Husain M, Birkenfeld AL, Donsmark M, et al.; PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019 Aug 29;381(9):841-851. doi: 10.1056/NEJMoa1901118.
Celso Amodeo, Sao Paulo, Brazil
ISCP Board of Directors
Summary of the trial
The trial titled Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes1 sought to assess noninferiority over placebo use of oral semaglutide in type 2 diabetes patients. The authors evaluated cardiovascular outcomes of once‐daily oral semaglutide in an event‐driven, randomized, double‐blind, placebo‐controlled trial involving patients at high cardiovascular risk (age <50 years with established cardiovascular or chronic kidney disease, or age >60 years with cardiovascular risk factors only). The primary outcome was the combined of death from cardiovascular causes, nonfatal myocardial infarction and/or nonfatal stroke. The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo. A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The 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. The median time in the trial was 15.9 months. 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). Results for components of the primary outcome were favorable to semaglutide group except nonfatal myocardial infarction. In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo.
This study showed that oral semaglutide provides a practical treatment option for patients with type 2 diabetes with favorable outcome in cardiovascular events compared to placebo. In the present study the hazard ratios were similar to SUSTAIN-62 which may suggest that the cardiovascular effect of semaglutide is independent of the route of administration. Also, the oral formulation is as effective as the subcutaneous form of semaglutide and at least as effective as liraglutide reducing weight and the episodes of hypoglycemia.
The main concern about this study was the low number of patients included and the time of follow-up. But, overall, the results showed no inferiority of the components of the primary outcome and the other cardiovascular outcomes (total mortality). Gastrointestinal adverse events were the major reason for discontinuation of oral semaglutide and worsening of diabetic retinopathy was more prevalent in the semaglutide group. In SUSTAIN-6, subcutaneous semaglutide was also associated with a higher risk of diabetic retinopathy complications than placebo. Most events occurred early in that trial, possibly due to the magnitude and rapidity of the reduction in glycated hemoglobin levels in patients with preexisting diabetic retinopathy. Other randomized trials of adequate power are needed to establish long-term efficacy and safety of oral semaglutide. A long term trial to investigate the effects of semaglutide on the development and progression of diabetic retinopathy is ongoing (ClinicalTrials.gov number, NCT03811561).
- Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz M, et al (2019) Oral semaglutide and cardiovascular outcomes in patients with type 2 Diabetes. N Eng J Med 381: 841-851.
- 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