Efficacy and safety of prolyl hydroxylase inhibitors for anemia in chronic kidney disease: a network meta-analysis

Abstract

This Bayesian network meta-analysis evaluated the efficacy and safety of six prolyl hydroxylase inhibitors (PHIs) versus erythropoiesis-stimulating agents (ESAs) or placebo for chronic kidney disease (CKD) anemia. Electronic databases were searched through 1 May 2025. The prespecified primary outcome was change in hemoglobin, while secondary outcomes included iron metabolism indices (serum iron, transferrin saturation [TSAT], ferritin, hepcidin) and overall composite adverse events (AEs). Surface under the cumulative ranking curve (SUCRA) was used for ranking. Forty-six randomized controlled trials with 32,305 patients were included. In non-dialysis CKD (ND-CKD), roxadustat yielded the greatest hemoglobin rise (MD = 1.21 g/dL, 95% CI: 0.72–1.71; SUCRA = 88.6%) versus placebo and ESA. In dialysis CKD (D-CKD), roxadustat again ranked the highest (MD = 1.78 g/dL, 95% CI: 1.32–2.24; SUCRA = 86.2%) versus ESA and other PHIs. For TSAT, ESA ranked best in ND-CKD (MD = 5.24%, 95% CI: 1.16–9.32), while daprodustat led in D-CKD (MD = 3.07%, 95% CI: 0.22–5.91). Roxadustat improved serum iron in D-CKD (MD = 6.19 μg/dL, 95% CI: 2.81–9.58), and vadadustat and roxadustat reduced hepcidin in ND-CKD. Consistency assessment revealed no statistically significant heterogeneity/inconsistency between direct/indirect comparisons, supporting the robustness of the results. Regarding safety, ESA had the lowest AE risk in ND-CKD (OR = 0.85, 95% CI: 0.74–0.98), while roxadustat ranked lowest (SUCRA = 18.4%). Roxadustat demonstrated the strongest efficacy in hemoglobin improvement but higher AE incidence in ND-CKD, whereas ESA and daprodustat showed safety and iron metabolism benefits, supporting individualized therapy for renal anemia.Registration number: PROSPERO (CRD420251066181).