Cardiorenal Hemodynamic Effects of SGLT2 Inhibitors Across Heart Failure Phenotypes: A Structured Narrative Review

Area of Science:

• Cardiology
• Nephrology
• Pharmacology

Background:

• Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are established treatments for heart failure with reduced ejection fraction (HFrEF).
• Their application is expanding to other heart failure phenotypes, but the exact mechanisms of their cardiorenal benefits remain unclear.
• The contribution of direct hemodynamic effects versus surrogate markers needs further elucidation.

Purpose of the Study:

• To review and evaluate the existing evidence on the cardiorenal effects of SGLT2 inhibitors in various heart failure phenotypes.
• To differentiate between hemodynamic effects and other mechanisms contributing to clinical outcomes.
• To synthesize findings from hemodynamic, renal physiology, biomarker, and clinical studies.

Main Methods:

• A narrative review of literature published between 2012 and 2026.
• Searches conducted in PubMed, Scopus, and Web of Science databases.
• Inclusion of randomized controlled trials, prospective studies, mechanistic studies, biomarker studies, and meta-analyses.
• Classification of evidence by study type: hemodynamic, renal physiology, surrogate markers, and clinical.

Main Results:

• SGLT2 inhibitors (dapagliflozin, empagliflozin) demonstrate efficacy in reducing heart failure exacerbations and cardiovascular deaths in HFrEF.
• Benefits in HFmrEF and HFpEF include reduced risk of heart failure-related complications and hospitalizations.
• Mechanisms include osmotic diuresis, natriuresis, restored tubuloglomerular feedback, blood pressure reduction, and renal function maintenance.
• Impact on myocardial bioenergetics, inflammation, endothelial health, and remodeling is primarily supported by indirect evidence.

Conclusions:

• SGLT2 inhibitors provide consistent clinical and renal benefits across heart failure phenotypes.
• The observed benefits cannot be attributed solely to a single hemodynamic mechanism.
• While biomarker improvements and clinical outcomes support biological plausibility, direct invasive hemodynamic data are limited.