Peptide Innovation for Early Diabetes Treatment 6 - PIONEER 6

Contribution To Literature:

The PIONEER 6 trial showed that the cardiovascular risk profile of oral semaglutide was noninferior to placebo. 


The goal of the trial was to evaluate oral semaglutide (glucagon-like peptide-1 [GLP-1] receptor agonist) compared with placebo among patients with type 2 diabetes at high cardiovascular risk. Safety has been established for subcutaneous semaglutide, but not for oral semaglutide.

Study Design

  • Randomized
  • Parallel
  • Placebo
  • Blinded

Patients with high cardiovascular risk were randomized to once-daily oral semaglutide, 14 mg target dose (n = 1,591) or placebo (n = 1,592).

  • Total number of enrollees: 3,183
  • Duration of follow-up: median 15.9 months
  • Mean patient age: 66 years
  • Percentage female: 32%
  • Percentage with diabetes: 100%

Inclusion criteria:

  • Age ≥50 years with established cardiovascular or chronic kidney disease
  • Age ≥60 years with cardiovascular risk factors only

Exclusion criteria:

  • Treatment with any GLP-1 receptor agonist, dipeptidyl peptidase 4 inhibitor, or pramlintide within 90 days before screening
  • New York Heart Association class IV heart failure
  • Planned coronary-artery, carotid-artery, or peripheral-artery revascularization
  • Myocardial infarction, stroke, or hospitalization for unstable angina or transient ischemic attack within 60 days before screening
  • Long-term or intermittent hemodialysis or peritoneal dialysis, or severe renal impairment (estimated glomerular filtration rate [GFR], <30 ml/minute/1.73 m2 of body-surface area)
  • Proliferative retinopathy or maculopathy resulting in active treatment

Principal Findings:

The primary outcome, cardiovascular death, myocardial infarction, or stroke, occurred in 3.8% of the semaglutide group compared with 4.8% of the placebo group (p for noninferiority < 0.001; p for superiority = 0.17).

Secondary outcomes:

  • Cardiovascular death: 0.9% with semaglutide vs. 1.9% with placebo (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.27-0.92)
  • All-cause death: 1.4% with semaglutide vs. 2.8% with placebo (HR 0.51, 95% CI 0.31-0.84)
  • Myocardial infarction: 2.3% with semaglutide vs. 1.9% with placebo (HR 1.18, 95% CI 0.73-1.90)
  • Stroke: 0.8% with semaglutide vs. 1.0% with placebo (HR 0.74, 95% CI 0.35-1.57)
  • Adverse event leading to permanent discontinuation of study medication: 11.6% with semaglutide vs. 6.5% with placebo; mostly due to gastrointestinal effects in 6.8% with semaglutide vs. 1.6% with placebo


Among patients with type 2 diabetes, oral semaglutide was noninferior to placebo in terms of cardiovascular safety. GLP-1 receptor agonists appear to have a favorable cardiovascular safety profile (lixisenatide and exenatide) or cardiovascular benefit (liraglutide, albiglutide, and semaglutide, dulaglutide), and this trial provides further evidence in that regard. Exenatide had been associated with acute kidney injury, presumably from nausea, vomiting, and diarrhea. All GLP-1 receptor agonists appear to be associated with increased gastrointestinal symptoms.


Husain M, Birkenfeld AL, Donsmark M, et al., on behalf of the PIONEER 6 Investigators. Oral Semaglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes. N Engl J Med 2019;381:841-51.

Keywords: Cardiovascular Diseases, Diabetes Mellitus, Type 2, Gastrointestinal Tract, Glucagon-Like Peptide 1, Kidney Diseases, Metabolic Syndrome, Myocardial Infarction, Primary Prevention, Renal Insufficiency, Chronic, Risk Factors, Stroke

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