The Reflex Dexamethasone Suppression Test: Development and Assessment of Reflexed Serum Dexamethasone Measurement for the Diagnosis of Cushing Syndrome

Posted on August 23, 2025 by MaryO

Abstract

Background

Screening for Cushing syndrome (CS; endogenous overproduction of ACTH or cortisol) is performed by the low-dose overnight serum dexamethasone suppression test (oDST) with the measurement of serum dexamethasone concentration to assure an effective dose.

Objective

We evaluated the utility of only measuring serum dexamethasone in samples with nonsuppressed serum cortisol using a conservative serum cortisol cutoff.

Methods

This retrospective study included 261 oDSTs completed before Reflex implementation (Pre-Reflex-oDST) and 281 oDSTs completed after (Post-Reflex-oDST). Serum cortisol and serum dexamethasone data were paired to the diagnosis and analyzed with comparative statistical tests and receiver operating characteristic curve (ROC) analysis.

Results

Endogenous hypercortisolism was diagnosed in 38 of 261 Pre-Reflex-oDSTs (14%) and 40 of 281 (14%) Post-Reflex-oDSTs. In oDSTs with SerCort >1.8 mcg/dL, there were 9% and 6% false positives in the Pre-vs Post-Reflex-oDST group, respectively. In the Pre-Reflex-oDST group, the median SerCort was 1.1 mcg/dL (95% CI: 0.8–1.5) in patients without CS and 3.9 mcg/dL (95% CI: 2.6–7.9) in those with CS (P < 0.001). The optimal ROC cutoff of SerCort in the Pre-Reflex-oDST group was 2.1 mcg/dL (sensitivity 92%, specificity 93%). In the Post-Reflex-oDST group, the median SerCort was 1.1 mcg/dL (95% CI: 0.8–1.5) in patients without CS and 2.9 mcg/dL (95% CI: 2.6–7.9) in those with CS (P < 0.001). The optimal ROC cutoff of SerCort in the Post-Reflex-oDST group was 2.1 mcg/dL (sensitivity 95%, specificity 93%; not different from Pre-Reflex-oDST group).

Conclusion

Reflex measurement of the serum dexamethasone did not affect oDST test performance while reducing costs.

Abbreviations

CS

Cushing syndrome
oDST

low-dose overnight serum dexamethasone suppression test
ROC

receiver operating characteristic
NH

neoplastic hypercortisolism
NNH

non-neoplastic hypercortisolism
HPA

hypothalamic pituitary adrenal
SerCort

serum cortisol
SerDex

serum dexamethasone
WDL

Wisconsin Diagnostic Laboratories
LOQ

limit of quantification
UFC

urine free cortisol

Highlights

  • •
    Reflexing only nonsuppressed serum cortisol samples for the measurement of serum dexamethasone does not negatively affect the performance of the overnight low-dose DST (oDST)
  • •
    Reflex implementation greatly reduced the number of serum dexamethasone measurements thereby decreasing unnecessary costs
  • •
    The oDST appeared to be valid as long as there was a measurable serum dexamethasone result (>50 ng/dL)

Clinical Relevance

We report a novel Reflex overnight dexamethasone suppression test (oDST) serum dexamethasone measurement protocol with the benefit of greatly lowering costs without loss of oDST performance supporting its implementation in screening for Cushing syndrome.

Introduction

Endogenous Cushing syndrome (CS) includes neoplastic hypercortisolism either due to autonomous cortisol production or excessive ACTH secretion.1 Non-neoplastic hypercortisolism (NNH) is also an important clinical entity that is characterized as bona fide cortisol excess caused by conditions such as depression, chronic kidney disease, and poorly controlled diabetes.2, 3, 4 Chronically elevated cortisol levels contribute to significant morbidity and mortality due to cardiovascular, metabolic, musculoskeletal, and immunologic effects, including hypertension, diabetes, osteoporosis, and increased susceptibility to infections5,6 leading to prolonged disease burden and worsening clinical outcomes.2,3
Biochemical evaluation is indicated for individuals presenting with features of hypercortisolism, as well as for those with adrenal incidentalomas, regardless of symptoms, in accordance with current guidelines.7 However, the workup is complicated by varying severities of hypercortisolism and diurnal rhythm of endogenous cortisol requiring screening tests to take advantage of predictable nadirs and negative feedback.1 One of the current first-line screening tests for CS is the 1 mg (low dose) overnight dexamethasone suppression test (oDST).8 Positive oDST results require additional testing such as late-night salivary cortisol and 24 h urine free cortisol measurements.8, 9, 10
The oDST takes advantage of decreased HPA negative feedback sensitivity in CS.11 An oral 1 mg dexamethasone dose is given between 2300 hours and 2400 hours and serum cortisol (SerCort) is then measured at 0800 h the following morning with levels <1.8 mcg/dL (50 nmol/L) representing normal suppression.8 A clinical sensitivity of 95% highlights the oDST as a useful screening tool; however, a specificity of ∼80% indicates a greater potential for false-positive results.10,12 A higher burden of false-positive results complicates diagnosis, leading to further testing, delays in diagnosis and treatment, and increased costs and resource utilization for both patients and the health care system. Therefore, the measurement of a serum dexamethasone (SerDex) in the next morning SerCort sample should identify insufficient SerDex levels that may result from factors such as mistiming of, or altogether missing the dexamethasone dose, differences in dexamethasone metabolism, variation in gastrointestinal absorption, increased cortisol binding globulin (eg, due to oral contraceptives), and medications that alter CYP3A4 activity.13, 14, 15, 16, 17
To reduce unnecessary and costly SerDex measurements, our institution implemented in 2023 a Reflex protocol in which SerDex is only measured if post-oDST SerCort is ≥ 1.6 mcg/dL (ie nonsuppressed). This approach was suggested but not evaluated by Genere et al.18 Since the purpose of this study was not to validate the concept of the oDST, we chose 1.6 mcg/dL as a conservative cutoff so that borderline SerCort with small variations around the accepted 1.8 mcg/dL cutoff would not bias the results. This study assessed equivalency in test performance between Pre- and Post-Reflex-oDST implementation and estimated the associated cost savings. As a secondary outcome, we evaluated therapeutic SerDex levels necessary for valid testing.

Materials and Methods

Study Design

A retrospective cohort study was performed on all oDSTs completed at Froedtert & the Medical College of Wisconsin and the affiliated Wisconsin Diagnostic Laboratories between May 2023 and April 2024. This study was approved by the Medical College of Wisconsin Institutional Review Board as a Quality Improvement Project under PRO00050802. All data in the database were de-identified and coded.

Study Population

The study population included patients aged ≥18 years who completed a oDST in the outpatient setting through the system with serum samples processed through Wisconsin Diagnostic Laboratories. Cohorts were divided into Pre- and Post-Reflex-oDST groups based on the date of Reflex implementation described below (October 31, 2023), with the Pre-Reflex-oDST group consisting of tests performed in the 6 months prior and the Post-Reflex-oDST group including tests from the 6 months following implementation. The ordering clinician still had the option to choose oDST AM cortisol alone without ordering a SerDex measurement. Exclusion criteria included repeat oDST for the same patient within the same 6-month period (Pre- or Post-Reflex-oDST groups); however, results from patients who underwent oDST during both the Pre- and Post-Reflex-oDST periods were included. Patients with SerDex <50 ng/dL were also excluded. At this time, all patients included in the analysis had either a confirmed hypercortisolism diagnosis or were determined not to have pathophysiological hypercortisolism based on clinical and biochemical evaluation.8 A combination of biochemical tests (24-hour free urine cortisol, late-night salivary cortisol, oDST), imaging (adrenal and pituitary CT/MRI), and other testing (DDVAP testing, surgical outcome, biopsy) were used to confirm the diagnosis of CS per the current guidelines.8 Hypercortisolism included both neoplastic causes (CS) and non-neoplastic causes (NNH).2 In our study, NNH included patients with chronic nausea and weight loss, chronic kidney disease, poorly controlled diabetes, excess alcohol intake, obesity with physiological stress, chronic pain, and opioid withdrawal. For simplicity, all hypercortisolism patients are abbreviated “CS” whether neoplastic or non-neoplastic.

Procedures

Patients were instructed to take 1 mg of dexamethasone at 11:00 pm and then had their blood sampled the next morning between 8:00 and 9:00 am SerCort level was measured using the Roche Elecsys Cortisol II Electrochemiluminescence immunoassay performed on a Cobas e801 module.19 In the Pre-Reflex-oDST group, individual orders for serum cortisol and dexamethasone were placed by the provider. Both tests were performed, regardless of the subsequently reported oDST serum cortisol value. In the Post-Reflex-oDST group, a single “Dexamethasone Suppression Cortisol Reflex” order was placed, that prompted a SerCort measurement. If SerCort was ≥1.6 mcg/dL (ie, nonsuppressed), an electronic order for a SerDex send-out measurement was automatically placed by the laboratory information system. The laboratory’s automated processing line removed the serum sample from storage, created an aliquot and placed it in a queue for samples to be sent to ARUP Laboratories. ARUP Laboratories measured SerDex by liquid chromatography-mass spectrometry (limit of quantitation [LOQ] = 50 ng/dL; reference interval: 140 – 295 ng/dL; https://ltd.aruplab.com/Tests/Pub/2003248).

Data Collection

Data acquired from each oDST, including date and time of collection, SerCort, and SerDex, were extracted from the laboratory information system. Additional data, including demographics, CS diagnosis, and treatment were collected from the electronic health record and securely stored in RedCAP (version 15.0.2; Nashville, TN). Patients with inconclusive test results were followed for several months after oDST until a diagnosis was established through additional testing and/or clinical evaluation.

Outcomes Assessment

The primary outcome of this study was to quantify the number of SerDex tests avoided while assessing whether implementation of the Reflex oDST affected overall test performance in the screening for endogenous hypercortisolism. Equivalency between Pre- and Post-Reflex-oDSTs was defined by the similarities in prevalence of a new diagnosis, average SerCort by diagnosis, and SerCort cutoffs by receiver operating characteristic (ROC) curve AUC, and optimal cutoff values. Secondary outcomes included quantification of avoided SerDex measurements to estimate the cost savings associated with Reflex implementation using the US Medicare Reimbursement Rate [20 Accessed 4/1/2025; CPT code 80 299)]. We also evaluated suppressed oDST’s SerDex concentrations to determine if there was a correlation between SerDex level achieved and the degree of suppression of SerCort.

Statistical Analysis

All statistical analyses were performed using Sigmaplot 15.0 (RRID:SCR_003210; https://scicrunch.org/resolver/SCR_003210; Systat Software, Inc, Inpixon, Palo Alto, CA). Continuous variables that were not normally distributed are presented as the median and interquartile ranges. Demographic data were analyzed by two-way analysis of variance and chi-square. Differences in SerCort and SerDex between Pre- and Post-Reflex-oDST groups and CS diagnosis were tested by Mann-Whitney U test and t-test. Optimal cutoff values for each group were determined by ROC analysis using Youden’s index and AUCs were compared with a DeLong test. A P value <0.05 was considered statistically significant. Post-hoc power analyses results are provided where appropriate.

Results

Study Population Characteristics

A total of 616 oDSTs (308 in the Pre-Reflex-oDST and 308 in the Post-Reflex-oDST groups) were screened for eligibility (Fig. 1). After excluding oDSTs with SerDex below the LOQ (n = 12) and repeated oDSTs in the same patient (n = 62), a total of 542 oDSTs were included for analysis. Demographic data are presented in Table 1. The without CS group was younger than the patients with CS group in both Pre- and Post-Reflex-oDST groups. There were no differences in the distribution of race between the groups with and without CS groups and the Pre-vs Post-Reflex-oDST groups. There were more females regardless of diagnosis, but the sex distribution was not different Pre vs Post-Reflex-oDST implementation.

  1. Download: Download high-res image (445KB)
  2. Download: Download full-size image

Figure 1. Flowchart of participants selection from 616 completed oDSTs completed 6 months before (n = 308) and after (n = 308) Reflex implementation. Subsequent oDSTs for the same patient and unmeasurable post-oDST serum dexamethasone (SerDex) (<50 ng/dL [Lower quantifiable limit]) were excluded from analysis. A total of 542 oDSTs were included for analysis and breakdown of CS diagnosis and etiology are shown. ACTH-dependent CS is further broken down to differentiate neoplastic (NH) versus non-neoplastic (NNH) etiologies. CS = Cushing Syndrome; NH = neoplastic hypercortisolism; NNH = nonneoplastic hypercortisolism; oDST = overnight dexamethasone suppression test; SerDex = serum dexamethasone.

