Response to Osilodrostat Therapy in Adrenal Cushing’s Syndrome

Posted on April 15, 2024 by MaryO

Authors Stasiak M , Witek P, Adamska-Fita E, Lewiński A

Received 27 December 2023

Accepted for publication 20 March 2024

Published 8 April 2024 Volume 2024:16 Pages 35—42

DOI https://doi.org/10.2147/DHPS.S453105

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Hemalkumar B Mehta

Magdalena Stasiak,1 Przemysław Witek,2 Emilia Adamska-Fita,1 Andrzej Lewiński1,3

1Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital—Research Institute, Lodz, Poland; 2Department of Internal Medicine, Endocrinology and Diabetes, Medical University of Warsaw; Mazovian Brodnowski Hospital, Warszawa, Poland; 3Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Lodz, Poland

Correspondence: Magdalena Stasiak, Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital—Research Institute, 281/289 Rzgowska Street, Lodz, 93-338, Poland, Tel +48502049292, Fax +48422711140, Email mstasiak33@gmail.com

Abstract: Cushing’s disease (CD) is the most common cause of endogenous hypercortisolism. Osilodrostat was demonstrated to be efficient in treating CD, and the mean average dose required for CD control was < 11 mg/day. Potential differences in osilodrostat treatment between cortisol-producing adenoma (CPA) and CD have not been reported. The aim of this study was to present two patients with CPA in whom significant differences in the response to therapy compared to CD were found. We demonstrated a case of inverse response of cortisol levels with adrenal tumor progression during the initial dose escalation (Case 1). Simultaneously, severe exaggeration of hypercortisolism symptoms and life-threatening hypokalemia occurred. A further rapid dose increase resulted in the first noticeable cortisol response at a dose of 20 mg/day, and a full response at a dose of 45 mg/day. We also present a case that was initially resistant to therapy (Case 2). The doses required to achieve the first response and the full response were the same as those for Case 1. Our study demonstrated that osilodrostat therapy in patients with CPA may require a different approach than that in CD, with higher doses, faster dose escalation, and a possible initial inverse response or lack of response.

Keywords: osilodrostat, adrenal adenoma, hypercortisolism, ACTH-independent, adverse events, hypokalemia

Introduction

Chronic persistent hypercortisolism is a life-threatening condition that requires effective treatment. Untreated exposure to excessive cortisol secretion leads to severely increased morbidity and mortality due to cardiovascular diseases, thromboembolic events, sepsis, visceral obesity, impairment of glucose metabolism, and dyslipidaea, as well as musculoskeletal disorders, such as myopathy, osteoporosis, and skeletal fractures. Moreover, neuropsychiatric disorders, such as impairment of cognitive function, depression, or mania, as well as impairment of reproductive function can frequently occur.1,2 Cushing’s disease (CD) – a disorder caused by a pituitary adenoma secreting adrenocorticotropic hormone (ACTH) – is the most common cause of hypercortisolism. Cushing’s syndrome (CS) includes all other causes of cortisol excess, including ectopic ACTH production as well as direct cortisol overproduction by adrenal adenoma (cortisol-producing adenoma [CPA]) or adrenocortical carcinoma (ACC). Approximately 10% of hypercortisolism cases result from CPA. The first line therapy is a surgical resection of the tumor, which is the source of hormone excess. However, in many patients surgery is not fully efficient and other therapies are required to reduce cortisol levels. Additionally, due to severe cardiovascular complications and unstable DM, the surgical approach sometimes entails unacceptable risk and it is frequently postponed until cortisol levels are lowered. Pharmacotherapy with steroidogenesis inhibitors reduces cortisol levels and improves the symptoms of hypercortisolism.1,2 As CD is the most common cause of cortisol excess, most studies have focused on the efficacy and safety of novel steroidogenesis inhibitors, including patients with CD only.3–6 This is exactly the case with osilodrostat – a new potent inhibitor of 11β-hydroxylase.3–6 More data are available for metyrapone efficacy and safety in CSA,7 as the drug has been available much longer than osilodrostat. A study by Detomas et al, which reported results of comparison of efficacy of metyrapone and osilodrostat, included 4 patients with adrenal CS, among whom one CPA patient was treated with osilodrostat.8 Osilodrostat is approved in the United States to treat CD in patients in whom pituitary surgery was not curative or is contraindicated.9 In Poland, osilodrostat therapy is available for patients with all kinds of endogenous hypercortisolism not curative with other approaches, within a national program of emergency access to drug technologies.10 Reports on osilodrostat application in CPA are highly valuable as data on potential differences in the treatment regimens between CD and CPA are scarce.

Here, we present two patients with CPA in whom the response and doses of osilodrostat were different from those reported in patients with CD. The main purpose of this study was to demonstrate that the efficacy of osilodrostat in CPA is high, although initial resistance to treatment or even deterioration of hypercortisolism can occur during the application of lower doses of the drug.

Materials and Methods

Study Design and Patients

We retrospectively analyzed medical files of two consecutive patients with CPA treated with osilodrostat. The analysis included medical history, laboratory and imaging results as well as a detailed reports of adverse events.

Laboratory and Imaging Procedures

Serum cortisol and ACTH levels were measured by electrochemiluminescence immunoassay (ECLIA) using a Cobas e601 analyzer (Roche Diagnostics, Indianapolis, IN, USA). UFC excretion was measured by chemiluminescent microparticle immunoassay (CMIA) using an Abbott Architect ci4100 analyzer (Abbott, Abbott Park, IL, USA). Cross-reactivity with 11-deoxycortisol for this method is very low (2.1% according to the manufacturer’s data). Potassium levels were measured by ion-selective electrode potentiometry using a Beckman Coulter DxC 700 AU Chemistry Analyzer (Beckman Coulter, Brea, CA, USA). Computed tomography (CT) imaging was performed using a Philips Ingenuity Core 128 system (Philips, the Netherlands).

Ethics Procedures

Informed consent was obtained from all subjects involved in the study. Written informed consent was obtained from the patients for publication of this paper. The approval of Institutional Ethics Committee was obtained to publish the case details (approval code KB 33/2023).

Presentation of the Cases

Case 1

A 51-year-old female was referred to our department in November 2021 because of CPA, disqualified from surgery because of severe hypertension with a poor response to antihypertensive therapy and uncontrolled DM despite high doses of insulin. Additionally, the patient presented with hyperlipidemia and severe obesity (BMI=50.7 kg/m2), gastritis, depression, and osteoarthritis. On admission, she complained of a tendency to gain weight, fragile skin that bruised easily, difficulty with wound healing, susceptibility to infections, and insomnia. Physical examination revealed a moon face with plethora, a buffalo hump, central obesity with proximal muscle atrophy, and purple abdominal striae.

The CPA diagnosis was initially made two years earlier, but the patient did not qualify for surgery due to a hypertensive crisis. Soon after this episode, the SARS-CoV-2 pandemic began, and the patient was afraid of visiting any medical center because her son had died of COVID-19. Therefore, she was referred to our center for life-threatening hypercortisolism two years later.

At the time of admission, computed tomography (CT) imaging revealed a right adrenal tumor of 34x24x37mm, with a basal density of 21 HU and a contrast washout rate typical for adenomas (83%). The size and CT characteristics were identical as they were two years earlier. High serum cortisol levels, undetectable ACTH concentrations, and a lack of physiological diurnal rhythm of cortisol secretion were observed (Table 1). Urinary free cortisol (UFC) excretion was 310 µg/24 h, with an upper normal limit (UNL) of 176 µg/24 h. No cortisol suppression was achieved in high-dose dexamethasone suppression test (DST) (Table 1). Other adrenal-related hormonal parameters were within normal ranges, with values as follows: DHEA-S 42.68 µg/dl, aldosterone 3.24 ng/mL, and renin 59.14 µIU/mL.

Table 1 Laboratory Results Before Osilodrostat Therapy – Case 1

Due to multiple severe systemic complications, including uncontrolled hypertension, decompensated DM, and cardiac insufficiency, treatment with osilodrostat was introduced for life-saving pre-surgical management. Osilodrostat was started at a dose of 1 mg twice daily and gradually increased to 6 mg per day with actually an inverse response of serum cortisol level. The late-night cortisol level increased from 16 µg/dl to 25 µg/dl. As the full effect of the osilodrostat dose can occur even after a few weeks, the patient was discharged from hospital and instructed to contact her attending doctor immediately if any health deterioration was noticed. In the case of improvement in the patient’s condition, the next hospitalization was planned 3 weeks later. After three weeks of no contact with the patient, she was readmitted to our department with life-threatening escalation of hypercortisolism, severe hypokalemia, and further deterioration of hypertension, DM, cardiac insufficiency, dyspnea, and significant edemas, including facial edema. Treatments of hypertension, cardiac insufficiency, and DM were intensified, as presented in Table 2. Despite active potassium supplementation, life-threatening hypokalemia of 2.1 mmol/l occurred. Previously observed depression was exaggerated with severe anxiety and fear of death. The dose of osilodrostat was increased to 8 mg/day, and after three days of treatment a further elevation of serum cortisol was found, with an increase in UFC up to 9 × UNL (1546.2 µg/24 h). Due to an entirely unexpected inverse cortisol response, CT imaging was performed and revealed progression of the adenoma size to 39 × 36 × 40 mm, with a slight increase in density up to 27 HU as compared to the previous CT scan performed a month earlier (Figure 1).

Table 2 Changes in the Most Important Parameters During Osilodrostat Therapy – Case 1
Figure 1 Progression of the adrenal adenoma size during the initial doses of osilodrostat: (a) CT scan directly before osilodrostat therapy – solid nodule 34x24x37 mm, basal density 21 HU; (b) CT scan during treatment with 8 mg of osilodrostat daily – solid nodule 39x36x40 mm, basal density of 27 HU.

