Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) increase hemoglobin (Hb) and improve iron metabolism in patients with renal anemia whether or not they are on dialysis, a new meta-analysis finds.

Investigators led by Xinzhou Zhang, PhD, of Jinan University in Shenzhen, China, performed a meta-analysis of 24 randomized controlled phase 2 or 3 trials published from 2015 to 2019 that included 3289 patients. The trials tested the safety and efficacy of roxadustat, daprodustat, vadadustat, enarodustat, and to a lesser extent molidustat and desidustat. Most trials were conducted in the United States, Japan, or China.

Treatment with HIF-PHIs significantly improved Hb by a weighted mean difference (WMD) of 1.4 and the Hb response rate (a Hb increase of 1.0 g/dL or more from baseline) by 6-fold compared with placebo or erythropoiesis-stimulating agents (ESAs), Dr Zhang’s team reported in Nephron. Total iron-binding capacity (TIBC) significantly increased by a WMD of 42.9. Concurrently, hepcidin, ferritin, and transferrin saturation (TSAT) all significantly decreased by a WMD of 40.4, 64.6, and 5.6, respectively. (All  P <.001). Serum iron did not differ significantly between groups.

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Half of HIF-PHI and control patients experienced at least 1 adverse event (AE) with no significant between-group differences in AEs or serious AEs (SAEs). Overall, AEs did not differ between patients on dialysis or not. In subgroup analyses, however, HIF-PHIs were associated with higher incidence of AEs than ESAs. Roxadustat also was associated with a higher incidence of AEs than the control group.

According to Dr Zhang’s team, “our meta-analysis provided evidence that HIF-PHIs could not only increase Hb level and the response rate of Hb but also improve TIBC without raising the incidence of AEs and SAEs in the short term. At the same time, HIF-PHIs reduced hepcidin, ferritin, and TSAT and had no effect on serum iron. Overall, patients with renal anemia can benefit from HIF-PHIs in the observation time.”

The investigators noted that more long-term studies are needed to prove the safety of HIF-PHIs and test their potential benefit in reducing cardiovascular events. This meta-analysis was limited by relatively short observation periods, variable drug dosing, and risk of bias.


Wen T, Zhang X, Wang Z, Zhou R. Hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with renal anemia: a meta-analysis of randomized trials. Nephron. doi:10.1159/000508812