Effects of oral semaglutide on heart failure outcomes in people with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease participating in SOUL trial

Abstract Background/Introduction In the SOUL trial, once-daily oral semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), reduced the risk of major adverse cardiovascular events (MACE) by 14% compared with placebo in people with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD). Purpose To evaluate the effect of oral semaglutide versus placebo on heart failure (HF) outcomes in the SOUL trial in relation to baseline HF history (no HF, HF with preserved ejection fraction HFpEF, or HF with reduced ejection fraction HFrEF) and other baseline characteristics. Methods In SOUL, 9650 participants with T2D (HbA1c 6.5–10.0%) and ASCVD and/or CKD, all receiving standard of care, were randomised to oral semaglutide or placebo. Prespecified and centrally adjudicated HF outcomes included time to first occurrence of HF requiring hospitalisation, urgent HF visit, or cardiovascular (CV) death (3-point composite outcome). Cox proportional hazard models with treatment as a fixed factor were used to estimate the hazard ratio (HR) for comparing oral semaglutide with placebo. Results Mean (±SD) follow-up was 47.5±10.9 months. At baseline, mean (±SD) age was 66.1±7.6 years, 28.9% were female, and 23.1% had HF (10.3% with HFpEF; 6.1% with HFrEF, and 6.7% unknown). Participants with HF at baseline had a greater BMI (31.8 vs 29.8 kg/m²; p0.0001), HbA1c (7.9 vs 7.7 %; p0.0001), diastolic blood pressure (78.0 vs 77.0 mmHg; p=0.0056), and high-sensitivity C-reactive protein (2.4 vs 1.9 ug/L; p0.0001) versus participants without HF at baseline. The HR with oral semaglutide for the primary MACE outcome were 0.83 (95% CI: 0.68–1.01) and 0.86 (95% CI: 0.75–0.98) in participants with vs without HF, respectively. In the overall population, oral semaglutide demonstrated a non-significant 10% reduction in risk of the composite outcome (HR 0.90; 95% CI 0.79–1.03). Among participants with HF at baseline, oral semaglutide significantly reduced the risk of the 3-point composite HF outcome (HR 0.78; 95% CI 0.63–0.96; p=0.0177) with no significant effect among participants without HF at baseline (Figure 1; interaction p-value=0.06). There was a trend towards more effective reduction in risk of the 3-point composite HF outcome with oral semaglutide versus placebo in participants with HFpEF and lower NYHA class, with relative risk reductions of 41% in HFpEF and 47% in NYHA Class I (Figure 2). Among participants with HF, serious adverse event proportions were similar with oral semaglutide (53.8%) and placebo (57.1%). Conclusion In individuals with T2D, ASCVD and/or CKD, oral semaglutide versus placebo reduced the risk of HF requiring hospitalisation, urgent HF visit, or CV death in those with a history of HF. This was attributed mostly to those with HFpEF and lower NYHA class, with no indication of harm in HFrEF. These data support the initiation of oral semaglutide in people with T2D and HF for reducing HF events.