Considering the extremely high risk associated with such a rapid cortisol increase and related complications, decision of fast osilodrostat dose escalation was made. The dose was increased by 5 mg every other day, up to 45 mg per day, and, finally, a gradual decrease in the cortisol level (Table 2) was achieved, with UFC normalization to 168 µg/24 h. During dose escalation, no deterioration in the adverse effects (AEs) of osilodrostat was observed. Conversely, hypokalemia gradually improved despite a simultaneous reduction in potassium supplementation (Table 2). Facial edema decreased and the level of anxiety improved significantly. The course of hypertension severity as well as a summary of the main parameters controlled during treatment and the medications used are presented in Table 2. As soon as the cortisol level normalized, the patient was referred for surgery and underwent right adrenalectomy without any complications. Histopathology results confirmed a benign adenoma of the right adrenal gland (encapsulated, well-circumscribed tumor consisting of lipid-rich cells with small and uniform nuclei, mostly with eosinophilic intracytoplasmic inclusions). After surgery, hydrocortisone replacement therapy was administered. A few days after surgery, blood pressure and glucose levels gradually decreased, and the patient required reduction of antihypertensive and antidiabetic medications. After 22 months of follow-up, the patient’s general condition is good with no signs of recurrence. Antidepressant treatment is no longer required in this patient. Body mass index was significantly reduced to 40 kg/m2. The antihypertensive medication was completely discontinued, and the glucose level is controlled only with metformin. The patient still requires hydrocortisone substitution at a dose of 30 mg/day.

Case 2

A 39-year-old female was referred to our department in November 2022 with a diagnosis of CPA and unstable hypertension, for which surgery was contraindicated. The patient was unsuccessfully treated with triple antihypertensive therapy (telmisartan 40 mg/day, nebivolol 5 mg/day, and lercanidipine 20 mg/day). The patient reported weight gain, muscle weakness, acne, fragile skin that bruised easily, and secondary amenorrhea. Other comorbidities included gastritis, hypercholesterolemia, and osteoporosis. Physical examination revealed typical signs of Cushing’s syndrome, such as abnormal fat distribution, particularly in the abdomen and supraclavicular fossae, proximal muscle atrophy, moon face, and multiple hematomas. A lack of a serum cortisol diurnal rhythm with high late-night serum cortisol and undetectable ACTH levels was found (Table 3). The short DST revealed no cortisol suppression (Table 3), and the UFC result was 725 µg/24 h, which exceeded the UNL more than four times. The serum levels of renin, aldosterone, and 24-h urine fractionated metanephrines were within the normal ranges. Computed tomography imaging revealed a left adrenal gland tumor measuring 25 × 26 × 22 mm, with a basal density of 32 HU and a washout rate typical for adenoma (76%).

Table 3 Laboratory Results Before Osilodrostat Therapy – Case 2

Osilodrostat therapy was administered for preoperative management. The initial daily dose was 2 mg/day, increased gradually by 2 mg every day with no serum cortisol response (late night cortisol levels 15.8–18.5 µg/dl) and no AEs of the drug (Table 4). After the daily dose of osilodrostat reached 10 mg, it was escalated by 5 mg every other day, initially with no serum cortisol reduction. The dose was increased to 45 mg daily (with the lowest detected late-night serum cortisol of 9.6 µg/dl) (Table 4).

Table 4 Changes in the Most Important Parameters During Osilodrostat Therapy – Case 2

After a week of administration of 45 mg daily, UFC normalization was achieved. Despite rapid dose escalation, no AEs were observed during the entire therapy period. Potassium levels were normal without any supplementation (the lowest detected serum potassium level was 3.9 mmol/l; all other results were over 4.0 mmol/l) (Table 4). After UFC normalization, left adrenalectomy was performed without complications. Histopathological examination revealed benign adrenal adenoma. Antihypertensive therapy was reduced only to 2.5 mg of nebivolol daily. The patient’s general condition improved significantly. Currently, hydrocortisone replacement therapy is administered at a dose of 15 mg/day.

Discussion

Osilodrostat is a novel potent steroidogenesis inhibitor whose efficacy and safety have been thoroughly analyzed in clinical trials of patients with CD, the most common cause of endogenous hypercortisolism. No clinical trial of osilodrostat therapy in CPA has been performed, as this disease constitutes only 10% of all cases of endogenous hypercortisolism. Moreover, osilodrostat is not approved by the FDA for hypercortisolism conditions other than CD.9 Therefore, data on potential differences in the treatment regimen are lacking.

During the course of already reported trials in CD, osilodrostat doses were escalated slowly, every 2–3 weeks,3,5,6 with an excellent response to quite low doses of the drug.3–6 In the LINC 2 extension study the median average dose was 10.6 mg/day,5 while in the LINC 3 extension study and the LINC 4 study it was 7.4 mg/day and 6.9 mg/day, respectively.4,6 In most cases, a significant decrease of hypercortisolism was reported with the low doses of osilodrostat (4 or 10 mg/day). Moreover, some patients received 1 mg/day or even 1 mg every other day, with a good response.6 Even in rare cases of CD in whom initial short-term etomidate therapy was given at the beginning of osilodrostat therapy, due to highly severe life-threatening symptoms of hypercortisolism, the final effective dose of osilodrostat was much lower than that in our patients with CPA (25 mg/day vs 45 mg/day) and no increase of cortisol level was observed.11

It should be underlined that many cases of adrenal insufficiency during osilodrostat therapy in patients with CD have been reported,3–6,12,13 and – therefore – low initial dose with slow gradual dose escalation is recommended in patients with CD.1,6,13

In the cases presented here, CPA led to severe hypercortisolism, the complications of which constituted contraindications for surgery. Therefore, osilodrostat therapy was introduced as a presurgical treatment. In Case 1, the therapy was started at low doses according to the approved product characteristics.14 Due to the severity of hypertension, which was uncontrolled despite of active antihypertensive therapy, as well as to unstable DM, the doses were increased faster than recommended. Surprisingly, we immediately observed a gradual increase in hypercortisolism, in both serum cortisol levels and the UFC, with simultaneous burst of complications related to both hypercortisolism itself and 11β-hydroxylase inhibition. Life-threatening episodes of hypertensive crisis responded poorly to standard therapies. Severe exaggeration of cardiac insufficiency could probably be related to these episodes as well as to deep hypokalemia, which occurred despite potassium supplementation. Hypokalemia is a typical complication of treatment with 11β-hydroxylase inhibitors due to the accumulation of adrenal hormone precursors. However, Patient 1 required much higher doses of potassium supplementation, both parenteral and oral, than ever described during osilodrostat therapy.3–6,13 The dose of 20 mg/day of osilodrostat was the first one which led to noticeable cortisol reduction and a decrease in systolic blood pressure (SBP) to below 170 mmHg. Surprisingly, instead of the expected deterioration of hypokalemia, parenteral potassium administration could be stopped with an osilodrostat dose of 20 mg/day and oral supplementation was gradually reduced simultaneously with osilodrostat dose escalation. The reason why such severe hypokalemia occurred with low doses of osilodrostat and did not deteriorate further seems complex. One possible reason is the administration of high doses of potassium-saving antihypertensive drugs such as spironolactone and the angiotensin II receptor antagonist telmisartan. Additionally, one can consider other possible mechanisms, such as downregulation of the receptors of deoxycorticosterone (DOC) or other adrenal hormone precursors. However, this hypothesis requires further research and confirmation. Such an improvement of the potassium level during osilodrostat dose escalation was previously demonstrated in a patient with CD.11 Interestingly, in our Patient 2, no potassium supplementation was required during the whole time of osilodrostat therapy, although the doses were increased intensively up to the finally effective dose, which was the same (45 mg/day) as for Patient 1. In Patient 2, no actual response to doses lower than 20 mg/day was observed. UFC normalization was achieved after a week of administration of 45 mg/day, five weeks from the beginning of therapy. Although UFC normalization is not always required in pre-surgical treatment, clinical symptoms significantly improved in our patients only after the UFC upper normal level was achieved.

The present paper is one of only a few reports focused on osilodrostat therapy in CPA, and the only one presenting a different therapy course as compared to patients with CD. No case of CPA resistance to low doses of osilodrostat has been described. It should be underlined that in our report “low doses” of osilodrostat were higher than the average mean doses of osilodrostat used in clinical trials in patients with CD.3–6 Therefore, they should not generally be considered low but only much lower than those which were effective in our patients. Malik and Ben-Shlomo presented a case of CPA treated with osilodrostat, with an immediate decrease in cortisol level at 4 mg/day and adrenal insufficiency symptoms after dose escalation to 8 mg/day.15 Similar to our two cases, their patient was a middle-aged female with normal results of all other adrenal parameters, such as renin, angiotensin, or metanephrine levels. However, a CT scan was not performed (or presented), while magnetic resonance imaging revealed an indeterminate adrenal gland mass without a typical contrast phase/out-of-phase dropout for adenoma.15 Therefore, different morphology of cortisol-secreting adrenal tumor can potentially be considered a reason of the different response to treatment. Tanaka et al performed a multicenter study on the efficacy and safety of osilodrostat in Japanese patients with non-CD Cushing’s syndrome.16 Five patients with CPA were included in the study, and none of them required osilodrostat doses higher than 10 mg/day to achieve UFC normalization. However, most of the patients presented by Tanaka et al were previously treated with metyrapone,16 whereas both of our patients were treatment-naive. Previous metyrapone therapy may be considered as a potential reason of better response to osilodrostat. This hypothesis was confirmed in the quoted study by Tanaka et al, who demonstrated that at week 12 the median percent changes in the mUFC values were higher in patients previously treated with metyrapone (–98.97%) than in treatment-naive cases (–86.65%).16 Detomas et al performed a comparison of efficacy and safety of osilodrostat and metyrapone, with one CPA patients included in a group treated with osilodrostat, however no data on a dose required for a disease control are available separately for this particular patient.8 To the best of our knowledge, no more CPA cases have been described and therefore no further comparison is available.

