doi: 10.2169/internalmedicine.2501-23
Intern Med Advance Publication
http://internmed.jp【 ORIGINAL ARTICLE 】

The Comparison between Vadadustat and Daprodustat
Regarding Dose, Cost, and Safety of Treatment for Renal
Anemia in Non-dialysis Patients with Chronic Kidney
Diseases
Enyu Imai 1-3 and Atsuhiro Imai 4

Abstract:
Objective We retrospectively compared the dose, cost, and safety of vadadustat and daprodustat for thetreatment of renal anemia in patients with chronic kidney diseases who were not undergoing dialysis.
Methods The primary outcome of this study was the change in dose and cost from the initiation ofvadadustat and daprodustat treatment. The secondary outcome was the drug safety.
Patients We treated 30 patients each with the hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIFPHIs) daprodustat and vadadustat. The hemoglobin (Hb) concentration was targeted at 11-13 g/dL, andtransferrin saturation was maintained at !20%, as per the 2018 Japanese guidelines for the diagnosis andtreatment of chronic kidney disease.
Results Hb levels increased from 10.7 to 11.5 g/dL after the first month of daprodustat administration,
whereas those for vadadustat patients remained relatively stable, going from 10.7 to 10.6 g/dL. After six
months, the Hb level reached 12.1 g/dL and 11.3 g/dL for daprodustat and vadadustat, respectively. The dosage of vadadustat was significantly increased by 46% and 70% after 3 and 12 months, respectively, comparedwith the initial doses, whereas that of daprodustat did not change substantially. The average cost of vadadustat also increased in the first 3 months and remained over 500 yen/day after 3 months, while that of daprodustat showed little change from the initial cost of 360 yen/day.
Conclusion These results suggest that heterogeneity exists in the drug potency and dosage required fortreatment between daprodustat and vadadustat. Serious adverse events (death, cardiovascular disease, end
stage renal disease (ESRD), and malignancy) occurred in more than 20% of participants with both HIF-PHIs.
Further studies are required to confirm the safety of HIF-PHIs.
Key words: Renal anemia, HIF-PH inhibitor, dose, cost, safety(Intern Med Advance Publication)(DOI: 10.2169/internalmedicine.2501-23)

pacity and reduces fatigue in patients with CKD, as demonstrated by the amelioration of the cardiorespiratory function
in patients with CKD undergoing hemodialysis (2).
Hypoxia-inducible factor prolyl-hydroxylase inhibitors(HIF-PHIs) are novel drugs that activate the HIF oxygensensing pathway and promote erythropoiesis by activating
endogenous erythropoietin and inhibiting hepcidin gene expression (3, 4). HIF-PHIs and erythropoiesis-stimulating
agents (ESAs) are used clinically for the treatment of renal

Introduction
Renal anemia is a universal comorbidity of advanced
chronic kidney disease (CKD) and is associated with a reduced quality of life in patients afflicted by the disease. Renal anemia also triggers the progression of chronic heart
failure and CKD, known as cardiorenal anemia syndrome (1). Treatment of anemia improves the physical ca１

Nakayamadera Imai Clinic, Japan, ２ Fujita Health University School of Medicine, Japan, ３ Aichi Medical University School of Medicine, Japanand ４ Department of Nephrology, Osaka University Graduate School of Medicine, Japan
Received: June 26, 2023; Accepted: August 31, 2023; Advance Publication by J-STAGE: November 6, 2023
Correspondence to Dr. Enyu Imai, ads12069@nifty.com

