For more than 30 years, erythropoiesis-stimulating agents (ESAs) have reigned supreme as the treatment for chronic kidney disease (CKD)–related anemia. Can hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) topple ESAs? HIF-PHIs are oral medications taken three times a week or daily and have been shown in trials to achieve and maintain goal hemoglobin to the same degree as ESAs. HIF-PHIs are small molecules that inhibit the prolyl hydroxylase enzyme that continually marks the HIF for degradation. Each dose transiently increases intracellular HIF2a, a transcription factor, leading to activation of a series of genes, including erythropoietin (EPO) and several iron transport genes. Consequently, endogenous EPO levels increase, and iron absorption and mobilization are enhanced (Table 1).
Phase 3 clinical trials of the HIF-PHI roxadustat show that it can replace ESAs in the dialysis population for anemia management and can reduce intravenous iron requirements. Roxadustat reduced major adverse cardiovascular event (MACE) rates compared to ESA in incident dialysis patients and had similar MACE rates to ESA in prevalent patients receiving dialysis. In CKD trials versus placebo, roxadustat achieved goal hemoglobin and did not significantly increase MACE.
It may not be clear sailing for HIF-PHIs, however. Recent phase 3 randomized clinical trials of vadadustat showed that it could replace ESA in managing anemia but raised serious safety issues. Two international trials in patients with CKD found that vadadustat significantly increased MACE rates compared to the ESA darbepoetin (hazard ratio [HR] 1.17, confidence interval [CI] 1.01–1.36). In those trials, the hemoglobin target was 10–11 g/dL in the United States, and 10–12 g/dL in all non-US sites.
An analysis showed MACE was not increased in the vadadustat arm versus the ESA arm in US patients (HR 1.01, CI 0.83–1.23) but was increased with vadadustat compared to ESA in the non-US patients (HR 1.29, CI 1.03–1.60). In contrast, two vadadustat vs. ESA trials in the dialysis population showed comparable anemia management, and no increase in MACE compared to ESA therapy.
Whether safety differences in trials to date reflect unique actions of particular HIF-PHI agents, differences in trial designs, or other factors remains to be answered. Phase 3 randomized clinical trials with daprodustat, another HIF-PHI, are completed in dialysis patients, and results will be released later in 2021. The daprodustat trial in CKD non-dialysis patients should be completed in April 2021.
The author participated as a site investigator in trials of roxadustat and daprodustat and has been a consultant to the manufacturer of all three HIF-PHIs.
