For individuals managing type 2 diabetes, ensuring the cardiovascular safety of new treatments is paramount. While subcutaneous semaglutide has established safety data, the oral form required thorough investigation. The Pioneer 6 trial was designed to assess the cardiovascular outcomes associated with once-daily oral semaglutide compared to placebo in a high-risk population.
The PIONEER 6 study was a randomized, double-blind, placebo-controlled trial. It enrolled patients with type 2 diabetes who were at high cardiovascular risk – either with pre-existing cardiovascular or chronic kidney disease, or with cardiovascular risk factors alone and aged 60 or older. Over 3,000 patients were randomly assigned to receive either oral semaglutide or a placebo, and were monitored for major adverse cardiovascular events (MACE), which included cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The trial aimed to confirm that oral semaglutide was not inferior to placebo in terms of cardiovascular safety.
The results of the PIONEER 6 trial, conducted over a median period of approximately 16 months, indicated that oral semaglutide was indeed non-inferior to placebo concerning cardiovascular risk. MACE occurred in 3.8% of patients in the oral semaglutide group and 4.8% in the placebo group, with a hazard ratio of 0.79 (95% CI, 0.57 to 1.11; P<0.001 for noninferiority). Notably, there was a significant reduction in cardiovascular deaths in the oral semaglutide group (0.9%) compared to placebo (1.9%), with a hazard ratio of 0.49 (95% CI, 0.27 to 0.92). While nonfatal myocardial infarction rates were numerically higher in the semaglutide group (2.3% vs 1.9%), and nonfatal stroke rates were numerically lower (0.8% vs 1.0%), neither reached statistical significance. All-cause mortality was also significantly lower with oral semaglutide (1.4%) versus placebo (2.8%). Gastrointestinal adverse events leading to treatment discontinuation were more frequent with oral semaglutide.
In conclusion, the PIONEER 6 trial demonstrated that oral semaglutide does not increase cardiovascular risk in patients with type 2 diabetes at high cardiovascular risk, when compared to placebo. These findings support the cardiovascular safety profile of oral semaglutide as a treatment option for this patient population. The PIONEER 6 trial is registered at ClinicalTrials.gov, number NCT02692716.
