The Efficacy Of Bisphosphonates For Osteoporosis In Young Cushing’s Disease Patients With Biochemical Remission

Posted on June 24, 2024 by MaryO

Background: Patients with Cushing’s disease (CD) often experience slow recovery of bone mineral density (BMD), and the effectiveness of anti-osteoporosis drugs in young CD patients who have achieved biochemical remission after surgery is not well understood. Therefore, we aimed to explore whether bisphosphonates could help accelerate the recovery of osteoporosis in young CD patients with remission.

Methods: We retrospectively enrolled 34 young patients with CD who achieved postoperative biochemical remission. All patients suffered from osteoporosis before surgery and were divided into postoperative bisphosphonate treatment group (16 cases) and without bisphosphonate treatment group (18 cases). Clinical data, BMD (Z Value), and bone turnover markers were collected at the time of diagnosis and one year after successful tumor resection.

Results: The Z values in the lumbar spine showed slight improvement in both groups at follow-up compared to baseline, but this improvement was not statistically significant. There was no significant difference observed between the two groups at follow-up. One year after operation, bone formation markers (OC and P1NP) were significantly higher than those at baseline in both groups. However, OC and P1NP in the bisphosphonate treatment group were lower than those in control group at one year follow-up. In without bisphosphonate treatment group, β-CTX from follow-up visit was higher than that at baseline, while no significant difference was observed in the bisphosphonate treatment group before and after surgery.

Conclusion: Young patients with Cushing’s disease combined with osteoporosis might not benefit from bisphosphonate therapy for osteoporosis recovery in the first year after achieving biochemical remission.

Introduction

Osteoporosis is one of common complications of Cushing’s syndrome (CS). 40–78% of CS patients have osteopenia at diagnosis and 22–57% have osteoporosis (1). Previous studies reported non-violent fractures in 16–50% of patients with CS at diagnosis (1–5).

The pathophysiological mechanism of glucocorticoid (GC)-induced osteoporosis is very complex. The main feature is a persistent decrease in bone formation accompanied by an early transient increase in bone resorption, which directly acts on osteoblasts, osteoclasts, and osteocytes (6–9). In addition, GC also can lead to bone loss through indirect effects, mainly including decreased sex hormone levels, intestinal and renal calcium absorption and reabsorption, muscle mass and mechanical sensitivity and increased parathyroid hormone levels, etc. (10).

Prevention strategies for osteoporosis in patients treated with long-term exogenous hormones were relatively mature, and drugs promoting bone formation or inhibiting bone resorption should be used. However, osteoporosis was often ignored in patients with Cushing’s syndrome. Previous studies had shown that BMD of patients with CS improved after achieving biochemical remission (11), but some patients still had osteoporosis for several years after remission, even though their BMD were improved compared to preoperative levels (1). A study showed that BMD increased due to high turnover of bone after CS remission, and no additional anti-osteoporotic treatment was considered (12). However, till now it remained unclear whether anti-osteoporosis treatment could help accelerate the recovery of osteoporosis in young CD patients with biochemical remission after surgery.

Therefore, the aim of this study was to determine the efficacy of bisphosphonates for osteoporosis in young Cushing’s disease (CD) patients with biochemical remission.

Materials and methods

Subjects

This study was a retrospective cohort study and was approved by the Human Investigation Ethics Committee at Huashan Hospital (No.2017M011). Thirty-four young CD patients combined with osteoporosis at diagnosis who were hospitalized in the Department of Endocrinology, Huashan Hospital, Fudan University from January 2010 to February 2021 were included. Patients’ selection was shown in Figure 1.

Figure 1

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Figure 1 Research flow chart.

Inclusion criteria were as follows: 1) the diagnostic criteria for Cushing’s disease were met, and the pituitary ACTH adenoma was confirmed by surgical pathology, 2) men ≥18 years old but younger than 50 years old at diagnosis; premenopausal women ≥ 18 years old and young women(<50 years old) with menstrual abnormalities which were associated with CD, 3) Z-score of BMD in lumbar spine or femoral neck ≤-2.0 at diagnosis of Cushing’s disease or with a history of fragility fractures, 4) attaining biochemical remission after transsphenoidal surgery, 5) receiving regular follow-up and bone mineral density was measured in our hospital at diagnosis and one year follow-up.

Enrolled patients were divided into two groups based on whether using bisphosphonates treatment after surgery or not. Biochemical remission of Cushing’s disease was defined as morning serum cortisol <2μg/dL (<55nmol/L) within the week after surgery and although serum cortisol at 8:00 a.m. was≥2 µg/dl or back to normal range immediate after surgery, it became hypocortisolemic at subsequent evaluation(s) and without relapse during the follow-up (13–15). Meanwhile, relapse was excluded by cortisol value < 1.8 µg/dL after 1-mg dexamethasone suppression test (DST) and 24-hour urinary free cortisol (UFC) in normal range (13).

Exclusion criteria included: 1) having comorbidities affecting BMD (e.g., hyperparathyroidism, hyperthyroidism, primary hypogonadism, rheumatic immune disease, gastric bypass, inflammatory bowel disease, etc.), 2) long-term use of glucocorticoid drugs for the treatment of immune related diseases (except for hypopituitarism hormone replacement therapy) or other drugs that significantly affect bone metabolism, 3) use of anti-osteoporosis drugs before surgery, 4) postoperative treatment with anti-osteoporotic drugs other than bisphosphonate, 5) Cushing’s syndrome other than pituitary origin, 6) loss of follow up, 7) uncured or relapse of CD during the follow up.

Clinical and biochemical methods

We collected data on demographic characteristics, duration of CD-related signs and symptoms, comorbidities, medications, laboratory tests, and bone mineral density.

Endocrine hormones included cortisol (F), 24-hour urinary free cortisol (24hUFC), adrenocorticotropic hormone (ACTH); growth hormone (GH), insulin-like growth factor (IGF-1), prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH), estrogen (E2), progesterone (P), testosterone (T), thyroid stimulating hormone (TSH), and free thyroxine (FT4). Hormonal measurements were carried out by chemiluminescence assay (Advia Centaur CP). Bone metabolism markers included osteocalcin (OC), type I procollagen amino-terminal peptide (P1NP), type I collagen C-terminal peptide degradation product (CTX), parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)VD], and they were measured in a Roche Cobas e411 analyzer using immunometric assays (Roche Diagnostics, Indianapolis, IN, USA).

Bone mineral density was measured by dual-energy X-ray absorptiometry of American HOLOGIC company Discovery type W in all patients at diagnosis of CD and one year follow-up after surgery. Z value was used for young CD patients and Z value = (measured value – mean bone mineral density of peers)/standard deviation of BMD of peers. In this study, osteoporosis was defined as a Z-value of -2.0 or lower or with a history of fragility fractures.

All patients were administered with 20mg of hydrocortisone 3 times daily after surgery to avoid steroid withdrawal syndrome, with a 10-day taper afterward. When hydrocortisone was reduced to 10mg once a day for 10 days, the patient was followed up for the first time after surgery. Then the hormone replacement dose was adjusted based on the patient’s blood level obtained before that day’s glucocorticoid intake and urine cortisol level. All patients were administered with calcium carbonate D3 tablet (one tablet a day, consisting of calcium 600mg and D3 125U) and vitamin D (0.25ug a day) at diagnosis of osteoporosis till the last follow-up.

Statistical analyses

Normal distributed continuous variables were expressed as mean values ± standard deviation (s.d.). Median, 25th percentile, and 75th percentile (Median [P25, P75]) for variables without a normal distribution. Independent t-tests for normally distributed continuous variables and non-parametric tests for variables without a normal distribution were used to compare data between groups. SPSS 20.0 (SPSS) was used. A two-tailed P value <0.05 was considered statistically significant.