1Intern Med Advance Publication

DOI: 10.2169/internalmedicine.2501-23

anemia. Japan is a leader in the treatment of renal anemia
via five HIF-PHIs (roxadustat, daprodustat, vadadustat,enarodustat, and molidustat), all of which are commerciallyavailable and approved by the Japan Pharmaceuticals andMedical Devices Agency (PMDA). Daprodustat was approved by the European Medicines Agency (EMA) and the
US Food and Drug Administration (USFDA/FDA). However, the FDA has approved it only for patients undergoing
dialysis.
The clinical doses and drug prices of the five HIF-PHIsvaried. The initial doses of roxadustat, daprodustat, vadadustat, enarodustat, and molidustat were 50, 2, 4, 2, 300, and25 mg, respectively, with initial doses costing 777.30,
179.70, 317, 366, 270.50, and 163.80 yen, respectively.
Roxadustat was administered three times per week, whereas
the other treatments were administered daily.
However, physicians with sufficient knowledge and experience in the use of ESAs are doubtful of the safety of HIFPHIs, expressing concern about the theoretical HIF-PHIinduced induction of vascular endothelial growth factor(VEGF), which can cause angiogenesis and vascular permeability (3, 4). These genes are associated with the growth ofexisting tumors and retinal neovascularization. Furthermore,thrombotic events increase with the use of HIF-PHIs and
ESAs (5-7). In a pooled analysis, the incidence of major adverse cardiac events(MACE) was significantly higher withvadadustat than with darbepoetin alfa (6, 8). Daprodustat has
not been approved by the FDA for patients not undergoing
dialysis because of the cardiovascular risk in the UnitedStates population (9).
We were interested in the differences in the efficacy andcost of renal anemia treatment among HIF-PHIs. We therefore retrospectively compared the doses and costs of
vadadustat and daprodustat for the treatment of renal anemia
in patients with CKD who were not undergoing dialysis. We
also studied the incidence of the adverse effects of vadadustat and daprodustat.

marketing surveillance of daprodustat were accepted. Ultimately, 11 patients treated with daprodustat were enrolled inthis study.
Clinically, we treated patients with HIF-PHIs by targetinga hemoglobin (Hb) level of 11-13 g/dL and a transferrin
saturation (TSAT) of !20%, according to the 2018 Guidelines for the Diagnosis and Treatment of Chronic Kidney
Disease (as published by the Japanese Society of Nephrology) (10).
The study protocol was approved by the Ethics Committee of Hyogo Medical Association (R4-005). As this study
was retrospective, we used an opt-out approach, and the requirement for written informed consent was waived. This
study was conducted in accordance with the principles of
the Declaration of Helsinki.
Patients’ follow-up and study outcomes

Patients visit every month for the treatment of CKD, including renal anemia. Clinical data were obtained from thepatients’ clinical records. We compared the values of Hb,ferritin, transferrin, TSAT, systolic blood pressure, serum potassium, HIF-PHI dose, and daily cost of HIF-PHIs between
patients treated with vadadustat and daprodustat. The primary outcome of this study was the difference in dose andcost between vadadustat and daprodustat after the initiationof treatment. The secondary outcomes were the drug safety,
BNP, serum potassium, and blood pressure, all of whichwere measured before initiating HIF-PHI treatment and at
six months post-treatment.
Statistical analyses

A t-test or Mann-Whitney U test was used to evaluate significant differences between the two groups. Multiple groupcomparisons were performed using Dunnett’s test. A oneway analysis of variance was performed, as indicated. Statistical significance was set at P <0.05 to indicate statisticalsignificance. Statistical analyses were performed using theGraphPad Prism 8.0 software program (GraphPad Software,
San Diego, CA, USA) or R 4.0.3. Data are expressed as themean ± standard deviation (SD) or median (interquartile
range).

Methods
Study protocol

Results

This was a retrospective, observational study. The
Nakayamadera Imai Clinic treats approximately 1,700 patients per month, 95% of whom have chronic noncommunicable diseases (mainly diabetes and CKD). The
number of patients with CKD stages G3b, G4, and G5 was235, 140, and 80, respectively. All patients treated withvadadustat or daprodustat between August 2020 and December 2022 were enrolled in this study. The first six patientswere treated with daprodustat, and the next five patientswere treated with vadadustat in August and September 2020.
We then accepted 10 cases of post-marketing surveillance
for daprodustat. Subsequently, 25 cases of post-marketingsurveillance for vadadustat were performed. After completing the vadadustat study, three additional cases of post-

