Side-Effect Profile of HIF-PHIs
Cardiovascular Events Thromboembolic Events Progression of Kidney Disease Hypertension and Hyperkalaemia Malignancy Retinopathy Cardiovascular Events Cardiovascular safety of HIF-PHIs in non-dialysis dependent CKD has not been definitively established ( Table 3 ). In contrast, with regards to cardiovascular events HIF-PHIs appear to be non inferior to conventional ESA in CKD patients on dialysis.
Hypertension and Hyperkalaemia
Cardiovascular Events
Cardiovascular safety of HIF-PHIs in non-dialysis dependent CKD has not been definitively established (Table 3). In contrast, with regards to cardiovascular events HIF-PHIs appear to be non inferior to conventional ESA in CKD patients on dialysis.
Table 3. Cardiovascular safety of HIF-PHI
Non-dialysis dependent CKD
| Trial | HIF-PHI | Comparator | MACE HR* |
| ASCEND-ND2 | Daprodustat | Darbepoetin alfa | 1.03 (0.89–1.19) |
| Pooled analysis15: - ALPS4 - ANDES5 - OLYMPUS6 |
Roxadustat | Placebo | 1.10 (0.96–1.27) |
| PRO2TECT8 | Vadadustat | Darbepoetin alfa | 1.17 (1.01–1.36) |
Dialysis dependent CKD
| Trial | HIF-PHI | Comparator | MACE HR* |
| ASCEND-D9 | Daprodustat | Darbepoetin alfa | 0.93 (0.81–1.07) |
| Pooled analysis15: - HIMALAYAS - PYRINEES - ROCKIES - SIERRAS |
Roxadustat | Epoetin or Darbepoetin alfa | 1.09 (0.95–1.26) |
| INNO2VATE | Vadadustat | Darbepoetin alfa | 0.96 (0.83–1.11) |
*HR of major adverse cardiovascular (MACE) event for HIF-PHI referenced to Comparator
Thromboembolic Events
HIF-PHI, particularly roxadustat, have been associated with increased risk of thrombotic events.16 It remains unclear whether this risk relates to rate of haemoglobin correction and whether dose adjustments to curtail the rate of raise of the haemoglobin concentration might reduce this risk.
Progression of Kidney Disease
Limited and contradictory data is available on the effect of HIF-PHI on CKD progression. No effect on GFR decline has been observed in trials involving daprodustat3 and vadadustat8, but accelerated rate of decline has been reported in a single phase 3 trial of roxadustat.12 Particular concern exists over the safety of HIF-PHI in CKD due to polycystic kidney disease, given the overexpression of HIF in animal models of the disease.17
Hypertension and Hyperkalaemia
Higher rates of hyperkalaemia have been reported for HIF PIHs in some studies.18 These results have, however, not been confirmed by larger trials. With regards to hypertension, so far, no significant blood pressure effects have been reported in any HIF-PHI phase 3 trials. Results from a dedicated blood pressure study with daprodustat (ASCEND-BP) are awaited.
Malignancy
The HIF pathway is an important mediator of malignancy progression through angiogenesis and cancer cell proliferation and survival,19 and a significant contributor to tumour growth in von Hippel-Lindau syndrome.20 As a result, HIF-PHIs may theoretically increase the risk of malignancy in at-risk patients; however, at present there exists limited data addressing the safety of these drugs in this patient group.
Retinopathy
Increased expression of VEGF by the HIF pathway has been associated with progression of diabetic retinopathy in murine models.21 Despite the theoretical risk posed to human patients living with diabetic kidney disease, no acceleration of retinopathy has been reported in human subjects living with diabetic kidney disease.
South African Nephrology Society (SANS). Consensus Statement on the Use of Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors (HIF-PHIs). South African Nephrology Society; 2023.