SGLT2 inhibitors in hemodialysis or peritoneal dialysis patients: rationale and state-of-the art

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk of end-stage kidney disease (ESKD), cardiovascular events, and all-cause mortality in chronic kidney disease (CKD), regardless of diabetes or baseline renal function. However, patients with severely impaired kidney function or on dialysis have been excluded from landmark randomized clinical trials (RCTs). Several off-target mechanisms of SGLT2i could be involved in the cardiac protection of patients with ESKD in which the reduced nephron mass strongly diminishes the tubular effects of SGLT2i. However, available evidence in patients undergoing hemodialysis (HD) and peritoneal dialysis (PD) is limited thus leaving efficacy and safety in this population uncertain. Pharmacokinetic studies confirm that dapagliflozin is not dialyzable and shows no significant accumulation in dialysis patients. Small exploratory trials reported favorable cardiovascular and electrophysiological effects of SGLT2i in HD, while retrospective studies suggest they may preserve residual kidney function in incremental dialysis and improve volume status without major safety concerns. Large retrospective cohort analyses of patients starting dialysis showed lower risks of cardiovascular events and mortality in SGLT2i users compared with non-users. When treated with PD, no study has reported outcome data, and findings on efficacy were mixed with some studies showing increased ultrafiltration and lower blood pressure, while others showed no effect on peritoneal glucose transport. The theoretic protection against cardiovascular and mortality risk of SGLT2i must be confirmed by ongoing large-scale trials that will clarify the role of this class of drugs in dialysis populations.