PROJECT SUMMARY Each year over 124,000 individuals initiate hemodialysis and there are over 490,000 patients receiving maintenance hemodialysis for end-stage kidney disease in the United States. Cardiovascular (CV) disease remains the leading cause of death, while each patient has 1.6 hospitalizations annually and around 34% of patients are readmitted within 30 days. Individuals initiating hemodialysis generally experience further decline in residual kidney function, a potent risk factor for further morbidity and mortality. Despite the massive burden of morbidity and morality, few therapies have been tested, with even fewer proven, to reduce the risk of mortality in this high-risk population. The development of sodium-glucose co-transporter 2 inhibitors (SGLT2i) has heralded a paradigm-shift in nephrology, with dedicated trials in patients with chronic kidney disease (CKD) reporting substantial reductions in the risk of CKD progression, proteinuria, and CV outcomes, including hospitalization for heart failure. Despite initial guidelines suggesting avoiding initiation of SGLT2i in individuals with moderate or severe CKD, in whom the glucose-lowering effects are attenuated, multiple trials, as well as our own analyses, demonstrate that the effects on glycemic control only mediate a small portion of the overall clinical benefits. Furthermore, SGLT2i provide potent kidney and CV risk reduction compared with placebo even in the absence of diabetes, while they are safe and effectively prevent morbidity and mortality in patients with advanced CKD. However, the safety and efficacy of these therapies have yet to be tested in end stage kidney disease patients requiring initiation of hemodialysis. We therefore propose a phase II, randomized, placebo-controlled, parallel group pilot clinical trial to test the safety and efficacy of empagliflozin among adult patients initiating hemodialysis. The results of our study will inform the design and development of a larger multi-center outcomes trial, which is urgently needed to address the unacceptably high rates of CV disease and associated mortality in this population. Our proposals are clinically relevant, feasible, innovative, and are supported by robust literature in non-hemodialysis patients with CKD. Building on the underlying pathophysiology, the clinical unmet need, and our collective experience in performance of clinical trials, our proposals have the potential to inform and improve the care of patients requiring initiation of HD globally.