Hypoxia-inducible Factor Prolyl Hydroxylase Inhibitors and Hypothyroidism: An Analysis of the Japanese Pharmacovigilance Database

Abstract

Background/Aim

Hypothyroidism induced by roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, was recently reported; however, information regarding roxadustat-associated hypothyroidism is still lacking. We explored the risk and time to onset of hypothyroidism associated with HIF-PH inhibitors using the Japanese Adverse Drug Event Report (JADER), a pharmacovigilance database.

Patients and Methods

The participants of this study were registered in the JADER database between April 2004 and March 2023. The association between HIF-PH inhibitors and hypothyroidism was evaluated using the reporting odds ratio (ROR) and information component (IC). We also calculated the period from the start of drug administration to the onset of hypothyroidism and determined the onset pattern using Weibull distribution.

Results

Roxadustat had positive signals for hypothyroidism among the HIF-PH inhibitors based on the ROR [31.03, 95% confidence interval (CI)=27.81-34.62] and IC (4.51, 95%CI=4.36-4.67) values, and a strong relationship was confirmed. In addition, the median time to roxadustat-associated hypothyroidism onset was 92 days, and over 50% of cases occurred within 100 days of starting treatment. Furthermore, the onset pattern was an early failure type.

Conclusion

There is a possible association between roxadustat and hypothyroidism. Therefore, enhanced thyroid function testing within 100 days of treatment initiation may help detect roxadustat-associated hypothyroidism. However, further research is required to confirm these findings, considering study limitations using databases of spontaneous adverse event reports.

The number of patients with chronic kidney disease (CKD) is expected to increase in an aging population. Renal anemia is caused by decreased erythropoietin production as renal function declines in patients with CKD, including those receiving hemodialysis. It affects the quality of life of patients with CKD and may increase cardiovascular disease-related morbidity, mortality, and risk of hospitalization. Treatment guidelines for renal anemia in Japan, the United States, and Europe have set target treatment levels for hemoglobin from the perspective of life prognosis (1-3). Renal anemia is conventionally treated using erythropoiesis-stimulating agents (ESA), iron preparations, or a combination (1). However, ESA is administered intravenously or subcutaneously, which can be painful for patients.

Hypoxia-inducible factor (HIF) is a transcription factor that is activated when cells are hypoxic. It is involved in the transcription of several genes, including erythropoietin, and is rapidly degraded by HIF prolyl hydroxylase (HIF-PH) under normal oxygen conditions. HIF-PH inhibition stabilizes HIF and stimulates endogenous erythropoietin production (4). Therefore, HIF-PH inhibitors have attracted attention as a new therapeutic strategy for renal anemia. Roxadustat was the first HIF-PH inhibitor to be clinically used worldwide and was approved for manufacturing and marketing in Japan in September 2019. Since then, five HIF-PH inhibitors have become available in Japan.

Roxadustat is as effective as ESA therapy for treating renal anemia in hemodialysis and non-hemodialysis patients (5,6). However, information regarding its adverse effects is scarce since clinical use of HIF-PH inhibitors began recently. Early clinical studies suggest a higher frequency of hyperkalemia and metabolic acidosis in the roxadustat group than in the placebo group; however, no thyroid-related adverse events were reported (5,6). Notably, roxadustat may affect thyroid function (4,7-9). It has a molecular structure similar to 3,3’,5-triiodothyronine (T3) and may cause decreased serum free thyroxine (FT4) and free T3 (FT3) levels by inhibiting thyroid-stimulating hormone (TSH) secretion as a thyroid hormone receptor (THR) β selective activator (10). In November 2022, the Japanese package insert of roxadustat was updated to include central hypothyroidism as a clinically significant adverse reaction. Hypothyroidism was also reported in post-marketing surveillance of daprodustat, another HIF-PH inhibitor. Furthermore, it may be more frequent in the roxadustat group than in the daprodustat group (11,12). However, the relationship between HIF-PH inhibitors and hypothyroidism remains unclear, and substantial data are lacking.

