Cushing’s disease is a progressive pituitary disorder in which there is an excess of cortisol in the body. While the disease can be treated surgically, this option is not possible for all patients. This is one of the approved medications that assist in controlling cortisol levels in people with Cushing’s disease.
Korlym (mifepristone), developed and marketed by Corcept Therapeutics , is an FDA-approved treatment for high blood sugar (hyperglycemia) in adults with Cushing’s syndrome who have type 2 diabetes or glucose intolerance, and for whom surgery is not an option, or failed to control their symptoms.
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How does Korlym work?
Cushing’s syndrome is characterized by high levels of cortisol in the body. Cortisol is a hormone that helps control a wide range of bodily functions, including blood pressure, salt levels, and blood sugar (glucose) levels. Too much cortisol may cause blood sugar levels to rise — a hallmark of both type 2 diabetes and glucose intolerance.
Cortisol exerts its effects by binding to glucocorticoid receptors on the surface of cells. Korlym works by blocking cortisol’s access to these receptors, thereby preventing the chain of events leading to elevated blood sugar levels and diabetes.
The medication is specifically meant to treat patients with endogenous Cushing’s syndrome, in which the body’s own overproduction of cortisol — usually due to the presence of a tumor — is the reason why hormone levels rise above healthy limits.
Korlym in clinical trials
Corcept conducted a Phase 3 trial (NCT00569582) to evaluate the safety and efficacy of mifepristone in 50 adults with endogenous Cushing’s syndrome and type 2 diabetes or impaired glucose tolerance, or high blood pressure alone.
In the group with diabetes, 60% of participants showed a clinically meaningful improvement in glucose control in a two-hour oral glucose test. In the high blood pressure group, an improvement in diastolic blood pressure — the pressure in the arteries while the heart rests between beats — was seen in 38% of participants.
In addition, an overall clinical improvement was seen in 87% of participants, as assessed by an independent review board. Board members looked at a range of symptoms, including body weight and composition, Cushing-like appearance, and psychological symptoms.
Common adverse events reported in the study included fatigue, nausea, headache, low potassium, joint pain, vomiting, and swelling, called edema. Thickening of the lining of the uterus was reported among female participants.
A pilot Phase 4 trial (NCT01990560) also demonstrated that mifepristone may be helpful in managing mild autonomous cortisol secretion (ACS), a subclinical form of Cushing’s syndrome in which patients do not display typical signs and symptoms of Cushing’s, despite having high cortisol levels.
That pilot trial enrolled eight patients who received 300 mg tablets once daily for six months. In two patients, this dose was upped to 600 mg after two months due to a lack of clinical response.
Treatment led to significant reductions in fasting glucose levels and insulin resistance — when certain cells no longer respond well to insulin, a hormone that controls how cells store and use glucose.
Another study also indicated that mifepristone can effectively treat patients with ectopic Cushing’s syndrome. This is a form of Cushing’s caused by tumors found outside the brain’s pituitary gland, in which case the condition is known as Cushing’s disease.
Korlym’s blood absorption is higher when the medication is given with food. Patients should, therefore, take the medication within one hour of having a meal, so as to increase its effectiveness.
Importantly, eating grapefruit or drinking grapefruit juice should be avoided while taking the medication, since both may interfere with its absorption. Korlym also may interact with a variety of other prescription meds, including cholesterol-lowering medicines simvastatin and lovastatin, the immunosuppressant cyclosporine, headache treatments ergotamine and dihydroergotamine, and opioid fentanyl.
The antifungal treatment ketoconazole (sold under the brand name Nizoral, among others), used off-label to treat Cushing’s in the U.S., also can change the way Korlym is absorbed in the body. Since both medications can be prescribed simultaneously to Cushing’s patients, doctors should carefully evaluate their benefits, taking into account the potential risks.
Additionally, mifepristone — Korlym’s active ingredient — blocks the action of the hormone progesterone, which is important for maintaining pregnancy. Taking Korlym during pregnancy will result in pregnancy loss. Therefore, Korlym should never be taken by women who are pregnant or by those who may become pregnant.
Treatment with Korlym also may cause blood potassium levels to drop, a condition known as hypokalemia. Potassium is a mineral that helps the body regulate fluid balance, nerve signals, and muscle contraction. As such, patients’ potassium levels should be monitored closely in the first weeks after starting or increasing Korlym’s dose, as well as periodically thereafter.