# Network meta-analysis of HIF-prolyl hydroxylase inhibitors for anemia in dialysis-dependent and non-dialysis CKD: effects on hemoglobin, iron markers, and adverse clinical outcomes

## TL;DR

This study compares different HIF-PHIs for treating anemia in kidney disease patients, finding that their effectiveness and safety vary depending on the drug and dialysis status.

## Contribution

A network meta-analysis comparing six HIF-PHIs and ESAs for anemia in CKD, with subgroup analyses by dialysis status.

## Key findings

- Roxadustat and daprodustat showed greater hemoglobin increases than ESAs or placebo.
- Daprodustat improved iron mobilization more in dialysis patients, while roxadustat was more effective in non-dialysis patients.
- Safety profiles varied by drug, with roxadustat linked to vascular events and daprodustat to gastrointestinal events.

## Abstract

HIF–prolyl hydroxylase inhibitors (HIF-PHIs) are oral alternatives to erythropoiesis-stimulating agents (ESAs) for anemia in chronic kidney disease (CKD). We performed a network meta-analysis comparing six HIF-PHIs (roxadustat, daprodustat, vadadustat, molidustat, enarodustat, desidustat) versus ESAs or placebo across hemoglobin efficacy, iron indices, and adverse events, with prespecified subgroup analyses by dialysis status. Forty-five randomized trials enrolling over 32,000 participants were analyzed using both frequentist and Bayesian frameworks with inconsistency checks. Outcomes included hemoglobin, ferritin, hepcidin, serum iron, total iron-binding capacity, and transferrin saturation; VEGF and lipid endpoints were not synthesized due to sparse, heterogeneous reporting. Across analyses, roxadustat and daprodustat increased hemoglobin more than ESA or placebo overall. Roxadustat tended to rank highest for hemoglobin, particularly in non-dialysis populations, whereas daprodustat showed advantages among dialysis-dependent patients and was associated with greater improvements in iron mobilization (lower hepcidin and ferritin, higher transferrin saturation). Estimates for desidustat and vadadustat were favorable but less precise, while evidence for enarodustat and molidustat was limited. Safety appeared class-neutral in aggregate; however, agent-specific patterns emerged—roxadustat showed higher rates of vascular occlusive events in some trials, daprodustat more gastrointestinal events, and molidustat a lower risk of hyperkalemia. Because SUCRA ranks reflect probability rather than effect magnitude, rankings were interpreted alongside absolute effects and study design. In sum, HIF-PHIs are not interchangeable; efficacy and safety vary by agent and dialysis status. Choice of therapy should consider inflammatory burden, iron handling, and adherence context. Head-to-head trials and real-world studies are needed to validate comparative findings and guide personalized use.

The online version contains supplementary material available at 10.1186/s12882-025-04561-x.