Predictive factors and the management of hyperglycemia in patients with acromegaly and Cushing's disease receiving pasireotide treatment: post hoc analyses from the SOM230B2219 study.

Introduction: Pasireotide, a somatostatin receptor ligand, is approved for treating acromegaly and Cushing's disease (CD). Hyperglycemia during treatment can occur because of the drug's mechanism of action, although treatment discontinuation is rarely required. The prospective, randomized, Phase IV SOM230B2219 (NCT02060383) trial was designed to assess optimal management of pasireotide-associated hyperglycemia. Here, we investigated predictive factors for requiring antihyperglycemic medication during pasireotide treatment. Methods: Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 µg subcutaneously twice daily during pre-randomization (≤16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks. Those who required additional/alternative antihyperglycemic medication to metformin were randomized to incretin-based therapy or insulin for an additional 16 weeks. Logistic-regression analyses evaluated quantitative and qualitative factors for requiring antihyperglycemic medication during pre-randomization. Results: Of 190 participants with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication; most were aged <40 years (acromegaly 62.5%, CD 86.7%), with baseline glycated hemoglobin (HbA1c) <6.5% (<48 mmol/mol; acromegaly 98.9%, CD 100%) and fasting plasma glucose (FPG) <100 mg/dL (<5.6 mmol/L; acromegaly 76.1%, CD 100%). By logistic regression, increasing baseline HbA1c (odds ratio [OR] 3.6; P=0.0162) and FPG (OR 1.0; P=0.0472) and history of diabetes/pre-diabetes (OR 3.0; P=0.0221) predicted receipt of antihyperglycemic medication in acromegaly participants; increasing baseline HbA1c (OR 12.6; P=0.0276) was also predictive in CD participants. Investigator-reported hyperglycemia-related adverse events were recorded in 47.9% and 54.2% of acromegaly and CD participants, respectively, mainly those with diabetes/pre-diabetes. Conclusion: Increasing age, HbA1c, and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment.

Drug development and potential targets for Cushing's syndrome.

Cushing's syndrome (CS) is a complex disorder characterized by the excessive secretion of cortisol, with Cushing's disease (CD), particularly associated with pituitary tumors, exhibiting heightened morbidity and mortality. Although transsphenoidal pituitary surgery (TSS) stands as the primary treatment for CD, there is a crucial need to optimize patient prognosis. Current medical therapy serves as an adjunctive measure due to its unsatisfactory efficacy and unpredictable side effects. In this comprehensive review, we delve into recent advances in understanding the pathogenesis of CS and explore therapeutic options by conducting a critical analysis of potential drug targets and candidates. Additionally, we provide an overview of the design strategy employed in previously reported candidates, along with a summary of structure-activity relationship (SAR) analyses and their biological efficacy. This review aims to contribute valuable insights to the evolving landscape of CS research, shedding light on potential avenues for therapeutic development.

Case report: Complete restoration of the HPA axis function in Cushing's disease with drug treatment.

This report describes a rare case of a 20-year-old man with an ACTH- and prolactin-secreting invasive pituitary macroadenoma causing hyperprolactinemia and Cushing's disease. He was later found to have an AIP mutation. Treatment with cabergoline (1.5 mg weekly) normalized prolactin concentrations and induced a major shrinkage of the adenoma. Not only was urinary free cortisol normalized for more than 14 years, but also the treatment induced normal hypothalamo-pituitary-adrenal (HPA) axis function as illustrated by the reappearance of a normal cortisol/ACTH circadian rhythm, cortisol suppression to dexamethasone, and disappearance of the excessive and aberrant responses to CRH and desmopressin, respectively. This case is the first description of complete restoration of the physiological characteristics of the HPA axis by a medication during the treatment of Cushing's disease. Although exceptional, it illustrates that drugs targeting the pituitary adenoma can bring true complete remission of Cushing's disease.

[Development of sarcoidosis after successful treatment of Cushing's disease].

