Introduction

The activity of Hypoxia-Inducible Factor (HIF), an oxygensensitive transcription factor involved in erythropoiesis, is regulated by HIF-prolyl hydroxylases. Reduced oxygen tension suppresses the activity of these enzymes, thereby increasing erythropoiesis. Chen et al. reported that the decrease in 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 long-term dialysis [1]. Chen et al. reported that in patients with chronic kidney disease who were not undergoing dialysis, TC levels decreased by 23% during eight weeks of roxadustat therapy [2]. Csiky et al. reported that roxadustat was superior to an erythropoiesis-stimulating agent (ESA) in decreasing LDL-C from baseline to an average of 12-28 weeks in patients with end-stage kidney disease on stable dialysis [3]. 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) levels in patients undergoing Hemodialysis (HD) has already been investigated [1], its effects on serum lipid levels have yet to be explored. Clarity regarding these effects is crucial because patients with chronic HD generally have lower plasma high-density lipoprotein cholesterol (HDL-C) levels than healthy participants. Low HDL-C levels are associated with an increased risk of death in patients undergoing chronic HD [4]. However, the effects of HIF-PHIs on dyslipidemia in patients undergoing HD remain unclear. This study aimed to investigate the effects of HIFPHIs on serum lipid levels in patients undergoing HD.

Materials and Methods

Study Design, Population, and Data Sources

To investigate the effects of HIF-PHIs, we measured the levels of Hb, serum TC, LDL-C, HDL-C, Triglycerides (TG), iron, Total Iron-Binding Capacity (TIBC), Transferrin Saturation (TSAT), and ferritin in all three groups. In Study 1, we evaluated the efficacy of roxadustat in 13 patients (1 female and 12 male) with hemodialysis-dependent CKD anemia and dyslipidemia over 24 weeks. We investigated Hb, TC, TG, LDL-C, HDL-C, iron, TIBC, TSAT, and ferritin levels. The patients were assigned an initial dose of roxadustat (20 mg/week ~ 200 mg/week), and they self-administered roxadustat at two- or three-day intervals. The doses were adjusted to maintain the Hb levels within 10-12 g/dL. In any case, the dose of roxadustat did not exceed 3 mg/kg. In Study 2, we evaluated the efficacy of daprodustat in nine patients (2 female and 7 male) with hemodialysis-dependent CKD anemia and dyslipidemia over 24 weeks. We investigated the levels of Hb and serum TC, TG, LDL-C, HDL-C, iron, TIBC, TSAT, and ferritin. Treatment with daprodustat (1 mg/week-40 mg/week) was initiated, and the dosage was adjusted daily within the 1-24 mg range to maintain Hb within the target range (10-12 g/dL).

In Study 3,we evaluated the efficacy of enarodustat in 15 patients (3 female and 12 male) with hemodialysis-dependent CKD anemia and dyslipidemia over 24 weeks. We investigated the levels of Hb and TC, TG, LDL-C, HDL-C, iron, TIBC, TSAT, and ferritin. The enarodustat dose was adjusted daily to within 1-8 mg range to maintain Hb within the target range (10-12 g/dL).

Statistical Analysis

Data are expressed as mean±standard deviation for continuous variables and frequency (percentage) for categorical variables. The Wilcoxon signed-rank test was used for proportional assessments. Statistical significance was set up at p < 0.05. All statistical analyses were performed using SAS Statistics software (version 9.4; SAS Institute, Cary, North Carolina, USA).

Ethics Statement

This study was approved by the ethics committee of the Zenjinkai Group (approval number: 0000408974) and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, the International Council Harmonization of Technical Requirements for Pharmaceuticals for Human Use guideline. Written informed consent was obtained from all patients before the study.

Results

In the Study 1 cohort, the mean age and HD vintage of the participant was 77.7 and 6.6 years, respectively (Table 1). After roxadustat treatment, no significant changes were observed in mean Hb values (from 10.4 to 10.7g/dL) or mean serum iron, TG, and ferritin levels. However, mean TC (from 138.4 to 106.6mg/dL, p=0.0002), LDL-C (from 77.7 to 53.8mg/dL, p=0.0002), HDL-C (from 43.3 to 35.9mg/dL, p=0.0005), and TSAT (from 32.6 to 31.2%, p=0.0479) decreased significantly. The mean TIBC levels increased significantly (from 220.5 to 265.1 μg/dL, p=0.0002) (Table 2).

Table 1: Baseline demographics and characteristics (N=37).

Hb: Hemoglobin; TIBC: Total Iron-Binding Capacity; TSAT: Transferrin Saturation; LDL-C: Low-Density Lipoprotein Cholesterol; HDL-C: High-Density Lipoprotein Cholesterol; TG Triglycerides (TG).

Table 2: Baseline demographics and characteristics in study 1 (roxadustat).

In Study 2 cohort, the mean age and HD vintage were 74.6 and 3.2 years, respectively (Table 1). After daprodustat treatment, no significant changes were observed in the mean Hb, TC, LDL-C, TG, TSAT, and ferritin levels. However, the mean HDL-C levels decreased significantly (from 50.4 to 45.3mg/dL, p=0.0117). Furthermore, 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) increased significantly (Table 3).

In Study 3cohort, the mean age and HD vintage were 69.3 and 8.9 years, respectively (Table 1). After enarodustat treatment, no significant changes were observed in the mean Hb, TC, LDL-C, HDL-C, TG, TSAT, ferritin, and iron levels. The mean TIBC increased significantly (from 230.0 to 259.4 μg/dL, p=0.0151) (Table 4).                          

Hb: Hemoglobin; TIBC: Total Iron-Binding Capacity; TSAT: Transferrin Saturation; LDL-C: Low-Density Lipoprotein Cholesterol; HDL-C: High-Density Lipoprotein Cholesterol; TG Triglycerides (TG).

Table 3: Baseline demographics and characteristics in study 2 (daprodustat).

Hb: Hemoglobin; TIBC: Total Iron-Binding Capacity; TSAT: Transferrin Saturation; LDL-C: Low-Density Lipoprotein Cholesterol; HDL-C: High-Density Lipoprotein Cholesterol; TG Triglycerides (TG).

Table 4: Baseline demographics and characteristics in study 3 (enarodustat).