Mifepristone May Benefit Patients with Mild Autonomous Cortisol Secretion, Pilot Trial Shows

Mifepristone, a synthetic steroid commonly used to taper high blood sugar levels and diminish insulin resistance in patients with Cushing’s syndrome, may also be helpful in managing mild autonomous cortisol secretion (ACS) due to adrenal tumors, a Phase 4 pilot trial shows.

Although ACS is considered a subclinical form of Cushing’s syndrome, with no evident signs of the disease, there is increasing evidence that ACS increases the risk of bone fractures, diabetes, and cardiovascular complications. Due to this, researchers maintain that these patients should not be left untreated, as is typical, and that mifepristone may be an option for some of them, including for those who are not eligible for surgery to remove the disease-causing tumor.

Trial findings were reported in the study, “Mifepristone treatment for mild autonomous cortisol secretion due to adrenal adenomas: a pilot study,” published in the journal Endocrine Practice.

ACS is a medical condition characterized by laboratory evidence of excessive cortisol levels, but without the typical clinical signs of Cushing’s syndrome, which is found in up to 20% of patients who have an adrenal incidentaloma, an asymptomatic tumor of the adrenal gland.

Patients with ACS are usually not treated for mild hypercortisolism (cortisol excess), but recent data show that even these people may experience adverse outcomes, including increased bone demineralization and risk of vertebral fractures, high blood pressure, type 2 diabetes, and cardiovascular issues.

Mifepristone, sold under the brand names Mifeprex and Korlym, is a glucocorticoid receptor blocker that works by halting the effects of glucocorticoid hormones such as cortisol. In the U.S., it is approved for the treatment of patients with endogenous Cushing’s syndrome who have type 2 diabetes or glucose intolerance, and have failed surgery or are not candidates for surgery.

A team led by researchers from the Icahn School of Medicine at Mount Sinai Hospital decided to assess the impact of mifepristone in patients with mild hypercortisolism or ACS, caused by adrenal incidentaloma, who were diabetic or prediabetic.

The pilot trial (NCT01990560) enrolled eight patients (four males and four females) who did not have physical signs of Cushing’s syndrome but tested positive for hypercortisolism in the overnight dexamethasone test.

Participants took 300 mg tablets of mifepristone once daily for six months. In two patients, the dose was increased to 600 mg after two months of treatment due to lack of clinical response.

Researchers conducted a series of clinical examinations, laboratory tests, and validated questionnaires — designed to determine health-related quality of life, anxiety, depression, hunger, fullness, and satiety — at the study’s start and again after three months and six months.

Data showed significant reductions in fasting glucose levels and insulin resistance — when the body stops responding well to insulin and is unable to counteract high blood glucose. These reductions were observed in all six patients for whom these measurements were available.

Improvements were also seen for depression and Cushing’s quality of life scores for most patients, while anxiety levels were increased. Still, none of these changes reached statistical significance.

During the study, no events of low blood pressure (hypotension) or low blood glucose (hypoglycemia) were reported in any of the participants, “indicating the relative clinical safety of using mifepristone in this setting,” the researchers wrote. However, two patients discontinued the treatment, one due to fatigue and the other due to symptoms of cortisol withdrawal.

There were no cases of uterine bleeding — a common adverse effect of mifepristone in women — likely because all women included were postmenopausal, the researchers noted.

“Mifepristone treatment of ACS may be considered as a medical option for patients with ACS due to adrenal adenomas with concomitant abnormal glucose parameters in whom surgical removal is not being considered,” they said.

Given the growing evidence that ACS is harmful for patients, especially in regard to cardiovascular health, complications associated with it “should be treated with available therapies,” the team suggests.

“With the advent of newer, more potent glucocorticoid receptor blockers and adrenal steroidogenesis inhibitors, future studies should be carried out to determine the effect of inhibition of glucocorticoid synthesis and/or action on metabolic, bone, mood and cardiovascular parameters in patients with ACS due to adrenal adenomas,” they concluded.