Higher doses of osilodrostat were administered to a group of seven patients with hypercortisolism due to adrenocortical carcinoma (ACC) presented by Tabarin et al.17 A full control of hypercortisolism was achieved in one patient for each dose of 4, 8, 10, and 20 mg/day, and in three patients treated with 40 mg/day.17 These patients, however received other therapies including mitotane and chemotherapy, which can significantly modify the response to osilodrostat.

Several authors have reported the phenomenon of a partial or total loss of response to osilodrostat.5,16,17 In such cases, a response to treatment was initially achieved and then lost during treatment with the same dose. A further increase in osilodrostat dose usually resulted in the response resumption.5,16,17 Such a situation could not be suspected in either of our cases.

The presented cases provide a novel insight into modalities of treatment with osilodrostat in patients with CPA and demonstrate for the first time that an inverse cortisol response is possible in CPA cases, especially those with a higher CT density of adrenal adenoma. Such a situation should not be considered a contraindication to dose escalation. Conversely, the dose should be increased more intensively so as to achieve the initial efficacy threshold, which was 20 mg/day in both of our patients. The fully efficient dose that allowed UFC normalization was more than twice as high (45 mg/day in both cases). A similar approach should be applied in patients who do not respond to lower doses, such as Patient 2. The safety of osilodrostat therapy is strictly individual and not dose dependent in patients with CPA. Adverse events, including hypokalemia, severe hypertension, and edema, can be of life-threatening severity or may not occur regardless of the dose. Moreover, AEs of high severity may decrease with osilodrostat dose escalation. Our study demonstrated that osilodrostat is efficient and can be used in patients with CPA as a pre-surgical therapy if surgery is contraindicated due to hypercortisolism complications.

Our study presented two cases of CPA treated with osilodrostat, and a small size of our group is the main limitation of this report. Future research is required to confirm our observations.

Conclusion

In some patients with CPA, the doses of osilodrostat required for disease control can be much higher than those previously reported. Acceleration of the dose increase can be fast, and the risk of overdosing, adrenal insufficiency, and later necessity of dose reduction seem to be much lower than it could be expected. Low initial doses (<20 mg/day in our study) can be entirely ineffective or can even cause exacerbation of hypercortisolism, whereas high doses (45 mg/day in the present study) are efficient in pre-surgery UFC normalization. AEs associated with osilodrostat can be rapid, with severe hypokalemia despite active potassium supplementation, or may not occur even if high doses of osilodrostat are applied. Therefore, close monitoring for potential AEs is necessary.

Acknowledgments

The abstract included some parts of this paper was presented at the European Congress of Endocrinology ECE2023 as a rapid communication. The abstract was published in the Endocrine Abstracts Vol. 90 [https://www.endocrine-abstracts.org/ea/0090/].

Funding

The publication of this report was financially supported by the statutory funds of the Polish Mother’s Memorial Hospital – Research Institute, Lodz, Poland.

Disclosure

Professor Przemysław Witek reports personal fees from Investigator in the clinical trials paid by Novartis and Recordati Rare Diseases, outside the submitted work; lectures fees from Recordati Rare Diseases, Strongbridge, IPSEN. The authors report no other conflicts of interest in this work.

References

1. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847–875. doi:10.1016/S2213-8587(21)00235-7

2. Pivonello R, Isidori AM, De Martino MC, et al. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4(7):611–629. doi:10.1016/S2213-8587(16)00086-3

3. 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):48–761. doi:10.1016/S2213-8587(20)30240-0

4. 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. doi:10.1530/EJE-22-0317

5. Fleseriu M, Biller BMK, Bertherat J, et al. Long-term efficacy and safety of osilodrostat in Cushing’s disease: final results from a Phase II study with an optional extension phase (LINC 2). Pituitary. 2022;25(6):959–970. doi:10.1007/s11102-022-01280-6

6. 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. doi:10.1210/clinem/dgac178

7. Daniel E, Aylwin S, Mustafa O, et al. Effectiveness of metyrapone in treating cushing’s syndrome: a retrospective multicenter study in 195 patients. J Clin Endocrinol Metab. 2015;100(11):4146–4154. doi:10.1210/jc.2015-2616

8. Detomas M, Altieri B, Deutschbein T, et al. Metyrapone versus osilodrostat in the short-term therapy of endogenous cushing’s syndrome: results from a single center cohort study. Front Endocrinol. 2022;13:903545. doi:10.3389/fendo.2022.903545

9. U.S. food and drug administration home page. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-cushings-disease. Accessed March 22, 2023.

10. Agency for health technology assessment and tariff system home page. Available from: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwj6ypGbsfT9AhUMzYsKHTgAD2EQFnoECA8QAQ&url=https%3A%2F%2Fbipold.aotm.gov.pl%2Fassets%2Ffiles%2Fwykaz_tli%2FRAPORTY%2F2020_010.pdf&usg=AOvVaw3P2Q85gwi3JcxKkW3uxfOb. Accessed March 22, 2022.

11. Dzialach L, Sobolewska J, Respondek W, et al. Cushing’s syndrome: a combined treatment with etomidate and osilodrostat in severe life-threatening hypercortisolemia. Hormones. 2022;21(4):735–742. doi:10.1007/s42000-022-00397-4

12. Ekladios C, Khoury J, Mehr S, et al. Osilodrostat-induced adrenal insufficiency in a patient with Cushing’s disease. Clin Case Rep. 2022;10(11):e6607. doi:10.1002/ccr3.6607

13. Fleseriu M, Biller BMK. Treatment of Cushing’s syndrome with osilodrostat: practical applications of recent studies with case examples. Pituitary. 2022;25(6):795–809. doi:10.1007/s11102-022-01268-2

14. Summary of product characteristics. Available from: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwim1_KdsvT9AhVq-ioKHUZKAc4QFnoECA4QAQ&url=https%3A%2F%2Fwww.ema.europa.eu%2Fen%2Fdocuments%2Fproduct-information%2Fisturisa-epar-product-information_pl.pdf&usg=AOvVaw0S8nayCTdqNh1LsEcXVLEu. Accessed March 24, 2023.

15. Malik RB, Ben-Shlomo A. Adrenal cushing’s syndrome treated with preoperative osilodrostat and adrenalectomy. AACE Clin Case Rep. 2022;8(6):267–270. doi:10.1016/j.aace.2022.10.001

16. 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. doi:10.1507/endocrj.EJ19-0617

17. 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. doi:10.1530/EJE-21-1008

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Hiding In Plain Sight: Florid Cushing’s Disease Presenting As A Severe Extremity Cellulitis

Posted on April 12, 2024 by MaryO

Abstract

Disclosure: C.M. Godar: None. E.B. Noble: None. N.O. Vietor: None. T.S. Knee: None.

Background: Cushing’s syndrome may rarely present as an emergency known as Florid Cushing’s Syndrome. Patients can exhibit severe hyperglycemia, hypertension, hypokalemia, infections, and hypercoagulability. Cushing’s syndrome is a rare disease, and the constellation of clinical features can be overlooked if clinicians are not aware of the manifestations of hypercortisolism. We present the case of a patient with Cushing’s syndrome that went unrecognized with life-threatening sequelae.

Case presentation: A 52-year-old woman with well-controlled type 2 diabetes and hypertension was admitted to the hospital for severe left lower extremity cellulitis. Prior to hospitalization she had noted rapid weight gain, fatigue, weakness, mental clouding, and moodiness. She was admitted for antibiotics and surgical debridement. The infection persisted despite broad spectrum antibiotics, multiple surgical debridements, and skin grafting. She became bacteremic, and extremity amputation was considered. She additionally developed hypertensive emergency, refractory hypokalemia, and hyperglycemia to 396 mg/dL. Exam was notable for facial plethora, supraclavicular fullness, dorsocervical fat pad, and violaceous abdominal striae. Cushing’s Syndrome was suspected, and labs revealed a significantly elevated random serum cortisol of 60.5mcg/dL (Ref 6.2-19.4), significantly elevated 24H urine cortisol of 2157mcg/24H (Ref 0-50), and ACTH elevated to 81.8pg/mL (Ref 7.2-63.3) that confirmed Cushing’s Disease. MRI sella and octreotide scans did not localize a lesion. Inpatient therapy included multiple antihypertensive agents, insulin drip, aggressive potassium repletion, and initiation of ketoconazole to reduce cortisol levels. Ketoconazole was maximally dosed and she underwent surgical exploration and removal of a small pituitary microadenoma. Following surgery, she developed transient adrenal insufficiency requiring hydrocortisone and she no longer required antihypertensives, insulin, or potassium therapy. Follow up 7 years later has revealed no recurrence of Cushing’s Disease.

Discussion: Cushing’s Syndrome may present with a variety of clinical features and rarely may present as a medical emergency. Delay in diagnosis can lead to Florid Cushing’s Syndrome which carries high risk for morbidity and mortality. This case illustrates the need for clinician awareness of the features of Cushing’s Syndrome: hypertension, hyperglycemia, rapid weight gain, cushingoid exam features, hypokalemia, hirsutism, virilization, infection, and/or hypercoagulable state. Severe hypercortisolism was responsible for this patient’s refractory infection, and if not controlled, she likely would have endured a lower extremity amputation. Rapid detection with elevated random serum and/or urine cortisol and treatment with a cortisol-lowering agent is critical and lifesaving.

Presentation: Thursday, June 15, 2023

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Long-Term Efficacy and Safety of Subcutaneous Pasireotide Alone or In Combination With Cabergoline in Cushing’s Disease

Posted on November 13, 2023 by MaryO

Objective: This study evaluated short- and long-term efficacy and safety of the second-generation somatostatin receptor ligand pasireotide alone or in combination with dopamine agonist cabergoline in patients with Cushing’s disease (CD).

