Ketoconazole with octreotide may be effective Cushing’s treatment
Sequential treatment seen working in some patients with mild disease
Sequential treatment with ketoconazole to lower cortisol levels and octreotide to help keep cortisol under control may be effective as a treatment for a subset of people with mild Cushing’s disease, according to a study from the Netherlands.
Two of the three patients who responded to treatment, reflected by normalization of cortisol levels, also experienced reductions in weight, waist circumference, and blood pressure, indicating a lessening of Cushing’s symptoms.
Ketoconazole is approved as an oral therapy for Cushing’s disease in Europe, where it is sold as Ketoconazole Esteve, but not in the U.S. It blocks enzymes involved in the production of cortisol, a hormone whose excess levels cause Cushing’s.
Octreotide, sold under the brand names Sandostatin and Bynfezia for other conditions, acts on a receptor protein found at the surface of cells of the tumor that causes Cushing’s disease. However, these receptors are thought to decrease with increasing cortisol levels.
The study, “A Prospective Trial With Ketoconazole Induction Therapy and Octreotide Maintenance Treatment for Cushing’s Disease,” was published in the Journal of the Endocrine Society. Its findings support the hypothesis that an initial reduction in cortisol levels is crucial to restore levels of octreotide’s target protein, so that it can exert its actions and effectively help maintain low cortisol levels in Cushing’s disease patients.
Surgery is first-line Cushing’s treatment
Cushing’s disease is caused by a tumor in the brain’s pituitary gland that produces an excessive amount of ACTH, a hormone that stimulates cortisol production. As a result, the body produces too much cortisol, a condition known as hypercortisolism. This can cause high blood pressure, weight gain, diabetes, and other Cushing’s symptoms.
Transsphenoidal surgery, a procedure to remove pituitary tumors, is the first-line treatment for Cushing’s disease. Drug therapy may be used before surgery or after the surgery for recurring or persistent disease.
Octreotide binds to a receptor protein called somatostatin receptor subtype 2 (SST2) on the surface of ACTH-producing tumor cells, promoting a reduction in ACTH production. It has been tested in a few cases of Cushing’s disease.
Results so far suggest limited efficacy in those with active disease. This is thought to be associated with the fact that high cortisol levels ultimately result in reduced SST2 production, meaning that octreotide’s target would be found at lower levels in tumor cells.
“Hence, it may be hypothesized that normalizing or lowering cortisol levels in patients with CD [Cushing’s disease] can result in a reciprocal increase in SST2 [levels] by [ACTH-producing] tumor cells,” the researchers wrote.
They assessed whether initial treatment with ketoconazole, which is known to help reduce cortisol levels in Cushing’s, would allow subsequent octreotide treatment to be effective in people with Cushing’s disease.
“Under such conditions, the use of octreotide could play a potential role in CD management based on its safer toxicity profile compared to [Signifor (pasireotide)],” the team wrote.
Signifor, an approved treatment for Cushing’s disease, also acts directly on pituitary tumor cells, but it’s use is often limited by side effects such as high blood sugar.
Study looks at sequential treatment
A total of 14 people (mean age 48.6, 64% women) with newly diagnosed or recurrent Cushing’s disease received the sequential treatment with ketoconazole and octreotide.
Most (86%) had never received treatment, and 71% had mild hypercortisolism at the study’s start. High blood pressure was the most common simultaneous health condition (93%), followed by diabetes (50%) and abnormal levels of fatty molecules (43%).
All patients began daily ketoconazole treatment with doses that depended on disease severity. Once their cortisol levels returned to normal, they started monthly injections of octreotide. Ketoconazole was discontinued after two months if cortisol levels remained controlled, while octreotide was continued until the end of the nine-month study period.
Most participants (79%) responded to ketoconazole alone, achieving normal cortisol levels within one to two months. These 11 patients then advanced to the combination therapy phase, during which nine (82%) maintained normal cortisol levels.
After ketoconazole was stopped, three people (27%) maintained normal cortisol levels for the rest of the study and were considered responders. Four others (36%) had partial responses, with one showing a sustained 57% drop in cortisol levels (but still higher than normal), while three others achieved normal levels for one or two months, but levels started to gradually increase after ketoconazole discontinuation.
The remaining four (36%), classified as nonresponders, saw a rapid return of high cortisol levels after ketoconazole discontinuation, even when the octreotide dose was increased.
The patients who responded best to octreotide had lower cortisol levels at study’s start.
All three responders had full recovery of their cortisol diurnal rhythm, the normal daily fluctuation in cortisol levels that is often lost in Cushing’s disease. Two of the three responders also showed clinical improvements, including weight loss, reduced waist size, and lower blood pressure.
Among partial responders, three also showed weight and waist size reduction, and two had improved blood pressure.
Analyses of tumor samples from patients who subsequently underwent surgery showed that those who responded well to treatment had higher SST2 levels in their tumors, while partial and nonresponders showed lower levels.
“This is the first prospective study [a study following patients over time] to evaluate the clinical efficacy of octreotide in CD,” the researchers wrote. “Additional studies with longer follow-up are warranted to confirm the long-term efficacy of this strategy.”
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