SGLT2 inhibitors reduce hospitalizations for heart failure with preserved ejection fraction through improved interstitial fluid clearance and preserved plasma volume.
SGLT2 inhibitors improve outcomes in HFpEF by targeting interstitial fluid retention and modulating hemodynamic, renal, and molecular pathways.
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Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all cases of heart failure and is associated with poor outcomes. Large clinical trials have demonstrated that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce hospitalizations for HFpEF and are now recommended as foundational therapy; these benefits have been authenticated in established HFpEF populations (EMPEROR-Preserved, DELIVER), whereas mechanistic and imaging studies have provided insights into the earlier pathogenesis of the disease. However, the precise mechanisms underlying their benefits in HFpEF remain incompletely understood. HFpEF represents a heterogeneous clinical syndrome encompassing multiple phenotypes, including obesity-related, amyloid, and congestion-predominant phenotypes. Among them, interstitial rather than intravascular fluid retention has emerged as a convergent mechanism particularly relevant to HFpEF in which congestion is the main symptom, driving myocardial stiffness, pulmonary congestion, and renal venous hypertension. Moreover, endothelial glycocalyx degradation and lymphatic dysfunction, often associated with comorbidities such as hypertension, diabetes, and obesity, further promote interstitial fluid accumulation, linking systemic inflammation and comorbidities to maladaptive cardiorenal interactions. Unlike conventional diuretics, SGLT2 inhibitors preferentially remove interstitial fluid while preserving plasma volume, potentially through enhanced lymphatic drainage and maintenance of capillary permeability, thereby improving diastolic function and alleviating pulmonary and renal congestion. However, although SGLT2 inhibitors alone provide sustained decongestion with good tolerability, their combination with loop or thiazide diuretics may result in greater interstitial fluid clearance and offer additional benefits in patients with overt congestion. Therefore, by targeting interstitial fluid retention-one of several key mechanisms contributing to HFpEF-SGLT2 inhibitors improve outcomes through integrated modulation of hemodynamic, renal, and molecular pathways. Targeting interstitial fluid retention and cardiorenal interactions in HFpEF: the role of SGLT2 inhibitors.
Masuda et al. (Tue,) reported a other. SGLT2 inhibitors reduce hospitalizations for heart failure with preserved ejection fraction through improved interstitial fluid clearance and preserved plasma volume.