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 co-transporter 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 1); 100 mg/kg/day, 42% (1); and 300 mg/kg/day, 42% (1); vs vehicle, 46% (1); P < .05], while bodyweight was numerically higher in all zibotentan groups compared with 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 = .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 = .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 Ahlström, 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 Sep 29;38(10):2289-2297

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PMID: 37102226

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