https://orcid.org/0000-0001-7836-4646
Figures
Abstract
Background
Osilodrostat is a medication recently approved for the treatment of Cushing’s syndrome. However, there is a current dearth of large-scale studies on the adverse events associated with Osilodrostat. Consequently, this study aims to comprehensively evaluate these adverse events using data from the FDA Adverse Event Reporting System (FAERS).
Methods
A disproportionality analysis was utilized to identify signals of adverse events linked to Osilodrostat. Furthermore, a Weibull distribution analysis was conducted to evaluate the temporal evolution of adverse events, and subgroup analyses were performed. The Wilcoxon test was applied to investigate differences in the temporal patterns of adverse events across different genders.
Results
A total of 1,078 cases related to Osilodrostat were identified, including 3,744 adverse events. The most frequent and severe signals of adverse events were investigations, off-label use, fatigue, nausea, and adrenal insufficiency. The median time to onset of adverse events related to Osilodrostat was 52 days after starting the medication. There was a gender difference in the median time to onset of adverse events, with a median of 15 days for males and 34 days for females.
Citation: Li L, Zhao W (2025) Safety assessment of Osilodrostat: The adverse event analysis based on FAERS database by means of disproportionality analysis. PLoS One 20(8): e0329088. https://doi.org/10.1371/journal.pone.0329088
Editor: Doa'a G. F. Al-u'datt, Jordan University of Science and Technology Faculty of Medicine, JORDAN
Received: February 5, 2025; Accepted: July 9, 2025; Published: August 7, 2025
Copyright: © 2025 Li, Zhao. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All publicly available datasets files are available from the FAERS database (https://www.fda.gov/drugs/drug-approvals-and-databases/fda-adverse-event-reporting-system-faers-database).
Funding: Natural Science Foundation of Hunan Province, 2022JJ40388, Ms Lijun Li.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Osilodrostat functions as a dual inhibitor within the biosynthesis pathways of glucocorticoids and mineralocorticoids. It achieves this by inhibiting the production of CYP11B1, which is the catalyst for the final step in cortisol synthesis. Additionally, it can also impede the production of CYP11B2, the enzyme that catalyzes the conversion of corticosterone to aldosterone [1]. In early 2020, Osilodrostat received approval from both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) for the treatment of Cushing’s syndrome (CS) [2,3]. Given its rapid onset of action and long half – life, it is emerging as a new ray of hope in the treatment of Cushing’s syndrome for patients who are ineligible for pituitary surgery or for whom such surgery has proven ineffective [4].
With the increasing acceptance and expanding application of Osilodrostat, it is crucial to explore the drug-related adverse events (AEs) associated with it. Although several studies have investigated these AEs, but all of them are faced with challenges such as small sample sizes and inconsistent findings. For instance, the studies by Pivonello [5] and Fleseriu [6] have identified nausea, headache, fatigue and adrenal insufficiency as the most common AEs related to Osilodrostat. In contrast, other studies have indicated that diarrhea, hypokalaemia, muscle spasms, vomiting [7], arthralgia [8], decreased appetite [9], gamma-glutamyl transferase increase, nasopharyngitis [10], depression [11] are the most prevalent AEs. Currently, the safety information regarding Osilodrostat mainly stems from case reports, clinical trials, and meta-analyses. However, these studies often target on the specific populations or include relatively limited sample sizes and selection criteria. As a consequence, there is a dearth of comprehensive safety data from large samples and real-world cohorts [12].
The FDA Adverse Event Reporting System (FAERS) holds the potential to overcome the existing limitations in research on drug-related AEs associated with Osilodrostat. Numerous prior studies have utilized the FAERS database to explore drug-related AEs [13–17]. FAERS, a publicly accessible, large-scale database managed by the FDA, is specifically designed to facilitate the post-marketing safety surveillance program for drugs and therapeutic biologics. Since 2004, it has encompassed all AE reports and medication error reports submitted to the FDA by healthcare professionals, consumers, and manufacturers [18].