Participants

We enrolled all the patients treated with either vadadustat
or daprodustat between August 2020 and December 2022.
Sixty patients were administered either vadadustat or daprodustat during this period. The mean age of all participants
was 75.5 years old, and 61.6% of them were men. Clinicalcharacteristics relevant to renal anemia were similar between
the groups (Table 1). The participants had advanced CKD
with a mean estimated glomerular filtration rate (eGFR) of
15 mL/min/1.73 m2. At baseline, the mean TSAT was 31%,with a mean serum ferritin level of 159 ng/mL, indicating
2

Intern Med Advance Publication
Table 1.

DOI: 10.2169/internalmedicine.2501-23

Baseline Characteristics of Patients.

Age (y.o)Sex (n(%))
Follow-up period (months)sBP (mmHg)
Cre (mg/dL)
eGFR (mL/min/1.73m2)
CKD stage
1 (n(%))
2 (n(%))
3a (n(%))
3b (n(%))
4 (n(%))
5 (n(%))Hb (g/dL)
Fe (μg/dL)
TIBC (μg/dL)
TSAT (%)
Ferritin (ng/mL)
Albumin (g/dL)
BNP (pg/mL)
K (mEq/L)
Cause of kidney disease
diabetes (n(%))
nephrosclerosis (n(%))
CGN (n(%))
ADPKD (n(%))
other (n(%))
Patients on peritoneal dialysis (n(%))
Previous treatment for renal anemia
epoetin beta pegol (n(%))
other HIF-PHIs (n(%))
no treatment (n(%))

Daprodustat (n=30)

Vadadustat (n=30)

p value

76±8
19 (63.3)
14 [13, 22.75]
133±15.
2.96 [2.01, 4.47]
15.0 [11.1, 24.4]

75±11
18 (60)16 [9, 16.75]
131±17
2.91 [1.71, 4.71]
15.6 [9.5, 30.7]

0.70
1.00
0.39
0.61
0.87
0.94

0 (0)
0 (0)
2 (6.7)2 (6.7)
11 (36.7)
15 (50)10.7±1.187.7±36.8
286.0±53.4
30.9±12.2
164±1073.7±0.6
48 [31, 124]
4.7±0.5

0 (0)
0 (0)
0 (0)
9 (30)
6 (20)
15 (50)10.7±0.885.3±22.2
278.4±50.8
31.1±8.5
154±903.7±0.5
44 [20, 76]
4.6±0.6

0.93
0.76
0.57
0.97
0.67
0.98
0.44
0.53

6 (20.0)
14 (46.7)
4 (13.3)0 (0)6 (20)
4 (13.3)

9 (33.3)
14 (46.7)
1 (3.3)3 (10)
3 (10)
4 (13.3)

0.55
1.00
0.35
0.24
0.47
1.00

16 (53.3)
5 (16.7)
9 (30)

21 (70)3 (10)
6 (20)

0.29
0.71
0.55

Mean±SD, median [interquartile range], or n (%)

that the iron status for erythropoiesis was adequate.

were 180 and 317 yen, respectively. The average cost of
vadadustat at 3 months was 565 yen, which was significantly higher than that of daprodustat (361 yen after 3
months). At 6 months, the costs of vadadustat and daprodustat were 551 and 327 yen, respectively. At 12 months, theaverage cost of vadadustat was 634 yen, which was morethan double that of daprodustat (316 yen) (Fig. 4).

