Patients with Type 2 diabetes who received oral semaglutide had a non-inferior cardiovascular outcome compared with placebo, according to a new phase 3 trial.
Mansoor Husain, MD, with the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto, and colleagues reported their findings in the August 29, 2019 issue of The New England Journal of Medicine.
Patient compliance with injectable medications, such as insulin and the glucagon-like peptide-1 (GLP-1) receptor agonists is a significant challenge in the treatment of diabetes. Oral formulations are favored by patients when compared to injectable medications and are more likely to be initiated earlier. Oral semaglutide is a new oral formulation of the subcutaneous GLP-1 receptor agonist of the same name and has similar pharmacokinetic properties and effects.
In 2008, the U.S. Food and Drug Administration (FDA) began requiring cardiovascular risk assessments for new glucose-lowering drugs. All currently approved GLP-1 receptor agonists, including subcutaneous semaglutide, have shown cardiovascular safety or benefit. This study, Peptide Innovation for Early Diabetes Treatment (PIONEER) 6, is a phase 3a, randomized, placebo-controlled, preapproval cardiovascular outcomes trial with the oral formulation of semaglutide. Study participants were patients with Type 2 diabetes, fifty years of age or older with known cardiovascular disease or chronic kidney disease, or sixty years of age or older if they had cardiovascular risk factors only. The difference in time from randomization to the first occurrence of a major cardiovascular event (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was compared between groups. 1591 patients were randomized to receive oral semaglutide 14 mg daily and 1592 patients to placebo. 3172 patients (99.7%) completed the trial.
A major cardiovascular event occurred in 3.8% of patients receiving semaglutide and 4.8% of those taking placebo, a 21% relative risk reduction (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority; P=0.17 for superiority).
More patients permanently discontinued semaglutide than placebo (11.6% vs. 6.5%, respectively). This difference was driven mainly by gastrointestinal side effects, including nausea, vomiting, and diarrhea. There were fewer serious adverse events in the semaglutide group (18.9%) compared with the placebo group (22.5%), and the authors reported no unexpected adverse events in either group.
The study was funded by Novo Nordisk.
Husain M, et al. Oral semaglutide and cardiovascular outcomes in patients with Type 2 diabetes. N Engl J Med. 2019; 381:841-51.
Comments
- the trial was relatively short because it was an event-limited trial (trial period ends when a minimum number of events occurs – median time in the trial was 15.9 months)
- the trial was powered for non-inferiority, not superiority
- trial validity is increased by the high completion rate (99.7%)
- the discontinuation rate in the semaglutide group was higher than in the placebo group but comparable to that observed with other (subcutaneous) GLP-1 receptor agonists
- patients in the semaglutide group showed decreased glycated hemoglobin, weight, and systolic blood pressure compared to those in the placebo group
- death from any cause was lower in the semaglutide group than in the placebo group (1.4% vs. 2.8%, respectively; hazard ratio, 0.51; 95% CI, 0.31 to 0.84).
- these results may lead to better patient compliance with (oral) GLP-1 receptor agonists and thus, better diabetic outcomes