Study design: This is an open-label, multicenter, non-comparative, Phase II study comprising 35-week core phase and an optional extension phase. All patients started with pasireotide, and cabergoline was added if cortisol remained elevated. Eligible patients had active CD, with or without prior surgery, were pasireotide naïve at screening or had discontinued pasireotide for reasons other than safety. Primary endpoint was proportion of patients with a mean urinary free cortisol (mUFC) level not exceeding the upper limit of normal (ULN) at week 35 with missing data imputed using last available post-baseline assessments.

Results: Of 68 patients enrolled, 26 (38.2%) received pasireotide monotherapy and 42 (61.8%) received pasireotide plus cabergoline during the core phase. Thirty-four patients (50.0%; 95% CI 37.6–62.4) achieved the primary endpoint, of whom 17 (50.0%) received pasireotide monotherapy and 17 (50.0%) received combination therapy. Proportion of patients with mUFC control remained stable during the extension phase up to week 99. Treatment with either mono or combination therapy provided sustained improvements in clinical symptoms of hypercortisolism up to week 99. Hyperglycemia and nausea (51.5% each), diarrhea (44.1%) and cholelithiasis (33.8%) were the most frequent adverse events.

Conclusion: Addition of cabergoline in patients with persistently elevated mUFC on maximum tolerated doses of pasireotide is an effective and well-tolerated long-term strategy for enhancing control of hypercortisolism in some CD patients.

Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01915303, identifier NCT01915303.

1 Introduction

Cushing’s disease (CD) is a rare condition arising from chronic overproduction of cortisol, secondary to an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor (1). Untreated hypercortisolism results in substantial multisystem morbidity, impaired quality of life (QoL) and premature mortality (1–4).

Pasireotide is a second-generation, multireceptor-targeted somatostatin receptor ligand (SRLs), with affinity for 4 of the 5 known somatostatin receptor subtypes (SSTRs) (5) and is approved for the treatment of patients with CD for whom surgery has failed or is not an option (6). Phase III trials of pasireotide monotherapy have shown sustained biochemical and clinical benefits up to 5 years (6–9). These benefits are also reflected in real-world evidence (10).

Cabergoline, a potent dopamine agonist with high affinity for dopamine type 2 receptors (D2), is commonly used off-label for the treatment of CD (2). Small, retrospective, non-randomized studies have demonstrated long-term urinary free cortisol (UFC) control (24−;60 months) in 23−;40% of patients with CD, especially those with mild hypercortisolism (11–13). A meta-analysis of individual patient data from six observational studies (n=124) reported normalization of mean UFC (mUFC) levels in 34% of patients (14, 15). However, a short prospective study on cabergoline monotherapy showed a limited value in controlling UFC, possibly linked to short duration (16). As most corticotropinomas co­express SSTR5 and D2, combining pasireotide and cabergoline in a stepwise approach could potentially improve efficacy with achieving more rapid biochemical control (17), a premise supported by results from an 80-day pilot study of 17 patients with CD treated with cabergoline- pasireotide combination, and low-dose ketoconazole (in case of lack of complete control with the two-drug combination) (18).

The current study aims to report the efficacy and safety of prolonged treatment with pasireotide alone or in combination with cabergoline from the largest prospective, multicentre study to date of a pituitary-targeting combination treatment regimen in patients with CD (NCT01915303).

2 Materials and methods

2.1 Patients

Adults (≥18 years) with a confirmed diagnosis of CD or de novo CD, if they were not candidates for surgery or refused surgery were enrolled. Cushing’s disease was defined by a mean 24-hour (24h) UFC level greater than the upper limit of normal (ULN, 137.95 nmol/24h), calculated from three 24h samples collected within 2 weeks; a morning plasma ACTH level within or above the normal range; and a confirmed pituitary source of Cushing’s syndrome, determined by MRI confirmation of pituitary adenoma >6mm or inferior petrosal sinus sampling (IPSS) gradient >3 after CRH stimulation (or >2 if IPSS without CRH stimulation) for those patients with a tumor ≤6mm. For patients who had prior pituitary surgery, histopathology confirming an ACTH staining adenoma was considered confirmatory of CD. Key exclusion criteria included optic chiasm compression requiring surgery, poorly controlled diabetes (glycated hemoglobin [HbA1c] >8%) and having risk factors for torsades de pointes (for further details, see the Supplementary Appendix).

2.2 Study design

This was a single-arm, open-label, multicenter, non-comparative, Phase II study. After 4 weeks of screening, patients were treated in a stepwise approach during the core phase. Patients received subcutaneous pasireotide 0.6 mg twice daily (bid) for 8 weeks. Patients with a mUFC level exceeding ULN after 8 weeks received pasireotide 0.9 mg bid for another 8 weeks. If mUFC level remained elevated with pasireotide 0.9 mg bid, oral cabergoline 0.5 mg once daily (qd) was added for 8 weeks and could be increased to 1.0 mg qd for another 8 weeks (Supplementary Figure S1). After 35 weeks of treatment in the core phase, patients could enter the extension phase of the trial. Addition or titration of cabergoline during the extension phase was at the discretion of investigators.

Collection of extension data commenced from week 43, and patients continued their current study treatment up to study end (4 September 2019; date of last patient visit), week 257. Data beyond week 99 are not reported here because of small patient numbers.

2.3 End points and assessments

The primary endpoint of the study was the proportion of patients with mUFC ≤ULN at week 35. Secondary endpoints (reported at 4-week intervals up to week 35 and 8-week intervals from week 43 to the date of the last patient visit) included changes from baseline in mUFC, plasma ACTH, serum cortisol, total cholesterol, and clinical signs (systolic/diastolic blood pressure, body mass index (BMI), weight, waist circumference, facial rubor, hirsutism, striae, supraclavicular and dorsal fat pads) and symptoms (CushingQoL). Treatment escape was defined as an increase in one UFC above the normal range during follow-up of complete responders (14). Cushing Quality of Life Questionnaire (CushingQoL) (19) scores were reported up to week 35 only. Details on the safety assessments are provided in the Supplementary Appendix.

2.4 Statistical analyses

No formal hypothesis testing was performed because of the exploratory design of the study. Efficacy analyses were conducted on full analysis set, i.e., all patients to whom study treatment was assigned. Safety analyses were conducted on all patients who received ≥1 dose of pasireotide per day during the study. For patients with missing mUFC value at week 35, including those who discontinued, the last available assessment was carried forward. Details on the post hoc analyses and sample size estimation is provided in the Supplementary Appendix. Enrolled patients, who were observed for failed inclusion or exclusion criteria during the monitoring visits, were classified under protocol deviation. However, patients with no safety concerns were allowed to continue in the study and included in the full analysis set as intention to treat – assessing the study outcome, while some patients were excluded from the per protocol analysis.

3 Results

3.1 Study population

A total of 68 patients were enrolled in the study. At baseline, 66 (97.1%) patients were pasireotide naïve, while 2 (2.9%) were treated with pasireotide previously with 4 weeks of washout period prior to screening (Table 1). Of 68 patients received treatment during the core phase, 26 (38.2%) received pasireotide monotherapy and 42 (61.8%) received combination therapy. Fifty-two (76.5%) patients completed the 35-week core phase while 16 (23.5%) discontinued (Figure 1). All 68 patients were included in the full analysis set based on the intention to treat (ITT) principle. One of the protocol deviations observed during the study, was inclusion of 3 patients with normal mUFC value at screening visit (baseline) and assigning a treatment. The deviation category for the 3 patients was ‘failed inclusion criteria’ with screening mUFC value ≤ULN (137.95 nmol/24h) or mUFC calculated using ❤ UFC values or 2 out of 3 UFC values ≤ULN. One of these patients (baseline mUFC 37.37 nmol/24h ≤ULN) was discontinued from the study at Week 2 and due to lack of post-baseline mUFC assessment, was classified ‘non-responder’ at Week 35 assessment. The 2nd patient’s baseline mUFC value of 135.20 nmol/24h was close to ULN (137.95 nmol/24h) and was rescreened. Based on the rescreened mUFC value 306.5 nmol/24h, this patient was included in study, and the mUFC at Week 35 was 192.30 nmol/24h (non-responder at Week 35 assessment). For all study assessments, the scheduled screening visit’s first mUFC value (≤ULN) was used as baseline value. The 3rd patient (baseline mUFC value 131.77 nmol/24h) was discontinued from the study at Week 26 and was also observed for non-compliant schedule visit and medication dosages. The mUFC value recorded at Week 26 (88.95 nmol/24h) was ≤ULN and this last observation was carried forward to Week 35. Hence, the patient was classified ‘responder’, leaving one patient included in the study as responder as a protocol deviation.

Table 1
www.frontiersin.orgTable 1 Patient demographics and baseline characteristics.

Figure 1
www.frontiersin.orgFigure 1 Patient disposition. *If the study drugs were locally available at the end of the core phase, patients could switch over to the commercial supply and exit the extension phase. Only in countries where the drug was not locally available were patients given the option to enter the extension phase. Percentage for patients not entering the extension phase was calculated from the total number of patients enrolled in the study.

Twenty-nine (42.6%) patients continued treatment in the extension phase; 10 (34.5%) received pasireotide monotherapy and 19 (65.5%) received combination therapy. Twelve (41.4%) patients completed the extension phase, while 17 (58.6%) discontinued treatment before study end, most commonly for unsatisfactory therapeutic effect (n=8). The most common reason for discontinuation was adverse events (AEs): 5 (17.2%) patients with pasireotide monotherapy and 2 (5.1%) patients with combination therapy.

3.2 Efficacy: biochemical response

Overall, 34/68 (50.0%; 95% CI 37.6–62.4) patients achieved the primary endpoint, of whom 17 (50.0%) were receiving pasireotide monotherapy and 17 (50.0%) were receiving combination therapy. Patients with mild hypercortisolism (mUFC 1.0–<2.0 x ULN) at baseline were more likely to respond to both pasireotide monotherapy and combination therapy (n=15; 22.1%, Figure 2). Seven of 17 patients in the pasireotide monotherapy group met the primary endpoint based on their last available assessment prior to week 35. Even if the 3 patients who had mUFC ≤ULN at baseline were excluded from the primary analysis, 33/65 (50.7%; 95% CI 38.1–63.4) patients would have achieved the primary endpoint. The results are similar to the original analysis (34/68 (50.0%; 95% CI 37.6–62.4) based on the full analysis set.

