Zibotentan in Combination with Dapagliflozin Compared with Dapagliflozin in Patients with Chronic Kidney Disease (ZENITH-CKD): a Multicentre, Randomised, Active-controlled, Phase 2b, Clinical Trial

Lancet. 2023; online ahead of print DOI: 10.1016/S0140-6736(23)02230-4

The risk of kidney failure persists in many patients with CKD, even when receiving optimal treatment including SGLT2i. Increased expression of endothelin-1 may contribute to CKD progression through several pathophysiological effects; however, high doses of non-selective endothelin receptor antagonists (ERAs) have been linked with fluid retention.

ZENITH-CKD is the first prospective study of a fixed-dose combination of an ERA (zibotentan) with an SGLT2i (dapagliflozin) on top of maximum tolerated renin-angiotensin-system inhibition (if tolerated) in adults with CKD. In this phase 2b trial, 449 patients were randomised 2:1:2 to low doses of 0.25 mg/day and 1.5 mg/day zibotentan in combination with dapagliflozin 10 mg/day or dapagliflozin 10 mg plus placebo.

The results showed robust and clinically meaningful reductions in albuminuria with low-dose zibotentan combined with dapagliflozin. Zibotentan 1.5 mg resulted in a modest additional albuminuria-lowering effect compared with that of zibotentan 0.25 mg (−34% and −27%, respectively, versus placebo), but resulted in higher rates of fluid retention (18% vs 9%, respectively, vs 8% with placebo), suggesting that the lowest dose of zibotentan may be optimal for future trials.