Contemporary medical therapy for heart failure with mildly reduced or preserved ejection fraction.

Treatment for heart failure with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) has evolved significantly in recent years. This period of therapeutic progress follows a span of over two decades during which randomized controlled trials (RCTs) of neurohormonal blockade and other therapies failed to definitively demonstrate clinical benefits. As such, traditionally, management guidelines for HFmrEF and HFpEF were limited to recommendations focused on optimization of volume status with diuretics, management of comorbidities, and consideration of certain medications such as angiotensin receptor-neprilysin inhibitor (ARNi) or steroidal mineralocorticoid receptor antagonists (MRA) to subsets of patients. After definitive results from multiple RCTs, sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently a main pillar in treating HFmrEF and HFpEF in European and American guidelines. However, other therapies, including non-steroidal mineralocorticoid receptor antagonists (nsMRA) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), are proving to be additional effective treatments for HFmrEF and HFpEF and preventing the progression of cardiovascular-kidney-metabolic (CKM) syndrome. There is now increasing justification for combining multiple proven treatments for HFmrEF and HFpEF to maximize potential benefits.