Figure 2
www.frontiersin.orgFigure 2 Patients achieving mUFC ≤ULN at week 35. †At baseline there were 23 patients with mild, 30 with moderate and 12 with severe hypercortisolism. mUFC, mean urine free cortisol; ULN, upper limit of normal.

For the overall study population (n=68), mUFC rapidly decreased from 501.6 nmol/24h (3.6 x ULN; SD: 488.66 nmol/24h) to 242.1 nmol/24h (1.8 x ULN; SD: 203.47 nmol/24h) at week 4 and mUFC remained below baseline levels up to week 35 (184.8 nmol/24h; 1.3 x ULN; SD:140.13 nmol/24h). For patients who received pasireotide monotherapy (n=26), mUFC( ± SD) decreased from baseline (442.1± 557.13 nmol/24h [n=26]; 3.2 x ULN) to week 35 (136.6 ± 127.77 nmol/24h [n=14]; 1 x ULN) and at the end of the study (111.2 ± 40.39 nmol/24h [n=5]; 0.8 x ULN) using the last-observation-carried-forward (LOCF). For those who did not normalize on pasireotide monotherapy (n=42), mUFC ( ± SD) decreased from baseline, i.e., last observation before starting cabergoline (280.20 ± 129.03 nmol/24h [n=40]; 2.0 x ULN) to week 35 (206.6 ± 141.96 nmol/24h [n=31]; 1.5 x ULN) and at the end of the study (219.60 ± 83.78 nmol/24h [n=7]; 1.6 x ULN) using the LOCF. During the core phase, mean serum cortisol decreased from 738.6 nmol/L (1.3 x ULN) at baseline to 538.2 nmol/L (0.95 x ULN) and ACTH levels from 16.3 pmol/L (2.7 x ULN) to 11.0 pmol/L (1.8 x ULN) at week 35.

During the extension phase, 25 patients had a mUFC assessment; of whom 12 (48%) had a mUFC ≤ULN at the end of the extension phase. During the extension phase, mUFC levels decreased slightly and fluctuated above and below the ULN up to the week 139 (Figure 3A), while mean serum cortisol remained below ULN (404 nmol/L; Figure 3B) and ACTH levels fluctuated from 8.2 pmol/L to 11.5 pmol/L) and remained above the ULN value (Figure 3C).

Figure 3
www.frontiersin.orgFigure 3 Mean actual change over time in (A) mUFC (B) serum cortisol, and (C) ACTH. ACTH, adrenocorticotropic hormone; mUFC, mean urine free cortisol; ULN, upper limit of normal .

Twenty-one of 38 (55%) patients achieved control with combination therapy at some point during the core or extension study, of whom 13 (62%) experienced escape (at least one UFC >ULN after previous control). The time to achieve control after starting cabergoline ranged from 14−;343 days. Notably, one patient received pasireotide 0.6 mg bid initially, dose increased to 0.9 mg bid at Week 17, followed by addition of cabergoline 0.5 mg od at Week 31. The patient achieved biochemical control (mUFC value of 120.15 nmol/24h) on the same day of the start of combination therapy. Clinically it is highly unlikely that biochemical control was achieved with single dose of cabergoline administration. Therefore, it could be considered that normalization was achieved while receiving pasireotide monotherapy. Also, the physician might have prescribed combination therapy before receiving the mUFC value of the (urinary) sample delivered on the morning of combination therapy initiation (while the patient was still on monotherapy). The patient continued combination therapy and maintained biochemical control up to Week 35 and beyond. Furthermore, at Week 59 the cabergoline dose was increased to 1.0 mg/day due to mUFC >ULN at previous visit (Week 51). The patient remained on pasireotide 0.9 mg bid/cabergoline 1.0 mg od combination therapy until the study end.

The median time to escape after achieving control with the addition of cabergoline was 58 days (range 28−;344). 10/13patients regained biochemical control with combination therapy. No patients on pasireotide alone experienced escape, probably due to the short observation time.

3.3 Clinical signs and symptoms of CD

Relative to baseline, pasireotide monotherapy was accompanied by reductions in median blood pressure, weight, BMI, waist circumference, and total cholesterol. Overall improvement in clinical measures persisted over time (Supplementary Table S1). Clinical improvements were also seen following the addition of cabergoline, particularly for hirsutism (Supplementary Figures S2, S3).

Mean( ± SD) standardized CushingQoL score was 41.6(± 20.2) at baseline and increased to 47.6(± 20.8) at week 35 (Supplementary Table S2), indicating improvements in patients’ QoL (19).

3.4 Safety and tolerability

Median duration of exposure to pasireotide was 35.0 weeks (range 0−;268), with a median dose of 1.53 mg/day (range 0.29−;1.80). Median duration of exposure to cabergoline was 16.9 weeks (range 1−;215), with a median dose of 0.50 mg/day (range 0.44−;0.97).

All patients (N=68) reported at least one AE and 28/68 (41.2%) patients had a grade 3/4 AE (Table 2). The most common AEs (≥30%) were hyperglycemia and nausea (51.5% each), diarrhea (44.1%) and cholelithiasis (33.8%). Treatment-related AEs (TRAEs) were reported in 66/68 (97.1%) patients; the most frequent TRAEs (≥30%) were hyperglycemia and nausea (47.1% each), diarrhea (39.7%), and cholelithiasis (32.4%). Fourteen (20.6%) patients had ≥1 AE leading to discontinuation.

Table 2
www.frontiersin.orgTable 2 Summary of adverse events (≥10%), overall and by treatment regimen.

The most common AEs leading to discontinuation were increased gamma-glutamyl transferase (GGT) and hyperglycemia (two patients each, 2.9%). Twenty-three (33.8%) patients had ≥1 AE leading to dose adjustment or interruption. Details on special safety assessments such as hyperglycemia-related AEs, blood glucose, HbA1c, IGF-1 as well as hematological and biochemical abnormalities are presented in the Supplementary Appendix.

Three (4.4%) patients died during the study, two (2.9%) during the core phase and one (1.5%) during the extension. All deaths were considered unrelated to study medication. The causes during the core phase were multi-organ dysfunction syndrome for one patient aged 79 years and unknown for the other aged 34 years. Uncontrolled hypertension was reported as the cause of death for the patient aged 47 during the extension phase.

4 Discussion

The severe morbidity and increased mortality with uncontrolled CD highlight the importance of identifying an effective medical strategy. This study explored the potential of a synergistic benefit of the addition of cabergoline to pasireotide treatment in patients with CD.

Complete normalization of cortisol production is required to reverse the risks of morbidity and mortality in patients with CD (1). Two small studies showed clinical improvement of normalized UFC when cabergoline and ketoconazole were combined (20, 21). Benefit has also been reported with triple therapy with pasireotide, cabergoline and ketoconazole (18) and triple therapy with ketoconazole, metyrapone and mitotane in severe CD (22). In the current study, 50% of patients achieved the primary endpoint of mUFC ≤ULN at week 35 and a similar proportion (48%) sustained biochemical control throughout the extension phase. Notably, combination treatment doubled the number of patients who attained mUFC ≤ULN from the core phase to the end of the extension phase. In particular, mUFC was rapidly reduced with treatment, i.e., in most patients within 2 months, while measures of patient-reported outcomes also improved including QoL. Twenty-three patients (33.8%) who completed the core phase did not enter the extension phase. This was because only patients from countries where a commercial supply was unavailable were given the option to enter the extension phase.

This study confirms previous reports that patients with mild hypercortisolism at baseline were more likely to achieve mUFC control with pasireotide monotherapy than patients with moderate or severe hypercortisolism (6, 23). In addition, patients with moderate hypercortisolism at baseline were more likely to achieve mUFC control with the addition of cabergoline. This supports that a combination therapy can be effective for patients with a wider range of disease severity. Accordingly, in vitro data may indeed indicate synergism between SSTR and D2 that might increase therapeutic efficacy (24, 25).

Improvements in clinical signs and symptoms with pasireotide monotherapy were consistent with published data (6, 10). In the core phase, an improvement of blood pressure and BMI was observed with pasireotide monotherapy and, to a lesser extent, with combination therapy which may related to the difference in duration of biochemical remission.

The overall safety profile was consistent with that expected for pasireotide, with most AEs being mild/moderate (26, 27). There were no new safety signals identified with the addition of cabergoline. Common AEs including nausea, headache, dizziness, and fatigue are suggestive of steroid withdrawal symptoms associated with the decrease in UFC, although direct drug effects cannot fully be excluded. Adrenal insufficiency was not reported as side effect. Rates of hyperglycemia-related AEs (68%) were consistent with those in previous reports of pasireotide monotherapy (6, 10). FPG increased with pasireotide monotherapy during the first 8 weeks of treatment and stabilized for the remainder of the study, including following the addition of cabergoline. These data highlight the vital role of blood glucose monitoring in these patients.