Outcomes

The mean Hb level increased from a baseline of 10.7 to11.5 g/dL at 1 month in the daprodustat group but showedno marked difference at the same point in the vadaustat
group (10.7 to 10.6 g/dL). However, the mean Hb level increased gradually and reached 12.1 g/dL in the daprodustat
group and as high as 11.3 g/dL in the vadadustat group at 6
months post-commencement of the study (Fig. 1).
Doses of daprodustat did not substantially change
throughout the study period, while the doses of vadadustat
significantly increased by 31% (394 mg) after 1 month, 46%(436 mg) after 3 months, and 70% (510 mg) after 12months (Fig. 2).
The cost of treatment for renal anemia was significantly
higher in patients receiving vadadustat than in those receiving daprodustat at all time points (Fig. 3). The price of
vadadustat at an initial dose of 300 mg was 366 yen, which
was higher than that of daprodustat. The initial doses of
daprodustat 2 mg (Hb !9 g/dL) and 4 mg (Hb <9 g/dL)

SafetyThe safety profiles of the two HIF-PHIs are listed in Table 2. Two patients administered daprodustat and three patients administered vadadustat died during the study period.
The cause of death for those receiving daprodustat wasacute heart failure due to aortic valve stenosis and cerebral
hemorrhaging. The causes of death in the patients receiving
vadadustat were pancreatic cancer and chronic renal failure(one patient on peritoneal dialysis and one patient undergoing conservative kidney management).
Two patients who received daprodustat experienced heart
failure (one died, as mentioned above). Three patients receiving vadadustat had malignancies [colon cancer, pancre3

Intern Med Advance Publication

DOI: 10.2169/internalmedicine.2501-23

****

ns
ns

ns

ns ns

Ref

Ref

ns
Ref

Ref

Ref

** ***

**

ns
ns ns

ns

*

**

ns

ns

24
16

24
15

Ref

Ref Ref

Daprodustat (n) 30 30 30 29
Vadadustat (n) 30 27 22 22

Daprodustat (n) 30 29 28 29
Vadadustat (n) 30 27 22 22

24
16

24
15

26
20

Figure 2. Changes in the HIF-PHI dose for treating renal
anemia. Patients with advanced CKD who were not on dialysis
were treated with daprodustat (n=30) or vadadustat (n=30)
and followed for 12 months. All results are presented as themean ± SDs; ns: not significant; Ref: reference. *p<0.05,**p<0.01, ***p<0.001, ****p<0.0001, ANOVA followed byDunnett’s post hoc test.

Figure 1. Change in Hb levels after treatment with HIF-PHI.
Patients with advanced CKD who were not on dialysis weretreated with daprodustat (n=30) or vadadustat (n=30) and followed for 12 months. All results are presented as the mean ±SDs; ns: not significant; Ref: reference. The multiple t-test wasapplied with Bonferroni’ correction, and a p-value <0.01 indicates statistical significance.

******* ****

*
Ref

***

ns

ns

ns

***

ns

ns

*

****
**

***

Ref

**

**

ns

ns

ns

24
16

24
15

ns ns

ns

Ref

ns

Ref

Daprodustat (n) 30 30 30 29
Vadadustat (n) 30 27 22 22

26
20

Daprodustat (n) 30 30 30 29
Vadadustat (n) 30 27 22 22

26
20

24
16

24
15

Figure 4. Daily cost of HIF-PHI after treatment of renal anemia. Patients with advanced CKD who were not on dialysis
were treated with daprodustat (n=30) or vadadustat (n=30)
and followed for 12 months. All results are presented as themean ± SDs; ns: not significant. *p<0.05, **p<0.01, ***p<0.001,****p<0.0001, ANOVA followed by Dunnett’s post hoc test.

Figure 3. The mean percent change in the HIF-PHI dose after treatment of renal anemia. Patients with advanced CKD
who were not on dialysis were treated with daprodustat (n=30)
or vadadustat (n=30) and followed for 12 months. All results
are presented as the mean ± SDs; ns: not significant; Ref: reference. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, ANOVA
followed by Dunnett’s post hoc test.

Discussion

atic cancer (having died, as mentioned above), andmyeloma].
Six patients treated with daprodustat and four patientstreated with vadadustat developed ESRD. Their mean eGFR
at baseline was 10.0±2.9 mL/min/1.73 m2. Three patients
discontinued vadadustat owing to allergic reactions. Threepatients discontinued vadadustat because of persistent diarrhea. The diarrhea was exacerbated by increasing the doseof vadadustat. No adverse gastrointestinal effects were observed after daprodustat treatment.