Therefore, the present study is aimed at evaluating the safety of Osilodrostat by analyzing data from the FAERS database. The intention is to offer a reference for the clinical application of Osilodrostat, facilitating more informed decision – making in its use within the medical field.
Materials and methods
Data sources, management, ethics statement and study design
The raw data for this study was obtained from the FAERS database. All adverse event (AE) reports in which Osilodrostat was identified as the primary suspect drug were retrieved from the database, spanning from the first quarter of 2004 to the third quarter of 2024 in the database. Deduplication was carried out in accordance with the method recommended by the FDA [19]. To eliminate duplicate reports, the PRIMARYID, CASEID, and FDA_DT fields were selected from the DEMO table. The reports were sorted by CASEID, FDA_DT, and PRIMARYID. For reports with the same CASEID, the one having the largest FDA_DT value was retained. In cases where both CASEID and FDA_DT were identical, the report with the largest PRIMARYID value was kept. Subsequently, the AEs’ names in the FAERS database were encoded using MedDRA 27.1. Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements. The detailed flowchart of the study design is shown in Fig 1.
Statistical analysis
Descriptive analysis was utilized to delineate the fundamental demographic data of the patients and the distribution of target drug’s AEs across different system organs. Four disproportionality analysis techniques were implemented for detecting signals of AEs related to Osilodrostat: the reporting odds ratio (ROR) [20], the proportional reporting ratio (PRR) [21],the multi - item gamma Poisson shrinker (MGPS) [22], and the Bayesian confidence propagation neural network (BCPNN) [23]. When two or more analysis methods were combined for detection, AEs that met the positive threshold of all the analysis methods used were considered potential AE signals. The interval between the occurrence of the AEs recorded in the DEMO file and the initiation of Osilodrostat treatment recorded in the THER file was defined as the onset time for Osilodrostat-related AEs. The Weibull distribution was applied to model the changes in the incidence of AEs over time. All statistical analyses were conducted using SAS 9.4.
Result
Descriptive analysis
A search was conducted for data in the FAERS database from the first quarter of 2004 to the third quarter of 2024 (Fig 2). After data cleaning, a total of 1078 Individual Case Safety Reports (ICSRs) related to Osilodrostat were retrieved, containing 3744 AEs. The clinical characteristics of these reports were shown in Table 1. Among all the included patients, females constituted 12.62% and males accounted for 4.55%. The mean age of the included patients was 49.66 ± 16.23 years, with the majority of patients in the age group of 45–64 years, accounting for 6.12%. The majority of reporters were consumers, accounting for 78.29%. Regarding geographical distribution, the United States had the highest number of occurrences and reports of Osilodrostat-related AEs (occurrences:86.09%, reports:85.44%)(S1A Fig). Similarly, North America was the continent with the most occurrences and reports of AEs related to Osilodrostat (occurrences:86.09%, reports:85.44%). In terms of the severity, 59.83% of the reports were classified as serious, while the remaining 40.17% were non-serious. As for the outcomes of the AEs, the occurrence of other serious medical events was the most prevalent outcome, accounting for 32.19%, followed by hospitalization (29.59%), death (9.93%), life-threatening (1.39%), and disability (0.28%)(S1B Fig).