Table 1. Demographic Characteristics of Patients Who Underwent oDST Before and After Reflex Implementation

Empty Cell Pre-Reflex Post-Reflex
Yes CS with NNH Yes CS without NNH No CS Yes CS with NNH Yes CS without NNH No CS
N 38 34 223 40 38 241
Age
 Mean (SD) 63.6 (13.8) 63.8 (14.4) 56.0 (15.1)a 63.8 (13.2) 63.1 (13.1) 55.3 (15.5)b
Sex
 Male (%) 6 (15.8) 4 (11.8) 57 (25.6) 11 (27.5) 11 (28.9) 67 (27.8)
 Female (%) 32 (84.2) 30 (88.2) 166 (74.4) 29 (72.5) 27 (71.1) 174 (72.2)
Race
 American Indian or Alaskan Native (%) 0 0 1 (0.4) 0 0 1 (0.4)
 Asian (%) 0 0 3 (1.3) 0 0 1 (0.4)
 Black or African American (%) 5 (13.2) 5 (14.7) 27 (12.2) 6 (15.0) 6 (15.8) 23 (9.5)
 Other (%) 2 (5.3) 1 (2.9) 8 (3.6) 1 (2.5) 1 (2.2) 9 (3.8)
 White (%) 31 (81.5) 28 (82.4) 184 (82.5) 33 (82.5) 31 (82.0) 207 (85.9)
Data are further stratified by Cushing syndrome (CS) diagnosis. Age is presented as mean (SD); sex and race as counts (percentages).
a
Age different from group with CS within Pre-Reflex-oDST (P = 0.005).
b
Age different from group with CS within Post-Reflex-oDST (P < 0.001) regardless of whether NNH cases are included. Male vs female distribution NS (χ2 = 2.533, 3 df, P = 0.469). Race distribution NS (χ2 = 4.37733, 12 df, P = 0.976).
Within the Pre-Reflex-oDST group, 38 patients (14%) were diagnosed with endogenous hypercortisolism (CS) with 13 being ACTH-dependent (9 pituitary and 4 non-neoplastic hypercortisolism) and 25 being ACTH-independent. Within the Post-Reflex-oDST group, 40 patients (14%) were diagnosed with CS with 11 being ACTH-dependent (8 pituitary, 2 non-neoplastic, and 1 ectopic ACTH) and 25 being ACTH-independent.

Prereflex-oDST vs Post-reflex-oDST Analysis

In the Pre-Reflex-oDST group, out of the 261 included subjects, 172 oDSTs (65%) suppressed to <1.6 mcg/dL, meaning that only 89 tests would have undergone reflex SerDex measurements after implementation of Reflex testing. Among these, 51 were determined not to have CS. In the Post-Reflex-oDST group, out of 281 subjects, 191 oDSTs (68%) suppressed to <1.6 mcg/dL, resulting in 90 reflexed SerDex measurements, of which 50 did not have CS. Within the Pre-Reflex-oDST group, there were 38 patients who had CS and in the Post-Reflex-oDST group 40 patients were found to have CS. There was no difference in CS prevalence between the Pre- and Post-Reflex-oDST groups (P = 0.52). Among oDSTs with SerCort levels >1.8 mcg/dL [the conventional cutoff 8], 24/262 (9% false positive) in the Pre-Reflex-oDST group and 21/281 (7% false positive) in the Post-Reflex-oDST group were later determined not to have CS by standard guidelines criteria.8 Reflex implementation resulted in a reduction of the number of SerDex measurements by 68% resulting in cost savings of at least $18.64 per ordered oDST.
In the Pre-Reflex-oDST group, the median SerCort was 1.1 mcg/dL (95% CI: 0.8–1.5) in patients who did not have CS and 3.9 mcg/dL (95% CI: 2.6–7.9) in those who had CS (P < 0.001). In the Post-Reflex-oDST group, the median SerCort was also 1.1 mcg/dL (95% CI: 0.8–1.5) in patients who did not have CS and 2.9 mcg/dL (95% CI: 2.6–7.9) in those who had CS (P < 0.001) (Fig. 2). There was no difference comparing the CS diagnosis status between Pre- and Post-Reflex-oDST groups. There was still no difference in median SerCort in patients with CS when comparing the Pre- and Post-Reflex-oDST groups with NNH cases excluded (P = 0.269). Furthermore, the NNH patients were biochemically indistinguishable from patients with neoplastic hypercortisolism (NH). In fact, when we compared post-oDST cortisol between NH (3.6 [2.4-7.7; N = 72) and NNH (3.4 [2.7-8.5; N = 6]), the P value was 0.729. There was also no difference between CS NH with NNH included vs CS NH excluding NH within the Pre-Reflex-oDST group and within the Post-Reflex-oDST group.

  1. Download: Download high-res image (195KB)
  2. Download: Download full-size image

Figure 2. Comparison of oDST serum cortisol (SerCort) levels Pre-vs Post-Reflex-oDST implementation. The medians are further stratified based on whether the patient did not have Cushing Syndrome (No CS – red) and those who had CS (Yes CS – blue). Each box represents the interquartile range and the horizontal line within represents the median. The error bars represent the 10th-90th percentiles and dots represent results outlying the 10th-90th percentiles. a, denotes significant difference of median SerCort levels between no CS vs CS in both Pre- and Post-Reflex-oDST groups (P < 0.001). There was no difference in medians following exclusion of NNH from Yes CS in both Pre- and Post-Reflex-oDST groups (P = 0.269). CS = Cushing Syndrome; NH = neoplastic hypercortisolism; NNH = nonneoplastic hypercortisolism; oDST = overnight dexamethasone suppression test; SerDex = serum dexamethasone.

A power analysis was performed to compare Pre-reflex oDST to Post-Reflex oDST SerCort values in patients with CS with the null hypothesis that there was no effect of implementing the reflex approach. Assuming a clinically significant effect of implementing the reflex test (a difference of oDST serum cortisol of 2 mcg/dL with a conservative SD of the difference of 2.5 mcg/dL) with sample sizes of 38 Pre-Reflex and 40 Post-Reflex in our study, the power was 0.937 with an alpha of 0.050. With an expected difference in serum cortisol of 0.8 mcg/dL and an SD of the difference of 1.0 mcg/dL, the power was 0.937 with an alpha of 0.05. Considering that the patients before and after reflex implementation were from the same population, institution, and ordering clinicians, we are confident that the Reflex testing did not influence the oDST performance and the laboratory data outcomes.
There was also no difference in SerCort between Pre- and Post-Reflex-oDST tests in the predictive performance for CS. The ROC curve AUC of SerCort in both the Pre- and Post-Reflex periods was 0.97. The optimal ROC cutoff of SerCort in the Pre-Reflex-oDST group was 2.1 mcg/dL (sensitivity 92%, specificity 93%). The optimal ROC cutoff of SerCort in the Post-Reflex-oDST group was 2.1 mcg/dL (sensitivity 95%, specificity 93%; not different from Pre-Reflex-oDST group) (Table 2). When NNH cases were excluded and ROC curves were rerun, there was no difference in ROC curve area, optimal SerCort cutoff values, or sensitivity and specificity in Pre- and Post-Reflex-oDST groups.

Table 2. Receiver operating characteristic (ROC) analysis of oDST SerCort results for Pre-vs Post-Reflex-oDST groups. A. Analysis including NNH patients are at the top; B. Analysis excluding NNH patients are at the bottom

Empty Cell Pre-Reflex Post-Reflex
A. Including NNH patients
 ROC Curve Area (SE) 0.97 (0.01) 0.97 (0.01)
 95% confidence interval 0.96-0.99 0.95-0.99
 P value P < 0.0001 P < 0.0001
 Sample size: No CS/Yes CS 223/38 241/40
Cutoff Sensitivity Specificity Cutoff Sensitivity Specificity
 Optimal 8 AM SerCort Cutoff (mcg/dL) 2.1 92% 93% 2.1 95% 93%
Empty Cell Pre-Reflex without NNH Post-Reflex without NNH
B. Excluding NNH patients
 ROC curve area (SE) 0.97 (0.01) 0.97 (0.01)
 95% confidence interval 0.96-0.99 0.95-0.99
 P Value P < 0.0001 P < 0.0001
 Sample size: No CS/Yes CS 223/34 241/38
Cutoff Sensitivity Specificity Cutoff Sensitivity Specificity
 Optimal 8 AM SerCort Cutoff (mcg/dL) 2.1 91% 92% 2.1 95% 93%
Area under the curve (AUC) was calculated and compared with a DeLong test (AUC = 0.97, P < 0.0001, for both). Using Youden’s Index, optimal cutoff values were determined by maximizing sensitivity and specificity. When ROC rerun without NNH, the sensitivity and specificity did not change in both Pre- and Post-oDST-Reflex groups.

Prereflex-oDST Comparison of SerDex vs SerCort

In comparing the Pre-Reflex-oDST group SerDex results of <140 ng/dL versus >140 ng/dL (the lower reference limit of the SerDex assay), median SerCort was 1.2 mcg/dL and 1.1 mcg/dL, respectively (P = 0.621) (Fig. 3A). The scatter regression plot illustrates that there was no relationship between SerDex (ng/dL) and SerCort (mcg/dL) by CS diagnosis (Fig. 3B). Each point represents an individual oDST, with red indicating patients who did not have CS (n = 223) and blue indicating those who had CS (n = 38). In patients who did not have CS, SerDex ranged from 61.5 to 908.9 ng/dL whereas in patients who had CS, SerDex ranged from 96.3 to 646.0 ng/dL. Theoretical linear regression lines are shown. In fact, no significant correlation between SerDex and SerCort was found in the group who did not have CS (r = 0.002; P = 0.972) nor the group who had CS (r = 0.114; P = 0.494) so the regression lines are only provided for visual clarity. When NNH cases were excluded, there was still no correlation between SerDex and SerCort in patients with CS (P = 0.432). Furthermore, analysis of only NNH cases also showed no correlation between SerDex and SerCort (P = 0.871).

  1. Download: Download high-res image (397KB)
  2. Download: Download full-size image

Figure 3. Comparison of post-oDST serum cortisol (SerCort) to serum dexamethasone (SerDex) in Pre-Reflex-oDST group. (A) Comparison of post-oDST SerCort and SerDex for no CS patients in the Pre-Reflex-oDST group. SerCort in the No CS patients stratified by the ARUP Lower limit of the reference range for SerDex (140 ng/dL). There was no significant difference in median SerCort with the SerDex <140 ng/dL (N = 20) and >140 ng/dL (N = 203) groups (1.2 vs 1.1 mcg/dL, respectively, P = 0.621). (B) Comparison of all Pre-Reflex-oDST group oDSTs stratified by patients with (blue) and without (red) CS. The black vertical solid line represents the limit of quantitation (LOQ) of SerDex (50 ng/dL). There was no correlation of SerDex and SerCort achieved in either group (see text for specifics). There was no correlation when NNH cases were removed as well (P = 0.432). CS = Cushing Syndrome; NH = neoplastic hypercortisolism; NNH = nonneoplastic hypercortisolism; oDST = overnight dexamethasone suppression test; SerDex = serum dexamethasone.

Discussion

The purpose of this study was to assess the usefulness of implementing a protocol to only reflex samples for the measurement of SerDex that do not suppress post-oDST SerCort (the “Reflex-oDST”) using a very conservative 8 AM cortisol cutoff. The major findings were as follows: (a) There was no detrimental effect on oDST-suppressed SerCort levels with the implementation of Reflex testing. That is, the SerCort levels in patients without CS were not different from each other Pre- and Post-Reflex-oDST. The same was found in the group who had CS. (b) There were comparable optimal SerCort ROC cutoff values in the Pre- and Post-Reflex-oDST groups, which also demonstrated a lack of a detrimental effect on test performance. (c) The Reflex protocol eliminated the need for SerDex measurement in 68% of oDSTs ordered without reducing the accuracy of the oDST. (d) No correlation was found between SerCort and SerDex indicating that the SerDex concentration achieved may not be an important factor in assessing the accuracy of the oDST; rather the presence of a detectible SerDex may be sufficient (ie, a Boolean function).
When comparing the Pre- and Post-Reflex-oDST groups, we observed no difference in patient population characteristics, including the prevalence of positive oDSTs, CS diagnosis, and CS etiology. Notably, patients who had CS were older than those who did not have CS in both groups. Ueland et al demonstrated a positive correlation between age and oDST SerCort, which may partially explain the significantly higher age in patients with CS.17 Age-related changes in HPA axis dynamics likely contributed to an increased prevalence of unsuppressed results.21 Additionally, older patients often have more comorbidities, which may lead clinicians to have a lower threshold for further evaluation, increasing the likelihood of identifying CS in this population.
To demonstrate that implementation of oDST Reflex protocol did not negatively affect diagnostic performance, we compared SerCort levels and false positive rates defined by unsuppressed SerCort later determined not to have CS through further testing. We found no difference in SerCort levels before and after implementation of Reflex testing (within the patients who did not have CS and within the patients who had CS). We observed a 7% false positive rate in the Pre-Reflex-oDST group that was comparable to 10% to 14% in previous studies.17,22 We found a comparable 9% false positive rate in the Post-Reflex-oDST group demonstrating preservation of test performance with Reflex implementation. These data are similar to those theorized by Genere et al18 and we have now validated the approach.
Implementation of reflex SerDex testing reduced the number of oDST SerDex measurements by ∼68% and resulted in a cost savings of $18.64 per ordered oDST using Medicare Clinical Diagnostic Laboratory Test reimbursement data, though this likely underestimates the true financial burden as patients are often billed at higher rates.20 Therefore, the Reflex protocol not only did not have a detrimental effect on test performance but also improved efficiency by reducing unnecessary costs and resource utilization. It is also important to point out that the approach is likely to save additional costs like avoiding additional analysis such as unnecessary plasma ACTH, salivary cortisols, UFCs, and even MRIs.
For the purposes of diagnosis of CS, we used accepted oDST SerCort cutoff of ≤1.8 mcg/dL (50 nmol/L) that yields a sensitivity of 95% and a specificity of ∼80%.10,12 We, like most clinicians, utilize a ≤1.8 mcg/dL SerCort diagnostic cutoff with concomitant measurement of SerDex to improve specificity by reducing false positives due to subtherapeutic dexamethasone levels. For the current study, we used the cutoff of 1.6 mcg/dL to determine when to reflex samples for SerDex in the Post-Reflex-oDST group to be as conservative as possible particularly when considering biological variability around a value of 1.8 mcg/dL.
To demonstrate equivalency, we found SerCort cutoff values that maximize specificity based on oDSTs performed similarly in both Pre- and Post-Reflex-oDST groups. Our calculated cutoff value for SerCort Pre- and Post-Reflex-oDST validated that a small increase in SerCort oDST cutoffs results in an increase in specificity to >95% (utilizing Youden’s index). However, given that the oDST is a screening test, sensitivity should be prioritized. While higher specificity reduces false positives, it may also increase the risk of missing mild CS cases. Notably, it has been shown that concomitant SerDex measurement reduces false positives by 20%,17 reinforcing the benefit of its inclusion.
To be conservative, we reanalyzed all of the data excluding the 6 patients with NNH. This had no effect on any of the outcomes. In fact, the oDST 8AM cortisol was almost identical when comparing NH to NNH patients further emphasizing the clinical challenge of distinguishing these highly overlapping groups in terms of their laboratory results.
Similar to previous studies, we found a broad range of SerDex levels across all oDSTs with minimal or no correlation to SerCort.9,23,24 To maximize specificity, Ueland et al proposed a SerDex cutoff value of 130 ng/dL [0.130 mcg/dL (3.3 nmol/L)], while Ceccato et al proposed a SerDex cutoff of 180 ng/dL [0.180 mcg/dL (4.5 nmol/L)] prioritizing specificity.17,25 SerCort levels the morning after taking 1 mg of dexamethasone (8 AM–9 AM) reflects delayed glucocorticoid negative feedback at the pituitary and hypothalamus that takes at least 1-2 h to be fully expressed.26 Therefore, differences in measured SerDex at 8 AM the morning after the 1 mg dose ingestion reflect the variability of HPA axis feedback sensitivity and the timing of the pharmacokinetics of dexamethasone metabolism that can be influenced by several factors, such as age, BMI, and concomitant medications.11,13,27,28 Our findings suggest that any detectible SerDex level (>50 ng/dL in our study), even if below the established reference interval (eg,140–295 ng/dL), is sufficient for a valid test and probably does not require repetition. That said, it may still be prudent to repeat the test if the SerCort does not suppress to <1.8 mcg/dL and the SerDex is < 100 ng/dL particularly with a high index of suspicion for CS.24 oDSTs with SerDex values below the laboratory’s detectable limits (LOQ) should still be considered invalid, most likely due to dexamethasone noncompliance or differences in absorption and/or pharmacokinetics as described above. It is also important to point out that the LOQ for some serum dexamethasone assays are higher than the assay we used, which makes this point even more important.18
An important final point is the practicability of the approach. Why not just store the serum cortisol sample and only test it for serum dexamethasone if requested18? This is very challenging for clinicians in practice who work with a variety of reference laboratories and are often not aware of the SerCort oDST results until after the sample has been discarded. By building the reflex approach into the ordering system, this problem is avoided as it does not require the intervention of the ordering clinician, thereby reducing the administrative burden while reducing laboratory costs. The significance of our novel study is confirmed by the fact that, subsequent to our implementation, a major reference laboratory has recently established a similar Reflex oDST test (https://www.labcorp.com/tests/503990/cortisol-dexamethasone-suppression-test-with-reflex-to-dexamethasone). Others are likely to follow. Our study, which is the first of its kind to our knowledge, should give the clinician assurance that this approach is appropriate. At our relatively small laboratory, this results in annual cost savings of $11,500 per year just for the dexamethasone levels not needed. The savings for each institutional and provider would obviously be different depending on their patient mix and test volumes.

