FDA approved subcutaneous semaglutide (ozempic) in December 2017. Clinical trials and experience have shown that semaglutide helps with A1c lowering and weight loss. Additionally, SUSTAIN 6 trial proved its cardiovascular safety.
The current study PIONEER 6, published in the New England Journal of Medicine, addresses the cardiovascular safety of oral semaglutide in patients with diabetes at “high risk” for adverse ASCVD events. Age greater than 50 with established cardiovascular disease or chronic kidney disease, or age greater than 60 with CVD risk factors defined the “high risk” status in study participants.
A group of 3200 adults was randomized to receive oral semaglutide or placebo. Patients’ mean age was 66 years. Investigators followed subjects for about 16 months. Final analysis revealed that participants receiving oral semaglutide experienced 20% less major adverse cardiovascular events (MACE) than placebo counterparts. Lower rates of CV death and death from any cause seem to be the main drivers of the reduced primary endpoint.
Although MACE occurred less frequently in the semaglutide group, the trial was designed to evaluate non-inferiority (safety) and not superiority (benefits). These findings are reassuring towards a positive FDA approval for the oral semaglutide. The endorsement would place the very first oral GLP-1 agonist on the market.
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N E J M
PIONEER 6
June 2019
BACKGROUND
Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide.
METHODS
We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established CVD or CKD, or age of ≥60 years with CVD risk factors only).
Primary outcome in a time-to-event analysis was the first occurrence of a MACE (major adverse cardiovascular event = death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke).
The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome).
RESULTS
A total of 3,183 patients were randomly assigned to receive oral semaglutide or placebo.
The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease.
The median time in the trial was 15.9 months.
MACE occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (HR 0.79, p<0.001 for noninferiority).
Results for components of the primary outcome were as follows:
- Death from CV causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (HR 0.49, p<0.05);
- Nonfatal MI, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (HR, 1.18, p>0.05)
- Nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (HR, 0.74, p>0.05)
- Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (HR 0.51; p<0.05).
- GI adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide.
CONCLUSIONS
In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo.