Both pasireotide and cabergoline are pituitary-targeted agents that act directly on the source of the disease via inhibition of ACTH release by the corticotroph tumor, which may be an advantage over steroid synthesis inhibitors. This study further confirms previous data reporting the benefits of pasireotide in combination with cabergoline in patients with CD (18). While not entirely elucidated, down-regulation of dopamine D2 receptors (D2R) expression, and post-receptor desensitization and/or tumor regrowth of corticotroph tumor cell were suggested as possible mechanisms for treatment escape (15). Moreover, different dopamine receptor patterns and/or D2R isoforms also influence the response and eventually the treatment escape. Treatment escape has been observed in some studies after long-term (7−;12 months) treatment with cabergoline (13), however it is possible that use of concomitant SRLs could potentially reduce the rate of escape. In this study, a total of 13 patients experienced treatment escape. However, 10 of these patients regained biochemical control. For 7 of these 10 patients, there was up titration of doses to a maximum of 1.8 mg/day of pasireotide and 1 mg/day of cabergolineAlthough pasireotide and cabergoline have shown long-term reduction in IGF-1 levels in patients with acromegaly (28, 29), there is little evidence for this effect in patients with CD (4, 30). One study (n=17) found significant decreases in IGF-1 after 28 days’ treatment with pasireotide that was independent of UFC reduction. One-third of patients had low IGF-1 (30). Our study showed that almost half of patients (47.6%) had IGF-1 levels either above ULN or below LLN prior to the addition of cabergoline, and IGF-1 levels decreased relative to the baseline, with majority of values within the normal range during the core and extension phases up to week 99. Baseline levels of IGF-1 may already be low because of the suppressive effect of excess cortisol on the somatotropic axis (31).

Although clinicians have several therapeutic options at their disposal to treat hypercortisolemia associated with CD, the optimal treatment approach should be based on the individual clinical situation and the benefit–risk considerations for each patient. In this study, 13 patients had history of pituitary radiation, with a duration of at least 2.6 years (median 3.3 years) between the last radiation treatment and the observed response date. However, only 7/13 patients achieved the therapeutic target. Although there was a gap of > 2 years, we cannot exclude the role of radiation in normalizing UFC. Contrastingly, 6/13 patients treated with radiation did not achieve mUFC ≤ULN (responders) at Week 35. The impact of the adjuvant radiation therapy remains unclear.

The strengths of this study are that this is the largest and longest prospective study with pituitary-directed pharmacotherapy, to date, evaluating the addition of cabergoline to pasireotide in patients with CD, and this stepwise approach reflects real-world clinical practice (18). The study is limited by the open-label design and the fact that it was not a head-to-head comparative study of pasireotide only versus pasireotide plus cabergoline. This may be of importance in interpreting patient-reported outcomes. Several patients continued treatment for almost 2 years; however, interpretation of long-term data should be made with caution because of the small patient numbers. Notably, the last available assessment was carried forward for patients with missing mUFC value at week 35 including those who discontinued and were considered for response analysis. It should also be noted that the definition of loss of response, also known as escape, used in this study (at least one UFC value >ULN after previously achieving UFC ≤ULN) may overestimate the rate of apparent escape as UFC values may have fluctuated about the ULN range or been marginally elevated. The definition of treatment escape differs across studies, and we have used a very stringent one in this study, requiring only a single high UFC to meet the classification as escape. Thus, it is likely that some loss of biochemical control interpreted as escape is actually fluctuation of cortisol around the upper limit of normal range.

Other limitations include protocol deviations in including 3 patients with normal UFC at baseline (one patient was uncontrolled at rescreen, and one was discontinued at 2 weeks – both classified as

non-responders), lack of data on impact of radiation therapy without study drug in patients who gained biochemical control with adjuvant radiation therapy, lack of pituitary magnetic resonance imaging to detect pituitary tumor changes, lack of data about effective cabergoline dose and absence of cardiac valve assessment for mild to moderate severity in the medium term. Both pasireotide and cabergoline can induce tumor shrinkage in CD (6, 9, 32–35) and it would be interesting to examine the combined effect on tumor size. This study used the subcutaneous formulation of pasireotide, whereas the most common usage currently is the long-acting formulation. Efficacy of long-acting pasireotide (36) seems higher compared to the subcutaneous formulation (7) and the effect of combination of long-acting pasireotide with cabergoline should be evaluated in future studies. No formal assessments were made for impulsive control disorders, which have been associated with dopamine agonists, including cabergoline (32, 33, 37, 38). The reason that several different terms were used for hyperglycemia-related AEs is that they were reported as per discretion of each investigator. No additional psychiatric AEs were reported, although they were not exhaustively searched.

5 Conclusions

This is the first study demonstrating that pituitary-targeted combination treatment with pasireotide and cabergoline doubled the number of patients who attained mUFC ≤ULN. Both short- and long-term safety profile are consistent with known data for pasireotide and cabergoline. The low rate of discontinuation due to AEs suggests that pasireotide alone or as combination treatment is generally well-tolerated if appropriately monitored, even with prolonged treatment. The addition of cabergoline to pasireotide treatment in patients with persistently elevated mUFC could be an effective long-term strategy for enhancing the control of CD in a subset of patients, with close monitoring for possible escape.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by Hospital Britanico, Buenos Aires, Argentina; Ethische commissie University Hospitals Leuven, Leuven, Belgium; Universitair Ziekenhuis Gent, Gent, Belgium; Comite de Etica em Pesquisa Hospital Moinhos de Vento, Porto Alegre-RS, Brazil; Comitê de Ética em Pesquisa do Hospital de Clı́nicas, Universidade Federal do Paraná, Curitiba-PR, Brazil; Comissão de Ética para Análise de Projetos de Pesquisa, São Paulo – SP, Brazil; Ethics Committee for clinical trials, Sofia, Bulgaria; Comité Corporativo de Ética en Investigación, Bogotá DC, Colombia; Comite De Protection Des Personnes, Groupe Hospitalier Pellegrin – Bat, Bordeaux Cedex, France; Friedrich-Alexander Universitat Erlangen-Nurnberg, Medizinische Fakultat, Erlangen, Germany;National Ethics Committee, Cholargos, Athens, Greece; Ethics Committee for Clinical Pharmacology (ECCP), Budapest, Hungary; Institute Ethics Committee, New Delhi, India; Institutional Review Board (IRB) Ethics Committee Silver, Christian Medical College, Vellore, Tamil Nadu, India; Institute Ethics Committee, PGIMER, Chandigarh, India; Comitato Etico Dell’irccs Istituto Auxologico Italiano Di Milano, Milano, Italy; Comitato Etico Universita’ Federico Ii Di Napoli, Napoli, Italy; Jawatankuasa Etika & Penyelidikan Perubatan (Medical Research and Ethics Committee), d/a Institut Pengurusan Keshatan Jalan Rumah Sakit, Kuala Lumpur, Malaysia; Institutd Nacional De Neurologia Y Neurocirugia, Mexico City, Mexico; Clinica Bajio (CLINBA), Guanajuato, Mexico; Medische Ethische Toetsings Commissie, Rotterdam; Netherlands; CEIm Provincial de Málaga, Málaga, Spain; Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey; WIRB, Puyallup, WA, USA; Research Integrity Office, Oregon Health & Science University Portland, OR USA. The studies were conducted in accordance with local legislations and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

All authors directly participated in the planning, execution, or analysis, and have had full control of complete primary data, and hold responsibility for data integrity and accuracy. All authors contributed to the article and approved the submitted version.

Acknowledgments

We thank Julie Brown, Mudskipper Business Ltd, and Manojkumar Patel and Sashi Kiran Goteti, Novartis Healthcare Private Limited, for medical editorial assistance with this manuscript. We would also like to thank all investigators, sub-investigators, study nurses and coordinators, and patients who have made this study possible.

Conflict of interest

HP and RM were Novartis employees and owned Novartis stocks. AMP was employed by Novartis and Recordati. AC is a Novartis employee and owns Novartis stocks. RF received research grants from Strongbridge and Corcept, consulting fee from Recordati, honoraria and financial support for meetings and/or travel from HRA Pharma and Recordati, and attended advisory boards for Recordati. MF has received research support to Oregon Health & Science University as a principal investigator from Recordati and Xeris Strongbridge and has performed occasional scientific consultancy for Recordati, HRA Pharma, Sparrow, and Xeris Strongbridge. PK attended advisory boards for Recordati. MB’s institution received consulting fee and attended advisory boards from Recordati. DG-D received research grants from Recordati Rare Disease and Bayer, consulting fee from Abbott-Lafrancol, Biotoscana, PTC lab, Glaxo/Helou, Recordati Rare Disease, and Bayer, honoraria from Valentech Pharma, Sanofi, and Bayer, travel grants from Recordati Rare Disease, advocacy groups and other leadership roles from Asociación Colombiana de Endocrinologia and Asociación Colombiana de Osteoporosis y Metabolismo, and other financial and non-financial interests include Asociacion Colombiana de Endocrinologia y Metabolismo, Hospital Universitario Fundación Santa Fé de Bogota, and Asociación Colombiana de Osteoporosis y Metabolismo. CB received research grants from Novartis and Recordati, and consulting and speaker fee from Novartis. BB served as the principal investigator for grants to Massachusetts General Hospital from Cortendo/Strongbridge Xeris, Millendo, and Novartis and has occasionally consulted for Cortendo/Strongbridge Xeris, HRA Pharma, Novartis Recordati, and Sparrow. RP and his institution received research grants and honoraria from Pfizer, Ipsen, Novartis, Merck Serono, IBSA Farmaceutici, Corcept, Shire, HRA Pharma, ICON, Covance, Neuroendocrine CAH, Camurus, Recordati, Janssen Cilag, and CMED Clinical Services, received consulting fee from Recordati Rare Disease, Organon Italia, Siunergos Pharma, Corcept, S&R Farmaceutici S.p.A., DAMOR Farmaceutici, and Pfizer, attended advisory boards from Crinetics Pharmaceuticals, Recordati Rare Disease, Pfizer, and HRA Pharma.

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

The authors declare that this study received funding from Novartis Pharma AG. Novartis was involved in the study design, analysis, interpretation of data, and providing financial support for medical editorial assistance of this article.

