What evidence supports the use of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) for management of anemia in chronic kidney disease (CKD)?

Background
Anemia is typically defined as a hemoglobin level of less than 13 g/dL in men and less than 12 g/dL in women.¹ It is a common complication of chronic kidney disease (CKD) that typically develops when the glomerular filtration rate (GFR) falls below 60 mL/min/1.73 m². Prevalence and severity of anemia increase with declining GFR; the condition affects up to 20% of patients with stage 3 CKD and at least 90% of those who become dialysis-dependent. Anemia of CKD is associated with reduced health-related quality of life, as well as increased hospitalizations, red cell transfusion requirements, risk of cardiovascular events, and mortality.^1,2 While multiple mechanisms have been proposed for anemia of CKD, the primary contributors are erythropoietin deficiency and impaired iron metabolism.^1,3

Management of anemia due to CKD has evolved substantially over the past 2 decades.¹ Historically, blood transfusions were the mainstay of therapy, but their use was associated with substantial risks, including infection, hemosiderosis, fluid overload, and transfusion-related reactions. The introduction of recombinant erythropoietin in the late 1980s, followed by erythropoiesis-stimulating agents (ESAs), transformed management. Although initially developed to reduce the need for transfusions, ESAs were subsequently shown to confer additional benefits, such as improvements in survival, quality of life, cardiac function, hospitalization rates, and overall healthcare costs. However, attempts to normalize hemoglobin levels in patients with CKD using ESAs were associated with increased risks of stroke, vascular access thrombosis, and mortality.² These safety concerns have prompted guideline recommendations supporting more conservative ESA use with only partial correction of anemia, and have also driven interest in newer therapeutic agents with more favorable safety profiles.

Hypoxia-inducible factor prolyl hydroxylase inhibitors
Hypoxia-inducible factor (HIF) is a transcription factor that serves as a central regulator of cellular adaptation to hypoxic conditions, promoting the expression of erythropoietin and numerous genes involved in iron metabolism.^1,4 Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a novel class of agents that stimulate erythropoiesis by stabilizing HIF, thereby increasing endogenous erythropoietin production and modulating iron metabolism through effects of hepcidin. In contrast to ESAs, which require intravenous or subcutaneous administration, HIF-PHIs offer an oral alternative for anemia management in CKD.

Despite early expectations that HIF‑PHIs would demonstrate superior cardiovascular safety in patients with CKD, no large global safety trial has confirmed a cardiovascular advantage of these agents over ESAs.⁴ In the U.S., 2 HIF-PHIs have received regulatory approval: daprodustat (approved in 2023) and vadadustat (approved in 2024). However, concerns regarding an increased risk of major adverse cardiovascular events (MACE) led to their approval being restricted solely to patients receiving maintenance dialysis. Roxadustat, another agent in this class, was not approved in the U.S. due to similar cardiovascular safety concerns, although it remains available in several other countries. Daprodustat, originally approved for treatment of anemia due to CKD in adults receiving dialysis for ≥4 months, was subsequently withdrawn from the U.S. market in 2024 for commercial reasons.⁵

Currently, vadadustat (Vafseo^®) is the only HIF-PHI approved and commercially available in the U.S, with its indication limited to adults with anemia of CKD who are receiving dialysis for ≥3 months.⁶ Vadadustat is not indicated for patients with CKD not on dialysis or as a substitute for urgent red blood cell transfusion. The recommended starting dose is 300 mg orally once daily, with titration in 150‑mg increments to maintain hemoglobin levels between 10 to 11 g/dL, using the lowest effective dose to reduce transfusion needs. Dose increases should occur no more often than every 4 weeks, while reductions may occur more frequently.

Similarly to ESAs, vadadustat carries a boxed warning for an increased risk of mortality, myocardial infarction, stroke, venous thromboembolism, and vascular access thrombosis, particularly when hemoglobin rises too rapidly or exceeds 11 g/dL.⁶ Additional warnings include hepatotoxicity, worsening hypertension, seizures, gastrointestinal erosions (including bleeding), and potential concerns in patients with active malignancy. Vadadustat is contraindicated in patients with uncontrolled hypertension or known hypersensitivity to the drug. The most common adverse reactions observed in clinical trials were hypertension and diarrhea, with other frequently occurring reactions including headache, fatigue, nausea, vomiting, and abdominal pain.

