The effect of HIF-PHIs on anemia in non-dialysis-dependent CKD patients: a systematic review and network meta-analysis

This study compared the effects of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) and erythropoiesis-stimulating agents (ESAs) on anemia in non-dialysis-dependent chronic kidney disease (ND-CKD), with emphasis on follow-up duration and iron-metabolism markers. We systematically searched databases for randomized controlled trials (RCTs) evaluating HIF-PHIs in patients with anemia. A Bayesian random-effects network meta-analysis was performed as the primary analysis, with fixed-effect models used as sensitivity analyses. Subgroup analyses were conducted at 6–8 and 16–24 weeks. Thirty-one RCTs involving 16,403 ND-CKD patients were included. Compared with placebo, ESAs and all six HIF-PHIs significantly increased hemoglobin (Hb) levels from baseline. Roxadustat showed the largest overall Hb increase (mean difference [MD] = 1.66, 95% credible interval [CrI], 1.36 to 1.97), followed by enarodustat (MD = 1.43, 95% CrI, 0.75 to 2.11). In the time-stratified analyses, differences among active agents were generally uncertain. For iron-related outcomes, enarodustat and daprodustat generally ranked highest for hepcidin reduction, although evidence for some agents was limited. Overall, HIF-PHIs decreased transferrin saturation (TSAT) and ferritin and increased total iron-binding capacity (TIBC). This network meta-analysis suggests that HIF-PHIs may differ in their effects on hemoglobin and iron metabolism in ND-CKD. These findings should be interpreted cautiously because rankings for some agents were based on limited direct evidence, heterogeneous trial protocols, and potential sponsorship-related influence. PROSPERO CRD42024559388.