Potential Therapeutic Effects of Empagliflozin Through Elevated Plasma Citrulline Levels in Heart Failure With Preserved Ejection Fraction

In large clinical trials, sodium-glucose cotransporter 2 (SGLT2) inhibitors have improved prognosis in heart failure with preserved ejection fraction (HFpEF). Although several beneficial pharmacological effects of SGLT2 inhibitors for HFpEF have been suggested, their presumed metabolic pathways remain insufficiently proven. We compared the metabolomic profile, determined using liquid chromatography-mass spectrometry, of 16 patients with HFpEF before and after empagliflozin therapy. Only citrulline levels (expressed as a ratio to methionine sulfone levels) were significantly elevated after therapy (3.57±1.88 vs. 6.47±3.78; P=0.006). Empagliflozin significantly increased citrulline levels in HFpEF patients. Although further studies are needed, it would be intriguing if this metabolite change were related to the cardiovascular protective effects of empagliflozin.