Conclusion

We demonstrated that the implementation of the Reflex protocol avoided unnecessary SerDex measurements without affecting test performance, highlighting its utility from both a resource and cost standpoint. Additionally, our findings suggest that any quantifiable SerDex level, even if below the established reference interval, does not invalidate the oDST.

Disclosure

Dr Carroll is an Editorial Board Member of this journal and was not involved in the editorial review or the decision to publish this article. Dr Nerenz receives research funding from Abbott Laboratories.

Acknowledgment

The authors thank the personnel at Wisconsin Diagnostic Laboratories for their work to develop and implement the Reflex Testing protocol. J.D.K. is a recipient of the 2024 Research Experience for Graduate and Medical Students (REGMS) award from the Endocrine Society (US).

References

Filed under: Cushing's, Diagnostic Testing | Tagged: , , , , | Leave a comment »

Osilodrostat Treatment of Cushing Syndrome in Real-World Clinical Practice

Posted on May 23, 2025 by MaryO
Abstract
Context
In clinical trials, osilodrostat (11β-hydroxylase inhibitor) effectively reduced cortisol levels in patients with endogenous Cushing syndrome (CS).
Objectives
A real-world study (ILLUSTRATE) was conducted evaluating osilodrostat use in patients with various etiologies of CS in the United States.
Methods
A retrospective chart-review study was conducted of adults with CS treated with osilodrostat between May 1, 2020, and October 29, 2021.
Results
A total of 42 patients (Cushing disease, n = 34; CS due to adrenal adenoma, n = 5; ectopic adrenocorticotropin syndrome [EAS], n = 3) were included. Starting doses were 2 mg twice daily in 27/42 patients (64.3%), maintenance doses were 2 mg twice daily in 6 of 9 patients (66.7%) attaining them. During osilodrostat treatment, urinary free cortisol (UFC) decreased below the upper limit of normal (ULN) in 14 of 20 patients (70.0%) with pretreatment UFC greater than the ULN. Osilodrostat response was observed across a range of doses (2-20 mg/day). In Cushing disease, median UFC and late-night salivary cortisol decreased from 3.03 and 2.39 × ULN, respectively, to 0.71 and 1.13 × ULN at last assessment in those with available data (n = 17 and 8, respectively). UFC decreased in all patients with adrenal CS or EAS with available data (n = 2 each). There were no unexpected safety signals; the most common adverse events (incidence ≥20%) were fatigue, nausea, and lower-extremity edema. Glucocorticoid withdrawal syndrome and/or adrenal insufficiency were reported in 12 of 42 patients (28.6%) after osilodrostat initiation, resulting in treatment discontinuation in 4.
Conclusion
In routine practice with dosing individualized according to clinical condition, response, and tolerability, osilodrostat was effective and well tolerated regardless of CS etiology and severity.
Cushing disease, ectopic adrenocorticotropin syndrome, adrenal Cushing syndrome, osilodrostat, retrospective, real world
Subject Pituitary and Neuroendocrinology
Issue Section: Clinical Research Article
Endogenous neoplastic Cushing syndrome (CS) is a serious endocrine condition characterized by excessive endogenous cortisol secretion [1, 2]. Untreated, hypercortisolism has serious cardiovascular, metabolic, neuropsychiatric, and infectious consequences, which negatively affect patients’ quality of life [2-4]. The risk of mortality is higher in patients with CS than in the general population, mainly because of greater mortality from cardiovascular and infectious diseases [2-5]. More recently, it has been shown that cancer risk is increased in population cohorts with CS [6, 7].
Most cases of CS are caused by excess secretion of adrenocorticotropin (ACTH) from a pituitary adenoma (Cushing disease), which results in excess cortisol release from the adrenal glands [2, 4]. However, some patients may present with ectopic ACTH syndrome (EAS; also referred synonymously as ectopic CS) or ACTH-independent cortisol excess from adrenal adenomas, adrenocortical cancers, or bilateral nodular adrenal hyperplasia (adrenal CS) [2, 4].
Osilodrostat is a potent oral inhibitor of 11β-hydroxylase, the enzyme that catalyzes the final step of cortisol synthesis in the adrenal cortex [8]. In phase 3 trials in patients with Cushing disease, osilodrostat was associated with a rapid and sustained reduction in cortisol levels, as well as improvements in cardiovascular and metabolic parameters, the physical manifestations of Cushing disease, and patients’ quality of life [9-13]. The clinical development program for osilodrostat also included a phase 2 study in patients with EAS or adrenal CS, which demonstrated that osilodrostat can lower cortisol regardless of the etiology of CS [14]. Based on these data, osilodrostat was licensed for use in adults with Cushing disease for whom pituitary surgery is not an option or has not been curative (United States) [15] and in adults/patients with endogenous CS (Europe [16]/Japan [17]).
Although prospective clinical trials are essential for demonstrating the efficacy and safety of drug therapies, they entail enrollment of selected patient populations and a tightly controlled research setting [18]. Real-world observational studies, in which the drug is used according to physicians’ clinical practice, provide complementary and helpful information in this context. Previous real-world studies conducted in patients with CS in Europe have shown that osilodrostat reduces cortisol levels and improves comorbidities, with no unexpected safety signals [19-22]. The present study, osIlodrostat reaL-worLd Utilization Study To Retrospectively Assess paTient Experience (ILLUSTRATE), was conducted in multiple clinical practices in the United States to evaluate the dosing, effectiveness, and safety of osilodrostat in patients with CS, irrespective of its etiology.
Materials and Methods
ILLUSTRATE was a retrospective chart-review study of patients in the United States treated with osilodrostat between May 1, 2020, and October 29, 2021. The index date for each patient was defined as the date of the first osilodrostat prescription (between May 1, 2020, and October 29, 2021). Preprescription data were collected from the 12 months before each patient’s index date to provide baseline data for that patient.
Patients were eligible for inclusion if aged 18 years or older, with a diagnosis of endogenous neoplastic CS (due to a pituitary adenoma, adrenal adenoma, or ectopic tumor) and a documented prescription for osilodrostat on or after May 1, 2020. As osilodrostat was approved for Cushing disease in the United States earlier the same year (March 6, 2020) [23], the start date for ILLUSTRATE was selected to avoid inclusion of patients treated with osilodrostat in clinical trials. The study was approved by a central independent review board (Western Institutional Review Board). As the study employed secondary data collection of anonymized patient data, a waiver of consent was granted under the privacy rule of HIPPA (the Health Insurance Portability and Accountability Act).
If available, the following data were extracted from patients’ medical records into an electronic case report form (eCRF): demographic details (age, sex, race, ethnicity); clinical history (date of CS diagnosis, signs and symptoms, prior surgery and/or radiotherapy); duration of disease prior to osilodrostat prescription; other therapies (cortisol-lowering medications, concomitant steroid use or replacement, antihypertensive and antidiabetic medications); laboratory data (urinary free cortisol [UFC], late-night salivary cortisol [LNSC], morning serum cortisol, serum potassium, testosterone [female patients only]); osilodrostat use (starting dose, uptitration, downtitration, duration of treatment); and adverse events (AEs). AEs were selected from a dropdown list that included the following: hypotension, hyperkalemia, hypokalemia, prolonged QT interval on electrocardiogram, lower-extremity edema, dizziness, rash, constipation, fatigue, alopecia, headache, nausea, vomiting, pituitary tumor size, hypertension, hirsutism, acne, irregular menstruation, brain fog or other cognitive changes, insomnia, striae, muscle weakness, depression, anxiety, other emotional changes, arthralgia/myalgia, and sleep changes.
The following variables were derived from the information recorded in the eCRF: time to maintenance dose (maintenance dose was defined as the first dose that was not modified between two consecutive visits, which could include the baseline visit); titration interval (time between osilodrostat dose changes; if patients had multiple dose changes, the average was reported); and proportion of patients on osilodrostat 6 months after the index prescription. In patients who had dose changes after reaching the maintenance dose, the time between these dose changes was included in the calculation of average titration interval.
Investigator-reported events of glucocorticoid withdrawal syndrome (GWS) and adrenal insufficiency (AI) were evaluated by two of the authors (J.L.S.-S. and K.C.D.) and adjudicated according to symptoms and the level of morning serum cortisol, where available. If the symptoms were consistent with GWS and serum cortisol at the time of the event was greater than 10 µg/dL (>276 nmol/L), these cases were classified as GWS. If the symptoms were more severe or cortisol levels were less than or equal to 10 µg/dL (≤276 nmol/L), AI could not be ruled out, and these cases were classified as such. If the investigator recorded GWS and AI in the same patient at the same visit, they were classified as a single event.
Descriptive statistics were used for all variables based on the number of patients with data available for each variable. Laboratory measures were reported as n times the upper limit of normal (ULN). Independent quality assessments were conducted to check content, inconsistencies, and missing fields in the eCRF.
Results
Overall, 42 patients were included in the study: 34 patients with Cushing disease, 5 patients with adrenal CS as a result of adrenal adenoma, and 3 patients with EAS. Two patients with Cushing disease had only a single clinical encounter and were included in the baseline results only. Four patients (9.5%), all with Cushing disease, discontinued osilodrostat during follow-up; in all cases, this was because of GWS or AI.
Baseline Characteristics
Baseline demographics and clinical characteristics are summarized in Table 1. Mean age was 43.7 years, and most patients (76.2%) were female. Mean disease duration before osilodrostat prescription was 57.3 months, and most patients had previously undergone surgery (81.0%) and/or received one or more medical therapies (61.9%). In the subgroup of patients with adrenal CS (n = 5), 2 patients had undergone surgery and 2 patients had expressed a preference not to undergo surgery; in the final patient, information on previous surgery was not recorded in the eCRF. In the overall study population, median UFC, LNSC, and morning serum cortisol levels were 2.54, 2.39, and 1.16 × ULN, respectively. Twelve and 5 patients, respectively, had morning serum cortisol levels and UFC less than the ULN at baseline; of these, 6 (50.0%) and 3 (60.0%), respectively, had received previous medical therapy.
Table 1.Open in new tabBaseline demographic and clinical characteristics (overall and by etiology)
  All patients
(n = 42) Cushing disease (n = 34) Adrenal CS (n = 5)a EAS
(n = 3)b
Mean age (SD), y 43.7 (15.0) 40.8 (13.9) 49.2 (14.0) 66.7 (3.5)
Sex, n (%)
 Female 32 (76.2) 27 (79.4) 2 (40.0) 3 (100)
 Male 10 (23.8) 7 (20.6) 3 (60.0) 0
Race, n (%)
 White 22 (52.4) 17 (50.0) 4 (80.0) 1 (33.3)
 Black or African American 10 (23.8) 8 (23.5) 1 (20.0) 1 (33.3)
 Asian 2 (4.8) 1 (2.9) 0 1 (33.3)
 Multiracial 1 (2.4) 1 (2.9) 0 0
 Unknown 7 (16.7) 7 (20.6) 0 0
Ethnicity, n (%)
 Hispanic, Latino, or Spanish origin
  Yes 8 (19.0) 8 (23.5) 0 0
  No 28 (66.7) 20 (58.8) 5 (100) 3 (100)
 Unknown 6 (14.3) 6 (17.6) 0 0
Mean age at CS diagnosis (SD), y 37.7 (14.8) 34.9 (12.7) 40.0 (14.8) 66.3 (3.1)
Mean duration of disease prior to osilodrostat prescription (SD), mo 57.3 (82.0) 64.8 (86.7) 30.4 (26.6) 1.2 (0.3)
Previous pituitary or adrenal surgery for CS, n (%) 34 (81.0) 32 (94.1) 2 (40.0) 0
Radiotherapy for CS in last 5 y, n (%) 10 (23.8) 10 (29.4) 0 0
Previous medical therapy for CS,c n (%) 26 (61.9) 21 (61.8) 3 (60.0) 2 (66.7)
 Pasireotide 3 (7.1) 3 (8.8) 0 0
 Cabergoline 7 (16.7) 7 (20.6) 0 0
 Ketoconazole 10 (23.8) 8 (23.5) 0 2 (66.7)
 Metyrapone 2 (4.8) 1 (2.9) 1 (20.0) 0
 Mitotane 1 (2.4) 0 1 (20.0) 0