Results

Patients’ characteristics at baseline

418 CD patients were hospitalized in the Department of Endocrinology, Huashan Hospital from January 2010 to February 2021. A total of 34 patients were included in our study, with an average age of 33.06 ± 7.37 years, 13 males (38.24%) and 21 females (61.76%). Sixteen patients were treated with bisphosphonates postoperatively (bisphosphonate group, including zoledronic acid and alendronate sodium), and eighteen patients were not treated with bisphosphonates postoperatively (without bisphosphonate group). Characteristics of the two groups were summarized in Table 1. Although there was a significant different in disease duration, there were no differences in age, gender, BMI, the proportion of hypertension, diabetes, dyslipidemia, liver function, kidney function, serum calcium, PTH, vitamin D level, bone metabolism markers, cortisol level, thyroid function, and growth hormone level between the two groups at baseline. Meanwhile, there was no significant difference in Z score of lumbar vertebra and femoral neck between two groups, -2.49 ± 0.56 (CV%=22.49%) vs-2.85 ± 0.61 (CV%=21.40%) and -1.74 ± 0.78 (CV%=44.83%) vs -1.93 ± 0.80 (CV%=41.45%) respectively. Therefore, the impact of different disease duration on the results was relatively small.

Table 1

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Table 1 Clinical Baseline Characteristics of Patients in two groups.

One year after achieving biochemical remission, BMD improved in both groups; however there was no significant difference between the two groups

For these patients with osteoporosis secondary to Cushing’s disease, the most important work was to remove the cause. Patients with a history of fragility fractures didn’t receive bisphosphonate after surgery partly because they refused to use it. As shown in Table 2, Figures 2A, B, there were no significant differences in the Z Score of lumbar vertebra and femoral neck between the two groups at baseline. The Z values in lumbar spine at one year follow-up of both groups were slightly improved but not significantly compared to baseline respectively. There was no significant difference in the Z score of lumbar vertebra [-2.40 ± 0.617 (CV%=25.71%) vs -2.81 ± 0.771 (CV%=27.44%), p=0.0766] or femoral neck [-1.9 ± 0.715 (CV%=37.63%) vs -2.01 ± 0.726 (CV%=36.12%), p=0.6378] between two groups at one year follow-up.

Table 2

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Table 2 Changes in bone mineral density and bone turnover markers before and 1 year after remission in the two groups.

Figure 2

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Figure 2 Comparison of BMD and bone turnover markers at baseline and one year after remission between bisphosphonate-treated and non-bisphosphonate-treated groups. (A) Z Score of lumbar vertebra; (B) Z Score of femoral neck; (C) levels of OC; (D) levels of P1NP; (E) levels of β-CTX. *P < 0.05, **P < 0.01, ***P < 0.001.

At one year follow-up, bone formation markers increased obviously in both groups compared to those at diagnosis, and they increased higher without bisphosphonate treatment

As shown in Table 2, Figures 2C–E, there were no significant differences in bone turnover markers including OC, P1NP, and β-CTX between the two groups at baseline. Serum OC levels were significantly higher than those before surgery in both groups at one year follow-up after achieving remission respectively (5.90 (2.40–8.03) ng/ml vs 46.7 (23.25–83) ng/ml in control group, p<0.0001, and 6.80 (4.50–8.60) ng/ml vs 33.8 (14.46–49.27) ng/ml in treatment group, p=0.009). However, the serum OC level in the control group at follow-up was significantly higher than that in the treatment group [46.7 (23.25–83) ng/ml vs 33.8 (14.46–49.27) ng/ml, p=0.0381]. Serum P1NP levels were also significantly higher than those before surgery in both groups at follow-up after achieving remission of Cushing’s disease respectively (34.72 (23.22–41.79) ng/ml vs 353.5(124.9–501.2) ng/ml in control group, p=0.003, and 22.57 (15.93–30.53) ng/ml vs 181.1(65.46–228.75) ng/ml in treatment group, p=0.001). Similarly, the serum P1NP level at follow-up in the control group was significantly higher than that in the treatment group [353.5 (124.9–501.2) vs 181.1 (65.46–228.75) ng/ml, p=0.0484].

In the group without bisphosphonate treatment, β-CTX at one year after remission was higher than that before surgery [0.97 (0.83–1.57) vs 0.42 (0.16–0.66) ng/ml, p=0.006]. However, there was no significant difference in the bisphosphonate treatment group between baseline and follow-up [0.59 (0.27–0.90) vs 0.72(0.47–1.50) ng/ml, p=0.115]. No significant difference was seen for β-CTX level at follow-up between the two groups [0.97 (0.83–1.57) vs 0.72(0.47–1.50) ng/ml, p=0.409].

Discussion

Osteoporosis is one of common complications of Cushing’s disease and the recovery of bone mineral density after remission is a slow process. An important clinically question is whether young patients with CD after remission would benefit from anti-osteoporotic drugs such as bisphosphonates. To our knowledge, this study was the first well-powered retrospective cohort study of the efficacy of bisphosphonates for osteoporosis in young CD patients with biochemical remission. Our data showed that BMD improved slowly in young CD patients with remission at the first- year follow-up regardless of whether bisphosphate was used or not, and no significant difference in BMD improvement was observed between two groups at follow-up.

It was well known that after cure of Cushing’s syndrome, there was a long recovery period for BMD. It had been shown that full recovery from BMD in cured adult CS patients could take up to a decade or more (1, 16). However, Hermus (17) had shown that some patients had a 2% or more reduction in BMD in the short term after surgery, especially in the first 6 months after surgery, and did not show consistent BMD increases until 24 months after surgery. It also showed that there was a highly significant inverse correlation between age and increase of BMD in the lumbar spine after surgery (17). The lack of significant improvements in BMD in our results might be related to the short duration of follow-up.

Current studies of endogenous Cushing’s syndrome had shown that bone metabolism was characterized by decreased bone formation and increased bone resorption, consistent with the classical effects of glucocorticoids (11). Successful treatment of endogenous Cushing’s syndrome resulted in a strong activation of bone turnover, characterized by increased bone formation and resorption. A retrospective study by Pepijn van Houten showed that sustained improvement in BMD continued for up to 20 years after CD treatment, and a large proportion of patients in this cohort were treated with anti-osteoporotic drugs (1). The study also showed that patients not receiving anti-osteoporosis drugs experienced significant spontaneous improvement in mean BMD. However, this retrospective study could not be used to answer the clinical question of whether anti-osteoporotic therapy was beneficial due to selection bias in enrolled patients. Leah T Braun showed that within 2 years of successful surgical remission in patients with Cushing’s syndrome, markers of bone formation suggested a high rate of bone turnover, resulting in a significant net increase in BMD in the majority of patients. The results strongly suggested that an observational approach to bone phenotype was justified as long as CS remission was assured (12). However, this retrospective study mentioned a significant mismatch in baseline BMD between the two groups (anti-osteoporotic medication group and without anti-osteoporotic medication group) and did not describe the type of anti-osteoporosis drugs (promoting bone formation or inhibiting bone resorption or both). Somma’s prospective study showed that a significant increase in lumbar and femoral BMD was observed in 21 CD patients who achieved remission after surgery and were either treated with alendronate for 12 months or not (18). It should be noted that this study included postmenopausal women, and there were no direct comparisons of clinical data, bone mineral density, and bone turnover markers at baseline and follow-up between the two groups.

Our study also showed that even bone formation markers increased at follow-up in bisphosphonate group, they were significantly lower compared to non- bisphosphonate users. Since bone metabolism was in a state of high turnover in the initial stage of biochemical remission from Cushing’s disease, our results indicated that bisphosphonates might affect bone formation in the first year after remission and was not conductive to the improvement of BMD. The mechanism of bisphosphonates in the treatment of osteoporosis lied in their high affinity with skeletal hydroxyapatite, allowing them to specifically bind to actively remodeling bone surface and inhibit the function of osteoclasts, thereby inhibiting bone resorption. Studies had shown that while bisphosphonates strongly inhibited bone resorption, they also significantly reduced bone formation. This reduced formation was often attributed to mechanisms that maintained the resorption/formation balance during remodeling (19).