Distribution of the AEs at the system organ class (SOC) level
A total of 26 SOCs were associated with the AEs related to Osilodrostat. The top 5 SOCs with the highest report frequencies were General disorders and administration site conditions (n = 625, ROR 0.95, PRR 0.96, IC −0.06, EBGM 0.96), Investigations (n = 441, ROR 2.04, PRR 1.92, IC 0.94, EBGM 1.92), Gastrointestinal disorders (n = 440, ROR 1.43, PRR 1.38, IC 0.47, EBGM 1.38), Injury, poisoning and procedural complications (n = 370, ROR 0.95, PRR 0.96, IC −0.06, EBGM 0.96), and Nervous system disorders (n = 313, ROR 0.98, PRR 0.98, IC −0.03, EBGM 0.98). In addition, the SOCs that were significantly associated with the AEs of Osilodrostat and met the criteria of ROR, PRR, BCPNN and MGPS, four detection methods, were investigations (n = 441, ROR 2.04, PRR 1.92, IC 0.94, EBGM 1.92), Gastrointestinal disorders (n = 440, ROR 1.43, PRR 1.38, IC 0.47, EBGM 1.38), Musculoskeletal and connective tissue disorders (n = 224, ROR 1.17, PRR 1.16, IC 0.21, EBGM 1.16), Metabolism and nutrition disorders (n = 160, ROR 2.01, PRR 1.97, IC 0.98, EBGM 1.97), Endocrine disorders (n = 118, ROR 12.80, PRR 12.43, IC 3.63, EBGM 12.42)and Surgical and medical procedures (n = 72, ROR 1.44, PRR 1.43, IC 0.52, EBGM 1.43) (Table 2).
Distribution of the AEs at the preferred terms (PT) level
When compared to using any single method, the precision of signal detection is notably higher when the ROR, PRR, BCPNN and MGPS methods are employed in combination compared to using any single method. Consequently, this study presented the top 30 PTs ranked according to the frequency of positive signals (Table 3) and the top 30 PTs ranked by the intensity of ROR positive signals (Table 4). All of these were detected through the combined application of these four methods. In the ranking based on the positive signal frequency of the target drug, the top five PTs were Off label use (n = 187, ROR 4.06, PRR 3.91, IC 1.97, EBGM 3.91), Fatigue (n = 177, ROR 3.92, PRR 3.79, IC 1.92, EBGM 3.78), Nausea (n = 148, ROR 3.19, PRR 3.10, IC 1.63, EBGM 3.10), Adrenal insufficiency (n = 63, ROR 100.11, PRR 98.45, IC 6.61, EBGM 97.79) and Decreased appetite (n = 62, ROR 4.28, PRR 4.22, IC 2.08, EBGM 4.22). Except for Off label use, which had the highest frequency of positive signals, the remaining PTs were mentioned in the prescribing information for Osilodrostat. In the ranking of positive signal intensity, the top five PTs were Mineralocorticoid deficiency (n = 3, ROR 3351.62, PRR 3348.94, IC 11.41, EBGM 2721.20), Cortisol free urine increased (n = 6, ROR 1645.51, PRR 1642.87, IC 10.53, EBGM 1475.90), Blood corticotrophin increased (n = 11, ROR 748.14, PRR 745.95, IC 9.47, EBGM 709.53), Cortisol decreased (n = 45, ROR 466.13, PRR 460.54, IC 8.80, EBGM 446.40) and Cortisol increased (n = 19, ROR 420.53, PRR 418.41, IC 8.67, EBGM 406.71). It is noteworthy that although these PTs had a lower frequency, their corresponding positive signal intensity was significantly higher than that of other PTs, potentially representing new and potential AE signals. The adverse events associated with Oseltrolizumab and Cushing’s syndrome are depicted in S2 Fig.
Time to event of the AEs
After excluding reports with incomplete records of the AEs’ occurrence time, we analyzed all the 397 reports that had detailed records of AEs occurrence time. As shown in Fig 3, nearly half of the AEs (45.09%) occurred within 0–30 days after the use of Osilodrostat. A significant number of AEs occurred between 181–360 days and after 360 days of Osilodrostat use. The proportion of AEs in these three time periods was considerably larger than that in other time periods. Fig 4 illustrated the cumulative incidence of to Osilodrostat – related over time. Moreover, there was a difference in the median occurrence time of AEs between males and females (Fig 5). Analysis using the Weibull distribution indicated an early-failure mode. The detailed parameters of this analysis are presented in Table 5.
Discussion
In this study, data from the FAERS database was utilized to evaluate the safety of Osilodrostat, with the objective of furnishing recommendations for its clinical utilization.