We observed slow and mild erythropoiesis with vadadustat during the first three months of treatment compared todaprodustat. The mean Hb level of vadadustat did not increase at 1 month and increased to 11.3 g/dL at 3 months,
which was 1 g/dL lower than that of daprodustat. Becauseof the slow erythropoiesis associated with vadadustat, itsdose was increased by 46% at 3 months and reached 70%
higher than the initial dose at 12 months. The daily cost of
vadadustat was significantly higher than that of daprodustat
at all the time points during the study period.
4Intern Med Advance Publication
Table 2.

DOI: 10.2169/internalmedicine.2501-23

Adverse Effects.
Daprodustat (n=30)

Death (n (%))
Acute heart failure
Cerebral Hemorrhage
Chronic renal failure
Cancer2 (6.6%)
1 (3.3%)1 (3.3%)0 (0%)

Vadadustat (n=30)
3 (10%)
0 (0%)
0 (0%)
2 (6.6%)0 (0%)

Heart failure (n (%))

2 (6.6%)0 (0%)ESRD (n (%))
HDPD

6 (20%)

4 (13.3%)
5 (16.7%)
1 (3.3%)

Malignancy (n (%))
Pancreas Cancer
Colon Cancer
Myeloma

0 (0%)
0 (0%)
0 (0%)
0 (0%)

Medication discontinuation (Exc cancer) (n (%))
Allergy (Drug eruption)
DiarrheaDizziness

0 (0%)
0 (0%)
0 (0%)
0 (0%)

1 (3.3%)2 (6.6%)2 (6.6%)

3 (10%)
1 (3.3%)1 (3.3%)1 (3.3%)7 (23.3%)
3 (10%)
3 (10%)
1 (3.3%)

Slow erythropoiesis with vadadustat, particularly in patients previously treated with ESA, was also observed inphase III trials when compared with darbepoetin
alfa (8, 11). In a Japanese phase III trial of vadadustat, Hblevels did not increase in the initial six weeks in patients
who had previously used ESAs (11). In patients previously
treated with ESAs, the dose of vadadustat was increased to
450 mg after 8 weeks. These results suggest that slow
erythropoiesis is characteristic of vadadustat at the initiationof treatment. Slow erythropoiesis has not been reported withdaprodustat in patients with CKD or in those on dialysis (12, 13). The reason for slow erythropoiesis remains unclear. The initial dose of vadadustat (300 mg) was approximately 100 times larger than that of daprodustat. Differencesin drug potency may contribute to differences in responses
to erythropoiesis. The initial dose of vadadustat may havebeen too low to increase Hb levels in the first month because Hb levels increased after administration of higher
doses of vadadustat (450 mg or 600 mg). In a phase II
study, vadadustat was initiated at 450 mg, and by the second
week, the mean Hb levels had increased significantly frombaseline, further increasing by 0.5 g/dL by the fourthweek (14).
Differences in potency between vadadustat and daprodustat were observed, with several possible causes. First, absorption and distribution differ among drugs. The maximum
plasma concentration (Cmax) of 300 mg of vadadustat and 5
mg of daprodustat after repeated administration represent anapproximate 425 times difference (vadadustat 39.6 μg/mL vsdaprodustat 93.0 ng/mL). Second, the inhibition of prolylhydroxylase domain (PHD)3 was stronger than that of PHD
2 by vadadustat, whereas inhibition by daprodustat was