 Mifepristone 6 (14.3) 5 (14.7) 1 (20.0) 0
UFC,d × ULN n = 32 n = 25 n = 4 n = 3
 Mean (SD) 7.67 (14.84) 3.14 (2.98) 13.93 (15.25) 37.03 (36.46)
 Median (min-max) 2.54
(0.09-75.20) 2.28
(0.09-11.17) 13.77
(0.42-27.76) 33.33
(2.57-75.20)
LNSC,d × ULN n = 18 n = 16 n = 1 n = 1
 Mean (SD) 4.80 (8.18) 5.25 (8.59) 0.55 1.82
 Median (min-max) 2.39
(0.44-36.33) 2.78
(0.44-36.33) 0.55 1.82
Morning serum cortisol,d × ULN n = 32 n = 24 n = 5 n = 3
 Mean (SD) 1.23 (0.77) 1.13 (0.42) 1.08 (0.97) 2.33 (1.78)
 Median (min-max) 1.16
(0.19-4.38) 1.18
(0.19-1.88) 0.83
(0.39-2.76) 1.43
(1.17-4.38)
Potassium levels,d mmol/L n = 41 n = 33 n = 5 n = 3
 Mean (SD) 4.1 (0.6) 4.3 (0.5) 3.7 (0.5) 3.6 (0.9)
 Median (min-max) 4.0
(2.6-5.6) 4.2
(3.6-5.6) 3.4
(3.3-4.5) 3.7
(2.6-4.4)
Potassium levels <LLN,e n (%) n = 37
5 (13.5) n = 30
1 (3.3) n = 5
3 (60.0) n = 2
1 (50.0)
Testosterone levels,f × ULN n = 11 n = 9 n = 1 n = 1
 Mean (SD) 1.00 (1.48) 0.96 (1.56) 0.07 2.29
 Median (min-max) 0.36
(0.03-5.02) 0.36
(0.03-5.02) 0.07 2.29
ULNs varied between study centers, ranging from 32 to 64 µg/24 hours (88.3-176.6 nmol/L) for UFC, 0.01 to 0.112 µg/dL (0.28-3.09 nmol/L) for LNSC, 18.4 to 25 µg/dL (507.8-690.0 nmol/L) for morning serum cortisol, and 41 to 100 ng/dL (1.42-3.47 nmol/L) for testosterone (female patients).
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome; LLN, lower limit of normal; max, maximum; min, minimum; ULN, upper limit of normal.
aAll patients had adrenal adenoma.
bIn 1 patient, the primary tumor could not be located; in the other 2 patients, the location of the ectopic tumor was not recorded.
cReasons for stopping these therapies and switching to osilodrostat were not collected as part of this study.
dNot all patients had values recorded at baseline (see n numbers in each column).
eLLN was not available for all patients with available potassium data.
fFemale patients only.
Osilodrostat Dosing
Information on osilodrostat dosing is summarized in Table 2. The most common starting dose of osilodrostat was 4 mg/day in 28 of 47 patients (66.7%; Fig. 1A), comprising 2 mg twice daily in 27 patients and 4 mg once daily in 1 patient. Some patients with Cushing disease and adrenal CS were initiated on lower doses (1 mg once daily [n = 2] or twice daily [n = 10], or 2 mg once daily [n = 1]).
A, Total osilodrostat daily starting dose* in all patients (n = 42) and B, dose changes postinitiation (by etiology) in patients with at least one clinical encounter after initiating osilodrostat (n = 40). *Osilodrostat starting doses were given twice daily in all except 3 patients with Cushing disease (initiated on 1 mg once daily, 2 mg once daily, and 4 mg once daily) and 1 patient with adrenal CS (initiated on 1 mg once daily).
Figure 1.A, Total osilodrostat daily starting dose* in all patients (n = 42) and B, dose changes postinitiation (by etiology) in patients with at least one clinical encounter after initiating osilodrostat (n = 40). *Osilodrostat starting doses were given twice daily in all except 3 patients with Cushing disease (initiated on 1 mg once daily, 2 mg once daily, and 4 mg once daily) and 1 patient with adrenal CS (initiated on 1 mg once daily).
Open in new tabDownload slide
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome.
Table 2.Open in new tabOsilodrostat treatment (overall and by etiology)
  All patients
(n = 42) Cushing disease (n = 34) Adrenal CS (n = 5) EAS
(n = 3)
No. of patients with initial dose information 42 34 5 3
Starting total daily dose, mg
 Mean (SD) 3.4 (1.1) 3.4 (1.1) 3.0 (1.4) 4.0 (0.0)
 Median (min-max) 4 (1-6) 4 (1-6) 4 (1-4) 4 (4-4)
Starting dose schedule, n (%)
 Twice daily 38 (90.5) 31 (91.2) 4 (80.0) 3 (100)
 Once daily 4 (9.5) 3 (8.8) 1 (20.0) 0
Starting dose and schedule, n (%)
 1 mg once daily 2 (4.8) 1 (2.9) 1 (20.0) 0
 1 mg twice daily 10 (23.8) 9 (26.5) 1 (20.0) 0
 2 mg once daily 1 (2.4) 1 (2.9) 0 0
 2 mg twice daily 27 (64.3) 21 (61.8) 3 (60.0) 3 (100)
 3 mg twice daily 1 (2.4) 1 (2.9) 0 0
 4 mg once daily 1 (2.4) 1 (2.9) 0 0
No. of patients with postinitiation clinical encounters 40 32 5 3
Patients who reached maintenance dose by last interaction, n (%) 9 (22.5) 7 (21.9) 1 (20.0) 1 (33.3)
Time to maintenance dose or end of follow-up, wk
 Mean (SD) 34.7 (18.0) 36.7 (19.1) 23.0 (11.7) 33.6 (3.3)
 Median (min-max) 33 (0.7-78.1) 37 (0.7-78.1) 17 (13.0-37.6) 32 (31.3-37.4)
Maintenance dose,a n (%)
 2 mg twice daily 6 (66.7) 4 (57.1) 1 (100) 1 (100)
 4 mg twice daily 2 (22.2) 2 (28.6) 0 0
 10 mg twice daily 1 (11.1) 1 (14.3) 0 0
Patients with dose change, n (%) 25 (62.5) 21 (65.6) 2 (40.0) 2 (66.7)
Titration period in patients with dose change, wk
 Mean (SD) 13.8 (12.4) 14.8 (13.2) 4.9 (3.2) 13.0 (0.0)
 Median (min-max) 11 (2.6-57.0) 11 (4.6-57.0) 5 (2.6-7.1) 13 (13.0-13.0)
Osilodrostat treatment interruption,b n (%) 9 (22.5) 7 (21.9) 1 (20.0) 1 (33.3)
Duration of exposure up to treatment interruption or study end, wk
 Mean (SD) 35.2 (22.0) 36.5 (22.5) 26.8 (26.3) 35.8 (4.5)
 Median (min-max) 35 (0.7-78.1) 38 (0.7-78.1) 14 (4.0-69.7) 37 (30.7-39.3)
Duration of treatment up to study end,c wk
 Mean (SD) 37.0 (20.9) 38.2 (21.5) 29.4 (24.0) 36.0 (4.2)
 Median (min-max) 37 (0.7-78.1) 40 (0.7-78.1) 17 (13.0-69.7) 37 (31.3-39.3)
Patients on osilodrostat for ≥6 mo prior to study end,c,d n (%) 28 (96.6) 23 (95.8) 2 (100) 3 (100)
Duration of therapy prior to study endc in patients with ≥6 mo persistence, wk
 Mean (SD) 47.3 (15.2) 48.5 (15.3) 51.6 (25.6) 36.0 (4.2)
 Median (min-max) 44.9 (28.1-78.1) 45.7 (28.1-78.1) 51.7 (33.6-69.7) 37.4 (31.3-39.3)
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome.
aIn those who reached a maintenance dose (defined as a dose that was not modified between 2 consecutive visits) by last interaction.
bDefined as a break in osilodrostat treatment for 30 days or longer.
cOr treatment discontinuation (n = 4).
dIn 29 patients with 6 months’ follow-up (n = 24, 2, and 3 for Cushing disease, adrenal CS, and EAS, respectively).
Mean titration interval was 13.8 weeks for all patients (4.9 weeks in patients with adrenal CS, 13.0 weeks in patients with EAS, and 14.8 weeks in patients with Cushing disease). Nine patients (22.5%; 7 patients with Cushing disease and 1 patient each with adrenal CS and EAS) achieved a maintenance dose of osilodrostat (defined as no dose modification between 2 consecutive visits) after a mean (SD) of 34.7 (18.0) weeks. The most common maintenance dose was 2 mg twice daily (see Table 2).
Overall, 25 of 40 patients (62.5%) had their osilodrostat dose adjusted during the study. In most of these cases (n = 20), the dose was increased; 2 patients had a dose decrease and 3 patients had doses both increased and decreased (Fig. 1B). In those who had an osilodrostat dose increase only, most (14/20; 70.0%) had only a single dose increase; in the remaining patients, 4 (20.0%) had 2 dose increases and 2 (10.0%) had 4 dose increases. In those who had dose adjustments, there was no observable pattern between starting and final osilodrostat doses (Table 3). Overall, 9 of 40 patients (22.5%) had osilodrostat treatment temporarily interrupted, which occurred in the first 3 months of treatment in 5 patients, between treatment months 3 and 6 in 2 patients, and after 6 months in 2 patients. Reasons for temporary interruption were hypocortisolism-related AEs, patient undergoing surgery, lack of availability of osilodrostat in the hospital setting, and insurance noncoverage.
Table 3.Open in new tabShift table showing starting and final doses for those patients who had dose adjustments during the study period (n = 26)
Starting dosea Final dose, No. of patients
  1 mg/d 2 mg/d 4 mg/d 5 mg/d 6 mg/d 8 mg/d 10 mg/d 14 mg/d 20 mg/d
Cushing diseaseb
1 mg/d (n = 1)1
2 mg/d (n = 10)811
4 mg/d (n = 11) 1 1 1 4 2 2
Adrenal CS
1 mg/d (n = 1)1
4 mg/d (n = 1)1
EAS
4 mg/d (n = 2)11
Some patients had the same starting and final doses as their doses were increased then decreased during the study.
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome.
aOsilodrostat starting doses were given twice daily in all except 3 patients with Cushing disease (initiated on 1 mg once daily, 2 mg once daily, and 4 mg once daily) and 1 patient with adrenal CS (initiated on 1 mg once daily).
bOne patient had only their osilodrostat starting dose reported.
Mean (SD) duration of follow-up was 37.1 (20.5) weeks, and mean (SD) duration of osilodrostat treatment was 37.0 (20.9) weeks; almost all patients with postinitiation clinical encounters (96.6%) received treatment for 6 months or longer (see Table 2).
Changes in Cortisol Levels During Osilodrostat Treatment
In patients with available assessments, median values for all cortisol parameters decreased during osilodrostat treatment, regardless of CS etiology (Table 4). In the subgroup of patients with Cushing disease, median UFC and morning serum cortisol levels were less than the ULN at the last assessment (0.71 and 0.68 × ULN, respectively), while median LNSC levels were slightly higher than the ULN (1.13 × ULN). In patients with UFC, LNSC, and morning serum cortisol levels greater than the ULN at baseline, 12 of 16, 3 of 8, and 8 of 15, respectively, had levels less than the ULN during osilodrostat treatment (Fig. 2); the final osilodrostat doses in these patients ranged from 1 to 20 mg/day. Neither of the patients who had a final dose of 20 mg/day were receiving concomitant glucocorticoids (ie, they were not being treated with a “block-and-replace” approach). In those with UFC and morning serum cortisol less than the ULN at baseline, levels remained less than the ULN in 1 of 1 and 7 of 8 patients, respectively.
Changes in A, UFC; B, LNSC; and C, morning serum cortisol in individual patients. *In patient 23, the first and last doses recorded were both 2 mg twice daily; during the follow-up period, 2 changes in dose were recorded the same day on 2 separate occasions.
Figure 2.Changes in A, UFC; B, LNSC; and C, morning serum cortisol in individual patients. *In patient 23, the first and last doses recorded were both 2 mg twice daily; during the follow-up period, 2 changes in dose were recorded the same day on 2 separate occasions.
Open in new tabDownload slide
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome; LNSC, late-night salivary cortisol; NA, not available; UFC, urinary free cortisol; ULN, upper limit of normal.
Table 4.Open in new tabMedian (minimum-maximum) urinary free cortisol, late-night salivary cortisol, and morning serum cortisol levels (overall and by etiology)
  All patients Cushing disease Adrenal CS EAS
UFC, × ULN n = 21 n = 17 n = 2 n = 2
 Baseline 3.73 (0.09-75.20) 3.03 (0.09-11.17) 14.40 (1.03-27.76) 54.27 (33.33-75.20)
 Last assessment 0.71 (0.02-11.82) 0.71 (0.07-4.19) 6.18 (0.53-11.82) 1.44 (0.02-2.86)
LNSC, × ULN n = 8 n = 8 n = 0 n = 0
 Baseline2.39 (1.44-5.89)2.39 (1.44-5.89)
 Last assessment1.13 (0.44-4.44)1.13 (0.44-4.44)
Morning serum cortisol, × ULN n = 30 n = 23 n = 5 n = 2
 Baseline 1.15 (0.19-4.38) 1.16 (0.19-1.88) 0.83 (0.39-2.76) 2.91 (1.43-4.38)
 Last assessment 0.67 (0.02-2.76) 0.68 (0.19-1.87) 0.61 (0.05-2.76) 0.47 (0.02-0.93)
Results are based on patients with both baseline and postosilodrostat prescription data available.
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome; LNSC, late-night salivary cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.
The effect of osilodrostat on UFC and morning serum cortisol levels in individual patients with adrenal CS or EAS and available data are shown in Fig. 2A and 2C, respectively. In patients with adrenal CS, UFC levels were reduced in the 2 patients with data available, and morning serum cortisol levels were reduced in 2 of 5 patients with data available. In patients with EAS, there were substantial reductions both in UFC and morning serum cortisol (n = 2).
The time course of cortisol changes and corresponding osilodrostat doses in 2 patients with Cushing disease and 2 patients with EAS are illustrated in Fig. 3.
Individual osilodrostat dosing, UFC, and serum cortisol levels during the study period in illustrative patients. ULN for UFC was 50 μg/24 hours for patients 11, 4, and 1 and 42 μg/24 hours for patient 2. *ULN for serum cortisol was not provided for this patient, so it was estimated to be approximately 18 µg/dL.
Figure 3.Individual osilodrostat dosing, UFC, and serum cortisol levels during the study period in illustrative patients. ULN for UFC was 50 μg/24 hours for patients 11, 4, and 1 and 42 μg/24 hours for patient 2. *ULN for serum cortisol was not provided for this patient, so it was estimated to be approximately 18 µg/dL.
Open in new tabDownload slide