The results indicated that the AEs related to Osilodrostat were more prevalent in women. This could potentially be attributed to the inhibitory effect of Osilodrostat on CYP11B1. Such inhibition leads to the accumulation of 11 – deoxycorticosterone and classic androgen precursors like DHEA and A4, which in turn promote androgen synthesis [6]. Excessive androgens can cause acne and hirsutism in women [24]. Furthermore, the observed gender difference might also be related to the fact that the majority of reports submitted to the FDA were from the consumers (78.29%). Socially, women tend to be more proactive in voicing their concerns and are thus more likely to report AEs [25]. Although some women may experience acne and hirsutism upon initiating Osilodrostat treatment, studies have shown that with extended follow-up, the levels of androgens in female patients gradually return to baseline levels, leading to progressive improvement in symptoms [5,6,26,27]. Therefore, in clinical practice, for patients experiencing acne and hirsutism, local treatments or the use of spironolactone to block the androgen receptor activity can be considered [28]. It is also crucial to reassure patients that these symptoms are transient to ease their concerns. The majority of reports come from the North America and Europe, likely because the EMA and FDA were the first regulatory agencies to approve Osilodrostat for the treatment of CS [2,3]. The number of the AEs reported in 2024 far exceeded those in other years, suggesting that Osilodrostat was being increasingly used in clinical settings. However, the proportion of severe AEs and hospitalizations caused by Osilodrostat remained high, indicating that vigilance should not be relaxed and monitoring of Osilodrostat-related AEs should be strengthened [29].
Through disproportionality analysis, we found that Investigations and Gastrointestinal disorders were not only among the top five most common AEs related to Osilodrostat across the entire SOC hierarchy, but also among the top five with the strongest signals. Gastrointestinal disorders have been mentioned in the drug’s package insert and multiple clinical studies [5,7,9], which validates the reliability of our findings. The use of Osilodrostat can lead to gastrointestinal symptoms such as nausea, vomiting, and diarrhea. This is associated with the rapid blockade of adrenal enzymes by Osilodrostat, resulting in a sudden decrease in cortisol and subsequent hypocortisolism [30,31]. However, Investigations were rarely mentioned. This might because Investigations represented the outcomes of the AEs. Patients using Osilodrostat undergo various examinations when AEs occur, which increased the frequency and signal strength of this SOC. However, in these cases, Investigations were not typically mentioned separately in drug package inserts or clinical studies.
In terms of PT analysis, our study found that Off label use, Fatigue, Nausea, and Adrenal insufficiency were the most frequently reported terms, and they also had the highest frequency of positive signals. The occurrence of Fatigue, Nausea, and Adrenal insufficiency was not surprising, as these PTs had been mentioned in numerous clinical studies and were also included in the drug information for Osilodrostat [5,7,9]. Additionally, Fatigue and Nausea corresponded to the most frequently occurring SOC, Gastrointestinal disorders.
The five PTs with the strongest signals were Mineralocorticoid deficiency, Cortisol free urine increased, Blood corticotrophin increased, Cortisol decreased, and Cortisol increased. The occurrence of these PTs was closely related to the pharmacological effects of Osilodrostat, as it regulated both glucocorticoid and mineralocorticoid levels in the body [32,33]. It is a dual inhibitor of the biosynthetic pathways for glucocorticoids and mineralocorticoids [33]. Inappropriate dosing can lead to abnormal levels of these hormones, which can have serious consequences [34]. Mineralocorticoid deficiency can cause hyponatremia, hyperkalemia, low blood pressure, and adrenal crisis [35,36]. Increased cortisol levels can lead to uncontrolled or worsening symptoms of CS, while decreased cortisol levels can result in hypotension, hypoglycemia, fatigue, dizziness, decreased appetite, nausea, vomiting, diarrhea, abdominal pain, and even syncope and adrenal crisis [37,38]. This provides two important insights. First, when using Osilodrostat clinically, it is crucial to strictly follow the standardized application procedures for the drug. Second, monitoring of mineralocorticoid and cortisol levels should be conducted during its use. It is particularly important to note that when measuring cortisol levels in patients, laboratory methods with minimal cross-reactivity with cortisol precursors (such as 11-deoxycorticosterone) should be prioritized to avoid overestimating cortisol levels [26,39]. Additionally, cortisol levels can fluctuate during fever, infection, or increased psychological stress, so more frequent and careful monitoring of cortisol levels should be conducted in these situations [40].
