Oral semaglutide reduced serious heart failure–related events in people with type 2 diabetes, a new secondary analysis of the SOUL trial published in JAMA Internal Medicine found. The benefit was strongest among participants with heart failure with preserved ejection fraction (HFpEF), a form of heart failure that has been difficult to treat.
Background and trial
People with type 2 diabetes face a high lifetime risk of heart failure, and the conditions frequently coexist. Prior evidence that GLP-1 receptor agonists improve cardiovascular outcomes came mainly from injectable formulations; whether oral formulations would confer similar benefits was unclear.
SOUL was a large randomized trial that tested daily oral semaglutide versus placebo in people with type 2 diabetes. The trial found that oral semaglutide lowered the risk of major adverse cardiovascular events (MACE: heart attack, stroke, and cardiovascular death). The published secondary analysis focused on heart failure–related outcomes.
Participants averaged 66 years of age and were 29% female. About one-quarter (2,229 participants) had preexisting heart failure at baseline: 44% of those had HFpEF, 27% had heart failure with reduced ejection fraction (HFrEF), and 29% had an unclassified subtype. After an average follow-up of four years, those with preexisting heart failure who received oral semaglutide experienced a 22% lower risk of serious heart failure–related outcomes (hospitalization or death) compared with placebo. The benefit was concentrated in the HFpEF subgroup, which showed a 41% lower risk, while no statistically significant benefit was seen in participants with HFrEF or in those without heart failure at baseline.
Interpretation
Experts called the findings confirmatory and encouraging. Nancy K. Sweitzer, editor-in-chief of Circulation: Heart Failure, noted the results reinforce the clinical importance of GLP-1 therapies for patients with HFpEF and obesity and said additional evidence may help with insurance coverage. Cheng-Han Chen, medical director of the Structural Heart Program at MemorialCare Saddleback Medical Center, described the results as “extremely encouraging” given the limited effective treatments for HFpEF.
Safety and implications
There was no safety signal in the analysis: serious adverse event rates were similar between the semaglutide and placebo groups. Because oral semaglutide can be easier for some patients to tolerate than injections, it may offer a new pharmacological option for people with type 2 diabetes and HFpEF.
Economic and clinical context
Heart failure carries a large economic burden—annual U.S. health care costs already exceed $30 billion and are projected to reach at least $70 billion by 2030. More than one in five people with type 2 diabetes have heart failure, a prevalence that is rising.
GLP-1 drugs such as semaglutide and the dual GIP/GLP-1 agonist tirzepatide are indicated for diabetes and obesity and have shown cardiovascular and heart-failure benefits in multiple trials. Notable related trials include SUMMIT, which showed a strong reduction in heart failure events with tirzepatide among participants with HFpEF, and STEP-HFpEF DM, where semaglutide reduced heart failure–related symptoms and physical limitations in people with HFpEF and diabetes.
Why HFpEF may respond
HFpEF differs from HFrEF in that the ejection fraction is typically preserved (about 50% or greater), but the left ventricle is stiff and does not fill properly. HFpEF is heterogeneous and can be driven by several conditions—obesity, hypertension, diabetes, atrial fibrillation, and renal disease among them. Treatments that improve diabetes control and cause weight loss, like semaglutide, may therefore reduce the risk or severity of HFpEF-related events by addressing these underlying contributors.
Limitations and next steps
The heart-failure findings derive from a secondary analysis, and most prior cardiovascular data for GLP-1 benefits came from injectable agents. While the SOUL results are the first large randomized evidence for oral semaglutide’s effects on heart failure in people with type 2 diabetes, further research will help clarify which patients benefit most and how oral GLP-1s compare directly with other therapies.