Established and emerging pharmacologic options and unmet need in HFpEF and HFmrEF

Published Feb 19, 2026ESC heart failure

Current and new drug treatments and remaining challenges in heart failure with preserved or mildly reduced pumping ability

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Abstract

Clinical trials indicate that sodium-glucose cotransporter 2 inhibitors may improve outcomes in heart failure with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF).

Few effective therapies exist for heart failure subtypes, particularly HFpEF and HFmrEF, despite their high prevalence.
Renin-angiotensin system inhibitors and other traditional treatments have not shown significant effects on primary outcomes for HFpEF or HFmrEF, although some may reduce hospitalization or mortality risk.
Beta blockers may be advantageous for patients with HFmrEF.
Finerenone has been associated with reduced heart failure events and cardiovascular deaths in patients with heart failure and ejection fraction of 40% or higher.
Novel treatments could be tailored to specific patient profiles, such as those with obesity or chronic kidney disease.
Preliminary trials of glucagon-like peptide-1 receptor agonists for HFpEF with obesity suggest improvements in hospitalization rates and quality of life.

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A decline in mortality due to heart failure (HF) with reduced ejection fraction (HFrEF) has been attributed to effective guideline-directed medical therapies. But few effective therapies are available for HF with preserved ejection fraction (HFpEF), despite a high burden of HF events, or for HF with mildly reduced ejection fraction (HFmrEF). Novel therapies are needed for these HF subtypes. Clinical trials have demonstrated the efficacy of sodium-glucose cotransporter 2 inhibitors for improving outcomes in HFpEF and HFmrEF. While renin-angiotensin system inhibitors, angiotensin receptor/neprilysin inhibitors, and steroidal mineralocorticoid receptor antagonists for HFpEF or HFmrEF have not demonstrated effects on primary trial outcomes, sub-analyses from large HF trials suggest they may reduce the risk of hospitalization for HF or mortality. Beta blockers may be beneficial for HFmrEF. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, reduced HF events and cardiovascular deaths in participants with HF and EF ≥40% in the FINEARTS-HF trial, and is under evaluation for HFpEF and HFmrEF in the REDEFINE-HF and CONFIRMATION-HF trials. As treatment for HFpEF and HFmrEF may be impacted by comorbidities, novel treatments could be tailored to specific phenotypes such as obesity and chronic kidney disease. Trials of glucagon-like peptide-1 receptor agonist (GLP-1 RA), semaglutide, and dual glucose-dependent insulinotropic polypeptide receptor agonist/GLP-1 RA, tirzepatide, for HFpEF with obesity, observed an impact on HF hospitalization events and quality of life. Trials of selective mineralocorticoid modulator, balcinrenone, and aldosterone synthase inhibitor, vicadrostat, will address key evidence gaps and help improve outcomes for patients with HFpEF and HFmrEF.

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Established and emerging pharmacologic options and unmet need in HFpEF and HFmrEF

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