Oral GLP-1s Benefit HF Patients: SOUL Trial Subanalysis

In a significant subanalysis from the SOUL trial, an oral GLP-1 medication—once-daily oral semaglutide (Rybelsus; Novo Nordisk)—demonstrated meaningful benefits for heart failure (HF) patients. Specifically, it lowered the risk of hospitalization or urgent visits for HF, as well as cardiovascular (CV) death, in individuals with HF at baseline who also had diabetes and atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD). This finding underscores the potential of oral GLP-1 receptor agonists in managing complex cardiometabolic conditions.

Understanding the SOUL Trial and Its HF Subanalysis

The SOUL trial, which randomized 9,650 patients from 444 centers across 33 countries, primarily evaluated oral semaglutide's impact on major adverse cardiovascular events (MACE) in patients with type 2 diabetes and established CV disease or multiple risk factors. The subanalysis zeroed in on 2,229 patients (mean age 66 years; 30% female) diagnosed with HF at baseline: approximately 44% had HF with preserved ejection fraction (HFpEF), 26% had HF with reduced ejection fraction (HFrEF), and the remainder had unknown subtype.

Compared with placebo, the risk of the composite outcome—time to first occurrence of HF hospitalization, urgent HF visit, or CV death—was 22% lower over approximately 4 years of follow-up in those with HF at baseline taking oral semaglutide. Notably, there was no reduction in this HF-oriented endpoint among patients without HF at baseline.

Breakdown of HF Events and CV Death Rates

• The rate of HF hospitalization or urgent HF visit was 6.5% in the oral semaglutide group versus 8.1% in placebo among HF patients; it was 2.0% versus 2.1% in those without HF.
• CV death rates were 10.1% with oral semaglutide and 11.7% in placebo for HF patients at baseline, and 5.1% in both groups without HF.
• Through 3 years, the HF composite outcome showed an absolute risk reduction of 3.5% with semaglutide versus placebo (P = 0.01), with a number needed to treat (NNT) of 29 to prevent one event.

Greater Protection in HFpEF vs. HFrEF

Those with preserved EF seemed to get more protection against HF events/CV death than those with reduced or unknown EF. In HFpEF patients, oral semaglutide reduced the risk of the first composite HF outcome by 41% compared with placebo, while there was no significant reduction in HFrEF patients.

For MACE (CV mortality, nonfatal MI, or nonfatal stroke), the overall population in the main SOUL analysis saw a 14% reduction with oral semaglutide at a mean follow-up of 47.5 months, driven by reductions in nonfatal MI. In the HF subgroup, MACE risk was 32% lower in HFpEF, 7% lower in HFrEF, and 11% lower in unknown HF subtype versus placebo.

Expert Perspectives on Oral Semaglutide in HF

"Another important observation is that the efficacy of the oral formulation of semaglutide has been now demonstrated. There were some concerns that with a daily oral medication, absorption or compliance issues may affect [its] efficacy on important outcomes," said Rodica Pop-Busui, MD, PhD (Oregon Health & Science University, Portland, OR), who led the analysis. "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 emphasized that prior concerns about GLP-1s' safety in HF patients have been alleviated: "there were some concerns about the potential effect of GLP-1s in people with heart failure regarding safety and that has obviously not been the case."

Barry Borlaug, MD (Mayo Clinic, Rochester, MN), who led the SUMMIT trial analysis showing tirzepatide (Zepbound; Eli Lilly) benefits in HFpEF and obesity, noted this subanalysis adds to evidence for GLP-1 receptor agonists in HF. "If you really want to individualize treatment, you want to identify those patients that are best positioned to respond," he 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 highlighted that data support GLP-1 benefits in non-obese patients, with no evidence of unnecessary weight loss.

Mechanisms Behind the Benefits: Why HFpEF Responds More

Pop-Busui and colleagues theorize that the larger treatment effect in HFpEF relates to mechanistic differences by HF subtypes. HFpEF is often driven by coronary microvascular dysfunction and compromised nitric oxide signaling, areas where GLP-1 receptor agonists like semaglutide may exert beneficial effects through improved endothelial function, reduced inflammation, and enhanced cardiac energetics.

About one-quarter of SOUL patients were on sodium-glucose co-transporter-2 (SGLT2) inhibitors at baseline, regardless of HF status or treatment arm. No meaningful interactions were seen between oral semaglutide's effects on HF outcomes and use of loop diuretics, mineralocorticoid receptor antagonists, or SGLT2 inhibitors. "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," Pop-Busui added.

Adverse safety events were numerically lower in HFpEF patients on oral semaglutide compared with placebo, addressing historical concerns about GLP-1s in HF.

Practical Guidance for Patients and Clinicians

For patients with type 2 diabetes, ASCVD/CKD, and HF—especially HFpEF—oral semaglutide offers a convenient alternative to injectables. In October 2025, the US Food and Drug Administration expanded Rybelsus' indication to reduce MACE in patients with type 2 diabetes and high CV risk based on SOUL results.

Discuss with your doctor if oral semaglutide fits your profile, particularly if injections are impractical due to frailty or access issues. Track symptoms like HF exacerbations or side effects using apps like Shotlee, which can log medication adherence, weight changes, and urgent visit triggers for better shared decision-making.

Cost is a factor, but Pop-Busui notes potential long-term savings: "the other part of the conversation is the potential to cut costs down the road by not only reducing the risk for events in this population, but also scaling back on some of their medications."

Key Takeaways from the SOUL HF Subanalysis

• Oral semaglutide reduced HF composite outcomes by 22% and showed 41% risk reduction in HFpEF.
• No preventive benefit in patients without baseline HF.
• Safety confirmed; benefits independent of SGLT2 or other HF therapies.
• Supports personalized care: "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," said Pop-Busui.
• Integrate tools in electronic medical records for comprehensive patient views to optimize treatment.

What This Means for Patients with HF and Diabetes

This subanalysis positions oral GLP-1s as a valuable tool in HF management, particularly for HFpEF, expanding access beyond injectables. While not a HF preventive, it offers robust event reduction in at-risk groups. Consult your healthcare provider to weigh benefits against individual factors like EF status and comorbidities.

In summary, the SOUL subanalysis reinforces oral semaglutide's role in reducing HF hospitalizations, urgent visits, and CV death, paving the way for tailored therapies in cardiometabolic care.