PIONEER 2, PIONEER 4 show benefits of oral semaglutide in type 2 diabetes
medwireNews: Data from the phase IIIa PIONEER 2 and PIONEER 4 studies show that semaglutide equals or betters both empagliflozin and liraglutide for the reduction of glycated hemoglobin (HbA1c) in patients with type 2 diabetes uncontrolled on metformin.
The findings, presented at the 79th ADA Scientific Sessions in San Francisco, California, USA, also showed similar results for body weight reductions.
Eduard Montanya (University of Barcelona, Spain) explained that for the open-label PIONEER 2 trial, patients were randomly assigned to receive the oral glucagon-like peptide (GLP)-1 inhibitor semaglutide 14 mg/day (n=411) or the sodium-glucose cotransporter (SGLT)2 inhibitor empagliflozin 25 mg/day for 52 weeks.
At baseline, mean HbA1c was 8.1% (65 mmol/mol) in both groups. By week 26, which was the primary study endpoint, it had fallen to 6.8% (51 mmol/mol) in the semaglutide group and to 7.2% (55 mmol/mol) in the empagliflozin group, resulting in a significant estimated treatment difference of 0.4%. The results were the same at week 52.
For the secondary endpoint of body weight change, semaglutide was noninferior to empagliflozin, with respective reductions of 3.8 kg versus 3.7 kg at week 26, and 3.8 kg versus 3.6 kg at week 52. However, when the researchers excluded data collected after discontinuation of the trial product or initiation of rescue medication, they observed significantly greater body weight loss with semaglutide than with empagliflozin at both weeks 26 and 52 (4.2 vs 3.8 kg and 4.7 vs 3.8 kg, respectively).
In the double-blind PIONEER 4 trial, which was simultaneously published in The Lancet, patients were randomly assigned to receive oral semaglutide 14 mg once daily (n=285), subcutaneous liraglutide 1.8 mg (n=284), or placebo (n=142) for 52 weeks.
Richard Pratley (AdventHealth Translational Research Institute for Metabolism and Diabetes, Orlando, Florida, USA) reported that, at 26 weeks, mean HbA1c had fallen by 1.2%, 1.1%, and 0.2% in the semaglutide, lirglutide, and placebo groups, respectively, from baseline levels of 8.0%, 8.0%, and 7.9%.
Analysis of the full data set showed that semaglutide was noninferior to liraglutide and superior to placebo at this time point, but when data collected after discontinuation of the trial product or initiation of rescue medication were excluded it was superior to both liraglutide and placebo (1.3 vs 1.1 vs 0.1% reductions, respectively).
At 52 weeks, the reduction in HbA1c with semaglutide was significantly greater than that with both lirglutide and placebo, at 1.2% versus 0.9% and an increase of 0.2%, respectively.
In addition, people receiving semaglutide lost an average of 4.4 kg of body weight by week 26 and 4.3 kg by week 52, which was significantly greater than the respective 3.1 kg and 3.0 kg loss achieved by people receiving liraglutide and the 0.5 kg and 1.0 kg loss among those receiving placebo.
In both trials, 11% of patients in the semaglutide group discontinued treatment early, typically due to nausea and other gastrointestinal events. The discontinuation rates with empagliflozin and liraglutide were 4% and 9%, respectively.
Pratley and co-authors note that PIONEER 4 “is the first comparison of orally and subcutaneously administered GLP-1 receptor agonists for the treatment of type 2 diabetes.”
They say: “Because many patients are reluctant to initiate or intensify therapy by injection, oral semaglutide might be an effective treatment option, potentially leading to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care.”
In an accompanying comment, Jens Juul Holst, from the University of Copenhagen in Denmark, notes that “[o]ral semaglutide has not yet been approved by the medical authorities, but in April, 2019, new drug applications were filed for regulatory approval with both the US Food and Drug Administration and the European Medicines Agency.”
He adds that the results of the PIONEER 4 study show “that the first oral GLP-1 receptor agonist has effects that are similar to those of one of the most widely used injectable agonists.”
Discussing the findings of both studies in a press release, PIONEER trial investigator Ildiko Lingvay, from the University of Texas Southwestern Medical Center in Dallas, USA, said: “Despite their proven safety and efficacy, GLP-1 receptor agonists are underutilized in clinical care.
“As a treating physician, I'm encouraged by these findings and the potential of investigational oral semaglutide to be the first oral GLP-1 receptor agonist available as a new treatment option for people living with type 2 diabetes.”
By Laura Cowen
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