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Review
. 2023 Oct 21;15(10):e47430.
doi: 10.7759/cureus.47430. eCollection 2023 Oct.

Safety and Efficacy of Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors vs. Erythropoietin-Stimulating Agents in Treating Anemia in Renal Patients (With or Without Dialysis): A Meta-Analysis and Systematic Review

Nanush Damarlapally  1 , Vijaylaxmi Thimmappa  2 , Hamza Irfan  3 , Muhammad Sikandari  4 , Krupa Madhu  5 , Aayushi Desai  5 , Peddi Pavani  6 , Syeda Zakir  7 , Manvi Gupta  8 , Maha Mushtaq Khosa  9 , Sohny Kotak  7 , Giustino Varrassi  10 , Mahima Khatri  11 , Satesh Kumar  12
Affiliations
Review

Safety and Efficacy of Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors vs. Erythropoietin-Stimulating Agents in Treating Anemia in Renal Patients (With or Without Dialysis): A Meta-Analysis and Systematic Review

Nanush Damarlapally et al. Cureus. .

Abstract

Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) are a novel group of drugs used to treat renal anemia, but their benefits vary among different trials. Our meta-analysis aims to assess the safety and efficacy of HIF-PHI versus erythropoiesis-stimulating agents (ESA) in managing anemia among patients with chronic kidney disease (CKD), regardless of their dialysis status. PubMed, Embase, and Google Scholar were queried to discover eligible randomized controlled trials (RCTs). To quantify the specific effects of HIF-PHI, we estimated pooled mean differences (MDs) and relative risks (RR) with 95% CIs. Our meta-analysis involved 22,151 CKD patients, with 11,234 receiving HIF-PHI and 10,917 receiving ESA from 19 different RCTs. The HIF-PHI used included roxadustat, daprodustat, and vadadustat. HIF-PHI yielded a slight but significant increase in change in mean hemoglobin (Hb) levels (MD: 0.06, 95% CI (0.00, 0.11); p = 0.03), with the maximum significant increase shown in roxadustat followed by daprodustat as compared to ESA. There was a significant decrease in efficacy outcomes such as change in mean iron (MD: -1.54, 95% CI (-3.01, -0.06); p = 0.04), change in mean hepcidin (MD: -21.04, 95% CI (-28.92, -13.17); p < 0.00001), change in mean ferritin (MD: -16.45, 95% CI (-27.17,-5.73); p = 0.03) with roxadustat showing maximum efficacy followed by daprodustat. As for safety, HIF-PHI showed significantly increased incidence in safety outcomes such as diarrhea (MD: 1.3, 95% CI (1.11, 1.51); p = 0.001), adverse events leading to withdrawal (MD: 2.03, 95% CI (1.5, 2.74), p = 0.00001) among 25 various analyzed outcomes. This meta-analysis indicates that HIF-PHIs present a potentially safer and more effective alternative to ESAs, with increased Hb levels and decreased iron usage in CKD patients without significantly increasing adverse events. Therefore, in these patients, we propose HIF-PHI alongside renal anemia treatment.

Keywords: and efficacy; anemia; dialysis; erythropoietin stimulating agents; hypoxic inducible factors prolyl hydroxylase inhibitors; kidney; renal; safety; treatment; without dialysis.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. PRISMA flow chart showing search strategy and study selection process.
PRISMA: Preferred Reporting Items for Systemic Review and Meta-Analysis.
Figure 2
Figure 2. Cochrane risk of bias tool for assessing publication bias in randomized controlled trials.
Figure 3
Figure 3. Funnel plot of (a) change in mean Hb, and (b) Hb response.
The above funnel plot clearly shows there was no publication bias in the study. MD: Mean difference; RR: Relative risk; SE: Standard error.
Figure 4
Figure 4. Forest plot showing subgroup analysis of change in mean Hb (g/dL) by HIF-PHI vs. ESA drugs.
The forest plot above shows a significant increase in the change in mean Hb for roxadustat (MD: 0.13, 95% CI: 0.06, 0.19; p: 0.0001, I2: 40%) and daprodustat (MD: 0.09, 95% CI: 0.01, 0.17; p: 0.03, I2: 64%), and a non-significant increase for molidustat and desidustat (MD: 0.09, 95% CI: -0.05, 0.23; p: 0.21, I2: 0%), respectively. MD: Mean difference; HIF-PHI: Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors; ESA: Erythropoietin-stimulating agents; Hb: Hemoglobin. Source: References [11-15, 17-29].
Figure 5
Figure 5. Forest plot showing subgroup analysis of Hb response by HIF-PHI vs. ESA drugs.
The forest plot above shows that various HIF-PHIs demonstrated an overall non-significant difference in Hb response (RR: 1.01, 95% CI: 0.95, 1.07; p: 0.81, I²: 76%) compared to ESAs. RR: Relative risk ratio; HIFI: Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors; ESA: Erythropoietin-stimulating Agents; Hb: Haemoglobin. Source: References [13, 14, 16-18, 20, 22-29].
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