The SOUL trial proved that oral semaglutide reduces major cardiovascular events by 14% in high-risk diabetes patients, establishing the first cardiovascular benefit for a pill-form GLP-1 drug.
HR 0.86 for MACE (p=0.006)A daily semaglutide pill reduced the combined risk of cardiovascular death, heart attack, and stroke by 14% over 4 years — the first oral GLP-1 drug to prove cardiovascular protection.
What the researchers found
The SOUL trial demonstrated that oral semaglutide (14 mg daily) significantly reduced the risk of major adverse cardiovascular events (MACE) by 14% compared to placebo in 9,650 high-risk adults with type 2 diabetes (HR 0.86, 95% CI 0.77-0.96, p=0.006). The primary composite outcome included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. The benefit was consistent across subgroups, including those already taking SGLT2 inhibitors. This was the first trial to establish cardiovascular benefit for an oral GLP-1 receptor agonist.
Why it matters
Until SOUL, cardiovascular benefit had only been proven for injectable GLP-1 drugs. This trial proves that a daily pill form of semaglutide provides the same cardiovascular protection, which could dramatically expand access to this life-saving peptide therapy. Many patients prefer pills over injections, and an oral option with proven heart benefits removes a major barrier to GLP-1 RA adoption.
The numbers in context
n=9,650 · oral semaglutide 14 mg vs placebo · MACE HR 0.86 (95% CI 0.77-0.96, p=0.006) · median follow-up 49.5 months · T2DM with ASCVD and/or CKD · consistent across SGLT2i subgroups
How the study worked
SOUL was a randomized, double-blind, placebo-controlled superiority trial. 9,650 adults with type 2 diabetes and established atherosclerotic cardiovascular disease, chronic kidney disease, or both were randomized to oral semaglutide 14 mg daily or placebo. The primary outcome was time to first cardiovascular death, non-fatal MI, or non-fatal stroke. Prespecified secondary analyses assessed expanded cardiovascular, kidney, peripheral artery, and heart failure outcomes. Median follow-up was 49.5 months.
Who was studied
9,650 adults with type 2 diabetes and established atherosclerotic cardiovascular disease, chronic kidney disease, or both
What this study cannot tell us
This is a review of the SOUL trial, not the primary trial publication itself. The trial enrolled only high-risk T2DM patients with established cardiovascular or kidney disease, so results may not generalize to lower-risk populations. The oral semaglutide dose (14 mg) may not have the same cardiovascular effect as higher injectable doses. Long-term effects beyond the median 49.5-month follow-up are unknown.
How to read the evidence
This is a review of the SOUL trial, a large (n=9,650), randomized, double-blind, placebo-controlled superiority trial with nearly 4 years of follow-up. The trial design represents the highest level of clinical evidence for cardiovascular outcomes.
When this study was published
Published in 2025, this review covers the landmark SOUL trial results, which established oral semaglutide as the first pill-form GLP-1 drug with proven cardiovascular benefit.
The bigger picture
The SOUL trial is a landmark in GLP-1 peptide therapeutics because it extends the proven cardiovascular benefits of this drug class from injections to pills. Combined with previous trials (LEADER for injectable liraglutide, SUSTAIN-6 and SELECT for injectable semaglutide), it solidifies GLP-1 receptor agonists as a cardiovascular protective drug class comparable in importance to statins. The oral formulation could democratize access to these benefits globally.
Questions still open
- Would higher oral semaglutide doses provide even greater cardiovascular protection?
- Can oral semaglutide's cardiovascular benefits extend to people without diabetes but with high cardiovascular risk?
- How does the cardiovascular benefit of oral semaglutide compare head-to-head with injectable semaglutide?
Common questions
How is oral semaglutide different from the injectable version?
Why does a diabetes drug protect the heart?
Read the original research
The impact of oral semaglutide on cardiovascular events in patients with type 2 diabetes: review of results from the SOUL trial.
Heart failure reviews, 31(1), 11
Citation
Lehenbauer, Katy S; Nelson, Adam J; Nodari, Savina; Sverdlov, Aaron L; Harrington, Josephine. (2025). The impact of oral semaglutide on cardiovascular events in patients with type 2 diabetes: review of results from the SOUL trial.. Heart failure reviews, 31(1), 11. https://doi.org/10.1007/s10741-025-10579-y