Front Pharmacol. 2026 Sep 16;17:1916346. doi: 10.3389/fphar.2026.1916346. eCollection 2026.
ABSTRACT
BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel oral agents for chronic kidney disease (CKD)-associated anemia. This study evaluated whether HIF-PHIs reduce red blood cell transfusion and intravenous iron exposure compared with placebo, standard care, or erythropoiesis-stimulating agents (ESAs) and assessed efficacy and safety.
METHODS: PubMed, Embase, and Web of Science were systematically searched. Randomized controlled trials comparing an HIF-PHI with placebo, standard care, or an ESA in adults with CKD-associated anemia were eligible. The primary outcomes were red blood cell transfusion and intravenous iron exposure. Secondary outcomes included changes in hemoglobin, cardiovascular events, and all-cause mortality, while safety was assessed using adverse event outcomes. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Furthermore, the certainty of evidence was assessed using the GRADE framework.
RESULTS: A total of 36 independent randomized controlled trials involving 27,680 participants with CKD-associated anemia were included. The trials evaluated six HIF-PHIs, namely, roxadustat, daprodustat, vadadustat, molidustat, enarodustat, and desidustat, against placebo, standard treatment or care, or an ESA. Compared with control interventions, HIF-PHIs significantly reduced the risk of any red blood cell transfusion (RR = 0.74, 95% CI: 0.58-0.93) and rescue red blood cell transfusion (RR = 0.70, 95% CI: 0.53-0.92). Intravenous iron outcomes generally favored HIF-PHIs, although neither the risk of any intravenous iron use (RR = 0.66, 95% CI: 0.38-1.14) nor the mean monthly intravenous iron dose (SMD = -0.19, 95% CI: -0.42 to 0.03) reached statistical significance, indicating residual uncertainty. Rates of major adverse cardiovascular events, all-cause mortality, and serious adverse events were not significantly increased with HIF-PHIs.
CONCLUSION: In patients with CKD-associated anemia, HIF-PHIs improved hemoglobin without significantly increasing major adverse cardiovascular events, all-cause mortality, or serious adverse events; however, the small increase in any adverse event and the hyperkalemia signal in non-dialysis-dependent patients warrant attention. Together with the significant reduction in red blood cell transfusion and the possible reduction in intravenous iron use, these findings support HIF-PHIs as a promising oral treatment option. Longer follow-up and continued post-marketing surveillance are required to clarify long-term safety and effects across patient subgroups.
SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261387833, Identifier CRD420261387833.
PMID:42819330 | PMC:PMC13623900 | DOI:10.3389/fphar.2026.1916346