Oral semaglutide 25 mg and 50 mg superior to 14 mg for HbA1c and weight reduction in diabetes patients: phase 3 trial

Researchers have found in phase III PIONEER PLUS trial that 50- and 25-mg doses of once-daily oral semaglutide (Rybelsus) were significantly better at reducing HbA1c levels and weight in type 2 diabetes patients compared with a 14-mg dose when added to stable doses of other oral antidiabetics.

When evaluating the effects of treatment taken as intended and from a mean baseline HbA1c of 9.0 %, people treated with 25 mg and 50 mg oral semaglutide achieved a statistically significant higher HbA1c reduction of 1.9 percentage points and 2.2 percentage points, respectively, compared with a reduction of 1.5 percentage points with oral semaglutide 14 mg.

From a mean baseline body weight of 96.4 kg, people treated with oral semaglutide 25 mg and 50 mg experienced a statistically significant higher weight loss of 7.0 kg and 9.2 kg, respectively, compared with a reduction of 4.5 kg with oral semaglutide 14 mg.

When applying the treatment policy estimand 2, people treated with 25 mg and 50 mg oral semaglutide achieved a superior HbA1c reduction of 1.8 percentage points and 2.0 percentage points, respectively, compared with a reduction of 1.5 percentage points with oral semaglutide 14 mg. People treated with oral semaglutide 25 mg and 50 mg experienced a superior weight loss of 6.7 kg and 8.0 kg, respectively, compared with a reduction of 4.4 kg with oral semaglutide 14 mg.

†Statistically significant/superior vs oral semaglutide 14 mg

In the trial, all doses of oral semaglutide appeared to have a safe and well-tolerated profile. The most common adverse events were gastrointestinal, the vast majority were mild to moderate and diminished over time and were consistent with the GLP-1 receptor agonist class. Gastrointestinal adverse events were most prominent during dose escalation and more frequent with oral semaglutide 25 mg and 50 mg than with oral semaglutide 14 mg.

“We are pleased to see the results from the PIONEER PLUS trial which add further evidence of the benefits of oral semaglutide for people living with type 2 diabetes,” said Martin Holst Lange, executive vice president for Development at Novo Nordisk. “The higher efficacy from 25 mg and 50 mg doses provides the option to progress to higher doses if additional glycemic control or weight loss are needed”.

Novo Nordisk expects to file for regulatory approvals in the US and the EU in 2023. The global roll-out of the 25 mg and 50 mg doses is contingent on portfolio prioritisations and manufacturing capacity.

About the PIONEER clinical programme

The PIONEER clinical development programme for oral semaglutide currently comprises nine phase 3 global clinical trials, including a cardiovascular outcomes trial, involving more than 10,000 adults with type 2 diabetes in total. Oral semaglutide 3 mg, 7 mg and 14 mg are approved under the brand name Rybelsus®, indicated for type 2 diabetes.