Slow and Steady With Osilodrostat Best in Cushing’s Disease

Gradual dose escalation had fewer adverse events, same therapeutic benefit, as quicker increases

by Kristen Monaco, Staff Writer, MedPage Today May 27, 2021 A more gradual increase in oral osilodrostat (Isturisa) dosing was better tolerated among patients with Cushing’s disease, compared with those who had more accelerated increases, a researcher reported.

Looking at outcomes from two phase III trials assessing osilodrostat, only 27% of patients had hypocortisolism-related adverse events if dosing was gradually increased every 3 weeks, said Maria Fleseriu, MD, of Oregon Health & Science University in Portland, in a presentation at the virtual meeting of the American Association of Clinical Endocrinology (AACE).

On the other hand, 51% of patients experienced a hypocortisolism-related adverse event if osilodrostat dose was increased to once every 2 weeks.

Acting as a potent oral 11-beta-hydroxylase inhibitor, osilodrostat was first approved by the FDA in March 2020 for adults with Cushing’s disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. The drug is currently available in 1 mg, 5 mg, and 10 mg film-coated tablets.

The approval came based off of the positive findings from the complementary LINC3 and LINC4 trials.

The LINC3 trial included 137 adults with Cushing’s disease with a mean 24-hour urinary free cortisol concentration (mUFC) over 1.5 times the upper limit of normal (50 μg/24 hours), along with morning plasma adrenocorticotropic hormone above the lower limit of normal (9 pg/mL).

During the open-label, dose-escalation period, all the participants were given 2 mg of osilodrostat twice per day, 12 hours apart. Over this 12-week titration phase, dose escalations were allowed once every 2 weeks if there were no tolerability issues to achieve a maximum dose of 30 mg twice a day.

After this 12-week dose-escalation schedule, additional bumps up in dose were permitted every 4 weeks. The median daily osilodrostat dose was 7.1 mg.

The LINC4 trial included 73 patients with Cushing’s disease with an mUFC over 1.3 times the upper limit of normal. The 48 patients randomized to receive treatment were likewise started on 2 mg bid of osilodrostat. However, this trial had a more gradual dose-escalation schedule, as doses were increased only every 3 weeks to achieve a 20 mg bid dose.

After the 12-week dose-escalation phase, patients on a dose over 2 mg bid were restarted on 2 mg bid at week 12, where dose escalations were permitted once every 3 weeks thereafter to achieve a maximum 30 mg bid dose during this additional 36-week extension phase.

Patients in this trial achieved a median daily osilodrostat dose of 5.0 mg.

In both studies, patients’ median age was about 40 years, the majority of patients were female, and about 88% had undergone a previous pituitary surgery.

When comparing the adverse event profiles of both trials, Fleseriu and colleagues found that more than half of patients on the 2-week dose-escalation schedule experienced any grade of hypercortisolism-related adverse events. About 10.2% of these events were considered grade 3.

About 28% of these patients had adrenal insufficiency — the most common hypercortisolism-related adverse event reported. This was a catch-all term that include events like glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased cortisol, Fleseriu explained.

Conversely, only 27.4% of patients on a 3-week dose escalation schedule experienced a hypercortisolism-related adverse event, and only 2.7% of these were grade 3.

No grade 4 events occurred in either trial, and most events were considered mild or moderate in severity.

“These adverse events were not associated with any specific osilodrostat dose of mean UFC level,” Fleseriu said, adding that most of these events occurred during the initial dose-escalation periods.

About 60% and 58% of all hypocortisolism-related adverse events occurred during the dose titration period in the 2-week and 3-week dose-escalation schedules, respectively. These events were managed via dose reduction, a temporary interruption in medication, and/or a concomitant medication.

Very few patients in either trial permanently discontinued treatment due to these adverse events, Fleseriu noted.

“Despite differences in the frequency of dose escalation, the time to first mUFC normalization was similar in the LINC3 and LINC4 studies,” she said, adding that “gradual increases in osilodrostat dose from a starting dose of 2 mg bid can mitigate hypocortisolism-related adverse events without affecting mUFC control.”

“For patients with Cushing’s disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response and tolerability aimed at normalizing cortisol levels,” Fleseriu concluded.