Clinical guidelines on treatment of anemia of CKD
In 2026, the Kidney Disease: Improving Global Outcomes (KDIGO) published their updated practice guideline for the management of anemia in CKD.⁷ According to the guideline, in individuals with anemia of CKD (regardless of dialysis status), the decision to use ESAs or HIF-PHIs should be guided by shared decision-making, with consideration of each individual’s symptoms, potential harms from red blood cell transfusions, and risk of adverse events (e.g., stroke, cardiovascular events, cancer). All reversible causes of anemia, including iron deficiency, should be corrected before initiating either therapy. Recommendations regarding HIF‑PHIs or ESAs are made for the drug class as a whole instead of any one agent.

For individuals in whom correctable causes of anemia have been addressed, KDIGO suggests using an ESA rather than a HIF-PHI as first-line therapy.⁷ This recommendation reflects the extensive evidence base regarding the efficacy and safety of ESAs, while placing lower value on the theoretical advantages of HIF‑PHIs, such as oral administration. Although head‑to‑head randomized controlled trials demonstrate noninferiority of HIF‑PHIs to ESAs for hemoglobin correction, some studies indicate a higher incidence of MACE and vascular access thrombosis associated with certain HIF‑PHIs in specific CKD populations. Furthermore, the long‑term safety profile of HIF‑PHIs outside clinical trial settings remains uncertain. KDIGO recommends avoiding HIF-PHIs in those at increased risk for adverse events; Table 1 summarizes considerations for those at increased risk of adverse events with HIF-PHIs as outlined by the guideline.

Combination therapy with ESAs and HIF‑PHIs is not recommended, including in individuals with ESA hyporesponsiveness.⁷ In patients treated with ESAs, targeting the hemoglobin level to $\lt$11.5g/dL is recommended; refer to the guideline for specific recommendations on ESA initiation and maintenance therapy. Although optimal hemoglobin thresholds for initiating or maintaining HIF‑PHI therapy are unknown, applying the same thresholds used for ESA therapy is considered reasonable. HIF‑PHIs should be administered at recommended starting doses and titrated to the lowest effective dose that improves anemia‑related symptoms and reduces transfusion requirements; doses should not exceed the recommended maximum dose. Hemoglobin should be monitored 2 to 4 weeks after therapy initiation or dose adjustment, and subsequently at 4‑week intervals. HIF‑PHI therapy should be discontinued after 3 to 4 months if an adequate erythropoietic response is not achieved. Treatment should also be suspended following cardiovascular or thromboembolic events, vascular access thrombosis, or newly diagnosed cancer. Decisions regarding reinitiation of HIF‑PHIs or initiation of ESAs should be individualized based on hemoglobin levels, clinical characteristics, and patient preferences.

In individuals with ESA hyporesponsiveness, a trial of HIF‑PHI therapy may be considered when raising hemoglobin is necessary to avoid transfusion or improve symptoms, following a discussion of potential benefits and risks.⁷ If used, HIF‑PHIs should be prescribed at the lowest dose capable of achieving symptom relief or reducing transfusion needs. Refer to the guideline for complete recommendations in the setting of ESA hyporesponsiveness.

Literature review
The focus of this literature review will be on studies assessing the efficacy and safety of vadadustat for anemia of CKD, as it is the only currently available HIF‑PHI in the U.S. This literature review does not include any studies conducted solely in patients with non-dialysis-dependent CKD since vadadustat is not approved for use in this population.

Phase 3 studies of vadadustat

The INNO₂VATE trials were 2 randomized, open-label, noninferiority phase 3 trials that evaluated the safety and efficacy of vadadustat, compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent CKD.² The primary safety outcome was the first occurrence of MACE, defined as a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke, pooled across the trials (noninferiority margin: upper bound of the 95% confidence interval [CI] of 1.25). The primary efficacy outcome was the mean change in hemoglobin from baseline to weeks 24 to 36, in each trial (noninferiority margin: lower bound of the 95% CI of -0.75 g/dL). Among 3923 patients randomized to vadadustat or darbepoetin alfa, a first MACE occurred in 18.2% and 19.3% of patients in the vadadustat and darbepoetin alfa, groups, respectively (hazard ratio, 0.96; 95% CI, 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g/dL (95% CI, -0.53 to -0.10) at weeks 24 to 36 in the incident DD-CKD trial and -0.17 g/dL (95% CI, −0.23 to −0.10) in the prevalent DD-CKD trial. Based on these findings, vadadustat was determined to be noninferior to darbepoetin alfa in terms of cardiovascular safety and the correction and maintenance of hemoglobin levels.