There are evidence-based guidelines available for assessing fracture risk during long-term exogenous glucocorticoid(GC) therapy in adults, as well as for initiating and selecting anti-osteoporosis therapy. Specifically, for patients at risk of fracture taking GC ≥2.5 mg/day for >3 months, treatment options include bisphosphonates, denosumab, or PTH analogs. Although there is currently no definitive evidence-based treatment regarding the choice and efficacy of anti-osteoporosis after glucocorticoid withdrawal, it is widely accepted that treatment should be continued based on bone density and fracture risk assessment. For patients at a high fracture risk level (T≤-2.5), it is recommended to either continue their current anti-osteoporosis treatment or switch to an alternative medication. The main challenge faced by individuals with endogenous glucocorticoid induced osteoporosis (GIOP) is that exogenous GIOP is not exactly the same as endogenous GIOP. Therefore, it is not appropriate to apply the same strategies of exogenous GIOP for CD patients with remission. The findings of this study indicated that bisphosphonate therapy might not be beneficial for osteoporosis recovery in CD patients achieving biochemical remission (20).

Our study, limited by retrospective clinical studies, a small sample size, and a short follow-up duration, might not optimally answer the question of whether patients with CD achieving remission would benefit from bisphosphonate therapy, although it was a relatively well-designed retrospective cohort study and reached the maximum number after strict inclusion criteria and matching baseline characteristics as much as possible. Therefore, prospective randomized controlled clinical trials with longer duration were needed in the future.

In conclusion, our study suggested that young patients with Cushing’s disease combined with osteoporosis might not benefit from bisphosphonate therapy for osteoporosis recovery in the first year after achieving biochemical remission.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by the Human Investigation Ethics Committee at Huashan Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

QS: Writing – original draft. WS: Writing – original draft, Formal analysis, Data curation. HY: Writing – review & editing, Supervision, Resources. SZ: Writing – review & editing, Supervision.

Funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The present study was supported by grants from initial funding of Huashan Hospital (2021QD023).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: Cushing’s disease, young patients, osteoporosis, bisphosphonates, bone turnover markers

Citation: Sun Q, Sun W, Ye H and Zhang S (2024) The efficacy of bisphosphonates for osteoporosis in young Cushing’s disease patients with biochemical remission: a retrospective cohort study. Front. Endocrinol. 15:1412046. doi: 10.3389/fendo.2024.1412046

Received: 04 April 2024; Accepted: 04 June 2024;
Published: 21 June 2024.

Edited by:

Daniela Merlotti, University of Siena, Italy

Reviewed by:

Catalina Poiana, Carol Davila University of Medicine and Pharmacy, Romania
Ming Chen, Chinese PLA General Hospital, China

Copyright © 2024 Sun, Sun, Ye and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Hongying Ye, janeyhy@163.com; Shuo Zhang, zhangshuo@huashan.org.cn

†These authors share first authorship

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Is Cushing Syndrome More Common in the US Than We Think?

Posted on June 11, 2024 by MaryO

I think members of the Cushing’s Help boards have been saying this forever!  Cushing’s isn’t all that rare.  Just rarely diagnosed,

 

BOSTON — The prevalence of Cushing syndrome (CS) in the United States may be considerably higher than currently appreciated, new data from a single US institution suggest.

In contrast to estimates of 1 to 3 cases per million patient-years from population-based European studies, researchers at the University of Wisconsin, Milwaukee, estimated that the incidence of CS in Wisconsin is a minimum of 7.2 cases per million patient-years. What’s more, contrary to all previous studies, they found that adrenal Cushing syndrome was more common than pituitary adrenocorticotropic hormone (ACTH)– secreting tumors (Cushing disease), and that fewer than half of individuals with adrenal Cushing syndrome had classic physical features of hypercortisolism, such as weight gain, round face, excessive hair growth, and stretch marks.

“Cases are absolutely being missed…. Clinicians should realize that cortisol excess is not rare. It may not be common, but it needs to be considered in patients with any constellation of features that are seen in cortisol excess,” study investigator Ty B. Carroll, MD, Associate Professor of Medicine, Endocrinology and Molecular Medicine, and the Endocrine Fellowship Program Director at Medical College of Wisconsin in Milwaukee, told Medscape Medical News.

There are several contributing factors, he noted, “including the obesity and diabetes epidemics which make some clinical features of cortisol excess more common and less notable. Providers get used to seeing patients with some features of cortisol excess and don’t think to screen. The consequence of this is more difficult-to-control diabetes and hypertension, more advance metabolic bone disease, and likely more advanced cardiovascular disease, all resulting from extended exposure to cortisol excess,” he said.

Are Milder Cases the Ones Being Missed?

Asked to comment, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York City, said “When we talk about Cushing [syndrome], we usually think of pituitary ACTH as more [common], followed by adrenal adenomas, and then ectopic. But they’re seeing more adrenal adenoma…we are probably diagnosing this a little more now.”

She also suggested that the Wisconsin group may have a lower threshold for diagnosing the milder cortisol elevation seen with adrenal Cushing syndrome. “If you screen for Cushing with a dexamethasone suppression test…[i]f you have autonomous secretion by the adrenal, you don’t suppress as much…. When you measure 24-hour urinary cortisol, it may be normal. So you’re in this in-between [state]…. Maybe in Wisconsin they’re diagnosing it more. Or, maybe it’s just being underdiagnosed in other places.”

She also pointed out that “you can’t diagnose it unless you think of it. I’m not so sure that with these mild cases it’s so much that it’s more common, but maybe it’s like thyroid nodules, where we didn’t know about it until everybody started getting all of these CT scans. We’re now seeing all these incidental thyroid nodules…I don’t think we’re missing florid Cushing.”

However, Wardlaw said, it’s probably worthwhile to detect even milder hypercortisolism because it could still have long-term damaging effects, including osteoporosis, muscle weakness, glucose intolerance, and frailty. “You could do something about it and normalize it if you found it. I think that would be the reason to do it.”

Is Wisconsin Representative of Cushing Everywhere?

Carroll presented the findings at the annual meeting of the Endocrine Society. He began by noting that most of the previous CS incidence studies, with estimates of 1.2-3.2 cases per million per year, come from European data published from 1994 to 2019 and collected as far back as 1955. The method of acquisition of patients and the definitions of confirmed cases varied widely in those studies, which reported CS etiologies of ACTH-secreting neoplasms (pituitary or ectopic) in 75%-85% and adrenal-dependent cortisol excess in 15%-20%.

The current study included data from clinic records between May 1, 2017, and December 31, 2022, of Wisconsin residents newly diagnosed with and treated for CS. The CS diagnosis was established with standard guideline-supported biochemical testing and appropriate imaging. Patients with exogenous and non-neoplastic hypercortisolism and those who did not receive therapy for CS were excluded.

A total of 185 patients (73% female, 27% male) were identified from 27 of the total 72 counties in Wisconsin, representing a population of 4.5 million. On the basis of the total 5.9 million population of Wisconsin, the incidence of CS in the state works out to 7.2 cases per million population per year, Carroll said.

However, data from the Wisconsin Hospital Association show that the University of Wisconsin’s Milwaukee facility treated just about half of patients in the state who are discharged from the hospital with a diagnosis of CS during 2019-2023. “So…that means that an actual or approximate incidence of 14-15 cases per million per year rather than the 7.2 cases that we produce,” he said.

Etiologies were 60% adrenal (111 patients), 36.8% pituitary (68 patients), and 3.2% ectopic (6 patients). Those proportions were similar between genders.

On biochemical testing, values for late-night salivary cortisol, dexamethasone suppression, and urinary free cortisol were highest for the ectopic group (3.189 µg/dL, 42.5 µg/dL, and 1514.2 µg/24 h, respectively) and lowest for the adrenal group (0.236 µg/dL, 6.5 µg/dL, and 64.2 µg/24 h, respectively). All differences between groups were highly statistically significant, at P < .0001, Carroll noted.

Classic physical features of CS were present in 91% of people with pituitary CS and 100% of those ectopic CS but just 44% of individuals with adrenal CS. “We found that adrenal-dependent disease was the most common form of Cushing syndrome. It frequently presented without classic physical features that may be due to the milder biochemical presentation,” he concluded.

Carroll reports consulting and investigator fees from Corcept Therapeutics. Wardlaw has no disclosures. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker.

