Comparison of the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiac Fibroblast Properties

Recent clinical trials have shown significant cardioprotective effects of antidiabetic sodium-glucose cotransporter 2 inhibitors (SGLT2i), including canagliflozin, empagliflozin, and dapagliflozin. These drugs significantly reduce hospitalizations for heart failure with reduced and preserved ejection fraction in both diabetic and non-diabetic patients. Yet, the mechanisms underlying their protective effects, beyond their glucose-lowering properties, remain poorly understood. This study aimed to elucidate the direct effects of SGLT2i on cardiac fibroblasts, key mediators of myocardial fibrosis, ventricular remodeling, and heart failure. Using primary human cardiac fibroblast cultures, we compared the impact of canagliflozin, empagliflozin, and dapagliflozin on fibroblast properties. All three inhibitors significantly prevented myofibroblast differentiation. Notably, only canagliflozin significantly reduced fibroblast proliferation and migration. While all SGLT2i increased AMP-activated protein kinase (AMPK) phosphorylation, their effects on myodifferentiation were AMPK-independent. In contrast, the effect of canagliflozin on migration was partially dependent on AMPK, as demonstrated using the AMPK inhibitor BAY-3827. These findings reveal distinct cellular effects of individual SGLT2i on cardiac fibroblasts, suggesting heterogeneous potential to modulate extracellular matrix remodeling. Among them, canagliflozin may be more potent in preventing myocardial fibrosis in the context of heart failure.