Notably, although vadadustat is not currently approved for patients with non-dialysis-dependent CKD, the PRO₂TECT trials showed it met the prespecified noninferiority criterion for hematologic efficacy but not for cardiovascular safety in this population when compared with darbepoetin alfa.⁸

Meta-analyses including vadadustat

Across multiple meta‑analyses assessing HIF‑PHIs for anemia of CKD, vadadustat consistently demonstrated hemoglobin‑raising efficacy comparable to ESAs in dialysis patients, with generally similar overall safety.^9-16 The largest network meta‑analysis to date, by Niu et al (2026), reinforces these findings within the broader HIF‑PHI class.⁹ This analysis included 46 randomized controlled trials (N=32,305) and compared the efficacy and safety of 6 HIF‑PHIs (roxadustat, daprodustat, molidustat, desidustat, enarodustat, and vadadustat) across both dialysis and non-dialysis CKD populations. Roxadustat demonstrated the most consistent and robust efficacy in improving hemoglobin levels among all HIF‑PHIs across both the dialysis and non-dialysis CKD populations. Furthermore, dialysis status-dependent effects on iron metabolism parameters were observed; vadadustat and ESAs demonstrated greater efficacy in enhancing transferrin saturation and reducing hepcidin among non-dialysis patients, while daprodustat and roxadustat had more favorable effects in dialysis patients. Notably, roxadustat significantly increased serum iron levels in dialysis-dependent patients, and both vadadustat and roxadustat were superior to ESAs in reducing hepcidin concentrations among non-dialysis patients. With respect to safety, ESAs were associated with the most favorable overall adverse event profile. Among the HIF-PHIs, roxadustat consistently ranked lowest in safety across both dialysis and non-dialysis populations.

Complementing these findings, a previous network meta-analysis by Sackeyfio et al (2024) provides more granular separation of dialysis versus non-dialysis CKD populations.¹⁰ Seventeen randomized controlled trials assessing 3 HIF‑PHIs (roxadustat, daprodustat, and vadadustat) were included in the analysis. Among non-dialysis patients (n=7957), there were no significant differences between the HIF-PHIs with respect to hemoglobin change from baseline or risk of MACE. In dialysis patients (n=12,320), hemoglobin change from baseline was higher with daprodustat and roxadustat compared with vadadustat (daprodustat,0.34 g/dL [95% credible interval, 0.22 to 0.45]; roxadustat, 0.38 g/dL [95% credible interval, 0.27 to 0.49], while there were no significant differences in the risk of MACE between the HIF-PHIs. Similar results were observed in ESA‑naïve and prevalent dialysis subgroups. Overall, these findings highlight that the benefit‑risk profile of vadadustat remains favorable in dialysis-dependent CKD but less consistent in non-dialysis patients, aligning with its U.S. approval limited to adults on dialysis for ≥3 months. Collectively, these analyses support vadadustat as an evidence‑based alternative to ESAs in the dialysis population while emphasizing the importance of population‑specific cardiovascular risk assessment.^9-16

Conclusion
Overall, the available evidence from randomized trials, meta‑analyses, and current KDIGO guidelines indicates that HIF‑PHIs are an effective, oral alternative to ESAs for patients with anemia of CKD, though their clinical role remains shaped by population‑specific safety considerations.^2,7,9-16 Vadadustat, the only HIF‑PHI currently available in the U.S., has demonstrated noninferior efficacy to ESAs and comparable cardiovascular safety in patients receiving maintenance dialysis, findings supported across multiple meta‑analyses and consistent with results from the INNO₂VATE phase 3 trials. In contrast, less consistent cardiovascular outcomes in non‑dialysis CKD, reflected in the PRO₂TECT trials and reinforced in network meta‑analyses, have shaped the restricted indication of vadadustat in the U.S.

