PIONEER 6: Oral Semaglutide Shows Cardiovascular Safety

Mads Krogsgaard Thomsen, PhD

Headline results from the PIONEER 6 trial of oral semaglutide demonstrate that the investigational GLP-1 receptor agonist is non-inferior to placebo with regard to major adverse cardiovascular events (MACE).

The PIONEER 6 primary endpoint was defined as the MACE composite outcome of the first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. The MACE composite had a hazard ratio (HR) of .79 in favor of oral semaglutide, reaching non-inferiority. However, the reduction of MACE with oral semaglutide did not reach statistical significance.

The double-blinded phase 3a trial included 3138 participants with type 2 diabetes at high risk for cardiovascular events who were randomized to receive oral semaglutide 14 mg once daily or placebo, both in addition to standard of care. Participants were either ≥50 years of age with cardiovascular disease, or ≥60 years of age with at least 1 cardiovascular risk factor.

The results of PIONEER 6 are based on 137 major adverse cardiovascular events accumulated over the course of the study. The median follow-up time was 16 months.

When analyzing the composite components separately, there was a significant reduction in cardiovascular (CV) death (51%; HR .49; P = .03). Non-significant differences between oral semaglutide and placebo were seen in non-fatal myocardial infarction (HR 1.18) and non-fatal stroke (HR .74). In addition, the study reported a statistically significant 49% reduction in all-cause mortality (HR .51, P = .008).

"We are very encouraged that PIONEER 6 demonstrated cardiovascular safety as well as a significant reduction in both CV and all-cause mortality following oral semaglutide treatment in people with type 2 diabetes at high cardiovascular risk," said Mads Krogsgaard Thomsen, PhD, DSc, executive vice president and chief science officer of Novo Nordisk, in a statement. "Based on the strong clinical data reported throughout the PIONEER clinical trial program, we have now established a solid efficacy and safety profile for oral semaglutide and we are looking forward to sharing the results with regulatory authorities during 2019."

Data about the study’s secondary outcome measures was not included in the company’s press release.

In 2017, the US Food and Drug Administration (FDA) approved an injectable form of semaglutide for use as a supplement to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Novo Nordisk plans to file an application for oral semaglutide with the FDA as well as with authorities in the European Union in the first half of 2019.