Oral semaglutide falls just short of cardioprotection in event-driven PIONEER 6
medwireNews: The PIONEER 6 trial demonstrates the noninferior cardiovascular safety profile of oral semaglutide compared with placebo, but fails to demonstrate superiority, despite an overall positive trend and significance for cardiovascular death.
Mansoor Husain (Toronto General Hospital, Ontario, Canada) presented the findings to reporters at the 79th ADA Scientific Sessions in San Francisco, California, USA. He explained that the trial was event-driven, and was stopped as soon as 122 primary endpoint events had been recorded, making it of relatively short duration and limiting its power to detect statistical superiority.
The requisite number of events accumulated at a median follow-up time of 15.9 months; 3.8% of the 1591 people randomly assigned to receive oral semaglutide 14 mg/day had a primary endpoint event, of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.
In addition 4.8% of the 1592 people in the placebo group met the primary endpoint, giving a nonsignificant hazard ratio for superiority of 0.79, with a confidence interval of 0.57–1.11.
This positive trend was driven by cardiovascular death, which occurred in 0.9% and 1.9% of the semaglutide and placebo groups, respectively, making it a significant 51% less likely to occur in people taking oral semaglutide, and there was a 49% reduction in the risk for all-cause mortality.
Treatment allocation did not influence people’s risk for nonfatal myocardial infarction, stroke, or hospitalization for unstable angina or heart failure.
The trial population as a whole was relatively high risk; of the 3183 people with type 2 diabetes who were enrolled, around 85% were at least 50 years old and had established cardiovascular disease or chronic kidney disease, with the remaining 15% being at least 60 years old and with cardiovascular risk factors. The participants’ diabetes had lasted an average of 15 years, their average BMI was 32 kg/m2 and their average estimated glomerular filtration rate was 74 mL/min per 1.73 m2.
In line with injectable glucagon-like peptide-1 receptor agonists, oral semaglutide was associated with an increased risk for gastrointestinal events. It was a major reason for discontinuation; 11.6% versus 6.5% of patients discontinued semaglutide versus placebo overall, and 6.8% versus 1.6% did so because of gastrointestinal issues.
“By eliminating the barrier of injection, oral semaglutide has potential for wide use in the treatment of type 2 diabetes, including in high-risk patients with [cardiovascular disease] and [chronic kidney disease],” said Husain.
The findings are also published in The New England Journal of Medicine.
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