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.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1165681/full#supplementary-material

References

1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet (2015) 386(9996):913–27. doi: 10.1016/s0140-6736(14)61375-1

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Feelders RA, Newell-Price J, Pivonello R, Nieman LK, Hofland LJ, Lacroix A. Advances in the medical treatment of Cushing’s syndrome. Lancet Diabetes Endocrinol (2019) 7(4):300–12. doi: 10.1016/s2213-8587(18)30155-4

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Newell-Price J. Mortality in cushing disease. Nat Rev Endocrinol (2016) 12(9):502–3. doi: 10.1038/nrendo.2016.118

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol (2021) 9(12):847–75. doi: 10.1016/s2213-8587(21)00235-7

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Schmid HA. Pasireotide (SOM230): Development, mechanism of action and potential applications. Mol Cell Endocrinol (2008) 286(1):69–74. doi: 10.1016/j.mce.2007.09.006

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al. A 12-month Phase 3 study of pasireotide in Cushing’s disease. N Engl J Med (2012) 366(10):914–24. doi: 10.1056/NEJMoa1105743

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Lacroix A, Gu F, Gallardo W, Pivonello R, Yu Y, Witek P, et al. Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial. Lancet Diabetes Endocrinol (2018) 6(1):17–26. doi: 10.1016/s2213-8587(17)30326-1

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Fleseriu M, Petersenn S, Biller BMK, Kadioglu P, De Block C, T’Sjoen G, et al. Long-term efficacy and safety of once-monthly pasireotide in Cushing’s disease: A Phase III extension study. Clin Endocrinol (2019) 91(6):776–85. doi: 10.1111/cen.14081

CrossRef Full Text | Google Scholar

9. Petersenn S, Salgado LR, Schopohl J, Portocarrero-Ortiz L, Arnaldi G, Lacroix A, et al. Long-term treatment of Cushing’s disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial. Endocrine (2017) 57(1):156–65. doi: 10.1007/s12020-017-1316-3

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Fleseriu M, Iweha C, Salgado L, Mazzuco TL, Campigotto F, Maamari R, et al. Safety and efficacy of subcutaneous pasireotide in patients with Cushing’s disease: results from an open-label, multicenter, single-arm, multinational, expanded-access study. Original Res Front Endocrinol (Lausanne) (2019) 10:436. doi: 10.3389/fendo.2019.00436

CrossRef Full Text | Google Scholar

11. Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, et al. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab (2009) 94(1):223–30. doi: 10.1210/jc.2008-1533

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Godbout A, Manavela M, Danilowicz K, Beauregard H, Bruno OD, Lacroix A. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol (2010) 163(5):709–16. doi: 10.1530/eje-10-0382

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Ferriere A, Cortet C, Chanson P, Delemer B, Caron P, Chabre O, et al. Cabergoline for Cushing’s disease: a large retrospective multicenter study. Eur J Endocrinol (2017) 176(3):305–14. doi: 10.1530/eje-16-0662

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Palui R, Sahoo J, Kamalanathan S, Kar SS, Selvarajan S, Durgia H. Effect of cabergoline monotherapy in Cushing’s disease: an individual participant data meta-analysis. J Endocrinol Invest (2018) 41(12):1445–55. doi: 10.1007/s40618-018-0936-7

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Palui R, Sahoo J, Kamalanathan S, Kar SS, Selvarajan S, Durgia H. Correction to: Palui R, Sahoo J, Kamalanathan S, Kar SS, Selvarajan S, Durgia H. Effect of cabergoline monotherapy in Cushing’ disease: an individual participant data meta-analysis. J Endocrinol Invest. 2018; 41(12):1445-1455. Doi: 10.1007/s40618-018-0936-7. J Endocrinol Invest (2022) 45(4):899–900. doi: 10.1007/s40618-021-01723-0

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Burman P, Edén-Engström B, Ekman B, Karlsson FA, Schwarcz E, Wahlberg J. Limited value of cabergoline in Cushing’s disease: a prospective study of a 6-week treatment in 20 patients. Eur J Endocrinol (2016) 174(1):17–24. doi: 10.1530/eje-15-0807

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Colao A, Filippella M, Pivonello R, Di Somma C, Faggiano A, Lombardi G. Combined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumours. Eur J Endocrinol (2007) 156:S57–63. doi: 10.1530/eje.1.02348

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Feelders RA, de Bruin C, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR, et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N Engl J Med (2010) 362(19):1846–8. doi: 10.1056/NEJMc1000094

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, et al. Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. Eur J Endocrinol (2008) 158(5):623–30. doi: 10.1530/eje-07-0762

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Barbot M, Albiger N, Ceccato F, Zilio M, Frigo AC, Denaro L, et al. Combination therapy for Cushing’s disease: effectiveness of two schedules of treatment: should we start with cabergoline or ketoconazole? . Pituitary (2014) 17(2):109–17. doi: 10.1007/s11102-013-0475-3

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Vilar L, Naves LA, Azevedo MF, Arruda MJ, Arahata CM, Moura E, et al. Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary (2010) 13(2):123–9. doi: 10.1007/s11102-009-0209-8

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Kamenický P, Droumaguet C, Salenave S, Blanchard A, Jublanc C, Gautier JF, et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab. (2011) 96(9):2796–804. doi: 10.1210/jc.2011-0536

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Boscaro M, Ludlam WH, Atkinson B, Glusman JE, Petersenn S, Reincke M, et al. Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, Phase II trial. J Clin Endocrinol Metab (2009) 94(1):115–22. doi: 10.1210/jc.2008-1008

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Patel YC. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science (2000) 288(5463):154–7. doi: 10.1126/science.288.5463.154

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Baragli A, Alturaihi H, Watt HL, Abdallah A, Kumar U. Heterooligomerization of human dopamine receptor 2 and somatostatin receptor 2 Co-immunoprecipitation and fluorescence resonance energy transfer analysis. Cell Signal (2007) 19(11):2304–16. doi: 10.1016/j.cellsig.2007.07.007

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Pivonello R, Ferrigno R, De Martino MC, Simeoli C, Di Paola N, Pivonello C, et al. Medical treatment of Cushing’s disease: an overview of the current and recent clinical trials. Front Endocrinol (Lausanne) (2020) 11:648. doi: 10.3389/fendo.2020.00648

CrossRef Full Text | Google Scholar

27. Capatina C, Hinojosa-Amaya JM, Poiana C, Fleseriu M. Management of patients with persistent or recurrent Cushing’s disease after initial pituitary surgery. Expert Rev Endocrinol Metab (2020) 15(5):321–39. doi: 10.1080/17446651.2020.1802243

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Colao A, Bronstein MD, Brue T, De Marinis L, Fleseriu M, Guitelman M, et al. Pasireotide for acromegaly: long-term outcomes from an extension to the Phase III PAOLA study. Eur J Endocrinol (2020) 182(6):583. doi: 10.1530/EJE-19-0762

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Marazuela M, Ramos-Leví A, Sampedro-Núñez M, Bernabeu I. Cabergoline treatment in acromegaly: pros. Endocrine (2014) 46(2):215–9. doi: 10.1007/s12020-014-0206-1

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Varewijck AJ, Feelders RA, de Bruin C, Pereira AM, Netea-Maier RT, Zelissen PMJ, et al. P3-535, Pasireotide treatment in cushing disease: effects on the IGF-I system. Endocr Rev (2011) 32(Suppl 1):1–3095. doi: 10.1210/endo-meetings.2011.PART4.P5.P3-535

CrossRef Full Text | Google Scholar

31. Mazziotti G, Giustina A. Glucocorticoids and the regulation of growth hormone secretion. Nat Rev Endocrinol (2013) 9(5):265–76. doi: 10.1038/nrendo.2013.5

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Batista RL, Musolino NRC, Cescato VAS, da Silva GO, Medeiros RSS, Herkenhoff CGB, et al. Cabergoline in the management of residual nonfunctioning pituitary adenoma: a single-center, open-label, 2-year randomized clinical trial. Am J Clin Oncol (2019) 42(2):221–7. doi: 10.1097/coc.0000000000000505

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Lacroix A, Gu F, Schopohl J, Kandra A, Pedroncelli AM, Jin L, et al. Pasireotide treatment significantly reduces tumor volume in patients with Cushing’s disease: results from a Phase 3 study. Pituitary (2020) 23(3):203–11. doi: 10.1007/s11102-019-01021-2

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Simeoli C, Auriemma RS, Tortora F, De Leo M, Iacuaniello D, Cozzolino A, et al. The treatment with pasireotide in Cushing’s disease: effects of long-term treatment on tumor mass in the experience of a single center. Endocrine (2015) 50(3):725–40. doi: 10.1007/s12020-015-0557-2

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Manavela MP, Danilowicz K, Bruno OD. Macrocorticotropinoma shrinkage and control of hypercortisolism under long-term cabergoline therapy: case report. Pituitary (2012) 15:33–6. doi: 10.1007/s11102-011-0309-0

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Lacroix A, Bronstein MD, Schopohl J, Delibasi T, Salvatori R, Li Y, et al. Long-acting pasireotide improves clinical signs and quality of life in Cushing’s disease: results from a phase III study. J Endocrinol Invest. (2020) 43(11):1613–22. doi: 10.1007/s40618-020-01246-0

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Hinojosa-Amaya JM, Johnson N, González-Torres C, Varlamov EV, Yedinak CG, McCartney S, et al. Depression and impulsivity self-assessment tools to identify dopamine agonist side effects in patients with pituitary adenomas. Front Endocrinol (Lausanne) (2020) 11:579606. doi: 10.3389/fendo.2020.579606

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Grall-Bronnec M, Victorri-Vigneau C, Donnio Y, Leboucher J, Rousselet M, Thiabaud E, et al. Dopamine agonists and impulse control disorders: a complex association. Drug Saf. (2018) 41(1):19–75. doi: 10.1007/s40264-017-0590-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: somatostatin, pasireotide, cabergoline, Cushing’s disease, hypercortisolism

Citation: Feelders RA, Fleseriu M, Kadioglu P, Bex M, González-Devia D, Boguszewski CL, Yavuz DG, Patino H, Pedroncelli AM, Maamari R, Chattopadhyay A, Biller BMK and Pivonello R (2023) Long-term efficacy and safety of subcutaneous pasireotide alone or in combination with cabergoline in Cushing’s disease. Front. Endocrinol. 14:1165681. doi: 10.3389/fendo.2023.1165681

Received: 14 February 2023; Accepted: 11 August 2023;
Published: 09 October 2023.