Cushing's disease is a rare severe neuroendocrine disorder caused by chronic overproduction of adrenocorticotropic hormone by a pituitary tumor. Supraphysiological concentrations of cortisol in endogenous hypercortisolism have an immunosuppressive and anti-inflammatory effect similar to therapy with systemic glucocorticosteroids. This may reduce the activity of the patient's concomitant autoimmune inflammatory diseases. On the other hand, a decrease in cortisol levels during treatment for Cushing's disease may be associated with a reactivation of the immune system that pose a risk of onset or recurrence of an autoimmune disorder. We present our own clinical case demonstrating the development of sarcoidosis after surgical treatment of Cushing's disease.

Discontinuation of Drug Treatment in Cushing's Disease Not Cured by Pituitary Surgery.

OBJECTIVE: When transsphenoidal surgery (TSS) does not cure Cushing's disease (CD), 4 treatments are available: drug treatment (DT), second TSS (2nd TSS), bilateral adrenalectomy (BA), and pituitary radiotherapy (PR). DT is attractive but supposes long-term continuation, which we aimed to evaluate. DESIGN AND METHODS: Retrospective study, in a center prioritizing 2nd TSS, of 36 patients, including 19 with TSS failure and 17 with recurrence, out of 119 patients with CD treated by a first TSS, average follow-up 6.1 years (95% confidence interval 5.27-6.91). Control was defined as normalization of urinary free cortisol (UFC) and final treatment (FT) as the treatment allowing control at last follow-up. We also analyzed discontinuation rates of DT in published CD prospective clinical trials. RESULTS: Control was achieved in 33/36 patients (92%). DT was initiated in 29/36 patients (81%), allowing at least 1 normal UFC in 23/29 patients (79%) but was discontinued before last follow-up in 18/29 patients (62%). DT was FT in 11/29 patients (38%), all treated with cortisol synthesis inhibitors. Second TSS was FT in 8/16 (50%), BA in 14/14 (100%), and PR in 0/5. In published trials, discontinuation of DT was 11% to 51% at 1 year and 32% to 74% before 5 years. CONCLUSION: DT allowed at least 1 normal UFC in 23/29 patients (79%) but obtained long-term control in only 11/29 (38%), as discontinuation rate was high, although similar to published data. Interestingly, a successful 2nd TSS was the cause for discontinuing efficient and well-tolerated DT in 5 patients. Further studies will show whether different strategies with cortisol synthesis inhibitors may allow for a lower discontinuation rate in patients not candidates for a 2nd TSS so that BA may be avoided in these patients.

A novel somatostatin receptor ligand for human ACTH - and GH -secreting pituitary adenomas.

OBJECTIVE: Somatostatin receptor ligands have come to play a pivotal role in the treatment of both ACTH- and GH-secreting pituitary adenomas. Clinical efficacy averages 30-50%, thus a considerable number of patients with Cushing's disease or acromegaly remain unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin receptor ligand selective for subtype 5 over subtype 2, thus with a different receptor profile compared to clinical somatostatin receptor ligands. DESIGN: Assessment of the effect of HTL0030310 on hormone secretion in human ACTH- and GH-secreting pituitary adenomas in vitro. METHODS: Primary cultures from 3 ACTH-secreting and 5 GH-secreting pituitary adenomas were treated with 1, 10 and 100 nM HTL0030310 alone or with 10 nM CRH or GHRH, respectively. Parallel incubations with 10 nM pasireotide were also carried out. ACTH and GH secretion were assessed after 4 and 24 hour incubation; SSTR2, SSTR3, SSTR5, GH and POMC expression were evaluated after 24 hours. RESULTS: HTL0030310 reduced unchallenged ACTH and POMC levels up to 50% in 2 ACTH-secreting adenomas and blunted CRH-stimulated ACTH/POMC by 20-70% in all 3 specimens. A reduction in spontaneous GH secretion was observed in 4 GH-secreting adenomas and in 2 specimens during GHRH co-incubation. SSTRs expression was detected in all specimens. CONCLUSIONS: This first study on a novel somatostatin receptor 5-preferring ligand indicates that HTL0030310 can inhibit hormonal secretion in human ACTH- and GH-secreting pituitary adenomas. These findings suggest a potential new avenue for somatostatin ligands in the treatment of Cushing's disease and acromegaly.

