Safety, Tolerability, and Feasibility of Empagliflozin Therapy in Patients Treated with Long-Term Hemodialysis

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Background: The safety and tolerability of SGLT2is in dialysis-dependent CKD (DD-CKD) have not been investigated, despite growing evidence that SGLT2is may exert off-target benefits to improve CV outcomes independent of renal SGLT2 inhibition. Methods: We performed a randomized, double-blind, placebo-controlled, three-arm, phase 1 study in 62 hemodialysis patients to evaluate safety and tolerability of empagliflozin and feasibility of conducting a phase 3 clinical trial. Participants were randomized to 10 mg or 25 mg of empagliflozin or placebo at 1:1:1 ratio and treated for 12 weeks. A detailed PK study of empagliflozin was performed in a subset of study participants. The primary safety and tolerability endpoint was the proportion of participants in each intervention group who adhere to the full randomized dose of empagliflozin at the end of the study. The result will be regarded as meeting the minimum benchmarks for proceeding to a phase 3 trial if at least 68% of the participants adhere to the assigned dose at the end of the study. Results: Out of250 screened, a total of 62 (25%) have enrolled in the study (N=20, Group 1; N=22, Group 2; N=20, Group 3). The participants had a mean age±SD of 58±13 years, and 68% were white males. Of the 62 participants, 13 (21%) have prematurely discontinued the study (7 withdrew for personal reasons; 1 was withdrawn by the investigator due to prolonged hospitalization judged unrelated to the study; 1 became lost to follow up due to relocation; 1 received kidney transplantation; 1 had sudden death; 2 (each from Group 1 and 2) withdrew due to serious adverse events of hypoglycemia and abnormal transaminases possibly related to the study drug). The discontinuation rate per study group to date has been 17% for Group 1, 20% for Group 2, and 28% for Group 3. There were 17 hospitalizations in 12 participants and were assessed to be unrelated to the study. No participants required dose reduction. The analyses of the study will be completed following the last study visit on 6/28/2025. Conclusion: Our results, while incomplete and limited by the small size, suggest reasonable safety and tolerance of empagliflozin in DD-CKD, and each study group is on track to meet the minimum benchmarks for proceeding to a phase 3 trial. Funding: NIDDK Support

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