#2768 DIFFERENT EFFECTS OF HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS ON SERUM LIPIDS LEVELS IN HEMODIALYSIS PATIENTS
Authors: Taira Takayasu 
Published: June 2023

Abstract

Background
The activity of hypoxia-inducible factor (HIF), an oxygen-sensitive transcription factor involved in erythropoiesis, is regulated by HIF-prolyl hydroxylases. With reduced oxygen tension, the activity of these enzymes is suppressed, resulting in increased erythropoiesis. Chen et al. reported that the decrease in that total cholesterol (TC) was greater with roxadustat than with epoetin alfa, as was the decrease in low density lipoprotein-cholesterol (LDL-C) in patients undergoing dialysis [1]. Csiky et al. reported roxadustat was superior to erythropoiesis-stimulating agent (ESA) in decreasing LDL-C levels from baseline in patients on dialysis [2]. Roxadustat is an oral HIF-prolyl hydroxylase inhibitor (HIF-PHI) developed for dialysis-dependent chronic kidney disease (CKD) anemia. While the impact of HIF-PHI on mean hemoglobin (Hb) change in patients on hemodialysis (HD) has been investigated [1], its effects on serum lipid levels have yet to be explored. Clarifying such effects is particularly important because HD patients usually have lower plasma high-density lipoprotein-cholesterol (HDL-C) levels than healthy individuals. Low HDL-C levels are associated with an increased risk of death in HD patients. The effects of HIF-PHIs on dyslipidemia in patients on HD are unclear. This study aimed to investigate the effects of HIF-PHIs on serum lipid levels in HD patients.

Methods
We investigated the effect of HIF-PHIs in three groups by measuring the levels Hb, serum TC, LDL-C, HDL-C, triglycerides (TG), iron, total iron-binding capacity (TIBC), transferrin saturation (TSAT), ferritin. Study 1: We evaluated the efficacy of roxadustat in 13 patients (1 female and 12 males) with HD-dependent CKD anemia and dyslipidemia over 24 weeks. Study 2: We evaluated the efficacy of daprodustat in 9 patients (2 females and 7 males) with HD-dependent CKD anemia and dyslipidemia over 24 weeks. Study 3: We evaluated the efficacy of enarodustat in 15 patients (3 females and 12 males) with HD-dependent CKD anemia and dyslipidemia over 12 weeks.

Results
Study 1: The mean age and mean HD vintage were 77.7 and 6.6 years, respectively. After roxadustat treatment, the mean Hb values (from 10.4 to 10.7 g/dL) did not significantly change. There were no significant changes in mean serum iron, TG, ferritin. However, the following parameters showed a significant decrease: mean TC (from 138.4 to 106.6 mg/dL, p = 0.0002), LDL-C (77.7 to 53.8 mg/dL, p = 0.0002), HDL-C (from 43.3 to 35.9 mg/dL, p = 0.0005), and TSAT (from 32.6 to 31.2%, p = 0.0479). There was a significant increases in the mean TIBC (from 220.5 to 265.1 μg/dL, p = 0.0002). Study 2: The mean age and mean HD vintage were 74.6 and 3.2 years, respectively. After daprodustat treatment, the mean Hb values did not significantly change. There were no significant changes in the mean TC, LDL-C, TG, TSAT, ferritin. However, the mean HDL-C levels showed a statistically significant decrease (from 50.4 to 45.3 mg/dL, p = 0.0117). Furthermore, there were significant increases in the serum iron level (from 72.5 to 89.1 μg/dL, p = 0.0078) and the mean TIBC level (from 229.7 to 272.8 μg/dL, p = 0.0039). Study 3: The mean age and mean HD vintage were 69.3 and 8.9 years, respectively. After enarodustat treatment, the mean Hb values did not significantly change. There were no significant changes in the mean TC, LDL-C, HDL-C, TG, TSAT, ferritin, iron. There was a significant increase in the mean TIBC (from 230.0 to 259.4 μg/dL, p = 0.0151).

Conclusions
We found that HIF-PHIs had different effects on serum lipids levels in HD patients. Roxadustat treatment improved iron metabolism stabilized Hb levels, and significantly decreased LDL-C levels. Daprodustat and enarodustat treatment improved iron metabolism, maintained stable Hb levels.