Abbreviations: BID, twice daily; EAS, ectopic adrenocorticotropin syndrome; UFC, urinary free cortisol; ULN, upper limit of normal.
Safety and Tolerability
Overall, 29 patients (69.0%) had an AE reported. The most common AEs (incidence ≥20%) were fatigue, nausea, and lower-extremity edema (Table 5).
Table 5.Open in new tabAdverse events reported during osilodrostat treatment (overall patient population)a
AE, n (%) n = 42a
Any AE 29 (69.0)
Fatigue 23 (54.8)
Nausea 12 (28.6)
Lower-extremity edema 11 (26.2)
Headache 6 (14.3)
Dizziness 6 (14.3)
Hypokalemia 6 (14.3)
Alopecia 4 (9.5)
Vomiting 3 (7.1)
Hypotension 2 (4.8)
Hyperkalemia 1 (2.4)
Prolonged QT interval on electrocardiogram 1 (2.4)
Abbreviation: AE, adverse event.
aIncludes 2 patients who had no postinitiation interaction before study end.
According to the events reported by the investigators, 13 patients had GWS (n = 3), AI (n = 3), or both (n = 7). Of these, osilodrostat treatment was interrupted in 3 patients, the dose was decreased in 2 patients, and there was no change in dose in 4 patients; in the remaining 4 patients, osilodrostat treatment was discontinued. Glucocorticoid use was reported in 4 patients overall; this included 2 patients in whom AI and/or GWS were reported. The first patient reported to have AI and GWS by the investigator was prescribed hydrocortisone 5 mg twice daily for 2 weeks. The second patient (AI) was also prescribed hydrocortisone at a dose of 20 mg/day (duration not specified).
On author adjudication, using the criteria outlined in “Materials and Methods,” 1 case of AI was reclassified as GWS and 5 cases reported to be both GWS and AI by the investigator were reclassified as AI only. Another case of AI was excluded as the symptoms of AI had started before initiation of osilodrostat; this patient had been treated with pasireotide in the 5 months before starting osilodrostat. Thus, the number of author-adjudicated cases during osilodrostat treatment was 12: 4 for GWS, 6 for AI, and 2 for both (ie, patients experiencing ≥1 distinct episode of GWS and AI).
To illustrate different presentations and management practices of AI and GWS, we describe details regarding individual cases. In 1 patient with GWS, symptoms were dizziness, nausea, and fatigue, with serum cortisol levels remaining above 10 µg/dL (276 nmol/L). The symptoms occurred early in the course of treatment and were managed by reducing the osilodrostat dose. In another patient with GWS, symptoms occurred after prolonged treatment, and osilodrostat was discontinued. In 2 patients with AI, symptoms were also dizziness, nausea, and fatigue, but serum cortisol levels were less than or equal to 10 µg/dL (≤276 nmol/L). In the first patient, osilodrostat was maintained at the same dose; symptoms resolved and cortisol levels increased slightly, to above 10 µg/dL (276 nmol/L). Treatment was interrupted in the second patient, but further information on the symptoms and cortisol levels were unavailable.
In patients with available data at baseline and last assessment (n = 38), median (minimum-maximum) serum potassium levels were 4.0 (2.6-5.6) and 4.3 (3.7-5.5) mmol/L, respectively. In those who were normokalemic at baseline (n = 30), 2 patients had potassium levels less than the lower limit of normal during osilodrostat treatment; in those who were hypokalemic at baseline (n = 4), 3 patients had potassium levels reverting to normal during treatment. In female patients with available data at baseline and last assessment (n = 4), mean testosterone levels were 1.48 × ULN at baseline and 1.52 × ULN at the last posttreatment assessment.
Discussion
This study evaluated the real-world use of osilodrostat in patients in the United States with CS during the period shortly after osilodrostat was approved by the US Food and Drug Administration for the treatment of adults with Cushing disease for whom pituitary surgery is not an option or has not been curative. The results highlight the importance of selecting a starting dose and titration regimen according to each patient’s circumstances, clinical response, and tolerability, as the dose required to normalize cortisol levels varies between patients and does not appear to depend on baseline levels. Most of the patients in the study (n = 34/42 [81.0%]) had Cushing disease, as expected. In this subgroup, most patients (n = 21/34 [61.8%]) were initiated on the approved starting dose of osilodrostat (2 mg twice daily), but many (n = 11/34 [32.4%]) were started on lower doses. All patients with Cushing disease who were initiated on doses lower than 2 mg twice daily required a dose increase during the study. A dose of 2 mg twice daily was also the most common maintenance dose in those with Cushing disease who reached a maintenance dose: a total of 57.1% remained on 2 mg twice daily, while 28.6% and 14.3% were uptitrated to 4 mg twice daily and 10 mg twice daily, respectively. In phase 3 clinical trials of osilodrostat in patients with Cushing disease (LINC 3 and LINC 4), median (interquartile range) average doses at the end of the extension periods were 7.4 (3.5-13.6) mg/day in LINC 3 and 4.6 (3.7-9.2) mg/day in LINC 4 [9, 11]. In the present study, most patients whose dose was uptitrated required only one dose increase. Mean duration of the titration period in patients with Cushing disease, defined as the period between any osilodrostat dose changes, was 14.8 weeks. In LINC 3 and LINC 4, doses were increased according to UFC levels in the first 12 weeks, after which dose adjustments were permitted during the remainder of the 48-week core period based on efficacy and tolerability [10, 12]. In both trials, starting and final osilodrostat doses were lower in Asian patients with Cushing disease than in non-Asian patients, regardless of body mass index, likely because of differences in bioavailability [24].
In the subgroup of patients with Cushing disease, most of those with UFC and morning serum cortisol levels greater than the ULN at baseline had their levels reduced to normal during treatment (12/16 and 8/15, respectively). Some patients had UFC and morning serum cortisol levels less than the ULN when osilodrostat was initiated, presumably reflecting a switch to osilodrostat from another medical therapy (eg, because of tolerability issues). More than 60% of patients had received one or more medical therapies before starting osilodrostat, but the reasons for stopping these therapies were not collected as part of the study. In patients with normal levels at study baseline, levels remained less than the ULN in 1 of 1 patient for UFC and 6 of 8 patients for morning serum cortisol. Median levels of UFC and morning serum cortisol in the subgroup of patients with Cushing disease decreased to within the normal range during osilodrostat treatment. These real-world results are consistent with those from the 48-week core phases of LINC 3 and LINC 4 [10, 12, 13].
The present study also included a small number of patients with adrenal CS (n = 5) and EAS (n = 3). The starting dose was 2 mg twice daily in all patients with EAS; in patients with adrenal CS, the starting dose was 2 mg twice daily (n = 3), 1 mg twice daily (n = 1), and 1 mg once daily (n = 1). Baseline median UFC, which was higher in the adrenal CS and EAS subgroups than in patients with Cushing disease, decreased during osilodrostat treatment but remained above the ULN. Median morning serum cortisol levels decreased from above to within the normal range in patients with EAS and remained within the normal range in patients with adrenal CS. Notably, baseline levels of morning serum cortisol, mean UFC, or LNSC did not necessarily predict the osilodrostat dose needed for biochemical normalization. Again, these results emphasize the need to individualize the starting dose and titration regimen based on each patient’s clinical circumstances and response to treatment. Differences in the pathophysiology of CS subtypes may also influence decisions about osilodrostat titration; for example, unlike in Cushing disease, ACTH rarely rises during inhibition of cortisol synthesis in EAS, and the rise in ACTH is delayed after cortisol normalization in adrenal CS. The results for the adrenal CS and EAS subgroups in the present study should be interpreted with caution given the small number of patients, and data from individual patients are perhaps more illustrative in this context. Individual UFC and morning serum cortisol levels were reduced in all patients with adrenal CS or EAS except for 2 patients (both with adrenal CS), whose morning serum cortisol levels did not change; in one of these patients, morning serum cortisol was within the normal range at baseline. Data on LNSC levels should also be interpreted with caution given the small number of patients with data available for this parameter.
The safety profile of osilodrostat was similar to that observed in clinical trials [10, 12, 14], with no unexpected safety signals. GWS and AI are recognized as potential side effects of osilodrostat based on its mechanism of action, but they can be difficult to differentiate as many of their symptoms overlap [25]. In the present study, there were 12 cases of GWS and/or AI after initiation of osilodrostat (28.6% of patients); this rate is lower than in the LINC 3 clinical trial (54.0% of patients with hypocortisolism-related AEs) [9] and similar to that seen in LINC 4 (27.4%) [11]. In LINC 3 and LINC 4, most hypocortisolism-related AEs were classified by the investigator as AI [11], but further evaluation to differentiate between this and GWS was not possible. For the present study, we were able to evaluate the symptoms and biochemical changes associated with these AEs, and we confirmed that it was often not possible for clinicians to accurately distinguish GWS and AI based on symptoms alone. As GWS and AI may require different management approaches, measurement of serum cortisol levels is essential to help guide the management strategy in these cases. In the present study, most cases of GWS and AI were managed by reducing the dose or temporarily interrupting treatment, which is consistent with the results from LINC 3 and LINC 4 [9-12]; only 4 patients (9.5%) with AI or GWS in the present study had discontinued treatment as a result. Treatment with glucocorticoids was recorded in 2 patients; the timing of treatment indicates that glucocorticoids were used to treat the symptoms of AI/GWS rather than as part of a “block-and-replace” strategy, in which glucocorticoids are administered concomitantly with osilodrostat [21, 26]. Slower dose escalation may reduce the risk of hypocortisolism-related AEs; the longer titration interval in LINC 4 (every 3 weeks) than in LINC 3 (every 2 weeks) may explain the lower incidence of hypocortisolism-related AEs during LINC 4 [10, 12]. Regardless, and as with all steroidogenesis inhibitors, all patients treated with osilodrostat should be monitored regularly and educated on the signs and symptoms of GWS and AI. Case reports have described rare episodes of delayed cortisol reduction during chronic osilodrostat therapy and prolonged AI after its discontinuation, which emphasizes the importance of lifelong, close monitoring of symptoms and serum cortisol levels [27-29].
The results of the present study are consistent with those of previous studies demonstrating the efficacy and safety of osilodrostat in patients with EAS or adrenal CS. In a prospective phase 2 study conducted in Japan, mean UFC levels decreased in all patients and normalized in most following 12 weeks of treatment [14]. In LINC 7, a retrospective study conducted in France, 103 patients with adrenal CS or EAS were followed up retrospectively for up to 36 months; at last assessment, mean UFC was normalized in most patients [30]. Compared with LINC 7, the starting and maintenance doses of osilodrostat were lower in the present study, once again emphasizing the importance of individualizing osilodrostat dosing. In a second real-world study in France, which was conducted in 30 patients with EAS, median UFC decreased significantly following osilodrostat monotherapy (when used both first and second line) and combination therapy with other cortisol-lowering drugs [21]. There were also substantial improvements in hypertension, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of concomitant treatments. Several other case series and case reports have documented effective control of cortisol levels and good tolerability in patients with adrenal CS or EAS [26, 31-38], adding to the body of evidence supporting the use of osilodrostat in patients with CS irrespective of severity and etiology.
