The sodium glucose co-transporter 2 inhibitor dapagliflozin ameliorates the fluid-retaining effect of the endothelin A receptor antagonist zibotentan.

Endothelin A receptor antagonists (ETARA) slow chronic kidney disease (CKD) progression but their use is limited due to fluid retention and associated clinical risks. Sodium glucose cotransporter 2 inhibitors (SGLT2i) cause osmotic diuresis and improve clinical outcomes in CKD and heart failure. We hypothesized that co-administration of the SGLT2i dapagliflozin with the ETARA zibotentan would mitigate the fluid retention risk using hematocrit (Hct) and bodyweight as proxies for fluid retention.Experiments were performed in 4% salt fed WKY rats. First, we determined the effect of zibotentan (30, 100 or 300 mg/kg/day) on Hct and bodyweight. Second, we assessed the effect of zibotentan (30 or 100 mg/kg/day) alone or in combination with dapagliflozin (3 mg/kg/day) on Hct and bodyweight.Hct at day 7 was lower in zibotentan versus vehicle groups (zibotentan 30 mg/kg/day 43% (standard error [SE] 1), 100 mg/kg/day, 42% (1); and 300 mg/kg/day 42% (1); versus vehicle 46% (1); p < 0.05); while bodyweight was numerically higher in all zibotentan groups compared to vehicle. Combining zibotentan with dapagliflozin for 7 days prevented the change in Hct (zibotentan 100 mg/kg/day and dapagliflozin 45% (1) vs vehicle 46% (1); p = 0.44) and prevented the zibotentan-driven increase in bodyweight (zibotentan 100 mg/kg/day + dapagliflozin 3 mg/kg/day = -3.65 g baseline corrected bodyweight change; p = 0.15).Combining ETARA with SGLT2i prevents ETARA induced fluid retention, supporting clinical studies to assess the efficacy and safety of combining zibotentan and dapagliflozin in individuals with CKD.© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.

Citation

Vandana Veenit, Hiddo J L Heerspink, Christine Ahlstrom, Peter J Greasley, Stanko Skritic, Natalie van Zuydam, Donald E Kohan, Pernille B L Hansen, Robert I Menzies. The sodium glucose co-transporter 2 inhibitor dapagliflozin ameliorates the fluid-retaining effect of the endothelin A receptor antagonist zibotentan. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2023 Apr 26

PMID: 37102226

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