Isturisa May Work Faster Than Metopirone to Control Cortisol Levels

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Metopirone (metyrapone) and Isturisa (osilodrostat) were both effective at controlling cortisol levels in people with endogenous Cushing’s syndrome over a 12-week period, according to a recent study.

However, Isturisa tended to lower cortisol levels faster, and appeared to be better at controlling blood pressure than Metopirone. Some heart rhythm abnormalities were observed in patients treated with Isturisa, but not in those given Metopirone.

The study, “Metyrapone Versus Osilodrostat in the Short-Term Therapy of Endogenous Cushing’s Syndrome: Results From a Single Center Cohort Study,” was published in the journal Frontiers in Endocrinoloy.

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Endogenous Cushing’s syndrome is characterized by excessive levels of cortisol, a stress hormone, most often caused by tumors. Usually, treatment involves surgery to remove the tumor or take out part or all of the adrenal glands, which produce cortisol.

Medications such as Metopirone and Isturisa are used before surgery, and sometimes afterward, to control persistent elevations in cortisol. Both are steroidogenesis inhibitors, which act by blocking an enzyme needed for cortisol production.

While Metopirone has long been used for this purpose, Isturisa was more recently approved in 2020, and thus studies directly comparing their efficacy are lacking.

Researchers in Germany conducted a retrospective analysis to evaluate and compare the short-term efficacy of Metopirone and Isturisa in a group of 16 patients with endogenous Cushing’s who were treated with either of the two medications at their clinic between December 2017 and December 2021.

The cause of endogenous Cushing’s was a pituitary tumor (i.e. Cushing’s disease) in seven people and a tumor outside the adrenal or pituitary glands (i.e. ectopic Cushing’s) in five people. The remaining four people had tumors in the adrenal glands — two had a noncancerous adrenal adenoma, while the other two had adrenocortical carcinoma, a cancerous tumor.

Eight people were given Metopirone and eight received Isurisa.

Patients used Metopirone for a mean time of 17 weeks (over four months), and Isturisa was used for a mean of 9.5 weeks (over two months). Cortisol levels were assessed before treatment initiation, and two, four, and 12 weeks thereafter.

Total blood cortisol levels before treatment were 27.8 micrograms per deciliter (mcg/dL) in the Metopirone group and 22.8 mcg/dL in the Isturisa group (normal range: 5–25 mcg/dL).

By week 12, all patients in both groups had normal cortisol levels — a mean level of 8.3 mcg/dL with Metopirone and 13 mcg/dL with Isturisa.

Urinary free cortisol (UFC), a parameter that measures the levels of the active form of the hormone in the urine over a 24-hour period, was also evaluated and compared against a normal range of 0–70 mcg per day (mcg/d). Mean UFC values fell from 758 to 53 mcg/d after 12 weeks in patients given Metopirone. In those using Isturisa, UFC values dropped from 817 to 131 mcg/d.

In the first two weeks of treatment, UFC values fell faster, but not significantly so, among Isturisa-treated patients (68.4%  decline) compared with Metopirone-treated patients (21.3% decline). By week 12, those on Metopirone had experienced a more pronounced 71.5% decline from baseline levels, with those on Isturisa experiencing a 51.5% decline, which was again considered not statistically significant.

While the efficacy of the two medications was comparable, “[Isturisa] might have a superior short-time efficacy compared to [Metopirone],” the researchers wrote, adding the study indicated that Metopirone had “an increasing efficacy over time.”

A drop in blood pressure was observed in patients on Isturisa after four weeks. This, in turn, allowed patients to stop using a mean of one blood pressure medication after two weeks.

Metopirone was discontinued due to side effects, including lack of energy and dizziness, in two people. One person stopped using Isturisa due to adverse events that included depression, lack of energy, and nausea, and two people stopped using it after they had tumor removal surgery. One person in each group was lost to follow-up.

Potassium replacement therapy was required in some patients on either medication throughout treatment, which successfully normalized potassium levels.

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A progressive change in the QT interval — a measure of the heart’s electrical activity — was seen in patients using Isturisa, with one patient needing to interrupt treatment at 12 weeks due to these changes. Such changes are associated with an increased risk of heart rhythm abnormalities. The researchers noted that such side effects should be carefully monitored in patients using Isturisa.

The findings are overall “relevant for daily clinical practice, facilitating the choice of a certain steroidogenesis inhibitor when a prompt decrease of cortisol levels is indicated,” the researchers wrote. Isturisa “might be superior in rapidly reducing cortisol excess, but also clinical parameters like blood pressure.”

The team cautioned, however, “the number of patients in both treatment groups is still very low and, therefore, the power for statistical comparisons is limited,” noting a need for larger future studies.