Edited by:

Renato Cozzi, Endocrinology Unit Ospedale Niguarda, Italy

Reviewed by:

Przemyslaw Witek, Warsaw Medical University, Poland
Athanasios Fountas, General Hospital of Athens G. Genimatas, Greece

Copyright © 2023 Feelders, Fleseriu, Kadioglu, Bex, González-Devia, Boguszewski, Yavuz, Patino, Pedroncelli, Maamari, Chattopadhyay, Biller and Pivonello. 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: Richard A. Feelders, r.feelders@erasmusmc.nl

†Present addresses: Alberto M. Pedroncelli, Chief Medical Office, Camurus AB, Lund, SwedenRicardo Maamari, Global Medical Affairs, Mayne Pharma, Raleigh, NC, United States

‡These authors have contributed equally to this work

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.

From https://www.frontiersin.org/articles/10.3389/fendo.2023.1165681/full

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Cushing’s Syndrome Presenting as Non-Atherosclerotic Myocardial Infarction and Heart Failure

Posted on November 6, 2023 by MaryO

Abstract

Cushing’s syndrome is a rare cause of myocardial infarction and heart failure. Herein, we report a female patient who presented acute myocardial infarction and heart failure with reduced ejection fraction. The patient was found to have hypercortisolism secondary to adrenocortical adenoma and responded well to therapy. This case underlines the effects of hypercortisolism on the cardiovascular system. The clinical presentation of this patient is unique because non-atherosclerotic myocardial infarction is rarely reported in Cushing’s syndrome patients.

Introduction

Cushing’s syndrome is an endocrine condition associated with excessive secretion of cortisol. Hypertension, vascular atherosclerosis, and chronic cardiac remodelling and dysfunction are commonly recognized cardiovascular complications in Cushing’s syndrome patients.1 Herein, we report a rare case of Cushing’s syndrome patient with a primary diagnosis of non-atherosclerotic myocardial infarction and heart failure (HF).

Case Report

A 61-year-old female with a past medical history of chronic obstructive pulmonary disease was admitted with sudden onset chest pain on 6 February 2018. Electrocardiogram showed ST-segment elevation in leads V3–V5. Blood biochemical results of 1 h after the onset of chest pain: cardiac troponin I (cTnI) 0.06 ug/L↑, creatine kinase (CK) 63 U/L, creatine phosphokinase-MB (CK-MB) 22 U/L, aspartate transferase (AST) 19 U/L, and lactic dehydrogenase (LDH) 482 U/L. Myocardial injury markers were markedly elevated at the time point of 18 h after onset: cTnI 13.9 ug/L↑, CK 613 U/L↑, CK-MB 102 U/L↑, AST 112 U/L↑, and LDH 833 U/L↑. Due to the acute ECG changes and elevated myocardial injury markers, the patient was preliminarily diagnosed as ST-segment elevation myocardial infarction (STEMI) and underwent coronary angiography, which showed no stenosis, occlusion or dissection of coronary arteries (Figure 1). Echocardiography showed enlarged left atrial dimension (LAD, 55 mm) and left ventricular end diastolic dimension (LVDd, 57 mm), and reduced ejection fraction (EF, 33%). The patient was treated for STEMI and HF, and was started on aspirin, statin, diuretic of furosemide and spirolactone, metoprolol, and Sacubitril/valsartan (SV, initiated June, 2020). The patient was strictly adherent to the medication prescribed (Table 1).

Details are in the caption following the image

Coronary angiogram demonstrating no significant obstruction in coronary artery circulation.
Table 1. Echocardiography results
2020-06-22 2020-09-02 2021-03-29 2021-06-02 2021-09-01 2021-10-22 2021-12-21
LAD (mm) 55 55 46 52 47 44 41
LVDd (mm) 57 57 53 55 54 51 55
IVS (mm) 10 10 11 10 10 10 11
LVPW (mm) 11 11 11 10 11 9 10
EF (%) 33 30 31 39 47 49 52.5
  • EF, ejection fraction; IVS, interventricular septum; LAD, left atrium dimension; LVDd, left ventricular end diastolic dimension; LVPW, left ventricular posterior wall.

However, the patient’s condition was not improved despite optimized medication. On 26 January 2021, the patient was re-admitted with recurrent chest distress and oedema, with new symptoms of facial plethora, centripetal obesity, and hyperglycaemia (Figure S1). Abdominal CT scan showed a right adrenal adenoma (Figure 2). Cardiac magnetic resonance imaging revealed enlarged LVDd (62 mm), and reduced EF, with delayed myocardial enhancement and evidence of myocardial fibrosis and fatty deposits (Figure 3). Laboratory findings showed hypokalaemia: potassium 3.0 mmol/L, elevated serum cortisol level, low plasma ACTH level, and positive 1-mg overnight dexamethasone suppression test. Based on the above findings, the patient was diagnosed with Cushing’s syndrome and started treatment with the glucocorticoid receptor inhibitor mifepristone on 5 February 2021.

Details are in the caption following the image

Abdominal CT scan showed adrenal adenoma at the right.

Details are in the caption following the image

Cardiac magnetic resonance imaging revealed enlarged LVDd, reduced EF, with delayed myocardial enhancement, evidence of myocardial fibrosis and fatty deposits.

With mifepristone added to the previous medical therapy (aspirin, statin, sacubitril/valsartan, metoprolol and diuretic of furosemide and spirolactone, and mifepristone), the patient’s condition and cardiac function improved, and echocardiography (21 December 2021) showed increased EF (52.5%). The patient underwent partial adrenalectomy on 22 December 2021. Postoperative pathology confirmed adrenal cortical adenoma. At last follow-up on 29 May 2023, the patient showed marked improvement in face and body shape, with no complaints of chest distress or oedema (Figure S2).

Discussion

In this case, the patient was first evaluated for STEMI due to her symptoms of chest pain, and the elevated ST-segment on ECG, along with the moderately elevated troponin I and other cardiac enzyme levels. However, coronary atherosclerotic heart disease was ruled out by the normal cardiac catheterization. We presume that a possible reason for acute myocardial infarction (AMI) might be vasospastic angina due to abnormal hormone levels with Cushing’s syndrome, leading to increased excessive myocardial metabolic demand and relative myocardial hypoxia, which eventually induced myocardial infarction. Although coronary atherosclerotic heart disease is the main cause of AMI, many non-atherosclerotic processes can lead to an imbalance between decreased coronary blood flow and increased myocardial metabolic demand. To date, non-atherosclerotic myocardial infarction has rarely been reported in Cushing’s syndrome patients. Vieira JT et al. reported that a patient with Cushing’s disease was considered to have spontaneous coronary artery dissection, which is a rare reason for AMI.2

Cushing’s syndrome is associated with an increased risk of cardiac failure,3 with both structural alterations and functional impairment. In our case, the patient’s CMR imaging showed typical features of cardiac geometry, function, and fibrosis, in accordance with previous reports.4 The underlying mechanisms may be the enhanced responsiveness to angiotensin II and activation of the mineralocorticoid receptor in direct response to cortisol excess.5

Our patient responded well to the therapy of conventional anti-HF medication of sacubitril/valsartan, metoprolol, and diuretic, once mifepristone was added. This favourable response to the pharmacological regimen supports the benefits of the agents for the normalization of excess cortisol. This case indicates that early diagnosis and effective treatment of Cushing’s syndrome may be crucial in preventing irreversible cardiac dysfunction secondary to cardiovascular events and heart failure.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81900409 and 82172182) and the PLA Youth Training Project for Medical Science (19QNP037).

Conflict of interest

The authors declares that there is no conflict of interest.

From https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14548

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Unique Gene Expression Signature in Periadrenal Adipose Tissue Identifies a High Blood Pressure Group in Patients With Cushing Syndrome

Posted on September 13, 2023 by MaryO

Abstract

Background:

Cushing syndrome (CS) is a rare disease caused by excess cortisol levels with high cardiovascular morbidity and mortality. Hypertension in CS promotes hypercortisolism-associated cardiovascular events. Adipose tissue is a highly plastic tissue with most cell types strongly affected by the excess cortisol exposure. We hypothesized that the molecular and cellular changes of periadrenal adipose tissue in response to cortisol excess impact systemic blood pressure levels in patients with CS.

Methods:

We investigated gene expression signatures in periadrenal adipose tissue from patients with adrenal CS collected during adrenal surgery.

Results:

During active CS we observed a downregulation of gene programs associated with inflammation in periadrenal adipose tissue. In addition, we observed a clustering of the patients based on tissue gene expression profiles into 2 groups according to blood pressure levels (CS low blood pressure and CS high blood pressure). The 2 clusters showed significant differences in gene expression pattens of the renin-angiotensin-aldosterone-system. Renin was the strongest regulated gene compared with control patients and its expression correlated with increased blood pressure observed in our patients with CS. In the CS high blood pressure group, systemic renin plasma levels were suppressed indicative of an abnormal blood pressure associated with periadrenal adipose tissue renin-angiotensin-aldosterone-system activation.

Conclusions:

Here, we show for the first time a relevant association of the local renin-angiotensin-aldosterone-system and systemic blood pressure levels in patients with CS. Patients from the CS high blood pressure group still had increased blood pressure levels after 6 months in remission, highlighting the importance of local tissue effects on long-term systemic effects observed in CS.

Footnotes

*U. Stifel and F. Vogel contributed equally.

For Sources of Funding and Disclosures, see page xxx.

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.123.21185.

Correspondence to: Martin Reincke, Department of Medicine IV, University Hospital, LMU Munich, GermanyEmail martin.reincke@med.uni-muenchen.de
Jan Tuckermann, Institute of Comparative Molecular Endocrinology (CME), Ulm University, GermanyEmail jan.tuckermann@uni-ulm.de

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From https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.123.21185

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