Limitations of the present study include the small patient numbers, particularly in the groups with adrenal CS and EAS. As the study was conducted shortly after osilodrostat was approved in the United States for patients with Cushing disease for whom pituitary surgery is not an option or has not been curative, the predominance of patients with Cushing disease was expected, albeit slightly higher (81%) than the overall prevalence of Cushing disease (up to 70%), vs other causes of CS in a clinical setting [2]. Another limitation is that data were extracted retrospectively from patients’ medical records rather than recorded prospectively according to a study protocol; this resulted in many missing data points, especially for laboratory data. Despite these limitations, the results provide invaluable information on the real-world use of osilodrostat in the United States, for which data are currently lacking. The design of the study also allowed adjudication of AI vs GWS events by the authors in some patients as morning cortisol levels were available. In addition, ILLUSTRATE is the only completed multicenter study in the United States to date that evaluates the effect of osilodrostat not only in Cushing disease, but also in adrenal CS and EAS, providing data on the cortisol-lowering effectiveness of osilodrostat across the spectrum of hypercortisolism etiologies.
Conclusions
Results of this real-world study are consistent with those from clinical trials and other real-world studies, showing that osilodrostat was effective and well tolerated in patients with varying etiologies and severities of CS when used by physicians in routine clinical practice. The results also highlight the importance of individualizing the osilodrostat dose and titration regimen according to each patient’s clinical condition, response, and tolerability.
Acknowledgments
We thank all clinicians and patients who participated in the study.
Funding
This work was supported by Recordati Rare Diseases Inc, Bridgewater, New Jersey, United States. AMICULUM provided medical editorial assistance, funded by Recordati Rare Diseases Inc.
Disclosures
M.F. reports grants to her university from Crinetics and Sparrow and occasional scientific consulting fees from Crinetics, Recordati Rare Diseases, Sparrow, and Xeris Pharmaceuticals; she served as a member of the LINC 3 steering committee. R.J.A. reports grants and personal fees from Xeris Pharmaceuticals, Spruce Biosciences, Neurocrine Biosciences, Corcept Therapeutics, Diurnal Ltd, Sparrow Pharmaceuticals, Crinetics Pharmaceuticals, and Recordati Rare Diseases and personal fees from Adrenas Therapeutics, Quest Diagnostics, H Lundbeck A/S, Novo Nordisk, and Besins Pharmaceuticals. W.H. reports grants to his institution from CinCor, Corcept, Crinetics, Spruce, and Ascendis and honoraria from Novo Nordisk, Recordati Rare Diseases, Chiesi, Crinetics, Neurocrine, Camurus, and Spruce. J.L.S.-S. reports research grants from Recordati Rare Diseases and scientific consulting fees from Crinetics, Recordati Rare Diseases, and Corcept. K.C.J.Y. reports grants to his institution from Corcept, Sparrow, Chiesi, and Ascendis and honoraria from Novo Nordisk, Ascendis, Chiesi, Recordati Rare Diseases, Xeris, Crinetics, Camurus, and Neurocrine. K.C.D. and J.P. are employees of Recordati Rare Diseases Inc. E.K.B. was an employee of Recordati Rare Diseases Inc at the time the study was conducted (current affiliation: Inizio Engage, Yardley, Pennsylvania, USA). A.K.D., C.C., and M.S.B. are employees of PHAR, which received funding from Recordati Rare Diseases Inc to conduct the analysis. A.G.I. reports grants to her university from Recordati Rare Disease, Xeris Pharmaceuticals, and Chiesi and occasional consulting fees from Xeris Pharmaceuticals, Crinetics, Camurus, and Chiesi.
Data Availability
Some data sets generated and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.
References
1 Fleseriu   M, Varlamov   EV, Hinojosa-Amaya   JM, Langlois   F, Melmed   S. An individualized approach to the management of Cushing disease. Nat Rev Endocrinol. 2023;19(10):581‐599.
Google ScholarCrossrefPubMedWorldCat
2 Gadelha   M, Gatto   F, Wildemberg   LE, Fleseriu   M. Cushing’s syndrome. Lancet. 2023;402(10418):2237‐2252.
Google ScholarCrossrefPubMedWorldCat
3 Braun   LT, Vogel   F, Reincke   M. Long-term morbidity and mortality in patients with Cushing’s syndrome. J Neuroendocrinol. 2022;34(8):e13113.
Google ScholarCrossrefPubMedWorldCat
4 Reincke   M, Fleseriu   M. Cushing syndrome: a review. JAMA. 2023;330(2):170‐181.
Google ScholarCrossrefPubMedWorldCat
5 Mondin   A, Ceccato   F, Voltan   G, et al.  Complications and mortality of Cushing’s disease: report on data collected over a 20-year period at a referral centre. Pituitary. 2023;26(5):551‐560.
Google ScholarCrossrefPubMedWorldCat
6 Rudman   Y, Fleseriu   M, Dery   L, et al.  Endogenous Cushing’s syndrome and cancer risk. Eur J Endocrinol. 2024;191(2):223‐231.
Google ScholarCrossrefPubMedWorldCat
7 Wu   WC, Wu   JL, Huang   TS, Li   CY, Li   HY. Cushing’s syndrome is associated with a higher risk of cancer—a nationwide cohort study. J Clin Endocrinol Metab. Published online June 13, 2024. Doi:10.1210/clinem/dgae405
WorldCatCrossref
8 Creemers   SG, Feelders   RA, de Jong   FH, et al.  Osilodrostat is a potential novel steroidogenesis inhibitor for the treatment of Cushing syndrome: an in vitro study. J Clin Endocrinol Metab. 2019;104(8):3437‐3449.
Google ScholarCrossrefPubMedWorldCat
9 Fleseriu   M, Newell-Price   J, Pivonello   R, et al.  Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension. Eur J Endocrinol. 2022;187(4):531‐541.
Google ScholarCrossrefPubMedWorldCat
10 Gadelha   M, Bex   M, Feelders   RA, et al.  Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab. 2022;107(7):e2882‐e2895.
Google ScholarCrossrefPubMedWorldCat
11 Gadelha   M, Snyder   PJ, Witek   P, et al.  Long-term efficacy and safety of osilodrostat in patients with Cushing’s disease: results from the LINC 4 study extension. Front Endocrinol (Lausanne). 2023;14:1236465.
Google ScholarCrossrefPubMedWorldCat
12 Pivonello   R, Fleseriu   M, Newell-Price   J, et al.  Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;8(9):748‐761.
Google ScholarCrossrefPubMedWorldCat
13 Pivonello   R, Fleseriu   M, Newell-Price   J, et al.  Improvement in clinical features of hypercortisolism during osilodrostat treatment: findings from the phase III LINC 3 trial in Cushing’s disease. J Endocrinol Invest. 2024;47(10):2437‐2448.
Google ScholarCrossrefPubMedWorldCat
14 Tanaka   T, Satoh   F, Ujihara   M, et al.  A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing’s syndrome other than Cushing’s disease. Endocr J. 2020;67(8):841‐852.
Google ScholarCrossrefPubMedWorldCat
15 Recordati Rare Diseases. Osilodrostat prescribing information. 2023. Accessed September 2024. https://isturisa.com/wp-content/themes/isturisa-patient/dist/pdf/isturisa-prescribing-information.pdf
16 European Medicines Agency. Osilodrostat summary of product characteristics. 2024. Accessed September 2024. https://www.ema.europa.eu/en/documents/product-information/isturisa-epar-product-information_en.pdf
17 Pharmaceuticals and Medical Devices Agency. Isturisa® Japan prescribing information. 2021. Accessed October 2024. https://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/24990A5
18 Dang   A. Real-world evidence: a primer. Pharmaceut Med. 2023;37(1):25‐36.
Google ScholarPubMedWorldCat
19 Bonnet-Serrano   F, Poirier   J, Vaczlavik   A, et al.  Differences in the spectrum of steroidogenic enzyme inhibition between osilodrostat and metyrapone in ACTH-dependent Cushing syndrome patients. Eur J Endocrinol. 2022;187(2):315‐322.
Google ScholarCrossrefPubMedWorldCat
20 Detomas   M, Altieri   B, Deutschbein   T, Fassnacht   M, Dischinger   U. Metyrapone versus osilodrostat in the short-term therapy of endogenous Cushing’s syndrome: results from a single center cohort study. Front Endocrinol (Lausanne). 2022;13:903545.
Google ScholarCrossrefPubMedWorldCat
21 Dormoy   A, Haissaguerre   M, Vitellius   G, et al.  Efficacy and safety of osilodrostat in paraneoplastic Cushing syndrome: a real-world multicenter study in France. J Clin Endocrinol Metab. 2023;108(6):1475‐1487.
Google ScholarCrossrefPubMedWorldCat
22 Dzialach   L, Sobolewska   J, Respondek   W, Szamotulska   K, Witek   P. Cushing’s disease: long-term effectiveness and safety of osilodrostat in a Polish group of patients with persistent hypercortisolemia in the experience of a single center. Biomedicines. 2023;11(12):3227.
Google ScholarCrossrefPubMedWorldCat
23 US Food and Drug Administration. FDA approves new treatment for adults with Cushing’s disease. 2020. Accessed September 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-cushings-disease
24 Shimatsu   A, Biller   BM, Fleseriu   M, et al.  Osilodrostat treatment in patients with Cushing’s disease of Asian or non-Asian origin: a pooled analysis of two phase III randomized trials (LINC 3 and LINC 4). Endocr J. 2024;71(12):1103‐1123.
Google ScholarCrossrefPubMedWorldCat
25 He   X, Findling   JW, Auchus   RJ. Glucocorticoid withdrawal syndrome following treatment of endogenous Cushing syndrome. Pituitary. 2022;25(3):393‐403.
Google ScholarCrossrefPubMedWorldCat
26 Hána   V, Brutvan   T, Krausová   A, Kršek   M, Hána   V. Severe Cushing’s syndrome from an ectopic adrenocorticotropic hormone-secreting neuroendocrine tumour treated by osilodrostat. Endocrinol Diabetes Metab Case Rep. 2023;2023(4):23-0076.
Google ScholarPubMedWorldCat
27 Castinetti   F, Amodru   V, Brue   T. Osilodrostat in Cushing’s disease: the risk of delayed adrenal insufficiency should be carefully monitored. Clin Endocrinol (Oxf). 2023;98(4):629‐630.
Google ScholarCrossrefPubMedWorldCat
28 Ferriere   A, Salenave   S, Puerto   M, Young   J, Tabarin   A. Prolonged adrenal insufficiency following discontinuation of osilodrostat treatment for intense hypercortisolism. Eur J Endocrinol. 2024;190(1):L1‐L3.
Google ScholarCrossrefPubMedWorldCat
29 Poirier   J, Bonnet-Serrano   F, Thomeret   L, Bouys   L, Bertherat   J. Prolonged adrenocortical blockade following discontinuation of osilodrostat. Eur J Endocrinol. 2023;188(6):K29‐K32.
Google ScholarCrossrefPubMedWorldCat
30 Tabarin   A, Bertherat   J, Decoudier   B, et al.  Safety and effectiveness of osilodrostat in patients with non-pituitary Cushing’s syndrome: results from the retrospective observational LINC 7 study. ENDO. 2024:poster SAT-671.
31 Amodru   V, Brue   T, Castinetti   F. Synergistic cortisol suppression by ketoconazole-osilodrostat combination therapy. Endocrinol Diabetes Metab Case Rep. 2021;2021:21-0071.
Google ScholarPubMedWorldCat
32 Bessiène   L, Bonnet   F, Tenenbaum   F, et al.  Rapid control of severe ectopic Cushing’s syndrome by oral osilodrostat monotherapy. Eur J Endocrinol. 2021;184(5):L13‐L15.
Google ScholarCrossrefPubMedWorldCat
33 Haissaguerre   M, Puerto   M, Nunes   ML, Tabarin   A. Efficacy and tolerance of osilodrostat in patients with severe Cushing’s syndrome due to non-pituitary cancers. Eur J Endocrinol. 2020;183(4):L7‐L9.
Google ScholarCrossrefPubMedWorldCat
34 Heleno   CT, Hong   SPD, Cho   HG, Kim   MJ, Park   Y, Chae   YK. Cushing’s syndrome in adenocarcinoma of lung responding to osilodrostat. Case Rep Oncol. 2023;16(1):124‐128.
Google ScholarPubMedWorldCat
35 Malik   RB, Ben-Shlomo   A. Adrenal Cushing’s syndrome treated with preoperative osilodrostat and adrenalectomy. AACE Clin Case Rep. 2022;8(6):267‐270.
Google ScholarCrossrefPubMedWorldCat
36 Sawabe   F, Hayafusa   R, Kosugi   R, Ariyasu   H. A case of an ectopic ACTH-producing tumor with adrenal shrinkage during osilodrostat administration. JCEM Case Rep. 2024;2(2):luae008.
Google ScholarCrossrefPubMedWorldCat
37 Stasiak   M, Witek   P, Adamska-Fita   E, Lewiński   A. Response to osilodrostat therapy in adrenal Cushing’s syndrome. Drug Healthc Patient Saf. 2024;16:35‐42.
Google ScholarCrossrefPubMedWorldCat
38 Tabarin   A, Haissaguerre   M, Lassole   H, et al.  Efficacy and tolerance of osilodrostat in patients with Cushing’s syndrome due to adrenocortical carcinomas. Eur J Endocrinol. 2022;186(2):K1‐K4.
Google ScholarCrossrefPubMedWorldCat
Abbreviations
ACTH
adrenocorticotropin
AE
adverse event
AI
adrenal insufficiency
CS
Cushing syndrome
EAS
ectopic adrenocorticotropin syndrome
eCRF
electronic case report form
GWS
glucocorticoid withdrawal syndrome
ILLUSTRATE
osIlodrostat reaL-worLd Utilization Study To Retrospectively Assess paTient Experience
LLN
lower limit of normal
LNSC
late-night salivary cortisol
UFC
urinary free cortisol
ULN
upper limit of normal
© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.

