Established and emerging pharmacologic options and unmet needs in HFpEF and HFmrEF.

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 ejection fraction ≥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.