Adrenal Insufficiency Can Follow Use of Isturisa, Case Study Reports

People with Cushing’s disease who are treated with Isturisa (osilodrostat) should be monitored for the possibility of developing adrenal insufficiency, a report highlights.

The case report, “Osilodrostat in Cushing’s disease: The risk of delayed adrenal insufficiency should be carefully monitored,” was published in the journal Clinical Endocrinology.

Cushing’s disease is caused by a benign tumor in the brain’s pituitary gland. The pituitary tumor triggers excessive production of a signaling molecule called adrenocorticotropic hormone, which prompts the adrenal glands to produce excessive amounts of the stress hormone cortisol. Elevated cortisol levels, a condition known as hypercortisolism, are mainly responsible for the disease’s symptoms.

Isturisa, an oral therapy, is approved to treat Cushing’s disease in the U.S., Europe, and Japan. The medication, which is marketed by Recordati, works by blocking the production of cortisol in the adrenal glands to lessen hypercortisolism.

Blocking cortisol production, however, can also lead to adrenal insufficiency — a condition in which the adrenal glands become unable to produce sufficient amounts of steroid hormones, particularly cortisol. Just as hypercortisolism can negatively impact health, so too can adrenal insufficiency.

Common symptoms of adrenal insufficiency include fatigue, low blood pressure, abdominal pain, and emotional disturbances.

Researchers in France described the cases of three people with Cushing’s disease who developed adrenal insufficiency while being treated with Isturisa on a stable dose. In all three cases, patients were started on the medication some time after undergoing surgery to remove a pituitary tumor, which failed to cure the condition.

The first patient, a male born in 1956, switched from other medications to Isturisa in mid-2020, after experiencing severe depression. He was also started on antidepressants, and his condition improved substantially.

He was first given Isturisa at a dose of 8 mg daily, which was later increased to 15 mg/day and then to 20 mg/day in order to control his hypercortisolism. While treatment was initially well-tolerated, the patient went to the hospital with complaints of nausea, diarrhea, and low blood pressure a few weeks after moving to the highest dose.

Lab tests showed that his cortisol levels were abnormally low. At this point, treatment with Isturisa was stopped, and the patient was given hydrocortisone, which is basically a replacement for cortisol. Once his condition stabilized, hydrocortisone was reduced and Isturisa re-started.

The other two patients — both females, one born in 1984 and the other in 1990 — had a similar experience: they were initially treated with a relatively low dose of Isturisa, which was gradually increased based on cortisol levels as appropriate.

While Isturisa was largely effective and well-tolerated — one was treated for over a year with no issues — both these patients later developed adrenal insufficiency.

In the older woman’s case, adrenal insufficiency was managed with Isturisa withdrawal and hydrocortisone treatment, similar to the first patient. For the younger woman, hydrocortisone treatment — while still on Isturisa — was enough to control adrenal insufficiency.

“These 3 cases emphasize the risk of delayed acute [adrenal insufficiency] in patients treated with a stable dose of osilodrostat [Isturisa] that allows eucortisolism [normal cortisol levels] to be reached,” the researchers wrote.

Patients and physicians should be aware of and knowledgeable about this risk, given that it occurs “in this setting of a highly effective drug,” they added.