Heart failure (HF) represents a prevalent and prognostically important complication in individuals with type 2 diabetes (T2D), contributing substantially to morbidity and mortality. Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefit in T2D, the impact of the once-daily oral semaglutide formulation on HF outcomes has not been fully characterized. The SOUL trial was a multinational, randomized, double-blind, placebo-controlled cardiovascular outcomes study in adults with T2D and atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD), originally designed to assess major adverse cardiovascular events (MACE). This secondary analysis evaluates the effect of oral semaglutide on HF outcomes according to HF status at baseline.
A total of 9 650 participants (median age 66.0 years; ~29% women) were randomized to once-daily oral semaglutide (up to 14 mg) or placebo, both in addition to standard of care, and followed for a mean of 47.5 months. Baseline HF status was determined by investigator report, with 2 229 participants (23.1%) having a history of HF at randomization, including HF with preserved ejection fraction (HFpEF), HF with reduced ejection fraction (HFrEF), or unknown subtype. The primary outcome for this analysis was a pre-specified composite HF outcome: first occurrence of HF hospitalization, urgent HF visit, or cardiovascular death. Cox proportional hazards models were used to compare risk between treatment groups, stratified by baseline HF status.
Among participants with baseline HF, oral semaglutide was associated with a lower risk of the composite HF outcome compared with placebo, despite a high background use of SGLT2 inhibitors and mineralocorticoid receptor antagonists; this benefit was most apparent in the HFpEF subgroup. In contrast, participants without HF at baseline did not show a consistent HF benefit with oral semaglutide. There were no meaningful increases in serious adverse events between treatment arms in either subgroup.
In this secondary analysis from the SOUL trial, oral semaglutide significantly reduced the risk of HF events in people with T2D and a history of HF—particularly HFpEF—without increasing serious adverse events, while offering limited HF benefit in those without prior HF. These findings support a potential role for oral semaglutide in reducing HF risk in T2D patients with established HF, providing evidence to inform clinical decision-making regarding therapy selection in high-risk individuals.
Link: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2844096
