On February 17, 2012, the Food and Drug Administration (FDA) approved mifepristone (Korlym) as a once daily oral medication to treat patients with Cushing’s syndrome. The specific indication was for the treatment of elevated blood sugar in patients with Cushing’s syndrome and type 2 diabetes mellitus. Mifepristone was approved for patients who had failed or were not candidates for surgical treatment of their Cushing’s syndrome.

Mifepristone is a unique medication that actually blocks the effect of excessive cortisol by means of antagonizing the cortisol receptors in the body. It decreases the clinical features of Cushing’s syndrome and helps to improve the metabolic derangements associated with cortisol excess. The drug is rapidly absorbed and since it has a very long half-life, it can be administered on a once daily basis.

There have been scattered case reports over the past 15 years of the use of mifepristone for the treatment of patients with all forms of Cushing’s syndrome (pituitary-ACTH-secreting tumors, ectopic ACTH-secreting tumors, and adrenal tumors). Recently, Corcept Therapeutics (the company who manufactures mifepristone) conducted a multicenter, 24-week study in the United States of 50 patients with various types of Cushing’s syndrome who had failed surgery or who were not candidates for surgical intervention. This study showed a rapid improvement in glucose control in patients with type 2 diabetes due to Cushing’s syndrome. In addition, approximately 50% of the Cushing’s syndrome patients with hypertension had either improvement in their blood pressure or decrease in their antihypertensive medications. Most importantly, an independent review panel evaluated the responses of the patients to many parameters including glucose levels, blood pressure, lipids, weight, body composition change, neuropsychological factors, and physical appearance. Their analysis showed that clinically significant improvement occurred in 87% of patients treated with mifepristone.

Although the FDA approval was based on the improvement in diabetes control, the patients in the study lost 8-10% of their body weight in 24 weeks and had a remarkable decrease in their waist circumference during this study. Parameters of neuropsychological function and quality of life also improved significantly in the vast majority of patients. In fact, at the end of the six month study, 30 of 34 patients wanted to stay on the medication and were enrolled in an extension trial.

Mifepristone is not without some potential adverse effects. Anytime you are treating patients with Cushing’s syndrome effectively, nausea and loss of appetite, muscle and joint discomfort, and fatigue may ensue. This is often referred to as the glucocorticoid withdrawal syndrome which is a poorly understood phenomenon that occurs in patients effectively treated with Cushing’s syndrome. This is often a very challenging situation for both the patient and their endocrinologist. Although mifepristone blocks the effect of cortisol on the body, it was surprising that significant adrenal insufficiency was quite unusual in this study and was effectively treated by withholding the mifepristone and giving large doses of oral steroids. Mifepristone can also cause low potassium levels (hypokalemia). Consequently, potassium supplementation and medications to block the steroid receptors in the kidney that mediate potassium loss may be necessary to correct this problem. Mifepristone also blocks the female steroid hormone progesterone. In premenopausal women, this may lead to irregular menstrual bleeding requiring some surgical intervention. In order to stay on this medication, three women actually underwent hysterectomies. Mifepristone cannot be used in women who have any interest in achieving pregnancy.

Because mifepristone blocks the effect of cortisol on the body, it does not actually lower the levels of cortisol. In fact, in most patients with Cushing’s syndrome, the cortisol levels actually increase significantly. This means that cortisol levels cannot be monitored to determine the effectiveness of mifepristone. The effectiveness of mifepristone must be determined on clinical factors such as improvement in blood sugar, blood pressure, weight loss as well as improvement in physical appearance and neuropsychological factors.

It is not yet clear where mifepristone will fit in the treatment of patients with Cushing’s syndrome. There are certainly other medications (non FDA-approved) that are used to treat patients with Cushing’s syndrome. Pituitary directed therapies include cabergoline (often used to treat other types of pituitary tumors) and a new medication, pasireotide. Pasireotide is a first cousin of another medication, Sandostatin, which is widely used to treat some types of pituitary tumors. An international study of 162 Cushing’s disease patients treated with pasireotide was recently published. In this study pasireotide directly lowered the production of ACTH from pituitary tumors associated with Cushing’s disease and lowered the cortisol levels to normal in approximately 25% of patients. Pasireotide is injected on a twice daily basis; in contrast to mifepristone, pasireotide was associated with an increase in blood sugar in many patients with Cushing’s syndrome. The FDA is currently reviewing pasireotide and it may be approved for use in the United States within the next 4-6 months. Another clinical trial of a long-acting form of pasireotide (pasireotide LAR) is about to commence in many centers all over the world.

There are also oral medications used to treat the adrenal glands by lowering cortisol production. The most common one of these in the United States is ketoconazole. Ketoconazole was actually developed as an antifungal drug that was subsequently found to lower cortisol levels in higher doses. It must be administered 2-3 times daily and does have some toxicity particularly on the liver. Another orally administered medication is metyrapone. Metyrapone was actually developed in the late 1950s as a diagnostic medication for patients with pituitary adrenal gland problems. This drug is difficult to get in the United States and can be only secured with compassionate use. Mitotane is an oral medication widely used to treat patients with Cushing’s syndrome who have adrenal cancer. It has many toxic side effects and is rarely used in patients with other forms of Cushing’s syndrome.

It should always be mentioned that bilateral adrenalectomy –- a procedure that can now be performed in many centers safely by laparoscopic technique –- is a uniformly effective treatment for patients with Cushing’s syndrome due to an ACTH-secreting tumor; however, it does cause permanent life-long adrenal insufficiency requiring steroid replacement. And, although the quality of life with adrenal insufficiency is often not as good as having normal adrenal glands, it is certainly much better than a life with Cushing’s syndrome.

Mifepristone is an effective oral medication to control the signs and symptoms and the metabolic effects of Cushing’s syndrome. Because of its unique mode of action and the possible adverse side effects, it must be prescribed by endocrinologists who are very familiar with the complexities and nuances of treating patients with Cushing’s syndrome. Corcept Therapeutics has initiated a support program for access and reimbursement for mifepristone. Patients who are candidates to be treated with mifepristone should be sure that they see an endocrinologist who is experienced with the evaluation and management of patients with Cushing’s syndrome.

Author: Dr. James Findling (Spring, 2012)

Editor’s Note: Dr. Findling is an Endocrinologist and Professor of Medicine at the Medical College of Wisconsin in Menomonee Falls, WI. Dr. Findling has a particular interest in Cushing’s and has diagnosed and treated many Cushing’s patients. He also conducts research in the area.

Selected References

• Mifepristone, a Glucocorticoid Receptor Antagonist, Produces Clinical and Metabolic Benefits in Patients with Cushing’s Syndrome. Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C; on behalf of the SEISMIC Study Investigators. J Clin Endocrinol Metab. 2012 Mar 30.
• A 12-month phase 3 study of pasireotide in Cushing’s disease. Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR, Biller BM; Pasireotide B2305 Study Group. N Engl J Med. 2012 Mar 8;366(10):914-24.