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Xeris Presents New Post Hoc Analysis on Effects of Levoketoconazole (Recorlev®) in Cushing’s Syndrome Patients at ENDO 2024

Posted on June 6, 2024 by MaryO

In patients with Cushing’s syndrome maintained on Recorlev, a lower baseline mUFC was associated with higher cortisol normalization rate.

Lower mUFC at baseline was also associated with lower maintenance dose requirements and lower rates of potentially clinically important liver-related adverse events and liver test abnormalities.

The SONICS study previously showed that Recorlev treatment was effective at normalizing cortisol across the spectrum of Cushing’s syndrome severity.

Xeris Biopharma Holdings, Inc. (Nasdaq: XERS), a growth-oriented biopharmaceutical company committed to improving patients’ lives by developing and commercializing innovative products across a range of therapies, today announced it presented a post-hoc analysis from its previously published SONICS study on the effects of levoketoconazole (Recorlev®) in adults with Cushing’s syndrome at ENDO 2024 in Boston, June 1-4, 2024.

“The results of this analysis suggest that patients with Cushing’s syndrome/disease with lower mUFC(s) normalize at a higher rate than those with more severe disease and may require lower doses of Recorlev and experience lower rates of liver-related adverse events. This exploratory analysis brings further perspective to the importance of individualizing and tailoring medical management,” said James Meyer, PharmD, Xeris’ Senior Director, Publications and Medical Communications.

Title: Effects of Levoketoconazole on 24-hour Mean UFC (mUFC) in the SONICS Study: Relation to Baseline mUFC in Adults with Cushing’s Syndrome: A Post-hoc Analysis (SAT-085)

This post-hoc exploration included all enrolled patients in SONICS who were treated and had a post-baseline mUFC, aiming to further elucidate relationships between baseline biochemical disease severity, drug dose, and intermediate-term mUFC response. For the current analyses, 92 patients treated with levoketoconazole and with baseline mUFC measurement (modified ITT) were stratified into 3 baseline mUFC subgroups: Group 1 (≤ 2.5x upper limit of normal (ULN)); Group 2 (>2.5x to ≤ 5x ULN); or Group 3 (>5x ULN) and analyzed in respect to mUFC response, average daily dose, and adverse events following 6 months of maintenance therapy. Groups 1 and 2 were similar in baseline characteristics; whereas Group 3 differed with younger age, fewer female participants, more recently diagnosed, and more frequently on prior therapy.

Group 2 (Baseline mUFC 267.9 nmol/D) had the highest apparent mUFC response rate (12/33 [36.4%]), 95% CI 0.20, 0.54) as compared with Group 1 (Baseline mUFC 498.7 nmol/D) (12/38 [31.6%], 95% CI 0.16, 0.47) or Group 3 (Baseline mUFC 1672.8 nmol/D) (5/21 [23.8%]; 95% CI 0.01, 0.55); Group 3 having a notably lower response.

Daily doses of levoketoconazole were related to baseline mUFC. Thus, Group 3 used a nominally higher average daily dose (631 mg and 741 mg) during maintenance therapy and at the last dose in the 6-month maintenance phase (regardless of completion status) than Group 1 (475 mg and 545 mg) or Group 2 (548 mg and 611 mg).

Group 3 had more liver-related AEs of special interest than Group 1 or 2 (14% vs 7.9% or 3.0%) and more AEs leading to discontinuation (24% vs 12% or 16%). Group 3 had a higher incidence of liver test (ALT, AST, GGT) abnormalities compared to Group 1 and Group 2.

This post hoc analysis demonstrated:

  • Normalization of mUFC with levoketoconazole in Cushing’s syndrome patients maintained on levoketoconazole in the SONICS study for up to 6 months appeared to vary inversely with baseline mUFC.
  • Lower mUFC at baseline was also associated with lower maintenance dose requirements and lower rates of potentially clinically important liver-related AEs and liver test abnormalities.
  • Whether observed baseline characteristic differences between the highest tertile of baseline mUFC and the 2 lower tertiles were simply coincidental to or confounders or mediators of the described relationships with mUFC remains to be explored.

About Cushing’s Syndrome

Endogenous Cushing’s syndrome is a rare, serious, and potentially fatal endocrine disease caused by chronic elevated cortisol exposure–often the result of a benign tumor of the pituitary gland. This benign tumor tells the body to overproduce high levels of cortisol for a sustained period of time, which often results in characteristic physical signs and symptoms that are distressing to patients. The disease is most common among adults between the ages of 30–50, and it affects women three times more often than men. Women with Cushing’s syndrome may experience a variety of health issues including menstrual problems, difficulty becoming pregnant, excess male hormones (androgens), primarily testosterone, which can cause hirsutism (growth of coarse body hair in a male pattern), oily skin, and acne.3

Additionally, the multisystem complications of the disease are potentially life threatening. These include metabolic changes such as high blood sugar or diabetes, high blood pressure, high cholesterol, fragility of various tissues including blood vessels, skin, muscle, and bone, and psychological disturbances such as depression, anxiety, and insomnia.3 Untreated, the five-year survival rate is only approximately 50%.4

About Recorlev®

Recorlev® (levoketoconazole) is a cortisol synthesis inhibitor for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.1 Endogenous Cushing’s syndrome is a rare but serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure.2 Recorlev is the pure 2S,4R enantiomer of ketoconazole, a steroidogenesis inhibitor.1 Recorlev has demonstrated in two successful Phase 3 studies to significantly reduce mean urine free cortisol.1

The Phase 3 program for Recorlev included SONICS and LOGICS, two multinational studies designed to evaluate the safety and efficacy of Recorlev when used to treat endogenous Cushing’s syndrome. The SONICS study met its primary and secondary endpoints, significantly reducing and normalizing mean urinary free cortisol concentrations without a dose increase.1,2 The LOGICS study, which met its primary endpoint and key secondary endpoint, was a double-blind, placebo-controlled randomized-withdrawal study of Recorlev that was designed to supplement the efficacy and safety information provided by SONICS.1 The ongoing open-label OPTICS study will gather further useful information related to the long-term use of Recorlev.

Recorlev was approved by the US FDA in December 2021 and received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing’s syndrome.

Indication & Important Safety Information for Recorlev®

BOXED WARNING: HEPATOTOXICITY AND QT PROLONGATION
HEPATOTOXICITY

Cases of hepatotoxicity with fatal outcome or requiring liver transplantation have been reported with oral ketoconazole. Some patients had no obvious risk factors for liver disease. Recorlev is associated with serious hepatotoxicity. Evaluate liver enzymes prior to and during treatment.

QT PROLONGATION

Recorlev is associated with dose-related QT interval prolongation. QT interval prolongation may result in life-threatening ventricular dysrhythmias such as torsades de pointes. Perform ECG and correct hypokalemia and hypomagnesemia prior to and during treatment.

INDICATION

Recorlev is a cortisol synthesis inhibitor indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.

Limitations of Use

Recorlev is not approved for the treatment of fungal infections.

CONTRAINDICATIONS

  • Cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT > 3 times the upper limit of normal, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease.
  • Taking drugs that cause QT prolongation associated with ventricular arrythmias, including torsades de pointes.
  • Prolonged QTcF interval > 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or prolonged QT syndrome.
  • Known hypersensitivity to levoketoconazole, ketoconazole or any excipient in Recorlev.
  • Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gp.

WARNINGS AND PRECAUTIONS

Hepatotoxicity

Serious hepatotoxicity has been reported in patients receiving Recorlev, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in patients using Recorlev. Avoid concomitant use of Recorlev with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with Recorlev. Routinely monitor liver enzymes and bilirubin during treatment.

QT Prolongation

Use Recorlev with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrythmias, and uncorrected electrolyte abnormalities, with more frequent ECG monitoring considered. Routinely monitor ECG and blood potassium and magnesium levels during treatment.

Hypocortisolism

Recorlev lowers cortisol levels and may lead to hypocortisolism with a potential for life-threatening adrenal insufficiency. Lowering of cortisol levels can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol levels may result in adrenal insufficiency that can be manifested by hypotension, abnormal electrolyte levels, and hypoglycemia. Routinely monitor 24-hour urine free cortisol, morning serum or plasma cortisol, and patient’s signs and symptoms for hypocortisolism during treatment.

