Long-acting pasireotide provides ‘sustained biochemical improvements’ in Cushing’s disease

For patients with persistent or recurring Cushing’s disease, monthly pasireotide therapy was safe and effective, leading to normal urinary free cortisol levels in 47% of patients after 2 years, according to findings published in Clinical Endocrinology.

Maria Fleseriu headshot 2019

Maria Fleseriu

“The management of Cushing’s syndrome, and particularly Cushing’s disease, remains challenging,” Maria Fleseriu, MD, FACE, professor of neurological surgery and professor of medicine in the division of endocrinology, diabetes and clinical nutrition in the School of Medicine at Oregon Health & Science University and director of the OHSU Northwest Pituitary Center, told Endocrine Today. “Long-acting pasireotide provided sustained biochemical improvements and clinical benefit in a significant proportion of patients with Cushing’s disease who elected to continue in this extension study. There were many adverse events reported overall, but no new safety signals emerging over long-term treatment.”

In the last decade, medical treatment for Cushing’s disease has progressed from a few steroidogenesis inhibitors to three novel drug groups: new inhibitors for steroidogenic enzymes with possibly fewer adverse effects, pituitary-directed drugs that aim to inhibit the pathophysiological pathways of Cushing’s disease, and glucocorticoid receptor antagonists that block cortisol’s action, Fleseriu, who is also an Endocrine Today Editorial Board member, said.

In an open-label extension study, Fleseriu and colleagues analyzed data from 81 adults with confirmed Cushing’s disease with mean urinary free cortisol not exceeding the upper limit of normal, who transitioned from a 12-month, randomized controlled trial where they were assigned 10 mg or 30 mg once-monthly intramuscular pasireotide (Signifor LAR, Novartis). During the main study, researchers recruited participants with mean urinary free cortisol level concentration 1.5 to five times the upper limit of normal, normal or greater than normal plasma and confirmed pituitary source of Cushing’s disease. Participants who elected to continue in the extension were considered biochemical responders or benefited from the study drug per the clinical investigator, Fleseriu said.

“As in all extension studies, the bias is inherent that patients deemed responders tend to continue, but for any type of treatment for pituitary tumors, and particularly Cushing’s disease, long-term, robust data on efficacy and safety parameters is essential,” Fleseriu said.

Median overall exposure to pasireotide at the end of the extension study was 23.9 months, with nearly half of patients receiving at least 1 year of treatment during the extension phase. Researchers found that improvements in clinical signs of hypercortisolism were sustained throughout the study and median urinary free cortisol remained within normal range. Overall, 38 participants (47%) had controlled urinary free cortisol at month 24 (after 12 months of treatment during the extension phase), with researchers noting that the proportion of participants with controlled or partially controlled urinary free cortisol was stable throughout the extension phase.

“Interestingly, the median salivary cortisol level decreased but remained above normal (1.3 times upper limit of normal) at 3 years,” Fleseriu said.

As seen in other pasireotide studies, and expected based on the mechanism of action, researchers observed hyperglycemia-related adverse events in 39.5% of participants, with diabetes medications initiated or escalated in some patients, Fleseriu said. However, mean fasting glucose and HbA1c were stable during the extension phase, after increasing in the main study. Within the cohort, 81.5% had type 2 diabetes at baseline (entering extension phase) and 88.9% patients had type 2 diabetes at last assessment.

“Pasireotide acts at the tumor level, and tumor shrinkage is seen in many patients,” Fleseriu said. “In this study, 42% and 32.1% had a measurable microadenoma or macroadenoma, respectively, on MRI at the start of pasireotide treatment; an adenoma was not visible in almost a quarter of patients at 2 years.”

Among patients with a measurable adenoma at baseline and at month 24 (n = 35), 85.7% experienced a reduction of at least 20% or a 20% change in tumor volume between the two time points. Improvements in median systolic and diastolic blood pressure, BMI and waist circumference were sustained during the extension, Fleseriu said.