Long-term efficacy and safety of subcutaneous pasireotide alone or in combination with cabergoline in Cushing's disease.

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.

Progression of a corticotroph tumour during durable medical therapy with osilodrostat in a patient with persistent Cushing's disease.

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Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension.

Objective: To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease. Methods: The multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing's disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed. Results: Of 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing's disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports. Conclusion: Osilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing's disease. Clinical trial registration: ClinicalTrials.gov, identifier NCT02180217.

Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas.

PURPOSE: Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production, ultimately affecting morbidity and mortality. Pasireotide is the only FDA approved tumor directed treatment for CD, but it is effective in only about 25% of patients, and is associated with a high rate of hyperglycemia. Neuromedin B (NMB), a member of the bombesin-like peptide family, regulates endocrine secretion and cell proliferation. Here, we assessed NMB and NMB receptor (NMBR) expression in human corticotroph adenomas and the effects of NMBR antagonist PD168368 on murine and human corticotroph tumors. METHODS: To investigate NMB and NMBR expression, real-time qPCR and immunostaining on human pathological specimens of corticotroph, non-functional and somatotroph adenomas were performed. The effects of PD168368 on hormone secretion and cell proliferation were studied in vitro, in vivo and in seven patient-derived corticotroph adenoma cells. NMB and NMBR were expressed in higher extent in human corticotroph adenomas compared with non-functional or somatotroph adenomas. RESULTS: In murine AtT-20 cells, PD168368 reduced proopiomelanocortin (Pomc) mRNA/protein expression and ACTH secretion as well as cell proliferation. In mice with tumor xenografts, tumor growth, ACTH and corticosterone were downregulated by PD168368. In patient-derived adenoma cells, PD168368 reduced POMC mRNA expression in four out of seven cases and ACTH secretion in two out of five cases. A PD168368-mediated cyclin E suppression was also identified in AtT-20 and patient-derived cells. CONCLUSION: NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.

Risk of impulse control disorders in patients with Cushing's disease: do not blame cabergoline but do not give up caution.

PURPOSE: To asses risk of new-onset impulse control disorders (ICDs) in patients with Cushing's disease (CD) who initiated cabergoline (CBG) and to determine frequency of ICDs in CBG-treated patients with CD. METHODS: This naturalistic observational study had prospective and cross-sectional arms which included patients at five referral centers based in Istanbul. Patients who were scheduled for CBG were assigned to prospective arm. These patients underwent neuropsychological tests (Barratt Impulsiveness Scale, Minnesota Impulsive Disorders Interview, Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale, Go/No-Go Task, Iowa Gambling Task, and Short Penn Continuous Performance Test) for assessment of impulsivity and psychiatric evaluations at baseline, 3, 6, and 12 months of CBG treatment. Impulsivity and new-onset ICDs were prospectively assessed. Patients with CD with current CBG treatment for ≥ 3 months and matched CBG-naïve patients with CD were included in cross-sectional arm. These patients underwent the same neuropsychological and psychiatric assessments. The impulsivity and frequency of ICDs were compared between CBG-treated and CBG-naïve patients with CD. RESULTS: The follow-up duration of prospective cohort (n = 14) was 7.3 ± 2.3 months. One patient developed major depressive episode and another patient developed compulsive gambling after CBG. We observed no significant changes in impulsivity scores during follow-up. In cross-sectional arm, CBG-treated (n = 34) and CBG-naïve patients (n = 34) were similar in impulsivity scores and frequency of ICDs [3 patients (8.8%) vs. 2 patients (5.9%) respectively, p = 1.0]. CONCLUSION: CBG-treated patients with CD appeared to have a low risk of ICDs, suggesting that CBG still holds promise as a safe agent in CD.

COVID-19 infection in a patient with Cushing's disease on osilodrostat treatment.

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Medical treatment of Cushing's disease with concurrent diabetes mellitus.