equal between PHD2 and PHD3. Consequently, the stabilization of HIF-2a by vadadustat is greater than that by HIF-1
a, whereas daprodustat stabilizes both HIF-1a and HIF-2a
equally (15). Interestingly, the target Hb levels for the treatment of anemia differ between countries. In the PRO2TECT
study, the risk of cardiovascular events in non-US countries
was significantly higher than that in the US (8). In thatstudy, the target Hb level was 10-11 g/dL in the UnitedStates (US) and 10-12 g/dL in other countries. The target
Hb level was therefore not consistent among countries, although the initial dose of vadadustat was 300 mg, which issimilar to the initial dose in Japan. The lower target Hblevel allowed the use of less vadadustat in the US, as there
might be fewer recorded cardiovascular adverse events there
than in non-US countries (8). In the present study, the target
Hb level was 11-13 g/dL, set according to the 2018 Japanese CKD guidelines (10); this required a relatively highdose of vadadustat. A high dose of vadadustat may cause ahigh incidence of adverse events, particularly cardiovasculardisease. Furthermore, our results suggest that the initial doseof 300 mg vadadustat may have been too low to target andmaintain Hb levels of 11-13 g/dL. The Japanese Guidelines
for the Diagnosis and Treatment of Chronic Kidney Disease
were revised in June 2023 (16), and the target Hb level forthe treatment of renal anemia was reduced to 10-13 g/dL.
This may improve the gap between guideline recommendations and real-world clinical practice. Furthermore, it may
reduce the adverse events caused by vadadustat.
Serious adverse events (death, cardiovascular disease,
ESRD, and malignancy) occurred in >20% of the participants in our study. HIF-PHIs and ESA potentially cause
thromboembolic diseases, such as myocardial infarction,
5

Intern Med Advance Publication

DOI: 10.2169/internalmedicine.2501-23

deep vein thrombosis, and cerebral infarction. It was reported that vadadustat did not meet its pre-specified noninferiority margin with respect to MACE (hazard ratio=1.17,
95% confidence interval=1.01-1.36) compared to darbepoetin alfa, suggesting a higher risk of MACE in vadadustat
cases than darbepoetin alfa (8). The incidence of thromboembolic diseases was, however, reported to be <1% forboth vadadustat and daprodustat (8, 10). In addition, recent
meta-analyses did not show a statistically significant difference between HIF-PHIs and placebo agents in terms of allcause mortality and MACE (15).
Daprodustat has only been approved by the FDA for use
in CKD patients on dialysis, not for those not on dialysis (18). This is because the hazard ratio of cardiovascular
endpoints was higher than 1.0 in daprodustat compared withdarbepoetin alfa in the ACEND-ND trial (10). The US population showed significantly greater hazard ratios for all-cause
mortality, hospitalization for heart failure, and thromboembolic events in cases of daprodustat use than in those of darbepoetin alfa use compared to the non-US population, although the target Hb level was the same (10-11 g/dL) inboth the US and non-US populations (9). In a meta-analysis,
the overall effect of daprodustat in increasing the risk of
hospitalization for heart failure was similar between daprodustat and ESAs, and the results were consistent between
the ASCEND-ND and ASCEND-D subgroups (20). In apooled analysis of Japanese patients (n = 369), the incidence
rate of heart failure events was nominally lower in the
daprodustat group than in the ESA group (21). These results
suggest a difference in susceptibility to cardiovascular diseases between US and non-US populations. The incidenceof cardiovascular diseases, particularly myocardial infarction
and heart failure, in the CKD population differed significantly between the US and Japan (22). In our study, 2 of the
30 patients treated with daprodustat developed heart failurethat required hospitalization. Further studies are needed toclarify concerns regarding heart failure.
Malignancy was observed after vadadustat treatment in
the present study. As mentioned above, the HIF pathway potentially activates tumor growth (3, 4). In ASCEND-ND,
cancer-related death, tumor progression, and recurrence weremore commonly observed with daprodustat than with darbepoetin alfa, with a relative risk of 1.47 (95% confidence interval=1.03-2.01) (12, 19). However, the increased risk ofcancer-related adverse events was attributed to differences indosing intervals between randomized treatment arms (19).
Increases in malignancy-related risks have not been observedwith vadadustat (8, 11).
Diarrhea is a common adverse event in HIF-PHI and isobserved more frequently with HIF-PHIs than with
ESAs (17). The incidence rate of diarrhea was higher in thevadadustat group in the present study and was aggravated bydose escalation. Elevated serum potassium levels and bloodpressure have been reported in patients with HIF-PHI and
ESA treatment. Hyperkalemia and hypertension were notobserved in the present study.

