“The Dynamic Duo”: The New Management of Drug Treatment for Heart Failure with Mildly Reduced or Preserved Ejection Fraction

Abstract The “Fantastic Four,” a term coined in 2021 to refer to the four key drug pillars in the treatment of heart failure with reduced ejection fraction (beta-blockers, renin-angiotensin system and neprilysin inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors, or SGLT2 inhibitors), has demonstrated excellent performance in reducing morbidity and mortality in this setting. However, in heart failure with mildly reduced or preserved ejection fraction, the same benefits were not observed with this combined treatment where, for many years, management in this context was limited to diuretics and comorbidity control. Recently, however, new therapeutic options have emerged, demonstrating effectiveness in reducing cardiovascular outcomes in this specific group: the “Dynamic Duo”—comprising SGLT2 inhibitors and Finerenone—has shown promising results, alongside the introduction of semaglutide as a potential “wild card” treatment for patients with obesity. Despite the ongoing need for therapies that significantly reduce overall mortality, these new treatments have effectively lowered hospitalization rates and improved symptoms in such patients. As a result, a new era in heart failure management is beginning.