An evaluation of pharmacological options for Cushing’s disease: what are the state-of-the-art options?

ABSTRACT

Introduction

Untreated Cushing’s syndrome (CS) is associated with significant morbidity and mortality. Cortisol normalization is a key goal to treatment. Pituitary surgery remains the first-line approach for Cushing’s disease, but sometimes it is impracticable, unsuccessful, or complicated by recurrence. Medical therapy has been historically considered a palliative. However, in the latest years, interest on this topic has grown due to both the availability of new drugs and the reevaluation of the old, commonly used drugs in clinical practice.

Areas covered

In this article, we will discuss the current options and future directions of medical therapy for CS, aiming at fitting best patients’ features. An extensive literature search regarding already approved and investigational principles was conducted (PubMed, ClinicalTrials.gov. Available drugs include inhibitors of ACTH secretion, steroidogenesis inhibitors, and glucocorticoid receptor antagonists; drugs acting at different levels can be also combined in uncontrolled patients.

Expert opinion

Since there is still no standardized pharmacological approach and the superiority of one drug over another has not been established yet in the absence of comparative studies, each time clinicians’ choices should be patient-tailored. Age, gender, tumor features, severity of hypercortisolism, comorbidities/complications, rapidity of action, side effects, drug–drug interactions, contraindications, availability, patients’ preferences, and costs should be all considered.

KEYWORDS:

• Cabergoline
• levoketoconazole
• ketoconazole
• metyrapone
• mitotane
• osilodrostat
• pasireotide
• relacorilant

Article highlights

• CS is associated with significant morbidity and mortality if it is not treated.

• Pituitary surgery remains the first-line approach in CD, but sometimes it is impracticable, unsuccessful, or complicated by recurrence.

• The rationale for medical treatment of CS varies considerably, ranging from a short-term bridge option to a real resource in the management of specific, difficult cases.

• If there is a need for a quick fall in cortisol levels, an adrenal steroidogenesis inhibitor is recommended: metyrapone and osilodrostat have the fastest action and are orally available, while etomidate can be used intravenously in very severe cases.

• Osilodrostat seems to have the most convenient dosing schedule for patients.

• Ketoconazole is easy to titrate but may cause hepatotoxicity (generally mild and reversible after drug withdrawal) and hypogonadism in men.

• Adrenal steroidogenesis inhibitors do not target directly the pituitary adenoma, and their use may increase the risk of tumor progression.

• Pituitary directed-drugs (cabergoline and pasireotide) are generally preferred in mild disease and in case of detectable residual tumor, as they may induce tumor shrinkage.

• Patients treated with pasireotide should be monitored for the risk of diabetes mellitus.

• Cabergoline should be avoided if there is a history of bipolar or impulse control disorder.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.