This study also analyzed the timing of the AEs. The median time for the occurrence of the AEs was 52 days after the medication use. However, subgroup analysis revealed differences in the median time of the AEs between males and females, with males experiencing them at a median of 15 days and females at 34 days. The reasons for this difference have not yet been elucidated by research. We should conduct more frequent and close monitoring of AEs in patients around these time points. Additionally, patients should be informed to pay attention to any discomfort they experienced around these time points and reported it promptly to their healthcare professionals. Through these measures, the AEs can be detected in a timely manner and interventions can be initiated early to ensure the patients’ safety.
In contrast to the previously available specification for Osilodrostat, we found that the appearance of off label use was unexpected, suggesting that future efforts should be focused on strengthening the supervision and management of Osilodrostat use and standardizing the procedures for healthcare professionals [41]. Furthermore, patient health education should emphasize the importance of following medical advice when taking medication. In addition, we found that “decreased appetite” appeared much more frequently in this study than in the drug package inserts. Similar to our study, Gadelha M et al. [9] also highlighted decreased appetite as a high incidence of adverse events in their study. This suggests that we still need to pay extra attention to the occurrence of decreased appetite in patients using Osilodrostat in the future and be prepared to provide additional nutritional support to patients using Osilodrostat to avoid nutritional imbalance caused by decreased appetite.
The strength of this study lies in its ability to conduct a large-sample analysis using the FAERS database, allowing for a comprehensive evaluation of the safety of Osilodrostat. However, the study inevitably has some limitations. Some of these limitations stem from the FAERS database itself [42], such as incomplete reports, underreporting, and selective reporting, which introduce biases. Additionally, the FAERS database does not provide certain clinical information about patients, such as comorbidities and medications being used, making it difficult to control for confounding factors [43]. Lastly, while disproportionality analysis assesses signal strength and establishes statistical associations, it does not provide sufficient evidence to determine the causal relationship between drug use and the AEs [44]. In future studies, high-quality randomized controlled trials (RCTs) could be added to confirm causal relationships.
Conclusion
We conducted a large-sample study using the FAERS database to comprehensively assess the safety of Osilodrostat. At the SOC level, Investigations and Gastrointestinal disorders were the most common and strongest signals of the AEs associated with Osilodrostat. At the PT level, Off-label use, Fatigue, Nausea, and Adrenal insufficiency were the most frequently reported AEs with the highest number of positive signals related to Osilodrostat. However, due to the inherent limitations of the FAERS database and the analysis methods used, biases may be introduced, confounding factors cannot be ruled out, and causality cannot be confirmed. Therefore, the results of this study should be interpreted and applied with caution. Additionally, future high-quality randomized controlled trials (RCTs) could be conducted to confirm the association between Osilodrostat and these AEs.
Supporting information
S1 Fig. The percentage of Osilodrostat use in five countries and the incidence of hospitalization, death, life-threatening events, and disability.
A:the percentage of Osilodrostat use in five countries; B: the incidence of hospitalization, death, life-threatening events, and disability.
https://doi.org/10.1371/journal.pone.0329088.s001
(TIF)
S2 Fig. The the adverse events related to Cushing’s syndrome associated with Osilodrostat use.
https://doi.org/10.1371/journal.pone.0329088.s002
(TIF)
Acknowledgments
We sincerely appreciate the significant contributions made by all the authors towards this study, their invaluable efforts have been instrumental in its success.
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