Key Points:
- Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of adverse clinical events, especially in patients with overweight, obesity, or type 2 diabetes.
- Whether semaglutide reduces heart failure (HF) events in patients with HFpEF remains an unresolved and important clinical question.
- This study aimed to investigate whether semaglutide reduces the risk of adverse HF events by conducting a pooled, patient-level analysis of participants with HFpEF from the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials.
On August 30, 2024 the results of “Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials” were presented at the ESC Congress 2024 with simultaneous publication in Lancet.
HFpEF is associated with high burden of symptoms, risk of cardiovascular (CV) death, and worsening HF events, with limited efficacious treatment options.
The STEP-HFpEF and STEP-HFpEF DM trials showed that semaglutide 2.4 mg compared to placebo improved HF-related symptoms and physical limitations, and reduced body weight in patients with obesity-related HFpEF, both with and without diabetes.
The SELECT trial randomized 17,604 patients with ASCVD and overweight or obesity without diabetes (12.9% of patients had HFpEF) to receive semaglutide 2.4 mg or placebo. Patients receiving semaglutide had a reduced incidence of CV death, nonfatal myocardial infarction, or nonfatal stroke.
The FLOW trial randomized 3,533 patients with diabetes and chronic kidney disease (9.2% of patients had HFpEF) to receive semaglutide 1.0 mg or placebo and found that semaglutide reduced the risk of clinically important kidney outcomes and CV death.
The objective of this post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials was to investigate whether semaglutide reduces the risk of a composite endpoint of CV death or worsening HF events (defined as hospitalizations and urgent visits due to heart failure), as well as worsening HF events alone and CV death alone, using a pooled, patient-level analysis of participants with HFpEF across the four trials above-mentioned trials.
Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). Both groups showed balanced demographics including average age of 64 years, just under 40% female, 2/3 of patients with NYHA class 2, and majority of patients with overweight or obesity and EF ³50%.
Findings of the study include a significant reduction in risk of the composite endpoint in the semaglutide group [5·4%] vs placebo group [7·5%] (HR 0·69 [95% CI 0·53–0·89]; p=0·0045) as well as significant reduction in worsening heart failure events alone [2·8%] vs placebo [4·7%] (HR 0·59 [0·41–0·82]; p=0·0019); however, no significant reduction in CV death alone was found. Furthermore, semaglutide was well tolerated, with fewer serious adverse events than placebo. Although there was potential heterogeneity in the magnitude of benefit seen across the four studies, the point estimates for each individual endpoint were favorable for semaglutide in all of the trials separately. This benefit remained consistent across subgroups including across EF and those receiving SGLT2is or MRAs, however heterogeneity was seen across severity of obesity in which a larger treatment effect was observed in those with a BMI ³35 kg/m2.
Dr. Mikhail Kasiborod, from St Luke’s Mid America Heart Institute, Kansas City, USA, concluded: “These data support semalglutide as an efficacious treatment option in patients with heart failure and preserved ejection fraction, not just in terms of improvement in symptoms and physical limitations as shown previously in the STEP-HFpEF and STEP-HFpEF DM trials, but also now in reducing clinical events.”