Oral Semaglutide Reduces Heart Failure Risk in Type 2 Diabetes: SOUL Trial
In a groundbreaking secondary analysis of the SOUL randomized clinical trial, oral semaglutide has been linked to a reduced risk of heart failure events specifically in type 2 diabetes patients with pre-existing heart failure. Published in JAMA Internal Medicine, these findings provide crucial insights into the cardiovascular benefits of this GLP-1 receptor agonist (GLP-1 RA), particularly at the intersection of type 2 diabetes and heart failure—a major public health concern.
The Growing Challenge of Type 2 Diabetes and Heart Failure
Individuals with type 2 diabetes face a substantially elevated risk of developing heart failure, and when both conditions coexist, outcomes are often poorer. GLP-1 RAs like semaglutide have gained prominence for managing blood sugar levels and reducing major adverse cardiovascular events (MACE), which include cardiovascular death, nonfatal heart attack, and nonfatal stroke. However, the precise effects on heart failure outcomes have remained under investigation until now.
The SOUL trial originally demonstrated cardiovascular benefits of oral semaglutide in people with type 2 diabetes and either atherosclerotic cardiovascular disease or chronic kidney disease. This secondary analysis builds on that foundation by focusing on heart failure outcomes and exploring variations based on baseline heart failure status.
Key Details of the SOUL Trial Analysis
The study drew from data on over 9,600 participants, with nearly 25% having a history of heart failure at baseline. Conducted across 444 sites in 33 countries, the trial randomly assigned nearly 10,000 individuals aged 50 or older—with type 2 diabetes (hemoglobin A1c between 6.5% and 10%) and conditions like coronary artery disease, cerebrovascular disease, symptomatic peripheral artery disease, or chronic kidney disease—to receive either oral semaglutide or placebo, alongside standard care. The median follow-up was 49.5 months, with an average participant age of 66.1 years. Those with end-stage kidney disease or on long-term kidney replacement therapy were excluded.
Primary Findings on Heart Failure Outcomes
Among participants with existing heart failure, oral semaglutide was associated with a significantly lower risk of a composite heart failure outcome: heart failure hospitalization, urgent heart failure visits, or cardiovascular death. Importantly, this reduction was not observed in those without heart failure at trial start, indicating semaglutide's benefits are most pronounced in those already affected rather than as primary prevention.
Subgroup Insights: HFpEF vs. HFrEF
Further breakdowns showed greater reductions in heart failure events for patients with heart failure with preserved ejection fraction (HFpEF) compared to heart failure with reduced ejection fraction (HFrEF). Ejection fraction measures the heart's blood-pumping efficiency per contraction. HFpEF, characterized by a stiff heart muscle that impairs filling, currently has limited treatment options, making these results especially promising. While not all subgroups reached statistical significance, they align with emerging data on GLP-1 RAs in HFpEF.
How Oral Semaglutide Works: Mechanisms Behind the Benefits
Semaglutide, an oral GLP-1 RA, mimics the glucagon-like peptide-1 hormone to enhance insulin secretion, suppress glucagon, slow gastric emptying, and promote satiety. These actions improve glycemic control and lead to weight loss, both critical for cardiometabolic health. In heart failure, potential mechanisms include reduced inflammation, improved endothelial function, hemodynamic effects like lowered blood pressure, and direct cardioprotective properties. While the SOUL analysis doesn't pinpoint exact pathways, it complements evidence from trials like SELECT, which explored semaglutide in obesity with prevalent heart failure.
