Management of heart failure with preserved ejection fraction: from neurohormonal antagonists to empagliflozin

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent syndrome with multifaceted pathophysiology. All approaches to neurohormonal modulation were shown not to improve survival in HFpEF, despite their well-established efficacy in heart failure with reduced ejection fraction (HFrEF). This might be attributed to suboptimal study design, inadequate diagnostic criteria, or statistical power, but is also likely to reflect a lack of consideration for its clinical heterogeneity. The attention then shifted to the phenotypic heterogeneity of HFpEF, with the ultimate goal of developing therapies tailored to individual patient phenotypes. Recently, the sodium-glucose co-transporter-2 inhibitor (SGLT2i) empagliflozin has been found to reduce the combined risk of cardiovascular death or hospitalization for HF in patients with HFpEF, a result driven by a reduction in HF hospitalizations. This paper recapitulates the journey from the failure of trials on neurohormonal antagonists to the attempts of personalized approaches and the new perspectives of SGLT2i therapy for HFpEF.

Keywords: Clinical trials; HFpEF; Heart failure; Preserved ejection fraction; Therapies.

Fig. 1

Central illustration. Management of HFpEF. A therapeutic strategy targeting the individual phenotypes of HFpEF patients has been proposed. This approach may implement a standardized treatment represented by empagliflozin and possibly other sodium-glucose co-transporter-2 inhibitors (SGLT2i) such as dapagliflozin. Some of the proposed mechanisms of cardiac protection by SGLT2i are reported in the figure. ACEi/ARB, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers; ARNI, angiotensin receptor/neprilysin inhibitor; CAD, coronary artery disease; CKD, chronic kidney disease; GC, guanylate cyclase; HFpEF, heart failure with preserved ejection fraction; MRA, mineralocorticoid receptor antagonists; NO, nitric oxide; PDE-5, phosphodiesterase-5; RAAS, renin–angiotensin–aldosterone system