Oral semaglutide may reduce cardiovascular mortality in patients with T2DM and CV or renal disease (NNT = 100 for 16 months)

Reference

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(9):841-851.

Synopsis

This noninferiority trial was mandated by the US Food and Drug Administration to evaluate the cardiovascular safety of the new oral version of semaglutide, a GLP1 agonist. The researchers identified 3183 patients with T2DM who were 50 years and older, with either cardiovascular or chronic kidney disease (85% of the study population), or were 60 years and older with cardiovascular risk factors. The mean age was 66 years, 32% were women, and the mean body mass index was 32 kg/m2. Patients were then randomized to receive oral semaglutide 14 mg once daily or placebo; 18% were shifted to a lower dose of the active drug because of adverse gastrointestinal effects. Groups were similar at baseline, analysis was by intention to treat, and outcomes were adjudicated by a committee masked to treatment assignment. This was a relatively short study; patients were followed up for a median of 16 months. The primary outcome was time to the first episode of a major cardiovascular event, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The primary outcome occurred in 3.8% of the semaglutide group and 4.8% in the placebo group, which indicates that semaglutide is both noninferior (no worse) and nonsuperior (no better) to placebo. Secondary outcomes were not adjusted for multiple comparisons, so should be considered exploratory according to the authors (they're correct). There was no differences in the likelihood of nonfatal stroke or nonfatal myocardial infarction, but there was a reduction in the risk of cardiovascular death (hazard ratio 0.49; 95% CI 0.27 - 0.92). This is a time-to-event analysis; the overall risk of cardiovascular death was 0.9% versus 1.9%, for a number needed to treat of 100 over 16 months. There was no difference in serious adverse events, but discontinuation of the drug due to adverse events was much more common in the semaglutide group (11.6% vs 6.5%, number needed to treat to harm = 20).