Hypersensitivity Reactions

Hypersensitivity to Recorlev has been reported. Anaphylaxis and other hypersensitivity reactions including urticaria have been reported with oral ketoconazole.

Risks Related to Decreased Testosterone

Recorlev may lower serum testosterone in men and women. Potential clinical manifestations of decreased testosterone concentrations in men may include gynecomastia, impotence and oligospermia. Potential clinical manifestations of decreased testosterone concentrations in women include decreased libido and mood changes.

ADVERSE REACTIONS

Most common adverse reactions (incidence > 20%) are nausea/vomiting, hypokalemia, hemorrhage/contusion, systemic hypertension, headache, hepatic injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory infection, myalgia, arrhythmia, back pain, insomnia/sleep disturbances, and peripheral edema.

DRUG INTERACTIONS

  • Consult approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE prior to initiating Recorlev.
  • Sensitive CYP3A4 or CYP3A4 and P-gp Substrates: Concomitant use of Recorlev with these substrates is contraindicated or not recommended.
  • Atorvastatin: Use lowest atorvastatin dose possible and monitor for adverse reactions for dosages exceeding 20 mg daily.
  • Metformin: Monitor glycemia, kidney function, and vitamin B12 and adjust metformin dosage as needed.
  • Strong CYP3A4 Inhibitors or Inducers: Avoid use of these drugs 2 weeks before and during Recorlev treatment.
  • Gastric Acid Modulators: See Full Prescribing Information for recommendations regarding concomitant use with Recorlev.

USE IN SPECIFIC POPULATIONS

Lactation: Advise not to breastfeed during treatment and for one day after final dose.

To report SUSPECTED ADVERSE REACTIONS, contact Xeris Pharmaceuticals, Inc. at 1-877-937-4737 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see Full Prescribing Information including Boxed Warning.

About Xeris

Xeris (Nasdaq: XERS) is a growth-oriented biopharmaceutical company committed to improving patient lives by developing and commercializing innovative products across a range of therapies. Xeris has three commercially available products; Gvoke®, a ready-to-use liquid glucagon for the treatment of severe hypoglycemia, Keveyis®, a proven therapy for primary periodic paralysis, and Recorlev® for the treatment of endogenous Cushing’s syndrome. Xeris also has a robust pipeline of development programs to extend the current marketed products into important new indications and uses and bring new products forward using its proprietary formulation technology platforms, XeriSol™ and XeriJect®, supporting long-term product development and commercial success.

Xeris Biopharma Holdings is headquartered in Chicago, IL. For more information, visit www.xerispharma.com, or follow us on X, LinkedIn, or Instagram.

Forward-looking Statement

Any statements in this press release other than statements of historical fact are forward-looking statements. Forward-looking statements include, but are not limited to, statements about future expectations, plans and prospects for Xeris Biopharma Holdings, Inc. including statements regarding expectations for the release of clinical data, post hoc analyses or results from clinical trials, including the SONICS study, the market and therapeutic potential of its products and product candidates, including the levoketoconazole (Recorlev®), the potential utility of its formulation platforms and other statements containing the words “will,” “would,” “continue,” “expect,” “should,” “anticipate” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on numerous assumptions and assessments made in light of Xeris’ experience and perception of historical trends, current conditions, business strategies, operating environment, future developments, geopolitical factors, and other factors it believes appropriate. By their nature, forward-looking statements involve known and unknown risks and uncertainties because they relate to events and depend on circumstances that will occur in the future. The various factors that could cause Xeris’ actual results, performance or achievements, industry results and developments to differ materially from those expressed in or implied by such forward-looking statements, include, but are not limited to, its financial position and need for financing, including to fund its product development programs or commercialization efforts, whether its products will achieve and maintain market acceptance in a competitive business environment, its reliance on third-party suppliers, including single-source suppliers, its reliance on third parties to conduct clinical trials, the ability of its product candidates to compete successfully with existing and new drugs, and its and collaborators’ ability to protect its intellectual property and proprietary technology. No assurance can be given that such expectations will be realized and persons reading this communication are, therefore, cautioned not to place undue reliance on these forward-looking statements. Additional risks and information about potential impacts of financial, operational, economic, competitive, regulatory, governmental, technological, and other factors that may affect Xeris can be found in Xeris’ filings, including its most recently filed Annual Report on Form 10-K filed with the Securities and Exchange Commission, the contents of which are not incorporated by reference into, nor do they form part of, this communication. Forward-looking statements in this communication are based on information available to us, as of the date of this communication and, while we believe our assumptions are reasonable, actual results may differ materially. Subject to any obligations under applicable law, we do not undertake any obligation to update any forward-looking statement whether as a result of new information, future developments or otherwise, or to conform any forward-looking statement to actual results, future events, or to changes in expectations.

1. Recorlev [prescribing information]. Chicago, IL: Xeris Pharmaceuticals, Inc.; 2021. 2. Fleseriu M, et al. Lancet Diabetes Endocrinol. 2019;7(11):855-865. 3. Pivonello R et al. Lancet Diabetes Endocrinol. 2016; 4: 611-29. 4. Plotz CM, et al. Am J Med. 1952 November;13(5):597-614.

Recorlev®, Xeris Pharmaceuticals®, Xeris CareConnectionTM, Keveyis®, Gvoke®, and Ogluo® are trademarks owned by or licensed to Xeris Pharmaceuticals, Inc. PANTHERx Rare Pharmacy is a service mark of PANTHERx Rare, LLC. All other trademarks referenced herein are the property of their respective owners. All rights reserved. US-PR-22-00001 1/22

From https://www.morningstar.com/news/business-wire/20240603311134/xeris-presents-new-post-hoc-analysis-on-effects-of-levoketoconazole-recorlev-in-cushings-syndrome-patients-at-endo-2024

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Cardiac Magnetic Resonance Reveals Biventricular Impairment In Cushing’s Syndrome

Posted on June 4, 2024 by MaryO

Purpose

Cushing’s syndrome (CS) is associated with severe cardiovascular (CV) morbidity and mortality. Cardiac magnetic resonance (CMR) is the non-invasive gold standard for assessing cardiac structure and function; however, few CMR studies explore cardiac remodeling in patients exposed to chronic glucocorticoid (GC) excess. We aimed to describe the CMR features directly attributable to previous GC exposure in patients with cured or treated endogenous CS.

Methods

This was a prospective, multicentre, case-control study enrolling consecutive patients with cured or treated CS and patients harboring non-functioning adrenal incidentalomas (NFAI), comparable in terms of sex, age, CV risk factors, and BMI. All patients were in stable condition and had a minimum 24-month follow-up.

Results

Sixteen patients with CS and 15 NFAI were enrolled. Indexed left ventricle (LV) end-systolic volume and LV mass were higher in patients with CS (p = 0.027; p = 0.013); similarly, indexed right ventricle (RV) end-diastolic and end-systolic volumes were higher in patients with CS compared to NFAI (p = 0.035; p = 0.006). Morphological alterations also affected cardiac function, as LV and RV ejection fractions decreased in patients with CS (p = 0.056; p = 0.044). CMR features were independent of metabolic status or other CV risk factors, with fasting glucose significantly lower in CS remission than NFAI (p < 0.001) and no differences in lipid levels or blood pressure.

Conclusion

CS is associated with biventricular cardiac structural and functional impairment at CMR, likely attributable to chronic exposure to cortisol excess independently of known traditional risk factors.

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Introduction

Cushing’s syndrome (CS), or chronic hypercortisolism, is associated with increased mortality mostly due to cardiovascular disease [1, 2], with infectious diseases and coexisting comorbidities also playing a role [1,2,3,4,5,6,7,8,9]. Older age at diagnosis, longer disease activity, uncontrolled hypertension, and diabetes mellitus are the main factors increasing mortality in CS [1, 2].

The higher cardiovascular risk in CS has traditionally been attributed to chronic hypertension, vascular atherosclerosis, and increased thromboembolism [2, 10,11,12,13,14], ultimately leading to an increased risk for myocardial infarction, cardiac failure, and stroke [2, 15].