Various analyses using pharmacovigilance databases were recently performed worldwide, and the results greatly contribute to the proper use of pharmaceuticals (13-15). In Japan, the Japanese Adverse Drug Event Report (JADER) database is maintained by the Pharmaceuticals and Medical Devices Agency (PMDA) and is open to anyone free of charge. Therefore, we elucidated the association between HIF-PH inhibitor use and hypothyroidism and the time to onset of hypothyroidism using data from the JADER database.

Patients and Methods

Data source. The participants of this study were registered in the JADER database between April 2004 and March 2023. The data stored in the JADER database was downloaded from the PMDA website (https://www.pmda.go.jp/index.html) as four CSV files ("Demo", "Drug", "Reac", and "Hist"). The Demo file contains demographic information, such as the patient's age, sex, weight, height, and the year reported. The "Drug" file contains information about the drug name, administration start date, and end date. In addition, drugs registered in this file are classified as "suspected drug", "concomitant drug", or "drug interaction", depending on the level of adverse events in each case. The "Reac" file contains information about the adverse events that occurred in the patient, its onset date, and clinical outcomes. The "Hist" file contains information about the patient's medical history. All data contained in these four files can be concatenated using identification numbers.

Survey content. The drugs of interest in this study were the five HIF-PH inhibitors (roxadustat, daprodustat, vadadustat, enarodustat, and molidustat) used in Japan. Considering the potential risk of hypothyroidism in patients with CKD, ESA was also investigated as a negative control. Only cases of "suspected drug" involvement were included in the analysis. Generally, adverse events in the JADER database are based on preferred terms (PTs) in the Medical Dictionary for Regulatory Activities/Japanese version (MedDRA/J) 26.0. "Hypothyroidism" was defined according to the standardized MedDRA queries (SMQ) (SMQ code: 2000160, containing 101 PTs).

Signal detection. We used the JADER, a database of spontaneous adverse event reports, and performed a disproportionality analysis based on the case/non-case method. In other words, we examined the association between drugs and adverse events by evaluating whether there was disproportionality in the reporting rate of specific adverse events depending on the target drug and other drugs. Reporting odds ratio (ROR) and information component (IC) were selected as a frequency-based method and as a Bayesian method, respectively (17). Both indicators were calculated by creating a 2×2 contingency table, defined as positive when the lower limit of the 95% confidence interval (CI) of the ROR was >1 and that of the IC was >0.

Time-to-onset analysis. The time to onset of adverse events was analyzed for cases in which the start date of HIF-PH inhibitor administration and the date of hypothyroidism onset were recorded. Additionally, the onset pattern of the adverse events was evaluated by applying the shape parameters of Weibull distribution. Weibull shape parameter (WSP) represents the failure rate distribution concerning time, and the failure rate corresponds to adverse reaction development. The onset pattern of the adverse event is a random failure type when the WSP is 1, which develops at a constant pace. A WSP of <1 represents the early failure type, and the incidence decreases with time. A WSP of >1 represents the wear-out failure type, and the incidence increases with time (13). Furthermore, the influence of sex, age group, and clinical outcomes on the time to onset of hypothyroidism was evaluated using Kaplan-Meier method and Log-rank test.

Ethical considerations. This study did not require approval from an ethics committee since it used open data downloaded from the PMDA website.

Statistical analyses. All statistical analyses were performed using JMP pro 17.0 (SAS Institute Inc., Cary, NC, USA). Differences at p-value <0.05 were considered to be statistically significant.

