PIONEER 6 showcases CV safety of oral semaglutide in T2D
Patients with type 2 diabetes (T2D) and high cardiovascular (CV) risk do not have an elevated risk of major adverse CV events (MACE)* when taking oral semaglutide alongside standard-of-care (SOC) therapy, according to findings of the PIONEER 6** trial presented at ADA 2019.
“PIONEER 6 showed oral semaglutide is safe in patients with T2D at high CV risk, with a non-significant 21 percent reduction in 3-component MACE over a median follow up of 15.9 months,” said study lead author Professor Mansoor Husain from the Toronto General Hospital and the University of Toronto in Ontario, Canada.
Participants were 3,183 patients with T2D (mean age 66 years, 68.4 percent male, mean body weight 90.9 kg, mean HbA1c 8.2 percent, mean eGFR 74 mL/min/1.73 m2) stratified by age according to CV disease (CVD) and chronic kidney disease (CKD) status (age ≥50 years for those with established CVD or CKD [n=2,695] or age ≥60 years for those with CV risk factors only). They were randomized 1:1 to receive oral semaglutide (target dose: 14 mg once/day) or placebo in addition to SOC therapy.
Over a median 15.9 months, MACE incidence was lower among patients assigned to semaglutide than placebo (3.8 percent vs 4.8 percent, hazard ratio [HR], 0.79, 95 percent confidence interval [CI], 0.57–1.11; pnoninferiority<0.001, psuperiority=0.17). [N Engl J Med 2019;doi:10.1056/NEJMoa1901118]
When analysed by CV component, patients on semaglutide had lower risks for death from CV causes (0.9 percent vs 1.9 percent for placebo, HR, 0.49, 95 percent CI, 0.27–0.92) and non-fatal stroke (0.8 percent vs 1.0 percent for placebo, HR, 0.74, 95 percent CI, 0.35–1.57), with non-fatal myocardial infarction numerically higher among semaglutide vs placebo recipients (2.3 percent vs 1.9 percent, HR, 1.18, 95 percent CI, 0.73–1.90).
All-cause death was also less common in the semaglutide compared with the placebo group (1.4 percent vs 2.8 percent, HR, 0.51, 95 percent CI, 0.31–0.84), and were mostly CV-related. Incidence of unstable angina leading to hospitalization was comparable between semaglutide and placebo recipients (0.7 percent vs 0.4 percent, HR, 1.56), as was incidence of heart failure hospitalization (1.3 percent vs 1.5 percent, HR, 0.86).
“Over the relatively short duration of follow up, and the relatively small total number of events, no statistically significant increase in the risk of any CV endpoint was observed in the oral semaglutide treatment group,” said Husain.
At trial end, semaglutide recipients had greater reductions than placebo recipients in terms of HbA1c levels (mean change from baseline, -1.0 vs -0.3 percentage points) and body weight (mean change from baseline, -4.2 vs -0.8 kg).
Permanent treatment discontinuation was more common in semaglutide than placebo recipients (11.6 percent vs 6.5 percent), mostly due to gastrointestinal adverse events (AEs; 6.8 percent vs 1.6 percent), namely nausea (2.9 percent vs 0.5 percent), vomiting (1.5 percent vs 0.3 percent), and diarrhoea (1.4 percent vs 0.4 percent). Severe hypoglycaemia occurred in 1.4 and 0.8 percent of semaglutide and placebo recipients, respectively, all in patients who were also receiving sulfonylureas or insulin.
Fewer patients on semaglutide than placebo experienced serious AEs (18.9 percent vs 22.5 percent), with 2.6 and 3.0 percent, respectively, permanently discontinuing treatment due to serious AEs.
Oral vs subcutaneous semaglutide?
The similarity between the results of PIONEER 6 and that of SUSTAIN-6*** which assessed CV safety with subcutaneous semaglutide “suggests that the CV effect of semaglutide is independent of the route of administration,” said Husain and co-authors. [N Engl J Med 2016;375:1834-1844]
“By eliminating the barrier of injection, oral semaglutide has potential for wide use in the treatment of T2D, including in high-risk patients with CVD and CKD,” said Husain.
“If approved [by various approval bodies including the EMA# and US FDA##], oral semaglutide will be the first oral formulation of a GLP-1 receptor agonist in a tablet,” said study investigator Professor John Buse from the University of North Carolina School of Medicine, Chapel Hill, North Carolina, US.
“GLP-1 receptor agonists are arguably the most powerful class of glucose-lowering drugs in … T2D and also are associated with weight loss and evidence of CV benefit. We hope that the availability of an oral formulation of a GLP-1 receptor agonist will increase the range of providers and patients who will feel comfortable with prescribing and taking GLP-1s,” he said.