Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure, but the mechanisms remain incompletely understood. Metabolic remodeling has been proposed as a key mediator. Methods and Results: Myocardial infarction (MI) was induced in cardiomyocyte-specific BDH1 knockout (BDH1-KO) wild-type (WT) mice and in liver-specific Fibroblast Growth Factor-21 knockout (FGF21-KO) mice. Following confirmation of reduced ejection fraction (EF), mice were randomized to empagliflozin (Empa, 10 mg/kg/day) or saline. After 4 weeks, untreated WT mice demonstrated progressive systolic dysfunction (ΔEF: −11.6 ± 6.3%), whereas Empa-treated WT mice showed significant improvement (ΔEF: 9.9 ± 4.3%). This benefit was completely abolished in BDH1-KO mice (ΔEF: −10.5 ± 2.8%) or FGF21-KO mice, suggesting that FGF21 regulation and cardiomyocyte ketone oxidation are required for Empa cardioprotection. In WT and hepatocyte-specific FGF21-KO mice, 1 week of Empa treatment increased cardiac BDH1 expression in WT but not FGF21-deficient mice. In human iPSC-cardiomyocytes, FGF21 induced BDH1 expression, whereas Empa had no direct effect on BDH1. In HepG2 liver cells, Empa increased both FGF21 and BDH1 expression. Conclusions: Empa activates the liver–heart metabolic axis. Loss of cardiomyocyte BDH1 or FGF21 production by the liver abolishes Empa-mediated improvement in post-MI cardiac function, identifying FGF21/ketone metabolism as a key mechanism of SGLT2 inhibitor cardioprotection.