Safety and Efficacy of Empagliflozin Main intenance HD (SEED)

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.

Grant Number: 5R01DK133871-03
NIH Institute/Center: NIH
Principal Investigator: David Charytan