Oral semaglutide, a medication used to treat type 2 diabetes, is associated with a reduced risk of heart failure events in individuals who already have the condition, according to a secondary analysis of the SOUL randomized clinical trial. The findings, published in in JAMA Internal Medicine, offer further insight into the cardiovascular benefits of this medication.
Heart Failure and Type 2 Diabetes: A Complex Relationship
The intersection of type 2 diabetes and heart failure represents a significant public health challenge. Individuals with type 2 diabetes are at a substantially increased risk of developing heart failure, and the presence of both conditions often leads to poorer outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), like semaglutide, have become established as effective treatments for managing blood sugar and reducing the risk of major adverse cardiovascular events (MACE) – a composite of cardiovascular death, nonfatal heart attack, and nonfatal stroke. However, the specific impact of these medications on heart failure outcomes has been an area of ongoing investigation.
The SOUL trial initially demonstrated cardiovascular benefits with oral semaglutide in people with type 2 diabetes and either atherosclerotic cardiovascular disease or chronic kidney disease. This recent secondary analysis delved deeper, specifically examining whether those benefits extended to heart failure outcomes and whether the effects varied depending on a patient’s heart failure status at the start of the study.
Significant Reduction in Heart Failure Events in Those With Existing Heart Failure
The analysis included data from over 9,600 participants, with nearly 25% having a pre-existing history of heart failure. Researchers found that among those with existing heart failure, oral semaglutide was linked to a significantly lower risk of a composite heart failure outcome. This outcome included heart failure hospitalization, urgent heart failure visits, or cardiovascular death. Notably, this reduction in heart failure events was not observed in participants who did not have heart failure at the beginning of the trial. This suggests that semaglutide’s benefit regarding heart failure may be most pronounced in individuals who already have the condition, rather than acting as a preventative measure for those without a prior diagnosis.
Benefits More Evident in Preserved Ejection Fraction
Further analysis revealed that the reduction in heart failure events appeared more substantial in participants with heart failure with preserved ejection fraction (HFpEF) compared to those with heart failure with reduced ejection fraction (HFrEF). Ejection fraction refers to the percentage of blood the heart pumps out with each contraction. HFpEF, where the heart muscle is stiff and doesn’t fill properly, often lacks effective treatment options, making these findings particularly relevant. While not all subgroup analyses reached statistical significance, the results align with emerging evidence suggesting that GLP-1 receptor agonists may be especially beneficial in HFpEF.
Importantly, the observed reduction in heart failure events did not appear to compromise patient safety. Rates of serious adverse events were similar between the groups receiving semaglutide and those receiving a placebo.
Cardiovascular Protection Remains Consistent
The positive effect of oral semaglutide on major adverse cardiovascular events (MACE) remained consistent regardless of whether participants had heart failure at baseline. This indicates that the heart failure benefit observed in patients with established disease complements the broader cardiovascular protection already associated with semaglutide therapy, rather than replacing it.
Implications for Clinical Practice
These findings reinforce the growing role of GLP-1 receptor agonists in the management of cardiometabolic disease. The study supports the use of oral semaglutide in individuals with type 2 diabetes and existing heart failure to reduce the risk of heart failure-related events, without raising safety concerns. The SOUL trial, which involved participants from 444 sites across 33 countries, randomly assigned nearly 10,000 individuals to receive either oral semaglutide or a placebo, in addition to their standard care. The median follow-up period was approximately 49.5 months, and the average age of participants was 66.1 years.
While these results are promising, further research is needed to fully elucidate the mechanisms underlying semaglutide’s heart failure benefits and to determine the optimal treatment strategies for different heart failure subtypes. The study included individuals aged 50 years or older with a diagnosis of type 2 diabetes and a hemoglobin A1c between 6.5% and 10%, and who had either coronary artery disease, cerebrovascular disease, symptomatic peripheral artery disease, or chronic kidney disease. Individuals with end-stage kidney disease or those receiving long-term kidney replacement therapy were excluded from the study.
The findings from the SOUL trial, initially presented on , and further analyzed, contribute to a growing body of evidence supporting the use of GLP-1 receptor agonists in patients with both type 2 diabetes and cardiovascular disease. A separate study, the SELECT trial, has also provided insights into the cardiovascular benefits of semaglutide in patients with obesity and prevalent heart failure.
Reference
Pop-Busui R et al. Oral semaglutide and heart failure outcomes in persons with type 2 diabetes: a secondary analysis of the SOUL randomized clinical trial. JAMA Intern Med. ;DOI:10.1001/jamainternmed.2025.7774.