Results

Data analyzed. A total of 846,693 cases were registered in the JADER database during the investigation period. Hypothyroidism was reported as an adverse event in 6,061 cases, and HIF-PH inhibitors were reported as suspected drugs in 419 cases. Among the HIF-PH inhibitors, roxadustat (n=410) was the most frequently reported cause of hypothyroidism, followed by daprodustat (n=9). Molidustat was a suspected drug for hypothyroidism in only one case; however, the patient had a history of roxadustat use, also reported as a suspected drug. No cases were reported wherein vadadustat and enarodustat were suspected drugs for hypothyroidism. Table I shows the demographic data and clinical outcomes of patients with hypothyroidism for whom roxadustat and daprodustat were suspected drugs. Roxadustat-associated hypothyroidism is more frequently reported in males and patients aged 70-89 years. Among the clinical outcomes of roxadustat-associated hypothyroidism, non-recovery and death accounted for 18.3% of cases. Similar trends were also observed for daprodustat. However, only nine patients were analyzed, and the results should be cautiously interpreted. Analysis of the reporting year revealed that the number of reports on hypothyroidism after initiation of HIF-PH inhibitors has rapidly increased from 2022 Q3 (October–December; Figure 1).

Table I. Demographic data and clinical outcomes in cases with hypothyroidism wherein roxadustat and daprodustat were reported as suspected drugs.

Figure 1. Changes in the numbers of reports on hypothyroidism after initiation of HIF-PH inhibitors.

Disproportionality analysis on hypothyroidism with HIF-PH inhibitors or ESA. Table II shows the ROR and IC values for hypothyroidism associated with roxadustat and daprodustat. Roxadustat had a positive signal in the ROR and IC. In contrast, daprodustat had a positive signal in the ROR but not in the IC. Moreover, there were only 5 hypothyroidism cases in which ESAs were reported as suspect drugs, and no signal was detected [Total cases=3,263, ROR=0.21 (95%CI=0.09-0.51), IC=–2.02 (95%CI=–3.20 - –0.84)].

Table II. Reporting odds ratio (ROR) and information component (IC) values of roxadustat and daprodustat for hypothyroidism.

95%CI: 95% confidence interval.

Time-to-onset analysis of roxadustat-associated hypothyroidism. The time-to-onset analysis included 210 patients with complete records of roxadustat start and onset dates of hypothyroidism. The median time of roxadustat-associated hypothyroidism was 92 days (1-1,063 days), and its pattern of occurrence was early failure type [WSP=0.88 (95%CI=0.79-0.97); Figure 2]. No statistically significant differences were detected in time to onset of hypothyroidism between groups classified according to patient sex, age group, and hypothyroidism outcome (Figure 3).

Figure 2. Histogram and Weibull parameter of roxadustat-associated hypothyroidism. WSP: Weibull shape parameter; 95%CI: 95% confidence interval.

Figure 3. The influence of sex (A), age group (B), and clinical outcomes (C) on the cumulative incidence of hypothyroidism after roxadustat use. A p-value of <0.05 was considered significant according to Log-rank test.

Discussion

This study evaluated the association and time-to-onset of HIF-PH inhibitors with hypothyroidism using a database of spontaneous adverse event reports. Roxadustat had positive signals for hypothyroidism among the HIF-PH inhibitors, based on the ROR and IC values, and a strong association was confirmed. Furthermore, the median onset time was 92 days, and the pattern of occurrence was early failure type.

THR is a nuclear receptor with THRα and THRβ isoforms. Roxadustat is a selective THRβ agonist owing to its structure and has a higher affinity for THRβ than T3 (10). In the human body, thyrotropin releasing hormone is secreted from the hypothalamus, and TSH is produced by TSH-producing cells in the pituitary gland when the T3 blood level is low. T3 binds to THR in TSH-producing cells when T3 is secreted from the thyroid gland owing to TSH, causing negative feedback to the pituitary gland, and suppressing TSH production (18). Therefore, Roxadustat, as a selective THRβ agonist acts, on the pituitary gland with negative feedback similar to that of T3, causing a decrease in TSH and thyroid hormones (10).

