What are the considerations for using desidustat in patients with anemia related to chronic kidney disease, particularly those with a history of cardiovascular disease?

Desidustat in CKD-Related Anemia with Cardiovascular Disease History

Desidustat can be used in patients with CKD-related anemia who have cardiovascular disease history, but critical cardiovascular safety data from large outcomes trials are lacking compared to other HIF-PHIs, and avoidance is mandatory in patients with active or recent malignancy. 1, 2

Efficacy Profile

Desidustat is non-inferior to ESAs for treating CKD-related anemia in both dialysis-dependent and non-dialysis patients. 1, 2

• In the DREAM-ND trial (non-dialysis patients), desidustat 100 mg three times weekly achieved a hemoglobin increase of 1.95 g/dL versus 1.83 g/dL with darbepoetin (difference: 0.11 g/dL; 95% CI: -0.12,0.34), meeting non-inferiority criteria. 1, 3

• Hemoglobin responders (≥1 g/dL increase) were significantly higher with desidustat (77.78%) compared to darbepoetin (68.48%, p=0.0181). 3

• In dialysis-dependent patients (DREAM-D), desidustat demonstrated similar non-inferiority with hemoglobin change of 0.95 g/dL versus 0.80 g/dL with epoetin alfa. 4

Cardiovascular Safety Considerations

The major limitation of desidustat is the absence of large cardiovascular outcomes trials comparable to daprodustat (ASCEND-ND), vadadustat, and roxadustat. 1, 2

• The three major phase 3 programs examining cardiovascular safety of HIF-PHIs (daprodustat, vadadustat, roxadustat) used non-inferiority designs with extensive cardiovascular endpoint data. 1

• Desidustat trials (DREAM-ND and DREAM-D) were shorter duration (24 weeks) and focused primarily on efficacy rather than cardiovascular outcomes. 1, 3, 4

• The theoretical advantage of avoiding high peak serum EPO concentrations seen with injectable ESAs may reduce cardiovascular risks, but this remains unproven for desidustat specifically. 1, 2

Practical Advantages

The oral route of administration provides significant benefit over injectable ESAs, particularly for non-dialysis and peritoneal dialysis patients. 1, 2

• Oral dosing eliminates injection-related pain and improves convenience. 1

• HIF-PHIs may enhance enteric iron absorption and iron utilization through hepcidin reduction, potentially beneficial in functional iron deficiency states. 1

• Desidustat significantly reduced hepcidin levels at weeks 12 and 24 compared to darbepoetin (p=0.0032 and p=0.0016, respectively). 3

Dosing and Monitoring Protocol

Start desidustat at 100 mg three times weekly for ESA-naïve patients, with dose adjustments based on hemoglobin response to maintain 10-12 g/dL. 1, 2, 3

• Monitor hemoglobin every 4 weeks during titration. 2

• Temporarily discontinue if hemoglobin exceeds 12-13 g/dL, following protocols similar to other HIF-PHIs. 1, 2

• Adjust doses in stepwise fashion based on current hemoglobin level and rate of change. 1

• Do not target hemoglobin levels higher than 10-12 g/dL, as available data do not support higher targets with HIF-PHIs than currently recommended for ESAs. 1, 2

Absolute Contraindications

Avoid desidustat in the following populations due to safety concerns or lack of data: 1, 2

• Polycystic kidney disease: HIF activation may enhance cyst expansion based on preclinical models. 1, 2

• Active or recent malignancy: Patients with history of recent or active malignancy were excluded from trials, and HIF pathway activation plays a role in tumor progression. 1

• Pediatric patients: All patients under 18 years were excluded from phase 3 trials. 1, 2

• Kidney transplant recipients: Limited data exist, and HIF-PHIs may affect immune cell function, potentially promoting graft rejection or malignancy. 1, 2

Additional Safety Monitoring

Monitor for potential adverse effects specific to the HIF-PHI class: 1

• Evaluate for drug-drug interactions when used with other oral medications. 1, 2

• The safety profile in DREAM-ND and DREAM-D showed predominantly mild adverse events with no deaths or serious adverse events directly attributed to desidustat. 3, 5, 4

• Unlike roxadustat, no specific signal for sepsis/septic shock or central hypothyroidism has been reported for desidustat, though post-marketing surveillance remains important. 1

Clinical Decision Algorithm for Cardiovascular Disease Patients

For CKD patients with cardiovascular disease history:

1. If no active/recent malignancy, not transplant recipient, and not polycystic kidney disease: Desidustat can be used, recognizing limited long-term cardiovascular safety data. 1, 2

2. If ESA-hyporesponsive due to inflammation: Consider desidustat as it may be more effective through hepcidin reduction, though data are limited. 1, 3

3. If requiring injectable therapy avoidance: Desidustat provides oral alternative with comparable efficacy to ESAs. 2, 3

4. If extensive cardiovascular disease with high-risk profile: Consider alternative HIF-PHIs with more robust cardiovascular outcomes data (daprodustat, vadadustat, roxadustat) if available in your region. 1