  • Kristen Monaco is a staff writer, focusing on endocrinology, psychiatry, and dermatology news. Based out of the New York City office, she’s worked at the company for nearly five years.

Disclosures

The LINC3 and LINC4 trials were funded by Novartis.

Fleseriu reported relationships with Novartis, Recordati, and Strongbridge Biopharma.

Primary Source

American Association of Clinical Endocrinology

Source Reference: Fleseriu M, et al “Effect of dosing and titration of osilodrostat on efficacy and safety in patients with Cushing’s disease (CD): Results from two phase III trials (LINC3 and LINC4)” AACE 2021.

From https://www.medpagetoday.com/meetingcoverage/aace/92824?xid=nl_mpt_DHE_2021-05-28&eun=g1406328d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily Headlines Top Cat HeC 2021-05-28&utm_term=NL_Daily_DHE_dual-gmail-definition

Metyrapone Effective and Safe in Endogenous Cushing’s Syndrome in Long Term

HRA Pharma Rare Diseases, an affiliate of privately-held French healthcare company HRA Pharma, has revealed data from the six-month extension of PROMPT, the first ever prospective study designed to evaluate metyrapone long-term efficacy and tolerability in endogenous Cushing’s syndrome.

After confirming good efficacy and safety of metyrapone in the first phase of the study that ran for 12 weeks, the results of the six-month extension showed that metyrapone successfully maintains low urinary free cortisol (UFC) levels with good tolerability.

The data will be presented at the European Congress of Endocrinology 2021 next week.

Metyrapone is approved in Europe for the treatment of endogenous Cushing’s syndrome. It works by inhibiting the 11-beta-hydroxylase enzyme, the final step in cortisol synthesis.

From https://www.thepharmaletter.com/in-brief/brief-metyrapone-effective-and-safe-in-endogenous-cushing-s-syndrome-in-long-term-says-hra-pharma-rare-diseases

What Causes Blood Sugar to Rise in Non-Diabetics?

High blood sugar or glucose, also called hyperglycemia, occurs when there is too much sugar in the blood. High blood sugar is the primary symptom that underlies diabetes, but it can also occur in people who don’t have type 1 or type 2 diabetes, either because of stress or trauma, or gradually as a result of certain chronic conditions.

It is important to manage high blood sugar, even if you don’t have diabetes, because elevated blood glucose can delay your ability to heal, increase your risk of infections, and cause irreversible damage to your nerves, blood vessels, and organs, such as your eyes and kidneys. Blood vessel damage from high blood sugar also increases your risk of heart attack and stroke.

Non-Diabetic Hyperglycemia and Prediabetes

You are considered to have impaired glucose tolerance or prediabetes if you have a fasting glucose level between 100–125 mg/dL, and hyperglycemia if your fasting blood glucose level is greater than 125 mg/dL, or greater than 180 mg/dL one to two hours after eating.

The body obtains glucose mainly through carbohydrate consumption, but also through the breakdown of glycogen to glucose—a process called glycogenolysis—or conversion of non-carbohydrate sources to glucose—called gluconeogenesis—that primarily occurs in the liver.

While 50% to 80% of glucose is used by the brain, kidneys, and red blood cells for energy, the remaining supply of glucose is used to produce energy. It is stored as glycogen in the liver and muscles, and can be tapped into at a later time for energy or converted into fat tissue.

In healthy people, blood glucose levels are regulated by the hormone insulin to stay at a steady level of 80–100 mg/dL. Insulin maintains steady blood sugar by increasing the uptake and storage of glucose and decreasing inflammatory proteins that raise blood sugar when there is an excess of glucose in the blood.

Certain conditions can increase your blood glucose levels by impairing the ability of insulin to transport glucose out of the bloodstream. When this occurs, you develop hyperglycemia, which puts you at an increased risk of prediabetes, diabetes, and related complications.

Common Causes

Cushing’s Syndrome

Cushing’s syndrome results from excess secretion of the adrenocorticotropic hormone, a hormone produced in the anterior portion of the pituitary gland that causes excess cortisol to be produced and released from the adrenal glands. Pituitary adenomas, or tumors of the pituitary gland, are the cause of Cushing’s syndrome in more than 70% of cases, while prolonged use of corticosteroid medication can also significantly increase the risk.

