A secondary analysis of the SOUL randomized trial found that oral semaglutide was associated with fewer heart failure events in participants who had baseline heart failure, published in JAMA Internal Medicine. Historical articles may no longer reflect current regulatory status. Check the cited primary source.
A secondary analysis of the SOUL (Semaglutide Cardiovascular Outcomes in Patients with Type 2 Diabetes) randomized controlled trial has found that oral semaglutide was associated with significantly fewer heart failure events in participants who had heart failure at baseline.
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The analysis was published in JAMA Internal Medicine (PMID: 41627802).
SOUL was a randomized, double-blind, placebo-controlled cardiovascular outcomes trial that enrolled patients with type 2 diabetes and established cardiovascular or chronic kidney disease. The primary endpoint was time to first major adverse cardiovascular event (MACE) — a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.
The primary SOUL results showed a statistically significant reduction in MACE with oral semaglutide (Rybelsus) versus placebo. This secondary analysis focuses specifically on the heart failure subgroup.
Participants with baseline heart failure who received oral semaglutide had fewer hospitalisations for heart failure and cardiovascular death compared to placebo. The effect was directionally consistent with the broader GLP-1 receptor agonist heart failure literature, including data from the STEP-HFpEF trials with injectable semaglutide.
This finding extends the cardiovascular benefit signal for semaglutide beyond MACE prevention into the heart failure endpoint specifically. Prior to these analyses, the heart failure data for oral semaglutide (as opposed to injectable semaglutide) was more limited.
The SELECT trial (injectable semaglutide, n=17,604) had already demonstrated a 20% relative risk reduction in MACE in non-diabetic obese patients, and the STEP-HFpEF trials had shown functional improvement in HFpEF patients specifically. SOUL's heart failure secondary analysis adds to this growing body of evidence supporting GLP-1 receptor agonists for cardioprotection beyond metabolic outcomes.
Semaglutide carries a confidence score of 5/5 on PeptideX — the highest evidence tier, reflecting multiple large-scale human RCTs across multiple indications. The GLP-1 compound category now has the deepest human evidence base of any category in the PeptideX index, including evidence for cardiovascular, metabolic, hepatic, neurological, and addiction-related outcomes.
See the full semaglutide compound profile for complete evidence context.
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A secondary analysis of the SOUL randomized trial found that oral semaglutide was associated with fewer heart failure events in participants who had baseline heart failure, published in JAMA Internal Medicine. This adds to the growing body of GLP-1 cardiovascular evidence.
Injectable semaglutide showed significant results in STEP-HFpEF trials specifically designed for heart failure with preserved ejection fraction. The SOUL secondary analysis now provides additional heart failure data for oral semaglutide (Rybelsus) in a broader cardiovascular outcomes context.
As of Q1 2026, semaglutide is FDA-approved for type 2 diabetes (Ozempic) and chronic weight management (Wegovy). Use for heart failure specifically would be off-label. The SELECT trial results have generated significant interest in potential label expansion.