PIONEER 6 - Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Last edited 12/2020 and last reviewed 10/2023

Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

The cardiovascular safety of oral semaglutide was investigated in the PIONEER-6 study

  • 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 cardiovascular or chronic kidney disease, or age of >=60 years with cardiovascular risk factors only)
  • primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke)
  • trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome)

Study results:

  • total of 3183 patients were randomly assigned to receive oral semaglutide or placebo (1)
  • patients were predominantly male (2176 patients, 68.4%), and 2695 patients (84.7%) were 50 years of age or older and had established cardiovascular disease or chronic kidney disease
  • 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
  • median time in the trial was 15.9 months
  • rimary outcome was the time from randomization to the first occurrence of a major adverse cardiovascular event, a composite of death from cardiovascular causes (including undetermined causes of death), nonfatal myocardial infarction, or nonfatal stroke.
    • major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority)
    • the trial did not reach stastical significance for superiority for the primary end point:
      • composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke (with events in 69 of 1591 patients [4.3%] and 89 of 1592 [5.6%], respectively; hazard ratio, 0.77; 95% CI, 0.56 to 1.05)

Conclusion:

  • cardiovascular outcomes trial met its primary objective of ruling out an 80% excess cardiovascular risk with oral semaglutide, confirming noninferiority to placebo for the primary outcome (hazard ratio, 0.79; 95% CI, 0.57 to 1.11). This finding is consistent with those of other published cardiovascular outcomes trials of GLP-1 receptor agonists, all of which confirmed the absence of excess cardiovascular risk
  • unlike the use of subcutaneous semaglutide in SUSTAIN-6, PIONEER-6 did not show statistical significance for the primary end point of composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke (2)
    • the study authors however noted that fewer events were observed in our trial (in 137 of 3183 patients) than in SUSTAIN-6 (in 254 of 3297) and so this may be part of the explanation for the non-significance of this finding when comparing oral to subcutaneous semaglutide

Editorial Commentary (3):

  • This was a cardiovascular safety trial - as were LEADER (subcutaneous liraglutide) and SUSTAIN-6 (subcutaneous semaglutide). However in both LEADER and SUSTAIN-6 there was also evidence of reduction of risk of the primary end point of composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke
    • the lack of reduction in the primary end point for oral semaglutide in comparison to subcutaneous semaglutide could be the result of fewer events as noted by the study authors. However this trial does mean that, at the time of publication of the trial (August 2019) there is evidence of benefit in terms of reduction of the combined cardiovascular end point (non-fatal myocardial infarction, nonfatal stroke, death of any cause) for the use of subcutaneous semaglutide but not oral semaglutide

Reference:

  • Husain M et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2. Diabetes N Engl J Med 2019; 381:841-851 DOI: 10.1056/NEJMoa1901118
  • Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-1844.
  • Editorial Commentary. Dr Jim McMorran, Editor-in-Chief, GPnotebook (December 8th 2020).

Related pages:

SUSTAIN - 6