Portland, OR, February 6, 2026 — A daily oral medication could significantly lower the risk of hospitalization or death for heart failure patients, particularly those with a specific type of the condition, according to new research. It’s a potentially game-changing finding, and it’s sparking debate about how best to personalize treatment for this vulnerable population.
Oral Semaglutide Shows Promise in Heart Failure Subanalysis
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A subanalysis of the SOUL trial suggests oral semaglutide may reduce heart failure events and cardiovascular death, but benefits appear strongest in patients with preserved ejection fraction.
- Over roughly four years, patients with heart failure who took once-daily oral semaglutide experienced a 22% lower risk of hospitalization, urgent visits, or cardiovascular death compared to those on placebo.
- The benefit was most pronounced in patients with heart failure with preserved ejection fraction (HFpEF), showing a 41% risk reduction.
- Researchers found no significant benefit for patients without a prior heart failure diagnosis.
- The findings reinforce the safety of GLP-1 receptor agonists in heart failure patients, addressing previous concerns.
Can an oral GLP-1 medication truly protect against heart failure and cardiovascular death? The answer appears to be yes, but with important nuances. The SOUL trial subanalysis revealed that oral semaglutide, taken daily, was associated with a 22% reduction in the risk of hospitalization, urgent heart failure visits, or cardiovascular death over approximately four years in patients already diagnosed with heart failure.
A Win for Oral Medications and Personalized Treatment
Rodica Pop-Busui, MD, PhD, of Oregon Health & Science University, who led the analysis, emphasized the implications for clinicians. “The findings provide clinicians with additional options when considering how to treat this population of patients,” she said. A key observation, she added, is the demonstrated efficacy of the oral formulation of semaglutide, addressing earlier concerns about absorption and adherence with a daily pill.
“That’s important because having an opportunity to give another medication, particularly to people who are more frail or who may not have the capability to access [and store] injections, offers much broader access to these drugs,” Pop-Busui explained.
The main SOUL analysis previously showed that oral semaglutide reduced the risk of cardiovascular mortality, nonfatal heart attack, or nonfatal stroke by 14% over a mean follow-up of 47.5 months, largely due to a reduction in nonfatal heart attacks. Based on these results, the US Food and Drug Administration expanded the drug’s indication in October 2025 to reduce major adverse cardiovascular events in patients with type 2 diabetes and high cardiovascular risk.
HFpEF Patients See the Biggest Benefit
Barry Borlaug, MD, of the Mayo Clinic, who led an analysis of the SUMMIT trial involving tirzepatide (another GLP-1 agent) and heart failure with preserved ejection fraction (HFpEF), noted that the new subanalysis adds to a growing body of evidence supporting GLP-1 receptor agonists in this patient group.
The SOUL trial data specifically showed a 41% reduction in the risk of a composite heart failure outcome event in HFpEF patients taking oral semaglutide, while those with heart failure with reduced ejection fraction (HFrEF) saw no significant benefit compared to placebo.
“If you really want to individualize treatment, you want to identify those patients that are best positioned to respond,” Borlaug said. “It looks like it’s a more favorable effect in HFpEF. It’s also interesting that in patients without heart failure history there was no evidence—not even really a suggestion—of a benefit, which would suggest that there doesn’t appear to be any kind of a role [for GLP-1s] in terms of preventing heart failure events.”
Borlaug also pointed out that accumulating data suggest even non-obese patients can benefit from GLP-1s without necessarily losing weight.
SOUL Trial Details
The SOUL trial involved 9,650 patients from 444 centers across 33 countries. The subanalysis focused on 2,229 patients (average age 66 years; 30% female) with a heart failure diagnosis at the study’s start: HFpEF in approximately 44%, HFrEF in 26%, and the remaining patients with an unknown subtype.
Among patients with heart failure, the rate of hospitalization or urgent visits was 6.5% in the oral semaglutide group and 8.1% in the placebo group. In those without heart failure at baseline, the rates were 2.0% and 2.1%, respectively. Cardiovascular death rates were 10.1% with semaglutide and 11.7% with placebo in those with heart failure, and 5.1% in both groups without a prior diagnosis.
An analysis of composite heart failure events over three years showed an absolute risk reduction of 3.5% with semaglutide versus placebo (P = 0.01), meaning roughly one event could be prevented for every 29 patients treated.
For major adverse cardiovascular events (MACE), the overall population experienced a 14% reduction with oral semaglutide. However, the benefit was more pronounced in HFpEF patients (32% lower risk), compared to HFrEF patients (7% lower) and those with an unknown subtype (11% lower).
“With all this knowledge and all this evidence that we are generating, we are now in a position to try to apply a more personalized care to our patients.” — Rodica Pop-Busui
Pop-Busui and colleagues theorize that the greater treatment effect in HFpEF may be linked to mechanistic differences between heart failure subtypes. HFpEF, they note, is often driven by coronary microvascular dysfunction and impaired nitric oxide production. Importantly, about one-quarter of all trial participants—regardless of heart failure status or treatment assignment—were already taking sodium-glucose co-transporter-2 (SGLT2) inhibitors at the study’s outset.
“Being able to see the benefits regardless of the SGLT2 use demonstrates the potential benefits of adding oral semaglutide [because] even in people who have been treated with another agent [you] still see a reduction in these hard outcomes,” she added.
No significant interactions were observed between the effects of oral semaglutide and the use of loop diuretics, mineralocorticoid receptor antagonists, or SGLT2 inhibitors. Adverse safety events were numerically lower in HFpEF patients receiving oral semaglutide compared to placebo.
Pop-Busui acknowledged that cost is always a consideration with GLP-1 agents, but also highlighted the potential for long-term cost savings by reducing the risk of adverse events and potentially scaling back on other medications.
“With all this knowledge and all this evidence that we are generating, we are now in a position to try to apply a more personalized care to our patients . . . and there are lots of opportunities to integrate tools in the electronic medical record that can give clinicians a more comprehensive view of what’s happening with a given patient at a given time [to help] make treatment choices,” she added.