“The long-term safety profile of pasireotide was favorable and consistent with that reported during the first 12 months of treatment,” the researchers wrote. “These data support the use of long-acting pasireotide as an effective long-term treatment option for some patients with [Cushing’s disease].”

Fleseriu said individualized treatment selecting patients who will derive benefit from therapy will be crucial, balancing both efficacy and the potential risks and costs. – by Regina Schaffer

Disclosures: Fleseriu reports she has received consultant fees and her institution has received research support from Novo Nordisk and Pfizer. Please see the study for all other authors’ relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B5da4611f-34b2-4306-80b8-46babd2aad4a%7D/long-acting-pasireotide-provides-sustained-biochemical-improvements-in-cushings-disease?page=2

Bilateral Adrenocortical Adenomas Causing Adrenocorticotropic Hormone-Independent Cushing’s Syndrome

Adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome (CS) is mostly due to unilateral tumors, with bilateral tumors rarely reported. Its common causes include primary pigmented nodular adrenocortical disease, ACTH-independent macronodular adrenal hyperplasia, and bilateral adrenocortical adenomas (BAAs) or carcinomas. BAAs causing ACTH-independent CS are rare; up to now, fewer than 40 BAA cases have been reported. The accurate diagnosis and evaluation of BAAs are critical for determining optimal treatment options. Adrenal vein sampling (AVS) is a good way to diagnose ACTH-independent CS.

A 31-year-old woman had a typical appearance of CS. The oral glucose tolerance test showed impaired glucose tolerance and obviously increased insulin and C-peptide levels. Her baseline serum cortisol and urine free cortisol were elevated and did not show either a circadian rhythm or suppression with dexamethasone administration. The peripheral 1-deamino-8-D-arginine-vasopressin (DDVAP) stimulation test showed a delay of the peak level, which was 1.05 times as high as the baseline level. Bilateral AVS results suggested the possibility of BAAs. Abdominal computed tomography showed bilateral adrenal adenomas with atrophic adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). Magnetic resonance imaging of the pituitary gland demonstrated normal findings. A left adenomectomy by retroperitoneoscopy was performed first, followed by resection of the right-side adrenal mass 3 mo later. Biopsy results of both adenomas showed cortical tumors. Evaluations of ACTH and cortisol showed a significant decrease after left adenomectomy but could still not be suppressed, and the circadian rhythm was absent. Following bilateral adenomectomy, this patient has been administered with prednisone until now, all of her symptoms were alleviated, and she had normal blood pressure without edema in either of her lower extremities.

BAAs causing ACTH-independent CS are rare. AVS is of great significance for obtaining information on the functional state of BAAs before surgery.

World journal of clinical cases. 2019 Apr 26 [Epub]

Yu-Lin Gu, Wei-Jun Gu, Jing-Tao Dou, Zhao-Hui Lv, Jie Li, Sai-Chun Zhang, Guo-Qing Yang, Qing-Hua Guo, Jian-Ming Ba, Li Zang, Nan Jin, Jin Du, Yu Pei, Yi-Ming Mu

Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China., Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China. guweijun301@163.com., Department of Pathology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China.

From https://www.urotoday.com/recent-abstracts/urologic-oncology/adrenal-diseases/112782-bilateral-adrenocortical-adenomas-causing-adrenocorticotropic-hormone-independent-cushing-s-syndrome-a-case-report-and-review-of-the-literature.html

Metyrapone Reduced Urinary-Free Cortisol Levels in Cushing Syndrome

Metyrapone treatments helped patients with Cushing syndrome reach normal, urinary-free cortisol levels in the short-term and also had long-term benefits, according to a study published in Endocrine.

This observational, longitudinal study evaluated the effects of the 11β -hydroxylase inhibitor metyrapone on adult patients with Cushing syndrome. Urinary-free cortisol and late-night salivary cortisol levels were evaluated in 31 patients who were already treated with metyrapone to monitor cortisol normalization and rhythm.

