https://doi.org/10.1007/s00392-025-02625-4
1Kath. Klinikum Bochum Institut für Forschung und Lehre (IFL), St. Josef Hospital Bochum, Deutschland; 2Klinikum der Ruhr-Universität Bochum Medizinische Klinik II, Kardiologie Bochum, Deutschland; 3Academic Medical Center University of Amsterdam Department of Cardiology Amsterdam, Niederlande; 4Kath. Klinikum Bochum Cellular Physiology Bochum, Deutschland
ABSTRACT
Introduction: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) like empagliflozin (EMPA) and glucagon-like peptide-1 (GLP-1) receptor agonists are primarily anti-diabetic drugs. Recently, these agents have shown promise as treatments for heart failure with preserved ejection fraction (HFpEF), though the exact mechanisms remain unclear. This study aims to elucidate the cardioprotective effects of EMPA and GLP-1 receptor agonists by examining their impact on metabolic and inflammatory signaling pathways in HFpEF patients, both with and without diabetes.
Methods and Results: Left ventricular (LV) myocardial biopsies from HFpEF patients with diabetes, HFpEF patients without diabetes, and non-failing controls (n=8) were examined. Immunoblotting revealed that both EMPA and GLP-1 agonists significantly improved insulin resistance signaling pathways in HFpEF patients with diabetes, reducing the elevated expression of phosphoinositide-3-kinase (PI3K), total and phosphorylated protein kinase B (AKT), and total and phosphorylated mammalian target of rapamycin (mTOR) to levels similar to those in non-failing controls. This improvement was accompanied by increased expression of insulin receptor substrate (IRS-1) and enhanced activity of glucose transporter (GLUT4) and fatty acid transporter (CD36) in membrane fractions of diabetic HFpEF myocardial tissue post-treatment.
Additionally, EMPA and GLP-1 agonists significantly increased endothelial nitric oxide synthase (eNOS) expression in both diabetic and non-diabetic HFpEF patients, which may help mitigate oxidative stress. These agents also played a critical role in reducing inflammation by significantly lowering the expression of nuclear factor-kB (NF-kB), p38 mitogen-activated protein kinase (p38 MAPK), and pro-inflammatory cytokine interleukin-6 (IL-6) in HFpEF patients regardless of diabetes status.
EMPA and GLP-1 agonists further improved Ca²⁺ handling proteins, significantly increasing the expression of total and phosphorylated phospholamban and sarcoendoplasmic reticulum calcium ATPase (SERCA), which supports enhanced LV relaxation and diastolic function. Both treatments also significantly decreased the elevated passive stiffness observed in cardiomyocytes from HFpEF patients (both with and without diabetes), aligning stiffness levels closer to those in cardiomyocytes from non-failing controls.
Conclusion: EMPA and GLP-1 receptor agonists showed cardioprotective effects in HFpEF by enhancing insulin signaling, reducing oxidative stress and inflammation, and improving Ca²⁺ handling. These treatments also reduced cardiomyocyte stiffness, supporting improved diastolic function and making them promising therapeutic options for HFpEF management