People with Cushing’s syndrome are at an increased risk of developing impaired glucose tolerance and hyperglycemia as a result of increased levels of cortisol throughout the body. Cortisol is a hormone that counteracts the effects of insulin by blocking the uptake of glucose from the bloodstream, thereby increasing insulin resistance and maintaining high blood sugar levels. Elevated cortisol levels also partially decrease the release of insulin from where it is produced in the pancreas.

Approximately 10% to 30% of people with Cushing’s syndrome will develop impaired glucose tolerance, while 40% to 45% will develop diabetes.

Corticosteroid medication is often prescribed to decrease inflammation throughout the body, but can lead to the development of Cushing’s syndrome and hyperglycemia because it activates specific enzymes that increase the conversion of non-carbohydrate molecules into glucose (gluconeogenesis). Corticosteroids also disrupt pancreatic cell function by inhibiting cell signaling pathways involved in the release of insulin from the pancreas.

Read other causes at https://www.verywellhealth.com/causes-blood-sugar-rise-in-non-diabetics-5120349

Rapid Control Of Ectopic Cushing’s Syndrome During The Covid-19 Pandemic in a Patient With Chronic Hypokalaemia

This article was originally published here

Endocrinol Diabetes Metab Case Rep. 2021 May 1;2021:EDM210038. doi: 10.1530/EDM-21-0038. Online ahead of print.

ABSTRACT

SUMMARY: In this case report, we describe the management of a patient who was admitted with an ectopic ACTH syndrome during the COVID pandemic with new-onset type 2 diabetes, neutrophilia and unexplained hypokalaemia. These three findings when combined should alert physicians to the potential presence of Cushing’s syndrome (CS). On admission, a quick diagnosis of CS was made based on clinical and biochemical features and the patient was treated urgently using high dose oral metyrapone thus allowing delays in surgery and rapidly improving the patient’s clinical condition. This resulted in the treatment of hyperglycaemia, hypokalaemia and hypertension reducing cardiovascular risk and likely risk for infection. Observing COVID-19 pandemic international guidelines to treat patients with CS has shown to be effective and offers endocrinologists an option to manage these patients adequately in difficult times.

LEARNING POINTS: This case report highlights the importance of having a low threshold for suspicion and investigation for Cushing’s syndrome in a patient with neutrophilia and hypokalaemia, recently diagnosed with type 2 diabetes especially in someone with catabolic features of the disease irrespective of losing weight. It also supports the use of alternative methods of approaching the diagnosis and treatment of Cushing’s syndrome during a pandemic as indicated by international protocols designed specifically for managing this condition during Covid-19.

PMID:34013889 | DOI:10.1530/EDM-21-0038

From https://www.docwirenews.com/abstracts/rapid-control-of-ectopic-cushings-syndrome-during-the-covid-19-pandemic-in-a-patient-with-chronic-hypokalaemia/

Severe Infection Including Disseminated Herpes Zoster Triggered by Subclinical Cushing’s Disease

Abstract

Background

Subclinical Cushing’s disease (SCD) is defined by corticotroph adenoma-induced mild hypercortisolism without typical physical features of Cushing’s disease. Infection is an important complication associated with mortality in Cushing’s disease, while no reports on infection in SCD are available. To make clinicians aware of the risk of infection in SCD, we report a case of SCD with disseminated herpes zoster (DHZ) with the mortal outcome.

Case presentation

An 83-year-old Japanese woman was diagnosed with SCD, treated with cabergoline in the outpatient. She was hospitalized for acute pyelonephritis, and her fever gradually resolved with antibiotics. However, herpes zoster appeared on her chest, and the eruptions rapidly spread over the body. She suddenly went into cardiopulmonary arrest and died. Autopsy demonstrated adrenocorticotropic hormone-positive pituitary adenoma, renal abscess, and DHZ.

Conclusions

As immunosuppression caused by SCD may be one of the triggers of severe infection, the patients with SCD should be assessed not only for the metabolic but also for the immunodeficient status.

Read the rest of the article at https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-021-00757-y

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