Effect of combination of endothelin A receptor antagonist plus SGLT2i on cardiometabolic markers in CKD

ERA 2024 – The ZENTITH CKD trial demonstrated a reduction of 27% in UACR with the combination of the endothelin A receptor antagonist zibotentan plus dapagliflozin compared with dapagliflozin alone in patients with CKD. What are findings of an analysis of effect on cardiometabolic markers?

This summary is based on the presentation of Philip Ambery (Gothenburg, Sweden) at the ERA Congress 2024 – Cardiometabolic benefits of low dose zibotentan and dapagliflozin 10 mg in the ZENITH-CKD study

Introduction and methods

Elevated levels of endothelin 1 activate the endothelin A receptor thereby contributing to the pathophysiology of kidney failure through various mechanisms, including vasoconstriction, inflammation and metabolic dysfunction. Inhibition of the endothelin A receptor may block these harmful effects. Indeed, findings from the SONAR and RADAR studies showed reductions in HOMA-IR, LDL-c, and HbA1c with the oral endothelin A receptor antagonist atrasentan. However, endothelial A receptor antagonists cause fluid retention and oedema, and therefore it was hypothesized that combining this drug with an SGLT2 inhibitor may lead to kidney protection while mitigating endothelin A receptor antagonist-induced fluid retention.

In the ZENITH CKD trial, the effect of the endothelin A receptor antagonist zibotentan in combination with dapagliflozin on urinary albumin-creatinine ration (UACR) compared with dapagliflozin alone was investigated in people with CKD with or without T2M, who received standard of care (including ACEi or ARB). In part B of the study, patients with CKD (defined as eGFR ≥20 mL/min/1.73m² with UACR ≥150 and ≤5000 mg/g were randomized to zibotentan1.5 mg combined with dapagliflozin 10 mg (n=179), zibotentan 0.25 mg combined with dapagliflozin 10 mg (n=91) or dapagliflozin with placebo (n=177). The primary outcome of change from baseline in log-transformed UACR at week 12 was -33.7% (90%CI: -42.5 to -23.5, P<0.0001) for zibotentan 1.5 mg plus dapagliflozin and -27.0% (90%CI: -38.4 to -13.6, P=0.0022) for zibotentan 0.25 mg plus dapagliflozin vs. dapagliflozin plus placebo.

In this analysis, the impact of zibotentan plus dapagliflozin on metabolic and cardiovascular risk markers was studied.

Main results

• The change from baseline to week 12 in HbA1c was -0.4 (SD 0.6) in the 0.25 mg zibotentan plus dapagliflozin group vs. -0.2 (SD 0.7) in the dapagliflozin alone group.
• The change in LDL-c was -0.17 (SD 0.46) in the 0.25 mg zibotentan plus dapagliflozin group vs. 0.01 (SD 0.76) in the dapagliflozin alone group.
• In the 0.25 mg zibotentan plus dapagliflozin group, change in uric acid was -44 (66.3) and this was -23 (66.7) in the dapagliflozin group.
• In the 0.25 mg zibotentan plus dapagliflozin group, change in SBP was -7.1 (90% CI -10.0 to -4.1) and change in DBP was -4.3 (90%CI: -6.2 to -2.5) and changes in the dapagliflozin group were -3.5 (90%CI: -5.8 to -1.0) and -1.4 (90%CI: -2.9 to 0.1), respectively.
• There were 8 of 91 patients in the 0.25 mg zibotentan plus dapagliflozin group who had a fluid retention event and 14 out of 177 patients in the dapagliflozin group. 
• Similar findings were observed when analyzing the data of the 1.5 mg zibotentan plus dapagliflozin group, except for the fluid retention events (a high number of events with the 1.5 mg dose - 33 out of 179 patients).
• With regard to safety events, there were more fluid-related adverse events in the 1.5 mg dose zibotentan group.

Conclusion

The point estimates of HbA1c, LDL, uric acid and blood pressure were lower in the zibotentan plus dapaglifozin group versus the dapagliflozin alone group at both doses of zibotentan. The low dose of zibotentan does not results in an increase in fluid related events. In the end, Ambery shortly presented the ZENITH trial – a phase 3 outcome trial to determine the efficacy and safety of zibotentan plus dapagliflozin, which will report in 2027/2028.

- Our reporting is based on the information provided at the ERA Congress 2024 -