In the present study, the cost of vadadustat for the treatment of renal anemia was significantly higher than that of
daprodustat alone. Regarding the reasons for this, the cost of
vadadustat in the first month was higher than that of daprodustat, as the cost of the initial dose of vadadustat was 366
yen higher than that of daprodustat [180 yen (2 mg) or 317
yen (4 mg)]. The dosage then had to be increased in thesecond month for 48.1% of patients receiving vadadustat because their Hb levels remained unchanged after the firstmonth. The dosage of vadadustat was further increased in
78.3% of the patients after the third month because slow
erythropoiesis continued throughout the second month. The
maximum dose of vadadustat is often required to maintainan Hb level of 11-13 g/dL. In fact, the maximum dose ofvadadustat [600 mg (732 yen)] was required by 45.5% and53.3% of the participants after 6 and 12 months, respectively. In contrast, 70% of the patients treated with daprodustat were administered an initial dose of 4 mg (317 yen)or less after 3 months. Taken together, these findings indicate that daprodustat had a lower cost of treatment for renal
anemia than vadadustat.
Several limitations associated with the present study warrant mention. First, this was a retrospective observational
study conducted at a single center. Therefore, randomization
could not be performed. Second, the sample size of thisstudy was small. Subtle changes in the clinical parameters
may not be detected in some patients; therefore, a real-worldprospective multicenter study is warranted.
In conclusion, we retrospectively compared changes in thedose and cost over 12 months between vadadustat anddaprodustat in patients with CKD not currently undergoing
dialysis. The dose of vadadustat was significantly increased
from the initial dose after the first three months and persisted after nine months, whereas that of daprodustat did notchange substantially. The average cost of vadadustat also increased in the first 3 months and remained over 500 yen/day
after 3 months, while that of daprodustat did not change
markedly compared with the initial cost of 360 yen/day.
These results show that heterogeneity was present among
HIF-PHIs. The difference in costs between drugs should beconsidered when treating renal anemia. Serious adverse
events (death, cardiovascular disease, and malignancy) wereobserved with both daprodustat and vadadustat. Further
studies will be required to confirm the safety of HIF-PHIs.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We would like to thank Editage (www.editage.jp) for the English language editing.

References
1. Silverberg DS, Wexler D, Iaina A, Steinbruch S, Wollman Y,
Schwartz D. : Anemia, chronic renal disease and congestive heart
failure--the cardio renal anemia syndrome: the need for coopera-

6Intern Med Advance Publication

DOI: 10.2169/internalmedicine.2501-23

J Med 385: 2313-2324, 2021.
13. Nangaku M, Hamano T, Akizawa T, et al. Daprodustat Comparedwith Epoetin Beta Pegol for Anemia in Japanese Patients Not on
Dialysis: A 52-Week Randomized Open-Label Phase 3. Trial Am J
Nephrol 52: 26-35, 2021.
14. Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH.
Vadadustat, a novel oral HIF stabilizer, provides effective anemia
treatment in nondialysis-dependent chronic kidney disease. Kidney
Int 90: 1115-1122, 2016.
15. Haase VH. HIF-prolyl hydroxylases as therapeutic targets inerythropoiesis and iron metabolism. Hemodial Int 21: S110-S124,
2017.
16. Japanese Society of Nephrology. The guideline for the diagnosis
and treatment of chronic kidney disease. 2023.
17. Mohamed MMG, Oyenuga M, Shaikh S, Oyenuga A, Kheiri B,
Nwankwo C. Hypoxia inducible factorprolyl hydroxylase inhibitors in anemic patients with non-dialysis dependent chronic kidneydisease: a meta-analysis of randomized clinical trials. Int Urol
Nephrol 55: 167-171, 2023.
18. [cited 2023 May 31]. Available from: https://www.fda.gov/advisor
y-committees/advisory-committee-calendar / updated-contact-inform
ation-october-26-2022-meeting-cardiovascular-and-renal-drugs-advisory.
19. Singh AK, Causland FRM, Claggett BL, et al. Analysis of ontreatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents - post hoc analyses of the
ASCEND-ND and ASCEND-D trials. Nephrol Dial Transplantgfac342, 2022, DOI: 10.1093/ndt/gfac342
20. Fatima K, Ahmed W, Fatimi AS, et al. Evaluating the safety andefficacy of daprodustat for anemia of chronic kidney disease: ameta-analysis of randomized clinical trials. Eur J Clin Pharmacol
78: 1867-1875, 2022.
21. Nangaku M, Akizawa T, Nagakubo T, et al. Safety of daprodustat
in patients with anemia of chronic kidney disease: A pooled analysis of phase 3 studies in Japan. Ther Apher Dial 26: 1065-1078,
2022.
22. Tanaka K, Watanabe T, Takeuchi A, et al; CKD-JAC Investigators.
Cardiovascular events and death in Japanese patients with chronic
kidney disease. Kidney Int 91: 227-234, 2017.