Cushing's disease (CD) is a severe endocrine disorder characterized by chronic hypercortisolaemia secondary to an overproduction of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. Cortisol excess impairs normal glucose homeostasis through many pathophysiological mechanisms. The varying degrees of glucose intolerance, including impaired fasting glucose, impaired glucose tolerance, and Diabetes Mellitus (DM) are commonly observed in patients with CD and contribute to significant morbidity and mortality. Although definitive surgical treatment of ACTH-secreting tumors remains the most effective therapy to control both cortisol levels and glucose metabolism, nearly one-third of patients present with persistent or recurrent disease and require additional treatments. In recent years, several medical therapies demonstrated prominent clinical efficacy in the management of patients with CD for whom surgery was non-curative or for those who are ineligible to undergo surgical treatment. Cortisol-lowering medications may have different effects on glucose metabolism, partially independent of their role in normalizing hypercortisolaemia. The expanding therapeutic landscape offers new opportunities for the tailored therapy of patients with CD who present with glucose intolerance or DM, however, additional clinical studies are needed to determine the optimal management strategies. In this article, we discuss the pathophysiology of impaired glucose metabolism caused by cortisol excess and review the clinical efficacy of medical therapies of CD, with particular emphasis on their effects on glucose homeostasis.

Clinical Utility of Osilodrostat in Cushing's Disease: Review of Currently Available Literature.

Cushing's disease (CD) is caused by endogenous hypercortisolism as a result of adrenocorticotropin (ACTH) secretion from a pituitary tumor. The condition is associated with multiple comorbidities and increased mortality. First-line therapy for CD is pituitary surgery, performed by an experienced pituitary neurosurgeon. Hypercortisolism may often persist or recur after initial surgery. Patients with persistent or recurrent CD will generally benefit from medical therapy, often administered to patients who underwent radiation therapy to the sella and are awaiting its salutary effects. There are three groups of medications directed against CD, including pituitary-targeted medications that inhibit ACTH secretion from tumorous corticotroph cells, adrenally-directed medications that inhibit adrenal steroidogenesis and a glucocorticoid receptor (GR) antagonist. The focus of this review is osilodrostat, a steroidogenesis inhibitor. Osilodrostat (LCI699) was initially developed to lower serum aldosterone levels and control hypertension. However, it was soon realized that osilodrostat also inhibits 11-beta hydroxylase (CYP11B1), leading to a reduction in serum cortisol levels. The focus of drug development then shifted from treatment of hypertension to treatment of hypercortisolism in CD. In a series of studies (LINC 1 through 4), osilodrostat was shown to be effective in normalizing 24-h urinary free cortisol (UFC) in the majority of treated patients and was approved for patients with CD who have failed surgery or are not surgical candidates. Further study is needed to examine the role of combination therapy as well as long-term outcomes of treated patients. Osilodrostat was shown to have an overall good safety profile. Most common adverse effects include nausea, headache, fatigue, arthralgias, dizziness, prolonged QTc interval, hypokalemia. In females, the drug can cause hirsutism and acne. Osilodrostat is administered twice daily, making it a good choice for patients with difficulty adhering to more complex regimens. Osilodrostat has an important, albeit adjunctive, role in the management of patients with CD.

Evidence of Persistent Mild Hypercortisolism in Patients Medically Treated for Cushing Disease: the Haircush Study.

