BACKGROUND: The cardiovascular safety of oral semaglutide, a glucagon-like peptide 1 receptor agonist, has been established in persons with type 2 diabetes and high cardiovascular risk. An assessment of the cardiovascular efficacy of oral semaglutide in persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both is needed.
METHODS: In this double-blind, placebo-controlled, event-driven, superiority trial, we randomly assigned participants who were 50 years of age or older, had type 2 diabetes with a glycated hemoglobin level of 6.5 to 10.0%, and had known atherosclerotic cardiovascular disease, chronic kidney disease, or both to receive either once-daily oral semaglutide (maximal dose, 14 mg) or placebo, in addition to standard care. The primary outcome was major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), assessed in a time-to-first-event analysis. The confirmatory secondary outcomes included major kidney disease events (a five-point composite outcome).
RESULTS: Among the 9650 participants who had undergone randomization, the mean (±SD) follow-up was 47.5±10.9 months, and the median follow-up was 49.5 months. A primary-outcome event occurred in 579 of the 4825 participants (12.0%; incidence, 3.1 events per 100 person-years) in the oral semaglutide group, as compared with 668 of the 4825 participants (13.8%; incidence, 3.7 events per 100 person-years) in the placebo group (hazard ratio, 0.86; 95% confidence interval, 0.77 to 0.96; P = 0.006). The results for the confirmatory secondary outcomes did not differ significantly between the two groups. The incidence of serious adverse events was 47.9% in the oral semaglutide group and 50.3% in the placebo group; the incidence of gastrointestinal disorders was 5.0% and 4.4%, respectively.
CONCLUSIONS: Among persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, the use of oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events than placebo, without an increase in the incidence of serious adverse events. (Funded by Novo Nordisk; SOUL ClinicalTrials.gov number, NCT03914326.).
| Discipline Area | Score |
|---|---|
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
| Cardiology | |
| Endocrine | |
| Nephrology | |
| Internal Medicine | |
This is another in the growing body of clinical trials demonstrating the cardiovascular benefits of GLP-1 RAs in patients at high cardiovascular risk. The findings are consistent with what is known using the subcutaneous formulation. So, while not completely novel, the evidence is solidified and the importance of this drug class is clear.
The SOUL study further elucidates the benefits of semaglutide for CV events by providing incremental data with the oral preparation. Reduction in MI was a driver for the endpoint, but the reduction in the secondary outcome of major adverse limb events (MALE) was also notable.
These results are reassuring but not surprising.
The unique feature of this study is that it uses the oral formulation of semaglutide. As a primary care physician, it is helpful to see that the oral form reduced CVD events in patients with diabetes, so I can confidently offer it to my patients who prefer a pill to an injection.
