 25 mg and 50 mg doses also experienced weight loss of 7 kg (15.4 lb) and 9.2 kg (20 lb) each during the study, compared with 4.5 kg (10 lb) for the approved dose. Patients entered the study with a mean weight of 96.4 kg (212.5 lb).

 Daily Rybelsus Dose 

 A1C Reduction 

 Weight Loss Reduction 

 14 mg

 1.9 percentage points 

 4.5 kg (10 lb) 

 25 mg

 2.2 percentage points

 7 kg (15.4 lb)

 50 mg

 1.4 percentage points

 9.2 kg (20 lb)


“In the trial, all doses of oral semaglutide appeared to have a safe and well-tolerated profile,” according to the statement. “The most common adverse events were gastrointestinal, the vast majority were mild to moderate and diminished over time.” The side effects were consistent with other GLP-1 receptor agonists, the company said, and gastrointestinal adverse events were more apparent during the period of time the dose was increased and more frequent with the 25 mg and 50 mg doses than with the lower 14 mg dose.

While other GLP-1 receptor agonist medications are given by injection, Rybelsus is the only drug in this class available on the market taken by mouth. With an oral semaglutide, Novo Nordisk hopes to fulfill the needs of people with type 2 diabetes and obesity who would benefit from a GLP-1 receptor agonist but are reluctant to use inject drugs. 

Rybelsus is currently available in 3 mg, 7 mg, and 14 mg oral tablets. In January 2023, the FDA gave the green light to Rybelsus being used as a first-line treatment for type 2 diabetes, meaning doctors can now prescribe it to patients first instead of starting with another medication.

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About the authors

Prior to joining The diaTribe Foundation in 2023, Susannah Chen was a longtime freelance writer and editorial content strategist with a focus on food, drink, and travel. A two-year saga... Read the full bio »