Prompt and effective treatment of cortisol excess is crucial for reversing comorbidities and reducing the mortality risk associated with CS [1, 2]. However, concomitant treatment for cardiovascular comorbidities should also be provided to mitigate cardiovascular damage [1, 2, 16]. Despite improved treatment modalities, comorbidities can persist in a significant proportion of patients even after remission of CS [2, 17], suggesting that the consequence of prolonged exposure to glucocorticoid (GC) excess can produce irreversible alteration in cardiac structure.

Alterations in cardiac kinetics and structure include abnormal relaxation patterns (decreased systolic strain and impaired diastolic filling) and concentric left ventricle hypertrophy [2, 18,19,20], the latter being more severe in CS patients when compared to hypertensive controls [2, 20]. Increased myocardial fibrosis, caused by enhanced responsiveness to angiotensin II and activation of the mineralocorticoid receptor in response to cortisol excess, further complicates the scenario [2].

Albeit myocardial fibrosis and cardiac abnormalities might improve [21], cardiovascular alterations can persist for up to 5 years since remission of GC excess [2, 22, 23], underscoring the importance of prompt diagnosis and treatment, but also monitoring of increased risk.

Most studies rely on 2D echocardiography to characterize cardiac alterations in patients with CS [24]. Still, cardiac magnetic resonance (CMR) is now the established non-invasive gold standard method for measuring left ventricle (LV) volume, LV mass (LVM), and cardiac function due to its higher accuracy, reproducibility, and lower variability [25]. Few controlled studies assess cardiac dysfunction in CS patients by CMR, with preliminary data confirming the 2D-echocardiography observation of altered LV function and structure [18, 24, 26,27,28,29].

Therefore, our study aims to provide a detailed characterization of cardiac alterations in patients who have been exposed to chronic GC excess using a CMR-based approach and help clarify which are directly attributable to GC excess by matching the CS cohort with randomly selected adrenal patients with proven intact hypothalamic-pituitary-adrenal-axis, but similar traditional cardio-metabolic risk factors.

Materials and methods

Study design and population

We performed a prospective, multicentric, case-control study. From September 2014 to January 2020, consecutive adult (>18 years) patients diagnosed with CS as per current criteria [30] (either cured or with an active drug-treated disease) were recruited from the endocrinology outpatient clinics of the Department of Experimental Medicine at “Sapienza” University of Rome and the Department of Clinical Medicine and Surgery at “Federico II” University of Naples. Disease remission following surgery was defined by urinary free cortisol (UFC) levels per upper limit of normal (ULN) < 1.0 and by serum morning cortisol levels <50 nmol/L following overnight 1 mg dexamethasone suppression, in the absence of any cortisol-lowering treatment. Disease control under chronic medical therapy was defined by UFC xULN <1.0 [16, 31]. Patients with contraindications (or unwilling to undergo) to CMR were excluded from the study. The control group consisted of randomly selected patients with non-functioning adrenal incidentalomas (NFAI) diagnosed according to current criteria [32] undergoing follow-up imaging for the adrenal lesion, comparable with patients in terms of sex, age, BMI, and traditional cardiovascular risk factors. Sixteen patients with CS and 15 NFAI entered the study. All patients must have been in stable condition, including hormonal control, for at least 6 months before entering the study. All patients provided written informed consent after fully explaining the purpose and nature of all procedures used. The study was approved by the Ethical Committee of Policlinico Umberto I (ref. number 4245). The study has been performed according to the ethical standards of the 1964 Declaration of Helsinki and its later amendments. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting.

Study procedures

Clinical and laboratory assessment

All patients underwent an accurate medical history review, including drugs used, hormonal assessment at diagnosis (UFC xULN, serum cortisol after dexamethasone suppression test), comorbidities (hypertension, glucose metabolism impairment, dyslipidemia, obesity), and cardiovascular risk factors (e.g., smoking habit). Subsequently, they were submitted to physical examination with measurement of anthropometric parameters and vital signs. Blood sampling for the assessment of biochemistry and hormones was performed at the local laboratory of each participating center; to better standardize results about disease activity, UFC levels were normalized by the upper limit of normal of each center’s laboratory. Clinical and laboratory findings and the prevalence of cardiometabolic complications have been compared between patient groups (CS vs NFAI) and cured and drug-treated patients (cured CS vs controlled CS). All patients were followed up for a minimum of 24-month timeframe.

Cardiac evaluation

All subjects underwent cardiac evaluation with CMR imaging performed as previously described [33] with a 1.5-T clinical magnetic resonance imaging system (Avanto, Siemens, Healthcare Solutions, Erlangen, Germany). During the examination, an ECG device was used for cardiac gating, and all acquisitions were made in apnea at the end of inspiration. In all cases, CMR imaging was performed by the same radiologist expert in cardiac imaging (N.G.) using the same acquisition protocol. CMR was performed at study entry, but not earlier than 6 months from any previous severe acute disease, event, or procedure.

T1-mapping for the evaluation of fibrosis

The T1-mapping technique has been used to quantify the degree of myocardial fibrosis non-invasively. The measured extracellular volume fraction (ECV) is highly sensitive and indicates diffuse myocardial fibrosis [34]. T1-mapping is automatically calculated as the average of the intensity of the individual pixels with and without contrast medium in T1 and expressed in msec (CMR 42 SW). The calculation of the ECV has been performed using the mathematical formula using the hematocrit value [DR1 myocardium: (1/T1 myocardial-post) − (1/T1 myocardial-pre); DR1 blood: (1/T1 blood-post) − (1/T1 blood-pre); Myocardial partition coefficient (λ) = (DR1 myocardial/DR1 blood); ECV = (1 − hematocrit) × (λ)]. A cut-off of ECV > 30% was used to identify increased interstitial fibrosis [35].

CMR findings have been compared between patient groups (CS vs NFAI). Moreover, the comparison of cardiac parameters has also been performed in CS patients according to cardiometabolic comorbidities, disease status, and sex.

The main steps of CMR image acquisition are shown in Fig. 1.

Fig. 1

figure 1

Cardiac magnetic resonance image acquisition protocol. T1-weighted, late gadolinium enhancement cardiac MR images of a 71-year-old female patient with Cushing’s disease, cured after successful neurosurgery. A Vertical long axis slice, coronal plane, two-chamber view. B Horizontal long axis slice, axial plane, four-chamber view. C Short-axis slice at the end of the diastole, sagittal plane. Red circle: endocardium; Blue circle: epicardium. LA left atrium, LV left ventricle, RA right atrium, RV right ventricle

Statistical analysis

Continuous variables are expressed as standard deviation (SD), median and 95% confidence interval (95%CI) as per data distribution, assessed through the Shapiro–Wilk test. Dichotomous variables are expressed as frequencies and percentages when relevant. According to variable distribution, the Student’s t-test or the non-parametric Mann–Whitney U test was performed to compare continuous variables between CS and NFAI and between cured and drug-controlled patients. Differences between groups regarding qualitative variables were evaluated by χ2 statistics. Bivariate correlations between numerical variables were analyzed using Pearson’s or Spearman’s correlation test, as appropriate. The statistical significance was set at p < 0.05. Statistical analyses were performed using SPSS 20.0 for MacOS (SPSS Inc.).

Results

Patient characteristics

The cohort characteristics are summarized in Table 1. Sixteen patients with CS (12 females, mean age 47 ± 12 years) and 15 with NFAI (7 females, mean age 55 ± 10 years) were enrolled during the study period. Twelve patients (75%) had been diagnosed with Cushing’s disease (CD), while four (25%) had ACTH-independent CS due to a cortisol-secreting adrenal adenoma.

Table 1 Baseline characteristics of patients with CS

At enrollment, eleven (69%) patients were cured and five (31%) had drug-treated CD. Among patients with CD, nine had previously undergone pituitary surgery, seven (58%) were cured, and five (42%) presented with a biochemically persistent disease. In the latter group, 3 patients had adequate biochemical control under medical therapy, whereas 2 patients were not entirely on target, because of low compliance and intolerance to medical treatments.

All patients with a cortisol-secreting adrenal adenoma had undergone unilateral adrenalectomy and were cured at the time of enrollment.

