HIF-PHIs May Offer Benefit over ESAs for Anemia With Dialysis-Dependent CKD

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) seem to be a feasible alternative to erythropoietin-stimulating agents (ESA) for treating anemia in people with dialysis-dependent chronic kidney disease (DD-CKD), according to a new systematic review and meta-analysis.1

Specifically, daprodustat exhibited a substantial net benefit over ESAs in reducing the need for intravenous iron supplementation while roxadustat had a less favorable safety profile.

“HIF-PHIs have been termed as a new breakthrough approach for managing anemia in patients with CKD, preferably because of its capability to enhance hematological outcomes.2 Other alternatives however like ESAs pose challenges in patients on dialysis like hyporesponsiveness in elderly patients, nonfatal myocardial infarction, congestive heart failure, and cerebral apoplexy. Therefore, these reasons make it feasible to use HIF-PHIs in DD patients with CKD for managing renal anemia,” lead investigator Jyoti Tyagi, MPH, Meta-Research and Evidence Synthesis Unit, The George Institute for Global Health, Delhi, India, and colleagues wrote.1

The analysis included 20 randomized controlled studies, involving 14,999 participants with anemia of kidney disease, that were identified across PubMed, CINAHL, and Cochrane Central Register of Controlled Trials databases and trial registries. Investigators assessed certainty of evidence by Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Two investigators also independently conducted screening, data extraction, and assessed risk of bias.

The included studies assessed roxadustat (n = 9), daprodustat (n = 5), vadadustat (n = 2), molidustat (n = 2), enarodustat (n = 1), and desidustat (n = 1). The trials included ESA-conditioned patients (n = 14), both ESA-conditioned and naïve patients (n = 4), and ESA naïve patients (n = 2). Furthermore, patients were undergoing hemodialysis (n = 11), peritoneal dialysis (n = 1), or both both peritoneal and hemodialysis (n = 8).

Tyagi and colleagues found that daprodustat showed a substantial net benefit, roxadustat showed more damage than benefit, and other HIF-PHIs inhibitors demonstrated little to no difference or a small benefit compared to ESAs.

Namely, daprodustat reduced the need for intravenous iron supplementation for up to 52 weeks as compared to ESAs (odds ratio [OR], 0.77; 95% CI, 0.53–1.13; P = .18 in 2 studies with 674 participants; GRADE, moderate certainty evidence). Conversely, roxadustat increased treatment-emergent adverse events for up to 6–52 weeks as compared to ESAs (OR, 1.45; 95% CI, 1.08–1.96; P = .01 in 6 studies with 1715 participants; GRADE, moderate certainty evidence).1

Looking specifically at desidustat for other comparative effects assessed, in 4 studies, the therapy showed little or no difference in change in the hemoglobin levels from baseline up to 52 weeks as compared to ESAs (mead difference [MD], 0.02 g/dL [95% CI, -0.14 to 0.18]; P = .80 in 4 studies with 3950 participants; GRADE, low certainty evidence). In 5 studies, daprodustat had little or no difference on all-cause mortality up to 52 weeks as compared to ESAs (OR, 0.98 [95% CI, 0.82–1.16]; P = .81 in 5 studies with 4035 participants; GRADE, low certainty evidence).1

“The results of this review can inform clinical practitioners to take decisions wisely and choose appropriate treatment for the patients and policy. The evidence would also aid in prioritizing funding and conducting high-quality clinical trials to provide evidence on the efficacy and safety of HIF-PHIs,” Tyagi and colleagues concluded.1

REFERENCES

1. Tyagi J, Kaur M, Ingale S, et al. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors for Anemia in Dialysis-Dependent Chronic Kidney Disease: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Indian J Nephrol. 2025;35(2):198-216. doi:10.25259/ijn_379_23

2. Haase VH. Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease. Kidney Int Suppl (2011) 2021;11:8–25. doi: 10.1016/j.kisu.2020.12.002.