Direct Cardiac Actions of Sodium Glucose Cotransporter 2 Inhibitors Target Pathogenic Mechanisms Underlying Heart Failure in Diabetic Patients

Abstract

Sodium glucose cotransporter 2 inhibitors (SGLT2i) are the first antidiabetic compounds that effectively reduce heart failure hospitalization and cardiovascular death in type 2 diabetics. Being explicitly designed to inhibit SGLT2 in the kidney, SGLT2i have lately been investigated for their off-target cardiac actions. Here, we review the direct effects of SGLT2i Empagliflozin (Empa), Dapagliflozin (Dapa), and Canagliflozin (Cana) on various cardiac cell types and cardiac function, and how these may contribute to the cardiovascular benefits observed in large clinical trials. SGLT2i impaired the Na⁺/H⁺ exchanger 1 (NHE-1), reduced cytosolic [Ca²⁺] and [Na⁺] and increased mitochondrial [Ca²⁺] in healthy cardiomyocytes. Empa, one of the best studied SGLT2i, maintained cell viability and ATP content following hypoxia/reoxygenation in cardiomyocytes and endothelial cells. SGLT2i recovered vasoreactivity of hyperglycemic and TNF-α-stimulated aortic rings and of hyperglycemic endothelial cells. Anti-inflammatory actions of Cana in IL-1β-treated HUVEC and of Dapa in LPS-treated cardiofibroblast were mediated by AMPK activation. In isolated mouse hearts, Empa and Cana, but not Dapa, induced vasodilation. In ischemia-reperfusion studies of the isolated heart, Empa delayed contracture development during ischemia and increased mitochondrial respiration post-ischemia. Direct cardiac effects of SGLT2i target well-known drivers of diabetes and heart failure (elevated cardiac cytosolic [Ca²⁺] and [Na⁺], activated NHE-1, elevated inflammation, impaired vasorelaxation, and reduced AMPK activity). These cardiac effects may contribute to the large beneficial clinical effects of these antidiabetic drugs.

Keywords: 2 type diabetes; SGLT2 inhibitors; cardiac fibroblast; cardiomyocyte; endothelial cell; heart failure; isolated heart; smooth muscle cell.

FIGURE 1

Mechanisms underlying and linking diabetes and heart failure, caused by cardiac metabolic overload and all other diseases with elevated risk for developing heart failure. These mechanisms include the disturbances of cellular ion levels, energetic disturbances, excessive ROS production and inflammation. Consistent dysregulation of these factors will sequentially instigate contractile, endothelial and mitochondrial dysfunction as well as cell death, as observed in the pathogenesis of heart failure.

FIGURE 2

Direct SGLT2i effects related to diabetes, heart failure and hypoxia/reoxygenation in the cardiomyocyte. SGLT2i exert beneficial cardiac cell effects in by directly regulating ionic homeostasis, mitochondrial respiration and cell viability in the cardiomyocyte. Reported intracellular SGLT2i effects are indicated in red arrow symbols. The relationship between SGLT2i and cardiac SGLT1 in the diabetic or failing cardiomyocyte is unknown (illustrated by dashed arrow line in the figure).

FIGURE 3

Direct SGLT2i effects related to hyperglycemia, inflammation or hypoxia/reoxygenation in vascular cells. SGLT2i directly alter endothelial cells and smooth muscle cells by reducing SGLT2-mediated glucose uptake, ameliorating vasorelaxation, increasing AMPK activity and maintaining cell viability in vascular cells. Reported intracellular SGLT2i effects are indicated in red arrow symbols. The presence of SGLT2 in endothelial cells, the interaction between SGLT1 and SGLT2i, the effects of SGLT2i on AMP/ADP and the attenuation of NF-kB-mediated adhesion molecule expression remains uncertain (illustrated by dashed arrow lines and question marks in the figure).

FIGURE 4

Direct SGLT2i in the LPS-stimulated myofibroblast. SGLT2i increase AMPK activity and inhibit inflammasome activation in the myofibroblast. Reported intracellular SGLT2i effects are indicated in red arrow symbols.