tion between cardiologists and nephrologists. Int Urol Nephrol 38:
295-310, 2006.
2. Macdougall IC, Lewis NP, Saunders MJ, et al. Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet 335: 489-493, 1990.
3. Sugahara M, Tanaka T, Nangaku M. Future perspectives of anemia
management in chronic kidney disease using hypoxia-inducible
factor-prolyl hydroxylase inhibitors. Pharmacol Ther 239: 108272,
2022.
4. Locatelli F, Del Vecchio L. Hypoxia-Inducible Factor-Prolyl Hydroxyl Domain Inhibitors: From Theoretical Superiority to ClinicalNoninferiority Compared with Current ESAs? J Am Soc Nephrol
33: 1966-1979, 2022.
5. Provenzano R, Szczech L, Leong R, et al. Efficacy and Cardiovascular Safety of Roxadustat for Treatment of Anemia in Patientswith Non-Dialysis-Dependent CKD: Pooled Results of Three Randomized Clinical Trials. Clin J Am Soc Nephrol 16: 1190-1200,
2021.
6. US Food and Drug Administration. Roxadustat for the treatmentof anemia due to chronic kidney disease in adult patients not on
dialysis and on dialysis. FDA Presentation: Cardiovascular andRenal Drugs Advisory Committee Meeting [Internet]. [updated
2021 Jul 15; cited 2023 May 27]. Available from: https://www.fda.
gov/media/150756/download.
7. Akebia Therapeutics Inc. Press Release. Akebia Therapeutics receives complete response letter from the FDA for vadadustat for
the treatment of anemia due to chronic kidney disease in adult patients. https://ir.akebia.com/news-releases/news-release-details/akebi
a-therapeutics-receives-complete-response-letter-fda.
8. Chertow GM, Pergola PE, Farag YMK, et al. Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD. N Engl J
Med 384: 1589-1600, 2021.
9. [cited 2023 May 31]. Available from: https://www.fda.gov/advisor
y-committees/advisory-committee-calendar / updated-contact-inform
ation-october-26-2022-meeting-cardiovascular-and-renal-drugs-advisory.
10. Japanese Society of Nephrology. The guideline for the diagnosis
and treatment of chronic kidney disease 2018. Tokyo Igakusya,
Topkyo, 2018.
11. Nangaku M, Kondo K, Kokado Y, et al. Phase 3 Randomized
Study Comparing Vadadustat with Darbepoetin Alfa for Anemia inJapanese Patients with Nondialysis-Dependent CKD. J Am Soc
Nephrol 32: 1779-1790, 2021.
12. Singh AK, Carroll K, McMurray JJV, et al. Daprodustat for theTreatment of Anemia in Patients Not Undergoing Dialysis. N Engl

The Internal Medicine is an Open Access journal distributed under the Creative
Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Toview the details of this license, please visit (https://creativecommons.org/licenses/
by-nc-nd/4.0/).

Ⓒ The Japanese Society of Internal Medicine
Intern Med Advance Publication

7