This study confirmed an association between roxadustat and hypothyroidism. However, the association between daprodustat and hypothyroidism is more unclear than that of roxadustat. Nine cases of hypothyroidism occurring after daprodustat administration are registered in the JADER database. In contrast, some studies show that patients receiving daprodustat have a lower risk of developing hypothyroidism than those receiving roxadustat (11,12). TSH reduction is caused by the drug binding to THR, and the strength of its activity is determined by its molecular structure (19). Roxadustat has the carboxyl head group common to T3 and other THR ligands. Additionally, it has a hydrophobic phenyl extension at the tail, associated with its high selectivity for THRβ (10). However, the daprodustat structure (especially its tail) is considerably different from those of T3 and roxadustat. Therefore, further investigation of the association between daprodustat and hypothyroidism is warranted despite the equivocal disproportionality analysis.

Kidneys are essential for metabolism and thyroid hormone excretion (20). End-stage kidney disease is also a risk factor for thyroid disorders, such as hypothyroidism and euthyroid sick syndrome (21). Therefore, there is a potential risk of hypothyroidism in patients with CKD, which may have affected the results of this study. We used ESAs as negative control and investigated its association with hypothyroidism. In the JADER database, there were only 5 hypothyroidism cases in which ESAs were reported as suspect drugs, and no signal was detected. Thus, the reporting rate of hypothyroidism increased with roxadustat and daprodustat compared with ESAs.

We performed a time-to-onset analysis of roxadustat-associated hypothyroidism. The median time to onset of hypothyroidism was 92 days and the onset pattern was the early failure type. Over 50% of roxadustat-associated hypothyroidism cases occurred within 100 days of treatment initiation. Therefore, we emphasize the importance of testing thyroid function during this period. This study investigated the time to onset of hypothyroidism in 210 of 410 cases, which is greater than the number of patients in any previous study on hypothyroidism caused by roxadustat (4,11,12). This is an advantage of studies using big data such as the JADER database, and the results of this study may help manage hypothyroidism associated with roxadustat use.

Recently, Kouki et al. evaluated the association between hypothyroidism and roxadustat or daprodustat using data between April 2004 and July 2022 from the JADER database (22). Although unexpected by us, the fact that there was a group attempting to conduct a similar study at approximately the same time is very favorable in assessing the validity of our study. In fact, their results are naturally similar to ours since their research methods were similar to ours. However, we included five HIF-PH inhibitors as target drugs, investigated the clinical outcomes, and the investigation period was 8 months longer than previous studies. Furthermore, the number of analyzed cases in this study was dramatically higher than in previous studies, even though only "suspected drugs" were included. The reason for the rapid increase in the number of reports of roxadustat-associated hypothyroidism after 2022 Q3 is considered to be because the package insert of roxadustat in the Japanese market was updated in November 2022. This fact provides an advantage for time-to-onset analysis in our study and also explains the need for continuous analysis of databases of spontaneous adverse event reports in the investigation of adverse events of new drugs.

Study limitations. It was conducted using the JADER database, which is a spontaneous report database. Therefore, the inability to calculate the incidence of adverse events and problems related to inaccuracies in the registration data was the same as those in previous studies using spontaneous report databases (17). In addition, a sufficient number of cases for analysis could not be obtained from the JADER database owing to the limited experience with some HIF-PH inhibitors. No adjustments were also made for background factors in this study. Therefore, prospective clinical trials or case-control studies with more sophisticated designs are needed to address these issues.

Conclusion

The results of this study suggest an association between roxadustat and hypothyroidism. Enhanced thyroid function testing within 100 days of treatment initiation may help detect early roxadustat-associated hypothyroidism. However, further investigation of the association between daprodustat and hypothyroidism is warranted despite the equivocal disproportionality analysis.

Conflicts of Interest

None of the Authors have any potential conflicts of interest associated with this research.

Authors’ Contributions

HT and TI conceived and designed the study. HT and AT analyzed the data. HT and TO wrote the article. All Authors read and approved the final version of the article.