Guideline recommendations emphasize shared decision‑making, careful monitoring, and prioritization of ESAs as first‑line therapy, while recognizing that HIF‑PHIs may offer benefits for select patients, such as those with barriers to parenteral administration.⁷ Ultimately, while the long‑term safety profile of HIF‑PHIs continues to evolve, existing evidence supports vadadustat as a viable treatment option for anemia in dialysis-dependent CKD when used with careful monitoring and individualized risk-benefit assessment.

References

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2. Eckardt KU, Agarwal R, Aswad A, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med. 2021;384(17):1601-1612. doi:10.1056/NEJMoa2025956
3. Badura K, Janc J, Wąsik J, et al. Anemia of chronic kidney disease-a narrative review of its pathophysiology, diagnosis, and management. Biomedicines. 2024;12(6):1191. doi:10.3390/biomedicines12061191
4. Haase VH, Tanaka T, Koury MJ. Hypoxia-inducible factor activators: a novel class of oral drugs for the treatment of anemia of chronic kidney disease. Hematology Am Soc Hematol Educ Program. 2024;2024(1):409-418. doi:10.1182/hematology.2024000655
5. Ernst D. GSK withdraws Jesduvroq from the US market. Haymarket Media, Inc. December 10, 2024. Accessed February 1, 2026. https://www.empr.com/news/gsk-withdraws-jesduvroq-from-the-us-market/
6. Vafseo. Package insert. Akebia Therapeutics, Inc.; 2024.
7. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO 2026 clinical practice guideline for the management of anemia in chronic kidney disease (CKD). Kidney Int. 2026;109(1):S1-S99. doi:10.1016/j.kint.2025.06.006
8. Chertow GM, Pergola PE, Farag YMK, et al. Vadadustat in patients with anemia and non-dialysis-dependent CKD. N Engl J Med. 2021;384(17):1589-1600. doi:10.1056/NEJMoa2035938
9. Niu Y, Wang T, Zhan Y, et al. Efficacy and safety of prolyl hydroxylase inhibitors for anemia in chronic kidney disease: a network meta-analysis. Ren Fail. 2026;48(1):2616572. doi:10.1080/0886022X.2026.2616572
10. Sackeyfio A, Lopes RD, Kovesdy CP, et al. Comparison of outcomes on hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) in anaemia associated with chronic kidney disease: network meta-analyses in dialysis and non-dialysis dependent populations. Clin Kidney J. 2023;17(1):sfad298. doi:10.1093/ckj/sfad298
11. Damarlapally N, Thimmappa V, Irfan H, et al. 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. Cureus. 2023;15(10):e47430. doi:10.7759/cureus.47430
12. Huang Q, You M, Huang W, et al. Comparative effectiveness and acceptability of HIF prolyl-hydroxylase inhibitors versus for anemia patients with chronic kidney disease undergoing dialysis: a systematic review and network meta-analysis. Front Pharmacol. 2023;14:1050412. doi:10.3389/fphar.2023.1050412
13. Chen D, Niu Y, Liu F, et al. Safety of HIF prolyl hydroxylase inhibitors for anemia in dialysis patients: a systematic review and network meta-analysis. Front Pharmacol. 2023;14:1163908. doi:10.3389/fphar.2023.1163908
14. Chen J, Shou X, Xu Y, et al. A network meta-analysis of the efficacy of hypoxia-inducible factor prolyl-hydroxylase inhibitors in dialysis chronic kidney disease. Aging (Albany NY). 2023;15(6):2237-2274. doi:10.18632/aging.204611
15. Huang Q, Liao Z, Liu X, Xia Y, Wang J. Efficacy and safety of vadadustat compared to darbepoetin alfa on anemia in patients with chronic kidney disease: a meta-analysis. Int Urol Nephrol. 2023;55(2):325-334. doi:10.1007/s11255-022-03316-z
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Prepared by:
Ena Kovač, PharmD, MPH, BS
PGY-1 Community-Based Pharmacy Resident
Walgreens/ University of Illinois at Chicago Retzky College of Pharmacy

Reviewed by:
Honey Joseph, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy

April 2026

The information presented is current as of March 3, 2026. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.