Sodium-glucose cotransporter 2 inhibitors (SGLT2i) like empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin, and sotagliflozin (both a sodium-glucose cotransporter 1 inhibitor [SGLT1i] and SGLT2i), are drugs that inhibit the action of sodium-glucose cotransporters in the proximal renal tubule and/or the intestine. Therefore, causing natriuresis, glucosuria, and reduced intestinal glucose absorption. Besides this mechanism of action, which determines glycemia reduction, there are multiple extra-glycemic mechanisms in extensive research in humans in-vivo, which, beyond in-vitro or experimental studies, is dissecting the mechanisms explaining the initially unanticipated and ultimately incredibly significant and welcomed cardiac and nephroprotective results of these drugs. This article centers on the cardioprotective effects of empagliflozin, namely, a reduction of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure, among others. These effects were demonstrated in the EMPA-REG and EMPEROR-Reduced clinical outcome trials, which will be initially summarized to later frame them in the results of the mechanistic trials EMPA-HEART, EMPIRE-HF (including sub-studies), EMPA-TROPISM, and “EMPA-PIG.” The mechanistic trials showed favorable changes in the left ventricular mass index, left ventricular end-systolic and end-diastolic volumes, extracellular and intravascular volumes, glomerular filtration rate, myocardial remodeling, among others. These were investigator-initiated studies to go beyond in-vitro and experimental evidence. The results and analysis allow us to understand myocardial energy remodeling as an intrinsic myocardial mechanism that underlies anatomical, functional, and neurohormonal myocardial remodeling. Together with other systemic actions, predominantly renal (not discussed in this article), contribute significantly to this drug's clinical benefit.