Oral semaglutide may reduce mortality in patients with T2DM and known CVD, but confirmation from a larger trial is needed

Référence

Husain M, Birkenfeld AL, Donsmark M, et al, for the PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841-851.

Sommaire

Semaglutide is the first oral GLP-1 agonist; several subcutaneously delivered GLP-1 agonists have previously been shown to improve cardiovascular outcomes. The US Federal Drug Administration mandated that new drugs for T2DM undergo trials that are sufficiently powered to evaluate cardiovascular safety in a noninferiority trial. That was the case here, with the study powered to detect an 80% increase in the risk of cardiovascular events. Although this was primarily a noninferiority trial, the authors also prespecified a single superiority assessment for the primary outcome of major adverse cardiovascular events (MACE, which includes cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke). They recruited a very-high-risk group of 3183 patients 50 years and older with T2DM and known cardiovascular or chronic kidney disease. Patients 60 years and older were recruited if they had cardiovascular risk factors only. The patients' mean age was 66 years, the mean glycated hemoglobin was 8.2%, and 85% had established cardiovascular disease or chronic kidney disease. They were then randomized to receive oral semaglutide in a target dose of 14 mg once daily or matching placebo. Outcomes were adjudicated by an external committee masked to treatment assignment. The authors do not describe how (or whether) allocation was concealed. Groups were balanced at the start of the study and the analysis was by intention to treat. Patients were followed up for a mean of 16 months, and there was very little loss to follow-up. There was no significant difference between groups for the primary MACE outcome (3.8% semaglutide vs 4.8% for placebo; hazard ratio 0.79, 95% CI 0.57 - 1.11). Thus, it was noninferior but not superior to placebo. All-cause mortality (1.4% vs 2.8%; number needed to treat [NNT] = 71) and cardiovascular mortality (0.9% vs 1.9%; NNT = 100) were both significantly less likely in patients who received semaglutide. However, there was no significant difference in any of the other 5 individual outcomes and no difference between groups for an expanded composite outcome. The authors acknowledge that the beneficial effects should be interpreted as exploratory given the design of the trial.