We show here that SGLT2i directly activate pantothenate kinase 1 (#PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin #B5) to coenzyme-A (CoA). Using stable-isotope infusion studies, we show that SGLT2i promote pantothenate consumption, activate CoA synthesis, rescue decreased levels of #CoA in human failing hearts, providing a likely explanation for the remarkable clinical benefits of #SGLT2i. https://www.biorxiv.org/content/10.1101/2024.07.26.605401v1