The average length of metyrapone treatment was 9 months, and 6 patients had 24 months of treatment. After 1 month of treatment, the mean urinary-free cortisol was reduced from baseline by 67% and mean late-night salivary cortisol level decreased by 57%.

Analyzing only patients with severe hypercortisolism, after 1 month of treatment, the mean urinary-free cortisol decreased by 86% and the mean late-night salivary cortisol level decreased 80%. After 3 months, normalization of the mean urinary-free cortisol was established in 68% of patients. Mean late-night salivary cortisol levels took longer to decrease, especially in severe and very severe hypercortisolism, which could take 6 months to drop. Treatment was more successful at normalizing cortisol excretion (70%) than cortisol rhythm (37%). Nausea, abdominal pain, and dizziness were the most common adverse events, but no severe adverse event was reported.

Future research is needed to evaluate a larger cohort with randomized dosages and stricter inclusion criteria to evaluate metyrapone’s effects on cortisol further.

Study researchers conclude that metyrapone was successful and safe in lowering urinary-free cortisol after just 1 month of treatment and controlling long-term levels in patients with Cushing syndrome.

This study was supported by Novartis.

Reference

Ceccato F, Zilio M, Barbot M, et al. Metyrapone treatment in Cushing’s syndrome: a real-life study [published online July 16, 2018]. Endocrine. doi: 10.1007/s12020-018-1675-4

From https://www.endocrinologyadvisor.com/general-endocrinology/metyrapone-cushing-syndrome/article/786716/

Repeat Checks of Cortisol Levels in Saliva May Improve Use of Metopirone as Cushing’s Treatment

Measuring cortisol levels in saliva multiple times a day is a convenient and useful way to determine the best course of treatment for patients with Cushing’s syndrome, a preliminary study shows.

The research, “Multiple Salivary Cortisol Measurements Are a Useful Tool to Optimize Metyrapone Treatment in Patients with Cushing’s Syndromes Treatment: Case Presentations,” appeared in the journal Frontiers of Endocrinology.

Prompt and effective treatment for hypercortisolism — the excessive amount of cortisol in the blood — is essential to lowering the risk of Cushing’s-associated conditions, including infections, cardiovascular disease, and stroke.

Steroid hormone inhibitors, such as HRA Pharma’s Metopirone (metyrapone), have been used significantly in Cushing’s syndrome patients.

These therapies not only suppress cortisol levels, but also avoid adrenal insufficiency (where not enough cortisol is produced) and restore the circadian rhythm, which is disrupted in Cushing’s patients. However, effective medical treatment requires monitoring cortisol activity throughout the day.

Salivary measurements of cortisol are a well-known method for diagnosing and predicting the risk of recurrence of Cushing’s syndrome. The method is convenient for patients and can be done in outpatient clinics. However, the medical field lacks data on whether measuring cortisol in saliva works for regulating treatment.

Researchers analyzed the effectiveness of salivary cortisol measurements for determining the best dosage and treatment timing of Cushing’s patients with Metopirone.

The study included six patients, three with cortisol-secreting masses in the adrenal glands and and three with ACTH (or adrenocorticotropin)-secreting adenomas in the pituitary glands, taking Metopirone. Investigators collected samples before and during treatment to assess morning serum cortisol and urinary free cortisol (UFC). Patients also had salivary cortisol assessments five times throughout the day.

Saliva samples were collected at 6 a.m. (wake-up time), 8 a.m. (before breakfast), noon (before lunch), 6 p.m. (before dinner), and 10 p.m. (before sleep).

Other studies have used UFC assessments to monitor treatment. However, the inability of this parameter to reflect changes in diurnal cortisol requires alternative approaches.

Results showed that although UFC was normalized in five out of six patients, multiple salivary cortisol measurements showed an impaired diurnal cortisol rhythm in these patients.

Whereas patients with cortisol-secreting adrenocortical adenoma showed elevated cortisol levels throughout the day, those with ACTH-secreting pituitary adenoma revealed increased levels mainly in the morning. This finding indicates that “the significance of elevated morning cortisol levels is different depending on the disease etiology,” the researchers wrote.

