The impact of oral semaglutide on cardiovascular events in patients with type 2 diabetes: review of results from the SOUL trial

Dec 10, 2025Heart failure reviews

Oral semaglutide and heart-related health in people with type 2 diabetes: findings from the SOUL trial

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Abstract

Oral semaglutide is associated with a 14% reduction in the risk of major adverse cardiac events (MACE) compared to placebo over a median follow-up of 49.5 months.

The study enrolled 9,650 adults with type 2 diabetes and cardiovascular risks.
The primary outcome measured was the time to first cardiovascular death, non-fatal heart attack, or non-fatal stroke.
Results showed a hazard ratio of 0.86 for the risk of MACE with oral semaglutide versus placebo.
Consistent results were observed across different subgroups, including those using sodium glucose co-transporter 2 inhibitors.

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Subcutaneous glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to reduce risk of major adverse cardiac events (MACE) for patients with type 2 diabetes (T2DM) who have or are at high risk of cardiovascular disease, but the evaluation of cardiovascular efficacy of oral GLP-1 RAs has yet to be performed. This article reviews results from the SOUL (Semaglutide Cardiovascular Outcomes) trial, whose aim was to assess the cardiovascular benefit in oral semaglutide in high-risk individuals. SOUL was a randomized, double blind, parallel-group, placebo-controlled superiority trial that enrolled 9,650 adults with T2DM who had established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both, to receive a maximum daily dose of 14 mg oral semaglutide or placebo. The primary outcome in this study was a composite of time to first CV death, non-fatal MI, or non-fatal stroke. In prespecified secondary analyses, treatment groups were analyzed for an expanded list of CV, CKD, PAD, and HF outcomes. Over a median follow-up of 49.5 months, the risk for MACE was significantly lower in the oral semaglutide compared with the placebo group (HR 0.86; 95% CI, 0.77; 0.96; p = 0.006), and these results were consistent across subgroup analysis, including by sodium glucose co-transporter 2 inhibitor (SGLT2i) drug use. Oral semaglutide reduces the risk of MACE in high-risk patients with T2DM.

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The impact of oral semaglutide on cardiovascular events in patients with type 2 diabetes: review of results from the SOUL trial

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