Table 2 details comorbidities and their therapies for CS and NFAI patients.

Table 2 Biochemical and clinical parameters in CS patients and NFAI

Biochemical and clinical evaluation

The main clinical and biochemical parameters are reported in Table 2. Sex, age, and BMI did not differ between the CS patients and NFAI. The two groups were similar concerning HbA1c, fasting insulin or homeostatic model assessment for insulin resistance, and lipid levels; fasting glucose levels were marginally lower in CS than in NFAI (p < 0.001). No differences were found in systolic and diastolic blood pressure, the prevalence of cardiometabolic complications or drugs (i.e., diagnosis of hypertension, dyslipidemia, obesity, and diabetes or prescriptions needed to control such comorbidities), suggesting that GC excess was resolved (or adequately controlled) at the time of enrollment for the great majority of patients.

Subgroup analysis of cardiac parameters in patients with Cushing’s syndrome

A subgroup analysis was performed to assess possible differences in cardiac parameters when the CS cohort was stratified according to disease status and cardiometabolic comorbidities (i.e., between patients with or without hypertension, glucose metabolism impairment, dyslipidemia, obesity), smoking, sex, and disease status.

Firstly, pharmacologically treated CS exhibited higher systolic and diastolic blood pressure levels than cured CS (p = 0.027), but no other differences were found regarding CMR parameters. Subgroup analysis according to the presence/absence of comorbidities revealed no significant effect on cardiac parameters, except for CS patients with impaired glucose tolerance, who showed a lower RV-EF compared with the remaining CS patients (p = 0.017).

Analyzing sex differences, male CS patients displayed higher RV-EDVi (p = 0.035) and RV-ESVi (p = 0.044), as well as a trend toward higher LV-EDVi (p = 0.067), LV-ESVi (p = 0.053) and LVMi (p = 0.066) compared to females. However, male CS patients only exhibited higher interventricular septum (IVS) thickness (p = 0.001) when compared to male and female reference ranges for the general population, age and sex-matched [36].

Comparison of cardiac parameters between patients and controls

A comparison of the main morphostructural and functional cardiac parameters between CS and NFAI in the left and the right ventricle is reported in Fig. 2 and Fig. 3, respectively. CMR cardiac morphology revealed an increased left ventricle-end systolic volume index (LV-ESVi) (31.0 ± 8.7 vs 24.1 ± 7.4, p = 0.027) in CS compared to NFAI (Fig. 2). Left ventricle mass index (LVMi) was also higher in CS (51.0 ± 11.8 vs 41.8 ± 6.9, p = 0.013) (Fig. 2), albeit none matched the criteria for left ventricular hypertrophy [37]. Regarding cardiac function, a trend toward lower left ventricle-ejection fraction (LV-EF) was measured in CS (57.1 ± 6.3 vs 61.9 ± 7.0, p = 0.056). Mirroring the alterations found in the left ventricle, higher indexed right ventricle-end systolic volume (RV-ESVi) (34.0 ± 7.7 vs 26.3 ± 6.0, p = 0.006) and right ventricle-end diastolic volume (RV-EDVi) (74.8 ± 14.2 vs 64.9 ± 9.3, p = 0.035), as well as lower right ventricle-ejection fraction (RV-EF) (54.6 ± 5.5 vs 59.5 ± 7.1, p = 0.044) were measured in patients with CS (Fig. 3). Dedicated T1 mapping technique did not reveal any difference between CS and NFAI, either before or after contrast administration. No patient had ECV greater than 30%, and no difference in ECV values was observed between groups.

Fig. 2
figure 2

Comparative analysis of left ventricle parameters in Cushing’s syndrome and NFAI patients. Left ventricle morphological and functional cardiac parameters in patients with Cushing’s syndrome (gray bars) and patients with NFAI (black bars). Data are expressed as mean ± SD. *p < 0.05. CS Cushing’s syndrome, CNT NFAI, LV-EDVi Left Ventricle End-Diastolic Volume index, LV-ESVi Left Ventricle End-Systolic Volume index, LV-SVi Left Ventricle Stroke Volume index, LVMi Left Ventricular Mass index, LV-EF Left Ventricle Ejection Fraction

Fig. 3
figure 3

Comparative analysis of right ventricle parameters in Cushing’s syndrome and NFAI patients. Right ventricle morphological and functional cardiac parameters in patients with Cushing’s syndrome (gray bars) and patients with NFAI (black bars). Data are expressed as mean ± SD. *p < 0.05; **p < 0.01; CS Cushing’s syndrome, CNT NFAI, RV-EDVi Right Ventricle End-Diastolic Volume index, RV-ESVi Right Ventricle End-Systolic Volume index, RV-SVi Right Ventricle Stroke Volume index, RV-EF Right Ventricle Ejection Fraction

No significant correlations were found between CMR parameters and UFC x ULN (assessed at diagnosis or date of CMR evaluation), serum cortisol after dexamethasone suppression test (at diagnosis) or disease duration from diagnosis. An explicative summary of cardiac parameters is shown in Table 3.

Table 3 Cardiac parameters in CS patients and NFAI

Discussion

The current study reveals that exposure to endogenous GC excess induces a peculiar early remodeling of affected patients’ left and right ventricles, which can persist after CS remission and is independent of traditional cardiometabolic risk factors. Namely, the higher LV and RV ESVi and EDVi observed in patients exposed to GC excess is accompanied by higher LVMi. However, LV and RV ejection fractions are only mildly reduced, suggesting that a morphological impairment anticipates a performance dysfunction. The fact that such alterations occur rapidly in CS and are partially irreversible after remission advocates the use of CMR to improve the management of fatal cardiac complications in this rare endocrine disease.

Several echocardiographic studies have evaluated cardiac structure and function in patients with CS and found LV systolic and diastolic dysfunction [19, 21, 38,39,40,41]. Albeit cardiac echocardiography is more practical in everyday clinical practice, CMR allows an evaluation of ventricular mass and volumes free of cardiac geometric assumption, ensuring a higher accuracy and reproducibility [29, 42].

Few controlled studies evaluating small cohorts have analyzed patients with CS using CMR [18, 26,27,28]. Kamenicky and coworkers compared 18 patients with active CS with 18 controls matched for age, sex, and BMI and found that patients had lower LV, RV, and left atrium ejection fractions, along with increased left and right ESVi and end-diastolic LV segmental thickness. Of note, successful treatment of CS was associated with an improvement in ventricular and atrial systolic performance [18]. A later study from the same group evaluated 23 patients with active CS and compared them with 27 controls matched for age, sex, and BMI, reporting increased left ventricular wall thickness, and reduced ventricular stroke volumes in patients [28]. A CMR study comparing CS patients with age and sex-matched controls showed that patients with active disease had higher LVMi than controls, as opposed to those in disease remission [27]. In all the studies mentioned above, patients and controls significantly differed in cardiovascular risk factors, with a worse cardiovascular profile in patients than controls. Conversely, our cohorts were largely homogeneous, without any significant difference between patients with CS and NFAI in glycometabolic profile, except for a surprisingly marginally lower fasting glucose levels in CS than in NFAI. This is likely because CS patients were either cured or drug-treated, and NFAI were comparable in terms of BMI and known CV risk factors.

As a result, the two groups did not significantly differ either in systolic and diastolic blood pressure levels or in the overall prevalence of cardiometabolic complications or the drugs prescribed to treat them. Nevertheless, our results confirmed the CMR findings of previous studies regarding higher cardiac volumes and mass and lower ejection fractions in patients with CS than in NFAI, advocating a direct effect of GC excess exposure in cardiac impairment beyond the known cardiovascular risk factors. Moreover, the results of the current study highlight the importance of a biventricular evaluation in this context, as opposed to most 2D-echocardiographic studies. Ultrasound measurement of RV volumes is challenging; therefore, most CS echocardiographic studies have mainly focused on the LV [19, 21, 38,39,40,41], whereas CMR studies suggest an impairment in both left and right ventricles. The RV is anatomically and functionally different from the LV. In the absence of clear alterations in pulmonary resistance, our findings suggest RV involvement is a direct effect of GC excess on cardiomyocytes, whose receptors are equally expressed in left and right ventricles in donor hearts and dilated cardiomyopathy [43].

