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. These agents have recently shown promise for treating heart failure with preserved ejection fraction (HFpEF), but the exact mechanism remains unclear. This study aims to investigate the effects of EMPA and GLP-1 receptor agonists by examining their impact on metabolic, inflammatory, and oxidative stress-related 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 and ELISA assays revealed that both EMPA and GLP-1 agonists significantly improved insulin resistance signaling pathways in HFpEF patients with diabetes by increasing expression of insulin receptor substrate (IRS-1), 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 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 and augmented the eNOS-NO-sGC-cGMP pathway 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), pro-inflammatory cytokines interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα) in HFpEF patients regardless of diabetes status.
EMPA and GLP-1 agonists further significantly reduced the elevated cardiomyocyte passive stiffness in diabetic and non-diabetic HFpEF patients, restoring stiffness levels closer to those in cardiomyocytes from non-failing controls. Both treatments significantly increased the expression of Ca²⁺ handling proteins, including total and phosphorylated phospholamban and sarcoendoplasmic reticulum calcium ATPase (SERCA), which supports enhanced LV relaxation and diastolic function.
Conclusion: EMPA and GLP-1 receptor agonists showed beneficial effects in HFpEF patients by enhancing insulin signaling, Ca²⁺ handling, reducing oxidative stress, inflammation, cardiomyocyte passive stiffness, and improving diastolic function, making them promising therapeutic options for HFpEF management.
