PROJECT ABSTRACT Cardiovascular (CV) disease is the leading cause of mortality in end-stage kidney disease (ESKD), accounting for 55% of total deaths. In particular, sudden cardiac death poses the greatest threat to the dialysis population. A diagnosis of heart failure (HF), a highly prevalent complication that is associated with an 80% mortality rate within three years in chronic dialysis patients, is a powerful predictor of sudden death in ESKD. A clustering of metabolic and myocardial abnormalities, including insulin resistance, impaired myocardial bioenergetics, left ventricular hypertrophy (LVH), myocardial fibrosis, and diastolic dysfunction, mediates development of HF and increases the risk of sudden death in ESKD. Regrettably, therapeutic options to ameliorate the CV risk remain very limited in ESKD. Development of novel and effective interventions to reduce HF risk and death, therefore, represents one of the greatest unmet needs for the dialysis population. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), a novel class of oral hypoglycemic medications that reduce glucose reabsorption in the renal proximal tubule, have recently demonstrated unprecedented efficacy to reduce HF hospitalization and CV deaths in patients with and without type 2 diabetes. Emerging data suggest that the benefits of SGLT2is include their efficacy to mitigate insulin resistance, enhance mitochondrial oxidative capacity in the heart, reverse LVH and improve diastolic dysfunction, and reduce cardiac fibrosis. Given that these CV benefits are hypothesized to be downstream consequences of renal SGLT2 inhibition (i.e. glycosuria and natriuresis), clinical trials have excluded those with advanced renal failure. There is compelling evidence, however, that SGLT2is may have direct effects on myocardium, independent of its action on the kidney, to restore myocardial electrophysiologic balance, enhance mitochondrial function, and reduce fibrosis, with a potential to reverse LVH and prevent HF and arrhythmia. These data raise a crucial question if SGLT2is may improve survival in ESKD. In order to perform a full-scale clinical trial to evaluate the CV and survival benefits of SGLT2is in ESKD, a pilot study is required to assess preliminary safety, tolerability, and feasibility. We hence propose a randomized, double- blind, placebo-controlled, 3-arm pilot study in 75 chronic hemodialysis participants to evaluate (1) safety and tolerability of empagliflozin, a selective SGLT2 inhibitor, including a steady-state pharmacokinetic (PK) study of two different daily doses and (2) feasibility of conducting a full-scale clinical trial. Our proposal is the first study to evaluate safety and tolerability of a SGLT2i in ESKD to date, including a detailed PK study of two doses to examine the effect of chronic administration. Positive findings will (1) provide the necessary preliminary safety, tolerability, and feasibility data to plan a larger, multi-center clinical trial in ESKD, and ...