Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes
In the SOUL trial, once-daily oral semaglutide reduced major adverse cardiovascular events by 14% versus placebo in high-risk type 2 diabetes with established atherosclerotic cardiovascular disease and/or chronic kidney disease, without increasing serious adverse events.
Background
Cardiovascular disease is the leading cause of death in type 2 diabetes, particularly in those with prior atherosclerotic events or chronic kidney disease. Injectable GLP-1 receptor agonists reduce cardiovascular events, but the cardiovascular efficacy of the oral formulation of semaglutide had not been established in a superiority trial.
Study design
SOUL was a double-blind, placebo-controlled, event-driven superiority trial that randomized 9,650 participants aged 50 or older with type 2 diabetes (HbA1c 6.5-10.0%) and known atherosclerotic cardiovascular disease, chronic kidney disease, or both, to 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 cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
Key findings
Over a mean follow-up of 47.5 months, a primary-outcome event occurred in 12.0% of the oral semaglutide group versus 13.8% of the placebo group (hazard ratio 0.86; 95% CI 0.77-0.96; P = 0.006). The confirmatory secondary outcomes, including major kidney disease events, did not differ significantly between groups. Serious adverse events were 47.9% with semaglutide versus 50.3% with placebo, and the benefit was consistent regardless of concomitant SGLT2 inhibitor use.
Clinical implications
Oral semaglutide is the first non-injectable GLP-1 receptor agonist shown to reduce cardiovascular events in high-risk type 2 diabetes, offering an option for patients unwilling or unable to use injectable therapies. The cardioprotective effect appeared independent of SGLT2 inhibitor co-therapy, supporting use of the two drug classes together.
Category
Research
Source
The New England Journal of Medicine
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