Shifting Paradigms: Exploring Enarodustat for Anemia in Chronic Kidney Disease in a Meta Analysis of Randomized Controlled Trials

Anemia commonly accompanies chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs), such as darbepoetin, are initiated for anemia in CKD. Additionally, hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors have demonstrated efficacy in treating CKD-associated anemia. This meta-analysis aims to compare the efficacy, safety, and tolerability of enarodustat in anemic CKD patients. Case report A systematic search of Cochrane CENTRAL, Ovid Medline R, PubMed, and Web of Science databases up to March 1, 2024, was conducted. Randomized controlled trials (RCTs) directly comparing enarodustat with darbepoetin were included. Data from four unique RCTs comprising an inverse variance-weighted random-effects model were utilized for the main analysis. Primary efficacy outcome measures included hemoglobin (Hb) change at weeks 4-6 and during follow-up, while primary safety outcomes focused on serious adverse events (SAEs). Subgroup analyses were performed based on dialysis status and prior use of ESA for the primary outcome. Four RCTs with 7 reports involving 586 patients were included in the main analysis. Enarodustat demonstrated superiority to control in terms of change in Hb levels at week 4-6 (RR 0.76, 95% CI 0.02 to 1.50, I2=96%, p=0.04) but non-inferiority during follow-up (MD 0.66, 95% CI -0.22 to 1.53, I2=91%, p=0.14). Enarodustat exhibited comparable effects for safety and tolerability parameters such as SAEs (RR 1.17, 95% CI 0.72 to 1.91, I2=0%, p=0.52), any adverse events (RR 0.95, 95% CI 0.82 to 1.08), any adverse events leading to discontinuation (RR 0.90, 95% CI 0.37 to 2.20), diarrhea (RR 1.50, 95% CI 0.05 to 43.15), hypertension (RR 0.89, 95% CI 0.43 to 1.84), and all-cause mortality (RR 0.63, 95% CI 0.08 to 5.08). Subgroup analysis by dialysis status revealed nonsignificant differences for change in Hb levels at week 4-6 and during follow-up, but comparator-based subgroup analysis demonstrated a significant difference only when comparing to placebo at week 4-6. Enarodustat exhibits promise as a treatment option for anemia associated with CKD, demonstrating superiority to control in terms of Hb change at week 4-6 and non-inferiority during follow-up. Moreover, it demonstrates comparable safety and tolerability profiles to darbepoetin, making it a potential alternative in the management of CKD-related anemia.