Cardiac morphological alterations in our cohort were not related to increased myocardial fibrosis, as we did not find any difference between patients and controls in T1 mapping evaluation, probably also due to the superimposable cardiometabolic profile of the two study groups. Albeit patients had non-significantly higher postcontrast T1 values, none had ECV values compatible with fibrosis. Similarly, Roux and coworkers evaluated 10 patients with active CD matched with 10 hypertensive and 10 healthy controls and performed a CMR study using the T1 mapping technique and found increased native myocardial T1 in CD, independently from hypertension, without differences in myocardial partition coefficient (λ) between groups. These results support the hypothesis of a potential role of T1 mapping in identifying early biomarkers of subclinical myocardial fibrosis in this disease [26].

Even though we didn’t find any significant correlation between indicators of hypercortisolism severity (UFC x ULN, disease duration) and CMR parameters, the independency of cardiac alterations from traditional cardiometabolic risk factors, claims a direct role of hypercortisolism on cardiac impairment, acting as a fingerprint of GC excess exposure. Our data point toward a persistent toxic effect on the heart, mediated directly through GC and/or mineralocorticoid receptors [2, 11, 44], that produces changes in cardiac structure that are clinically silent but long-lasting, as if the heart retained a memory of GC excess exposure. The mineralocorticoid pathway increases collagen secretion by activating fibroblasts [45]. In addition, stimulating mineralocorticoid receptors decreases myocyte contractility and stimulates mitosis, resulting in myocardial hypertrophy and dysfunction [46]. However, previous data on mineralocorticoid antagonism in GC-induced hypertension did not prove convincing [47], disclosing the need for direct control of GC receptors (for example, via selective GC receptor antagonists such as relacorilant). Indeed, there is evidence supporting the role of GCs in driving alterations in vasoactive substances, thus impacting the balance between vasoconstriction and vasodilation (including catecholamines, nitric oxide, and atrial natriuretic peptide), as well as the activation of the renin-angiotensin system, leading to cardiac hypercontractility [11, 48].

The present study has shown more structural rather than functional changes at CMR in CS patients without evidence of fibrosis, thus suggesting the latter probably as a late phenomenon.

Additive to the direct role of cortisol, almost 60% of our patients presented hypertension, which could have contributed to the development of cardiac impairment. Similarly, the impact of other CS-related cardiovascular risk factors, such as visceral obesity, glucose intolerance and dyslipidemia, cannot be entirely ruled out.

Finally, our study showed for the first time that sex might affect cardiac morphological changes induced by GC excess. Male CS patients exhibited higher IVS thickness compared to females after adjusting for population age and sex reference ranges, independently from the prevalence of hypertension, supporting sex-related differences as observed in other cardiovascular diseases [49, 50]. Recently, a study by Wolf et al. showed that male sex was an independent predictor of increased epicardial and pericardial fat [28], which may play a role in the pathogenesis of CS cardiomyopathy. However, among CS patients, we did not find any differences in the prevalence of male and female hypogonadism (50% vs 42%, p = 1.000). Still, we can not exclude that estrogen exposure could have protected GC-related cardiomyopathy [51].

Very few studies have evaluated cardiac structure and function in CS using CMR, and this is a strength of the current study. However, it does have some limitations. The cross-sectional design and the lack of sample size in such a small and heterogeneous study population with different etiologies of endogenous CS, including both cured and well-controlled patients, might have underestimated the cardiac impairment. Anyway, considering that CS is a rare disease, we opted for a study design closer to a CS clinic’s real-life setting; this aspect represents a strength of this study. Nevertheless, according to the published evidence, as well as to our results, it is likely that cardiac dysfunction might persist in CS even after disease remission. Indeed, although our CS patients had higher biventricular volumes, the subgroup comparison between surgically cured and drug-treated patients revealed no differences in cardiac morphology or biochemical or cardiometabolic complications prevalence, althoghut the lack of standardization of the evaluation period. A previous paper found a significantly higher LVMi in active patients than in remission [27]. Anyway, longitudinal studies (baseline versus post-treatment) with larger population are needed to better clarify the reversibility of cardiac changes after treatment.

We propose a novel approach to cardiac disease in CS, going beyond the traditional cardiometabolic risk factors and evaluating both ventricles, preferably with CMR. Moreover, the present study highlights the importance of a sex-oriented approach in the management of CS complications, taking into account the sex-related differences in cardiac damage of these patients, for whom cardiac complications still represent the major cause of death, very often occurring during remission [2].

Conclusions

In CS biventricular cardiac remodeling associated with functional impairment, has been ascribed to a multifactorial pathogenesis. Our findings highlight the greater contribution of direct effect of GC excess exposure on myocardium than on cardiovascular risk factors, suggesting a sex-related differences in cardiac impairment. More importantly, the maladaptive change triggered by chronic exposure to GC excess, even if the latter is resolved, is persistent and clinically silent and could be detected though a more sensitive and precise approach with CMR.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the PRecisiOn Medicine to Target Frailty of Endocrine-metabolic Origin (PROMETEO) project (NET-2018-12365454) by the Ministry of Health and the European Union – NextGenerationEU through the Italian Ministry of University and Research under PNRR – M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” to Andrea Isidori CUP B53C22004000006. Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement.

Author information

Author notes

  1. These authors contributed equally: Tiziana Feola, Alessia Cozzolino
  2. These authors jointly supervised this work: Andrea M. Isidori, Elisa Giannetta

Authors and Affiliations

  1. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Tiziana Feola, Alessia Cozzolino, Dario De Alcubierre, Federica Campolo, Andrea M. Isidori & Elisa Giannetta

  2. Neuroendocrinology, Neuromed Institute, IRCCS, Pozzilli, Italy

    Tiziana Feola & Dario De Alcubierre

  3. Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford University Hospitals, NHS Trust, Oxford, UK

    Riccardo Pofi

  4. Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy

    Nicola Galea & Carlo Catalano

  5. Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Naples, Italy

    Chiara Simeoli, Nicola Di Paola & Rosario Pivonello

  6. Centre for Rare Diseases (ENDO-ERN accredited), Policlinico Umberto I, Rome, Italy

    Andrea M. Isidori

Contributions

A.M.I., E.G., T.F., A.C. contributed to the idea and design of the study, analysis of the data, and writing of the manuscript. D.D.A., R.P., C.S., N.D.P., F.C. and R.P.i. contributed to the design of the study, analysis of the data, and revision of the report. T.F., A.C., D.D.A., N.G. and C.C. analyzed the data. All authors contributed to the interpretation of the data and the writing of the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Andrea M. Isidori or Elisa Giannetta.

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RPi has received research support to Università Federico II di Napoli as a principal investigator for clinical trials from Novartis Pharma, Recordati, Strongbridge Biopharma, Corcept Therapeutics, HRA Pharma, Shire, Takeda, Neurocrine Biosciences, Camurus AB, and Pfizer, has received research support to Università Federico II di Napoli from Pfizer, Ipsen, Novartis Pharma, Strongbridge Biopharma, Merk Serono, and Ibsa, and received occasional consulting honoraria from Novartis Pharma, Recordati, Strongbridge Biopharma, HRA Pharma, Crinetics Pharmaceuticals, Corcept Therapeutics, Pfizer, and Bresmed Health Solutions. AMI has been a consultant for Novartis, Takeda, Recordati, and Sandoz companies and has received unconditional research grants from Shire, IPSEN, and Pfizer. All the other authors have nothing to disclose.

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The authors affirm that human research participants provided informed consent for publication of the images in Fig. 1.

Ethics approval and conset to participate

All patients provided written informed consent after fully explaining the purpose and nature of all procedures used. The study was approved by the Ethical Committee of Policlinico Umberto I (ref. number 4245). The study has been performed according to the ethical standards of the 1964 Declaration of Helsinki and its later amendments.

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Feola, T., Cozzolino, A., De Alcubierre, D. et al. Cardiac magnetic resonance reveals biventricular impairment in Cushing’s syndrome: a multicentre case-control study. Endocrine (2024). https://doi.org/10.1007/s12020-024-03856-7

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