What oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors (HIF-PHIs) are used to treat anemia in patients with chronic kidney disease?

Oral HIF-PHI Agents for CKD Anemia

Six oral hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently available in various jurisdictions for treating anemia in chronic kidney disease: daprodustat, desidustat, enarodustat, molidustat, roxadustat, and vadadustat. 1

Available Agents and Mechanism

The six HIF-PHIs work by inhibiting prolyl hydroxylation, which stimulates endogenous erythropoietin (EPO) production primarily in the kidney and liver, while also enhancing iron absorption and utilization through hepcidin suppression 1. These agents achieve substantially lower peak serum EPO levels compared to injectable erythropoiesis-stimulating agents (ESAs), which may reduce cardiovascular risk associated with high ESA doses 1.

Key Advantages Over Injectable ESAs

• Oral administration eliminates the need for subcutaneous injections, particularly beneficial for non-dialysis and peritoneal dialysis patients 1
• Room temperature stability simplifies storage requirements 1
• Enhanced iron utilization through decreased hepcidin levels may improve efficacy in patients with chronic inflammation or functional iron deficiency 1
• Lower peak EPO exposure potentially reduces cardiovascular risks seen with high-dose ESAs 1

Efficacy Profile

Phase 3 trials demonstrate that all six HIF-PHIs are:

• Non-inferior to ESAs in achieving and maintaining target hemoglobin ranges 1
• Superior to placebo in correcting anemia 2, 3
• Effective across subgroups based on age, sex, race, and dialysis modality 1

Network meta-analyses show no clinically meaningful differences in hemoglobin response between daprodustat, roxadustat, and vadadustat in non-dialysis patients, though in dialysis patients, daprodustat and roxadustat showed slightly higher hemoglobin increases compared to vadadustat 4.

Dosing Approach

Starting Doses

• Lower starting doses for ESA-naïve patients compared to those transitioning from ESAs 1, 5
• Drug-specific dosing following manufacturer label recommendations, as marked differences exist in potency and pharmacokinetics between agents 1

Dose Adjustments

• Maintain or adjust doses stepwise based on current hemoglobin level and rate of change, typically assessed over 4-week periods 1
• Target hemoglobin range: 10-12 g/dL, consistent with current ESA guidelines 5
• Temporarily discontinue when hemoglobin exceeds 12-13 g/dL 1, 5

Critical Safety Considerations and Contraindications

Absolute Contraindications

Avoid HIF-PHIs in patients with:

• Active or recent malignancy - post-marketing surveillance is needed to confirm cancer risk; avoidance is recommended in patients with malignancy history 1
• Polycystic kidney disease - HIF activation may enhance cyst expansion based on preclinical models 1, 5
• Pediatric patients under 18 years - insufficient data as all phase 3 trials excluded children 1, 5

Use With Extreme Caution

Kidney transplant recipients:

• Limited experience with immunosuppression 1
• Potential concerns about graft rejection and malignancy risk due to HIF effects on immune cell function 1
• Kidney transplant recipients were excluded from roxadustat and vadadustat phase 3 trials 1

Agent-Specific Safety Concerns

Roxadustat:

• Approximately 2-fold increased risk of sepsis and septic shock in non-dialysis CKD patients 1
• Central hypothyroidism reported; Japanese regulatory agency added this to package insert due to molecular similarity to triiodothyronine (T3) 1

Drug-drug interactions:

• Risk present with all HIF-PHIs, particularly when combined with other oral agents 1

Theoretical Risks Not Yet Confirmed

• Diabetic retinopathy/macular degeneration - theoretical concern due to vascular endothelial growth factor upregulation, but not reported to worsen in trials to date 1
• Cardiovascular events - network meta-analyses show no clinically meaningful differences in major adverse cardiovascular events (MACE) risk between HIF-PHIs and ESAs 4, 3

Monitoring Requirements

• Regular hemoglobin monitoring to maintain 10-12 g/dL target 5
• Iron parameters including ferritin, transferrin saturation, and total iron binding capacity 1
• Thyroid function particularly with roxadustat 1
• Adherence assessment - more difficult than with in-clinic ESA administration 1

ESA-Hyporesponsive Patients

Limited evidence supports superiority in ESA-hyporesponsive patients despite theoretical advantages through hepcidin lowering 1. Preliminary data suggest HIF-PHIs may not require dose escalation with elevated C-reactive protein levels as ESAs do, but trial participants had only slightly elevated inflammatory markers 1.

Combination therapy with ESAs is not supported by available data and should not be used in clinical practice 1.

Comparative Considerations Between Agents

While no head-to-head trials directly compare the different HIF-PHIs 1, indirect comparisons suggest:

• Daprodustat may provide greater improvement in quality of life (SF-36 Vitality score) compared to roxadustat 4
• Cardiovascular safety appears comparable across agents, though precision of estimates is limited 4, 3
• Desidustat has more limited long-term cardiovascular safety data compared to roxadustat, vadadustat, and daprodustat 5