Filed under: Cushing's, Treatments | Tagged: , , | Leave a comment »

Mortality in Cushing’s Syndrome: Declining Over Two Decades but Remaining Higher Than the General Population

Posted on April 18, 2025 by MaryO

Abstract

Objective

Patients with endogenous Cushing’s syndrome (CS) have elevated mortality, particularly during active disease. A recent meta-analysis reported reduced mortality rates after 2000 in adrenal CS and Cushing disease (CD), though many studies lacked population-matched controls.

Methods Nationwide retrospective study (2000–2023) in Israel using the Clalit Health Services database to assess all-cause mortality in patients with endogenous CS matched 1:5 with controls by age, sex, socioeconomic-status, and BMI. Primary outcome was all-cause mortality. Secondary outcomes included cause-specific mortality, impact of hypercortisolism remission, disease source, and mortality risk factors.

Results The cohort included 609 cases with CS (mean age 48.1±17.2 years; 65.0% women) and 3,018 matched controls (47.9±17.2 years; 65.4% women). Over a median follow-up of 16 years, 133 cases (21.8%) and 472 controls (15.6%) died (HR=1.44, 95% CI, 1.19–1.75). Both patients with CD (HR=1.73, 95% CI, 1.27–2.36) and adrenal CS (HR=1.31, 95% CI, 1.00–1.81) had increased mortality risk. Patients without remission within 2 years had a higher mortality risk than those achieving remission (HR=1.44, 95% CI, 1.00–2.17). Mortality was similar for CD and adrenal CS (HR=0.83, 95% CI, 0.56–1.24). Older age, male gender, and prior malignancy were independent risk factors for mortality.

Conclusion This is the largest national cohort study on mortality risk in CS over the past two decades, showing a significantly higher risk compared to matched controls in a homogeneous database. While etiology had no impact, remission significantly affected mortality, highlighting the importance of disease control for long-term survival.

Request the full article at https://www.researchgate.net/publication/390437820_Mortality_in_Cushing’s_Syndrome_Declining_Over_Two_Decades_but_Remaining_Higher_Than_the_General_Population

Filed under: Clinical trials, Cushing's | Tagged: , , , | Leave a comment »

Myocardial Work Impairment in Patients With Cushing’s Syndrome

Posted on April 4, 2025 by MaryO

The following is a summary of “Impact Of Hypercortisolism Beyond Metabolic Syndrome On Left Ventricular Performance: A Myocardial Work Analysis,” published in the March 2025 issue of Cardiovascular Diabetology by Sahiti et al.

Endogenous Cushing’s Syndrome (CS) is associated with an increased cardiovascular (CV) and metabolic risk profile, yet the specific impact of hypercortisolism on myocardial function remains inadequately understood. Myocardial Work analysis, a novel echocardiographic technique utilizing left ventricular pressure-strain loops, allows for the assessment of cardiac performance independently of afterload, offering valuable insight into myocardial function in CS. This cross-sectional study aimed to evaluate left ventricular function across four distinct groups: patients with overt endogenous CS (n = 31; mean age 47 ± 12 years; 71% women), patients in long-term remission following successful medical treatment (CS-LTR; n = 49; mean age 53 ± 12 years; 78% women), a healthy control group (n = 439; mean age 49 ± 11 years; 57% women), and individuals with metabolic syndrome (n = 305; mean age 59 ± 10 years; 37% women).

Both CS groups exhibited a more unfavorable metabolic and CV risk profile than healthy controls, although they presented a relatively better profile compared to individuals with metabolic syndrome. Adjusted analyses accounting for sex and age demonstrated significantly increased Wasted Work in both the overt CS group (median: 105 mmHg%; interquartile range: 74–147) and CS-LTR group (97 mmHg%; 69–158) when compared to healthy individuals (75 mmHg%; 54–109; p < 0.01). Additionally, wasted work values in patients with CS were slightly elevated in comparison to those observed in patients with metabolic syndrome (95 mmHg%; 65–136; p < 0.05), indicating persistent myocardial dysfunction. This impairment in myocardial performance translated into a significant reduction in Work Efficiency (p < 0.05), even in patients with CS who had achieved biochemical remission.

The findings suggest that hypercortisolism contributes to persistent left ventricular dysfunction beyond the effects of traditional CV risk factors. Furthermore, despite the biochemical resolution of CS, patients in long-term remission continue to exhibit myocardial abnormalities, reinforcing the notion that prior exposure to excess cortisol may induce lasting structural and functional cardiac alterations. These findings underscore the utility of Myocardial Work analysis in detecting subclinical yet clinically relevant myocardial dysfunction in patients with CS, both in its active state and after remission. Given the persistence of myocardial impairment even following the resolution of hypercortisolism, long-term cardiovascular monitoring may be warranted in this patient population. This study highlights the need for further research to determine whether targeted interventions could mitigate residual myocardial dysfunction in patients with a history of CS, ultimately improving their cardiovascular outcomes.

Source: cardiab.biomedcentral.com/articles/10.1186/s12933-025-02680-1`

Filed under: Cushing's, symptoms | Tagged: , , | Leave a comment »

Higher Risk and Earlier Onset Glaucoma in Cushing’s Syndrome

Posted on November 27, 2024 by MaryO

Abstract

Purpose

Glaucoma incidence in patients with endogenous Cushing’s syndrome (CS) has never been established. We aim to assess the risk for glaucoma among CS patients compared to controls and determine the age of disease onset.

Methods

A nationwide retrospective matched-cohort study of patients with endogenous CS diagnosed between 2000 and 2023. Patients with CS were matched in a 1:5 ratio, with a control group individually matched for age, sex, socioeconomic status and body mass index. Main outcomes were the incidence of glaucoma and disease onset.

Results

A total of 609 patients [396 women (65%); mean age 48.1 ± 17 years] were included in the CS group and 3018 controls. Follow-up duration was 14.6 years (IQR 9.8–20.2) for the study group. The aetiology of hypercortisolism was divided into pituitary (259, 42.6%), adrenal (206, 33.8%) and unconfirmed aetiology (144, 23.6%) patients. At baseline, 44 (7.2%) CS patients had a diagnosis of glaucoma, compared with 151 (5%) controls. The overall risk for glaucoma was 74% higher in patients with CS compared with matched controls (hazard ratio = 1.74, p = 0.002). Patients with CS who developed glaucoma were younger (mean age of 62 ± 14.7 years) than controls (mean ± SD age, 62 ± 14.7 years), (p = 0.02). The overall risk for glaucoma in CS was high for both patients in remission and patients with persistent hypercortisolism (p = 0.048). Patients with active hypercortisolism experienced an earlier glaucoma onset (82.1 ± 88.0 months).

Conclusions

Endogenous CS is associated with increased risk for glaucoma regardless of remission status and develops at a younger age compared with the general population.

1 INTRODUCTION

Glaucoma is a chronic, irreversible vision-threatening disease affecting more than 80 million people worldwide (Quigley & Broman, 2006). It is the leading cause of irreversible blindness and the second cause of overall global blindness after cataracts (Tham et al., 2014).

Steroid-induced glaucoma, categorized as secondary open-angle glaucoma, is commonly associated with exogenous topical steroid administration rather than endogenous glucocorticoid overproduction (Phulke et al., 2017). Approximately, 30% of the general population are classified as steroid responders, experiencing elevated intraocular pressure (IOP) following corticosteroid administration (Becker, 1965).

Cushing syndrome (CS) is an endocrine disorder which results from excess cortisol production. The most common cause of CS is exogenous steroid use, followed by endogenous cortisol overproduction (Gadelha et al., 2023). In most cases (60%–70%), the corticotropin excess is produced by an adrenocorticotropic-hormone (ACTH)-secreting pituitary adenoma, followed by adrenal aetiologies (20%–30%) and ectopic ACTH-producing neuroendocrine tumours (Gadelha et al., 2023; Reincke & Fleseriu, 2023).

The treatment of CS typically commences with surgical intervention to remove the source responsible for excessive cortisol production, followed by medical therapies (Fleseriu et al., 2021).

There is a known higher risk of glaucoma in patients treated with glucocorticoids; however, data concerning the risk for developing high IOP and glaucoma in patients with CS are limited to case reports and small studies (Blumenthal et al., 1999; Gupta et al., 2015; Haas & Nootens, 1974; Khaw et al., 2010; Tsushima et al., 2019; Virevialle et al., 2014).

In this retrospective matched-cohort study, we aim to assess the risk for glaucoma in patients with CS, as compared with age, sex, socioeconomic status and body mass index (BMI)-matched controls. Furthermore, we assess the glaucoma risk according to the CS aetiology, degree of UFC elevation and remission status.

2 MATERIALS AND METHODS

A retrospective matched-cohort study compared patients with CS to controls without hypercortisolism. Data were sourced from Clalit Health Services (CHS), serving over 4.8 million members. Institutional ethics committee approval was obtained from Rabin Medical Center, adhering to the Declaration of Helsinki and good clinical practice (RMC-0779-22, 11.12.2022). As data were anonymized, written consent was deemed unnecessary.

Using International Classification of Diseases (ICD-10) codes, clinical diagnoses with matching dates were identified. Data were extracted from the electronic health record database via the CHS research data-sharing platform, operated by MDClone. Collected information for potential cases included patient demographics and clinical features at CS diagnosis, along with diagnoses of various comorbidities, including glaucoma.

Diagnosis time was defined as the first occurrence of elevated UFC, CS diagnosis or pituitary/adrenal surgery. Glaucoma diagnoses for both the patients with CS and control groups were acquired through ICD-10 coding. Patients with a diagnosis of glaucoma were identified by the appropriate ICD-10 coding, given by the treating ophthalmologist and incorporated to the patient’s medical record. Each patient with CS was matched 1:5 with controls by age, sex, socioeconomic status and BMI; notably, these controls have never had testing for hypercortisolism.

The follow-up duration commenced from the diagnosis date for both patients with CS and their matched controls, extending until death, CHS membership cessation or the data collection cut-off of 30 September 2023. Early biochemical remission was established as of 24-h UFC levels normalization without requiring medical intervention for hypercortisolism or necessitating glucocorticoid replacement therapy following pituitary or adrenal surgery, occurring within 26 months from the initial diagnosis of CS. The main outcome was defined as the timing of glaucoma diagnosis following the diagnosis of CS in the study group.

In secondary analyses, the occurrence of glaucoma was compared between patients who achieved biochemical remission and those who did not as well as by aetiology of CS and degree of maximal UFC elevation.

2.1 Statistical analysis

Statistical analysis was generated using SAS Software, Version 9·4, SAS Institute Inc., Cary, NC, USA. Continuous variables were presented by mean ± standard deviation or median and interquartile range [IQR]. Categorical variables were presented by (N, %). The t-test, the Mann–Whitney U-test, and the Chi-squared test were used for comparison, between cases and controls, of normally distributed, non-normal and categorical variables, respectively. Cumulative incidence plots, for glaucoma after CS, where death without glaucoma was treated as a competing risk, were created. The Cox proportional hazard model, with death without glaucoma treated as a competing risk, was used to calculate hazard ratios (HR). The appropriateness of the proportional hazard assumption was assessed visually. Two-sided p-values less than 0.05 were considered statistically significant.

3 RESULTS

3.1 Study cohort and patient characteristics

Between 1 January 2000 and 30 September 2023, a cohort of 609 patients (65% women) with CS was included, with a mean age of 48.1 ± 17 years. Each patient was matched with up to five controls based on age, sex, socioeconomic status and BMI, resulting in a control group comprising 3018 patients. (Table 1).

TABLE 1. Demographics and Clinical Characteristics of Study Patients.
CS patients/controls All
CS patients Controls
Patients, n 609 3018 3627
Age at diagnosis, Mean ± SD 48 ± 17.17 47.97 ± 17.19 47.99 ± 17.18
Gender
Male 213 (35%) 1043 (35%) 1256 (35%)
Female 396 (65%) 1975 (65%) 2371 (65%)
Glaucoma 44 (23%) 151 (77%) 195 (5%)
Socioeconomic statusa
Low 74 (13%) 371 (13%) 445 (13%)
Middle 349 (60%) 1719 (60%) 2068 (60%)
High 153 (27%) 760 (27%) 913 (27%)
Smoking statusa
Never 198 (60%) 910 (63%) 1108 (62%)
Current/Past smoker 133 (40%) 544 (37%) 677 (38%)
BMI at diagnosis, Mean ± SDb 30.9 ± 7.6 30 ± 6.9 30.2 ± 7.01
Diabetes mellitus at diagnosis 140 (23%) 396 (13%) 536 (15%)
HTN at diagnosis 343 (56%) 957 (32%) 1300 (36%)
Dyslipidaemia at diagnosis 258 (42%) 874 (29%) 1132 (31%)
CAD at diagnosis 70 (11%) 191 (6%) 261 (7%)
History of stroke 27 (4%) 82 (3%) 109 (3%)
  • Abbreviations: BMI, body mass index; CAD, coronary artery disease; CS, Cushing’s syndrome; HTN, hypertension; N, number; SD, standard deviation.
  • a Data were not available for all patients.
  • b Number of patients were: 363 (60%) cases, 1549 (51%) controls and 1912 (53%) total.

