Oral Semaglutide May Reduce Heart Failure Risk in Patients With T2D

Oral semaglutide may reduce heart failure (HF) events in patients with type 2 diabetes (T2D) and HF, according to a secondary analysis of the phase 3b SOUL trial.1

HF is among the most prevalent cardiovascular complications in patients with T2D, affecting roughly 57% of the 462 million individuals with T2D worldwide. Patients with T2D and HF also have a higher risk for hospitalization and mortality compared to those with T2D without HF. Given these factors, several previous clinical trials have evaluated the efficacy of multiple GLP-1 receptor agonists to reduce the risk of major adverse cardiovascular events.1

“The aim of this secondary analysis of the SOUL trial was to evaluate the effect of oral semaglutide compared with placebo on HF and ASCVD outcomes in participants with or without a history of HF at baseline,” Rodica Pop-Busui, MD, PhD, professor and chief of the division of endocrinology, diabetes, and clinical nutrition, department of medicine, Oregon Health and Science University, and colleagues wrote.1

SOUL was a double-blind, randomized, placebo-controlled, event-driven, phase 3b cardiovascular outcomes trial conducted across 444 centers in 33 countries. It compared oral semaglutide 14 mg daily to placebo, both of which were administered on top of standard of care, among patients with T2D and established atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD).2

A total of 9650 patients were enrolled in the SOUL trial and randomly assigned in a 1:1 ratio to once-daily treatment with either oral semaglutide or matching placebo. To avoid adverse gastrointestinal symptoms due to semaglutide treatment, patients in both arms followed a blinded dose-escalation regimen, beginning with 3 mg oral semaglutide or placebo for 4 weeks, followed by 7 mg for 4 weeks and then 14 mg for the remainder of the trial. Trial visits occurred at weeks 4, 8, and 13 after randomization and roughly every 13 weeks afterwards.2

The SOUL trial ultimately saw primary-outcome events occur in 579 of the 4825 participants in the oral semaglutide group versus 668 of the 4825 participants in the placebo group (HR, 0.86; 95% CI, 0.77-0.96; P = .006). Confirmatory secondary outcomes did not differ significantly between the groups.3

This secondary analysis included a main prespecified outcome of time to the first occurrence of a centrally adjudicated composite HF outcome, comprising HF events – including HF hospitalization or urgent HF visits – or cardiovascular death. Changes from baseline to week 104 of SOUL in clinical parameters, including HbA1c, body weight, high-sensitivity C-reactive protein (hsCRP), and systolic and diastolic blood pressure, were also prespecified secondary outcomes.1

Of the 9650 patients enrolled in SOUL, 2229 (23.1%) had a history of HF – 991 with preserved ejection fraction (HFpEF), 592 with reduced ejection fraction (HFrEF), and 646 with an unknown subtype. Among participants with HF at baseline, the hazard ratio for risk of the composite HF outcome with oral semaglutide versus placebo was 0.78 (95% CI, 0.63-0.96), and was 1.01 (95% CI, 0.84-1.2) for those without HF at baseline (P = .06).1

Among HF subtypes, patients with HFpEF had an HR of 0.59 (95% CI, 0.39-0.86), while those with HFrEF saw an HR of 0.98 (95% CI, 0.7-1.38). The team found no heterogeneity in the risk reduction of major adverse cardiovascular events with oral semaglutide in patients with a history of HF (HR, 0.83; 95% CI, 0.68-1.01) or without (HR, 0.86; 95% CI, 0.75-0.98) (P = .77). Serious adverse event occurrence among patients with HF was similar with oral semaglutide (n = 594) and placebo (n = 642).1

“Given the high prevalence of HF (and particularly HFpEF) in people with T2D and in those with obesity, these data provide additional information for clinicians when considering therapy choices and impact on HF outcomes in people with or without known HF,” Pop-Busui and colleagues wrote. “Compared with those without T2D, individuals with HFpEF and T2D exhibit worse prognosis, likely driven by higher burden of comorbidities, underlying microvascular dysfunction, insulin resistance, autonomic imbalance, and mitochondrial abnormalities.”1

References

1. Pop-Busui R, Rasmussen S, Deanfield JE, et al. Oral semaglutide and heart failure outcomes in persons with type 2 diabetes. JAMA Internal Medicine. Published online February 2, 2026. doi:10.1001/jamainternmed.2025.7774

2. McGuire DK, Busui RP, Deanfield J, et al. Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial. Diabetes, Obesity and Metabolism. 2023;25(7):1932-1941. doi:10.1111/dom.15058

3. McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. New England Journal of Medicine. 2025;392(20):2001-2012. doi:10.1056/nejmoa2501006