CONTEXT: Cortisol-lowering drugs may not restore a normal cortisol secretion in Cushing disease (CD). OBJECTIVE: This work aimed to assess the long-term cortisol exposure in medically treated CD patients using hair-cortisol (HF) and hair-cortisone (HE) measurement. METHODS: This multicenter prospective study included 3 groups of female patients: CushMed = 16 treated with a stable cortisol-lowering drug dosage and normal urinary free cortisol (UFC); CushSurg = 13 cured by pituitary surgery; CushBla = 15 receiving stable recommended doses of hydrocortisone following bilateral adrenalectomy. Patients were evaluated for 3 months with their usual treatments. Two late-night saliva and 24-hour urine samples were collected monthly in CushMed, and at study end in CushSurg and CushBla patients. A 3-cm hair sample was collected at study end from all patients. Main outcome measures included clinical score and centralized measurement of UFC, late-night salivary cortisol (LNSF), late-night salivary cortisone (LNSE), HE, HF. RESULTS: Despite having almost all UFCs normalized, CushMed patients exhibited increased HE as compared to CushSurg controls (P = .003). CushMed patients also had increased clinical score (P = .001), UFC (P = .03), LNSF, LNSE (P = .0001), and variability in the latter parameters (P = .004). CushBla patients had increased HF and HE, contrasting with LNSEs similar to CushSurg patients. Six of 15 CushMed patients exhibited increased HE concentrations and had increased antihypertensive drug dosage compared to CushMed patients with normal HE (P = .05). CONCLUSION: Despite normalized UFCs, a subset of medically treated CD patients displays an altered circadian rhythm of serum cortisol. A single HE measurement identifies chronic mild persistent hypercortisolism and could replace multiple saliva analyzes to monitor medical treatments in CD patients once UFC is normalized.

Ketoconazole as second-line treatment for Cushing's disease after transsphenoidal surgery: systematic review and meta-analysis.

Introduction: The first-line treatment for Cushing's disease is transsphenoidal surgery for pituitary tumor resection. Ketoconazole has been used as a second-line drug despite limited data on its safety and efficacy for this purpose. The objective of this meta-analysis was to analyze hypercortisolism control in patients who used ketoconazole as a second-line treatment after transsphenoidal surgery, in addition to other clinical and laboratory criteria that could be related to therapeutic response. Methods: We searched for articles that evaluated ketoconazole use in Cushing's disease after transsphenoidal surgery. The search strategies were applied to MEDLINE, EMBASE, and SciELO. Independent reviewers assessed study eligibility and quality and extracted data on hypercortisolism control and related variables such as therapeutic dose, time, and urinary cortisol levels. Results: After applying the exclusion criteria, 10 articles (one prospective and nine retrospective studies, totaling 270 patients) were included for complete data analysis. We found no publication bias regarding reported biochemical control or no biochemical control (p = 0.06 and p = 0.42 respectively). Of 270 patients, biochemical control of hypercortisolism occurred in 151 (63%, 95% CI 50-74%) and no biochemical control occurred in 61 (20%, 95% CI 10-35%). According to the meta-regression, neither the final dose, treatment duration, nor initial serum cortisol levels were associated with biochemical control of hypercortisolism. Conclusion: Ketoconazole can be considered a safe and efficacious option for Cushing's disease treatment after pituitary surgery. Systematic review registration: https://www.crd.york.ac.uk/prospero/#searchadvanced, (CRD42022308041).

An evaluation of pharmacological options for Cushing's disease: what are the state-of-the-art options?

INTRODUCTION: Untreated Cushing's syndrome (CS) is associated with significant morbidity and mortality. Cortisol normalization is a key goal to treatment. Pituitary surgery remains the first-line approach for Cushing's disease, but sometimes it is impracticable, unsuccessful, or complicated by recurrence. Medical therapy has been historically considered a palliative. However, in the latest years, interest on this topic has grown due to both the availability of new drugs and the reevaluation of the old, commonly used drugs in clinical practice. AREAS COVERED: In this article, we will discuss the current options and future directions of medical therapy for CS, aiming at fitting best patients' features. An extensive literature search regarding already approved and investigational principles was conducted (PubMed, ClinicalTrials.gov. Available drugs include inhibitors of ACTH secretion, steroidogenesis inhibitors, and glucocorticoid receptor antagonists; drugs acting at different levels can be also combined in uncontrolled patients. EXPERT OPINION: Since there is still no standardized pharmacological approach and the superiority of one drug over another has not been established yet in the absence of comparative studies, each time clinicians' choices should be patient-tailored. Age, gender, tumor features, severity of hypercortisolism, comorbidities/complications, rapidity of action, side effects, drug-drug interactions, contraindications, availability, patients' preferences, and costs should be all considered.