Follow-up duration was 14.6 years (IQR 9.8–20.2) for the study group and 14.8 (IQR 9.9–20.2) for the matched controls.

Diabetes mellitus, hypertension, coronary artery disease, dyslipidaemia and stroke exhibited higher prevalence among CS patients compared to their matched controls (p < 0.01) (See Table 1).

The aetiology of hypercortisolism was divided into pituitary CS (pCS) in 259 (42.6%) patients and adrenal CS (aCS) in 206 (33.8%) patients. Disease aetiology could not be ascertained from the available data in 144 (23.6%) patients.

3.2 Risk factors for glaucoma in Cushing’s syndrome

Overall, 78 (78/609, 12.8%) patients with CS and 250 (250/3018, 8.3%) patients without CS developed glaucoma up to the last follow-up. When stratified by age group at the time of glaucoma diagnosis, patients with CS had the following distribution: 1.5% (nine patients) were diagnosed before the age of 40; 6.2% (38 patients) between the ages of 40 and 65; and 5% (31 patients) at the age of 65 and older. In comparison, among controls, the proportions were 0.3% (eight patients), 3.7% (113 patients) and 4.3% (129 patients) for the respective age groups.

These groups were further divided into patients with a history of glaucoma before and after the study baseline (CS diagnosis).

Reported prior history of glaucoma before CS diagnosis was noted in 34 patients with CS (5.58%), whereas among the controls, 99 patients (3.28%) had a history of glaucoma before the study baseline (p < 0.0089).

Following the diagnosis of CS, 44 (7.2%) patients with CS developed glaucoma, compared with 151 (5%) controls. (Table 1) The difference between groups was statistically significant (HR 1.74, 95% CI 1.17–2.60, p = 0.002).

The risk assessment for glaucoma, with death considered as a competing risk, revealed that by the end of the follow-up period, CS patients had a 74% higher overall risk for glaucoma compared to their matched controls (p = 0.002), (Figure 1).

Details are in the caption following the image

Overall risk for glaucoma with death as a competing event. CS = Cushing’s syndrome.

Patients with CS experienced glaucoma onset at a notably younger age than controls. The mean age of glaucoma onset among those with a history of glaucoma before CS diagnosis was 56.6 ± 12.9 years, in contrast to controls with a mean age of 61.6 ± 10.1 years (p = 0.005). After CS diagnosis, the age of glaucoma onset remained significantly younger in CS patients compared to their matched controls (mean age of 62 ± 14.7 years vs. 66 ± 11.3 years, respectively; p = 0.02).

We performed a subgroup analysis of patients with CS and glaucoma by the source of the excessive production of cortisol, including pituitary, adrenal and unknown-origin CS. No difference was observed in the risk for glaucoma in patients with either pituitary, adrenal or unknown-origin CS, compared to their matched controls. In the CD group, 15 patients (7%) were diagnosed with glaucoma, whereas in the control group, 47 patients (4%) developed glaucoma. Similarly, among patients with adrenal CS, 12 patients (7%) were diagnosed with glaucoma, compared with 45 (5%) individually-matched controls.

A univariate analysis to examine the effect of specific variables, including diabetes mellitus, BMI, smoking history, ischemic heart disease, hypertension, dyslipidaemia, history of stroke, socio-economic status and gender in CS patients with and without glaucoma was performed.

Severity of CS disease was evaluated by the maximal UFC levels that were ≥5 times higher in 8.1% (14/172) of patients with glaucoma, and ≤5 times higher in 8.8% (15/170). There was no correlation between maximal UFC levels and the risk for glaucoma (p = 0.19).

Of the 44 patients with CS diagnosed with glaucoma following a CS diagnosis, 13 cases (29%) had comorbid diabetes mellitus, compared to 85 of 441 (19.3%) patients without glaucoma. This suggests a trend towards an 82% higher risk of glaucoma in patients with diabetes mellitus compared to those without it (p = 0.06).

Additionally, a history of stroke was found to be more prevalent among patients with CS with glaucoma (three cases, 6.8%) compared to those without glaucoma (17 cases, 3.8%); however, the difference did not reach statistical significance. Gender did not emerge as a risk factor for glaucoma as the female-to-male ratio was consistent among patients with and without glaucoma.

3.3 Risk for glaucoma following remission of Cushing’s syndrome

Data on early biochemical remission status following a CS diagnosis were available for 471 patients; 312 (66%) achieved early biochemical remission, while 159 (34%) had persistent hypercortisolaemia. Overall, 62 (13%) patients CS, either with or without remission, had glaucoma in this study group. To assess the risk for glaucoma following a CS diagnosis, we excluded 28 patients who developed glaucoma before the CS diagnosis. Among the remaining 34 glaucoma patients diagnosed after a CS diagnosis, 22 (7.5%) achieved early biochemical remission, while 12 (7.9%) did not. The overall risk of glaucoma in Cushing’s syndrome was elevated for both individuals experiencing remission and those with persistent hypercortisolism (p = 0.048) (Figure 2). However, the difference between those who achieved remission and those who did not was not statistically significant (Table 2). Compared to their matched controls, patients with CS without early biochemical remission did not exhibit a statistically significant higher risk for glaucoma (p = 0.18). However, while the time span between CS diagnosis and glaucoma diagnosis was comparable between CS patients in remission and controls (88.6 ± 73.06 and 88.9 ± 88.4 months, respectively), CS patients not in remission experienced an earlier onset of glaucoma (82.1 ± 88.0 months).

Details are in the caption following the image

Risk for glaucoma in patients with and without early biochemical remission with death as a competing event.
TABLE 2. Patients with glaucoma and Cushing’s syndrome, with and without disease remission.
CS Glaucoma Glaucoma prior to CS
Total N. 471 34 28
Remission (n, %)a 312 (66%) 22 (65%) 20 (71%)
No remission (n, %) 159 (34%) 12 (35%) 8 (29%)
  • Abbreviations: CS, Cushing’s syndrome; N, number.
  • a Remission is defined as a normal 24-h UFC level without treatment for hypercortisolism, or hypocortisolism necessitating glucocorticoid replacement after pituitary or adrenal surgery, within 24 months following diagnosis of CS.

4 DISCUSSION

While data on glucocorticoid treatment and glaucoma are more established, the incidence of glaucoma in patients with CS is not known. In this nationwide retrospective matched-cohort study, the first of its kind to assess the risk for glaucoma in patients with CS, we demonstrated that individuals with endogenous CS exhibit a heightened risk of early-onset glaucoma. Additionally, patients with CS tended to develop glaucoma at a significantly younger age compared to matched controls from the general population. Importantly, this difference persisted even after excluding both cases and controls with a prior diagnosis of glaucoma.

The mechanism of steroid-induced glaucoma is not well understood; decreased trabecular meshwork outflow due to increased resistance is suspected to be the main cause of IOP elevation (Kersey & Broadway, 2005).

The overall prevalence of glaucoma in the general population increases with age and ranges from 1.5% to 1.9% in ages 40 to 65 years, increasing to 2% to 7% in patients 65 and older (Friedman, 2004). In our cohort, we observed that while the incidence of glaucoma in the control group increased with age, among patients with CS, the highest incidence of glaucoma was observed among those aged between 40 and 65 years. Additionally, the incidence of glaucoma before the age of 40 was five times higher among patients with CS compared to controls, highlighting a significantly elevated risk of early-onset glaucoma among individuals with hypercortisolism. Glaucoma prevalence in Israel is similar to worldwide reported rates (Levkovitch-Verbin et al., 2014). The higher incidence of glaucoma observed in both the study and control groups in our study as compared to the literature may be attributed to the study’s definition of glaucoma, which is based on ICD-10 codes in patients’ medical records. Furthermore, patients receiving medications potentially increasing IOP were not excluded. Thus, despite the overall higher glaucoma rates observed here, since both the study and control groups rely on the same diagnostic criteria, the increased incidence of glaucoma in patients with CS as compared to matched controls in our study is significant and warrants attention.

In addition, patients with CS experienced the onset of glaucoma at a notably younger age compared to controls, with CS patients exhibiting glaucoma onset 4 years earlier than controls. When examining the ages of patients before their CS diagnosis, those diagnosed with glaucoma were statistically significantly younger than controls, with mean ages of 56 and 61 years, respectively. This observation, coupled with the well-documented diagnostic delay of CS (Rubinstein et al., 2020), suggests that the hypercortisolism before the formal diagnosis of CS did put them at a heightened risk of developing glaucoma at a younger age.

Notably, we did not find any correlation between maximum elevation of UFC and the risk of developing glaucoma. We postulate that extended hypercortisolism exposure could exert a more significant influence than the maximum UFC levels measured in the urine, which has known significant variability also.

The association between diabetes mellitus and glaucoma remains inconclusive due to conflicting findings in cohort and epidemiological studies (de Voogd et al., 2006; Hennis et al., 2003). However, a comprehensive meta-analysis published in 2014 suggested that individuals with diabetes mellitus face an elevated risk of developing glaucoma (Zhou et al., 2014). In our study, we observed that patients with CS and diabetes mellitus were more likely to develop glaucoma compared to those without diabetes mellitus. Another significant risk factor for developing high IOP and consequently glaucoma is chronic corticosteroids use, specifically topical steroids. When the IOP remains high for a prolonged duration, damage to the optic nerve (steroid-induced secondary glaucoma) may occur (Kersey & Broadway, 2005).

Though it seems intuitive that endogenous CS could match the exogenous CS numbers, there are no large population studies examining the association between CS and glaucoma. Several studies suggested a role for endogenous cortisol in the development of ocular hypertension and glaucoma, noting increased plasma and aqueous humour cortisol levels in glaucoma patients (Patel et al., 2023). However, only a few small cohort clinical studies have been performed on endogenous hypercortisolism in patients with CS causing increased IOP and glaucoma (Jonas et al., 1990; Ma et al., 2022), while another study showed no correlation between endogenous hypercortisolism and increased IOP (Mishra et al., 2017). There are several published case reports on endogenous hypercortisolism as a cause for secondary glaucoma; Virevialle et al. reported a case of a young female with painless loss of vision who had severe open-angle glaucoma with uncontrolled high IOP, requiring glaucoma surgery, which later was found to be secondary to CS related to an adrenal adenoma (Virevialle et al., 2014). Another case report published by Blumenthal et al. described a 33-year-old man with increased IOP represented as a manifestation of hypercortisolism caused by ectopic CS. Importantly, after surgical removal of the tumour, the high IOP resolved (Blumenthal et al., 1999). CD has also led to ocular hypertension and glaucoma in two cases, with IOP returning to normal levels in all four eyes after transsphenoidal tumour resection (Gupta et al., 2015). Noteworthy, in some of the reports, ocular hypertension and glaucoma were the presenting manifestations for CS diagnosis (Jonas et al., 1990; Ma et al., 2022; Mishra et al., 2017).

The overall risk for glaucoma was high for both patients with early biochemical remission and patients with no remission, which can be due to the limited number of patients in each group. However, patients with persistent hypercortisolaemia were diagnosed with glaucoma approximately 6 months earlier compared to both patients with CS in remission and controls. This observation could be attributed to the prolonged hypercortisolaemia in patients with CS without remission, leading to elevated IOP and subsequent development of glaucoma.

This study has several strengths, including a sufficiently large sample size for the primary analysis, long-term follow-up, and strict criteria for diagnosing CS, along with consideration of disease aetiology and remission status. The control group was carefully matched to minimize the influence of factors like age, sex, socioeconomic status and BMI on cancer risk. Additionally, the database encompasses the entire population, eliminating the risk of selection bias. Given the increased mortality associated with CS, we accounted for death as a competing risk in all analyses. Lastly, we performed necessary sensitivity analyses to ensure the robustness of our results.

The limitations of this study include the potential for missing data, which, due to its retrospective design, may have affected our ability to identify patients with CS and glaucoma, as well as to determine disease aetiology or remission status in some cases. Additionally, ascertainment bias cannot be excluded, as patients with CS may have been diagnosed with glaucoma more frequently due to more regular ophthalmologic examinations. Surveillance bias, where patients with more frequent healthcare visits or monitoring are more likely to be diagnosed with additional conditions due to being examined more often than others, could also result in an overestimation of the association between CS and glaucoma.

In this large nationwide retrospective matched-cohort study, we have shown for the first time that endogenous CS, whether caused by a pituitary or adrenal adenoma, is associated with an increased risk for glaucoma and a clinical manifestation at an earlier age versus general population, regardless of remission status or degree of UFC elevation. A delay in diagnosing both CS and glaucoma can result in significant ocular and systemic morbidities. Guidelines should also incorporate recommendations for periodic monitoring for intraocular pressure and/or glaucoma development to be routinely performed for patients with CS, especially if they also have concomitant comorbidities. Further research using larger multinational databases is warranted to validate our findings and uncover additional insights.

FUNDING INFORMATION

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

CONFLICT OF INTEREST STATEMENT

Y.S., A.Z., Y.R., S.K., I.S. and T.S. do not have any financial or personal relationships with other people or organizations to disclose. A.A. has received occasional scientific fee for scientific consulting and advisory boards from Medison, C.T.S. pharma and Neopharm. M.F. has received research support from Oregon Health & Science University as a principal investigator from Recordati, Sparrow and Xeris and has performed occasional scientific consultancy for Recordati, Sparrow and Xeris.

From https://onlinelibrary.wiley.com/doi/10.1111/aos.16787

Filed under: Cushing's, symptoms | Tagged: , | Leave a comment »

« Previous Page — Next Page »