SGLT2 inhibitors provide robust, disease-modifying benefits in HFpEF through pleiotropic mechanisms including improved cardiac energetics, reduced inflammation, and decreased myofilament stiffness.
What are the mechanisms of benefit of SGLT2 inhibitors in heart failure with preserved ejection fraction?
This review highlights the pleiotropic mechanisms by which SGLT2 inhibitors improve cardiac energetics and function in HFpEF, supporting their role as foundational therapy.
For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF.
Pandey et al. (Thu,) conducted a review in Heart failure with preserved ejection fraction (HFpEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors was evaluated. SGLT2 inhibitors provide robust, disease-modifying benefits in HFpEF through pleiotropic mechanisms including improved cardiac energetics, reduced inflammation, and decreased myofilament stiffness.