In a prospective case study to better assess the effectiveness of performing multiple salivary cortisol assessments, the research team analyzed one of the participants who had excessive cortisol production that was not controlled with four daily doses of Metoripone (a daily total of 2,250 mg).

Results revealed that cortisol levels increased before each dosage. After the patient’s treatment regimen was changed to a 2,500 mg dose divided into five daily administrations, researchers observed a significant improvement in the diurnal cortisol pattern, as well as in UFC levels.

Subsequent analysis revealed that performing multiple salivary cortisol measurements helps with a more precise assessment of excess cortisol than analyzing UFC levels, or performing a unique midnight salivary cortisol collection, the researchers said.

Although more studies are required, the results “suggest that multiple salivary cortisol measurements can be a useful tool to visualize the diurnal cortisol rhythm and to determine the dose and timing of metyrapone [Metopirone] during the treatment in patients with [Cushing’s syndrome],” the researchers wrote.

Future studies should include a larger sample size, evaluate changes over a longer term, use a standardized protocol for treatment dosing and timing, and evaluate changes in a patient’s quality of life, the investigators said.

From https://cushingsdiseasenews.com/2018/02/15/multiple-saliva-cortisol-checks-cushings-metyrapone-study/

Pregnant Women with Hypertension and Hypercortisolism May Have Cushing’s

Pregnant woman with hypertension and significant signs of hypercortisolism (high cortisol levels) may have Cushing’s disease, according to a new case report.

The report, titled “A Case of Cushing’s Syndrome in Pregnancy,” was published in the Iranian Journal of Medical Sciences.

While Cushing’s rarely occurs in women during pregnancy, high cortisol levels can lead to major complications for both the mother and the fetus, such as premature birth and high fetal mortality.

However, it can be difficult to diagnose pathological hypercortisolism in these women as the symptoms might resemble other diseases that commonly occur during pregnancy, such as preeclampsia (high blood pressure during pregnancy) and gestational diabetes.

Unfortunately, there are no effective long-term medical therapies for Cushing’s. The most definitive therapy is the surgical removal of the pituitary or adrenal adenoma, if that is the case of hypercortisolism.

The case report details that a 29-year old women in the 27th week of pregnancy presented to the Ghaem Hospital clinic in Mashhad, Iran, with edema, weakness, and hypertension. Her symptoms also included truncal obesity, moon face (her face had a rounded appearance), purple steria on her upper and lower limbs and abdomen, excessive edema, and wet skin.

At first, she was hospitalized for suspected preeclampsia, but the diagnosis was later excluded.

The patient’s hormonal profile showed high levels of 24-hour urine cortisol. There were also low levels of adrenocorticotropic hormone (ACTH), which results from a negative feedback due to excessive cortisol. However, plasma cortisol is generally elevated during pregnancy, and therefore may not be the best method for diagnosis.

An abdominal ultrasonography revealed a well-defined mass in the right adrenal gland.

While hospitalized, the patient experienced two crises of blood pressure, and while preeclampsia was ruled out, the physicians could find no more plausible explanation than eclampsia (the onset of seizures in a women with preeclampsia).

Since eclampsia was suspected, the physicians terminated the pregnancy at 28th week of gestation using misoprostol. The woman delivered a male infant weighing 1.94 pounds.

Two days after birth, the physicians conducted a computed tomography (CT) scan and again found a mass in the right adrenal gland.

As a result, the patient underwent a laparoscopic right adrenalectomy to remove the mass one week after giving birth. The patient’s blood pressure normalized and cortisol levels declined. Her condition remained stable after surgery.

“Cushing’s syndrome should be considered in hypertensive pregnant patients with remarkable signs of hypercortisolism,” the researchers concluded. “The best results would be achieved through a collaboration between obstetricians, endocrinologists, and surgeons.”

From https://cushingsdiseasenews.com/2017/12/19/pregnant-women-hypertension-hypercortisolism-may-have-cushings-disease/

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