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US Endocrinology Highlights Exciting Developments in the Medical Management of Cushing’s Disease Susan L Samson, MD, PhD, FRCPC, FACE 1–3 1. Associate Professor, Baylor College of Medicine, Houston, Texas, US; 2. Medical Director, The Pituitary Center, Baylor St Luke’s Medical Center, Baylor College of Medicine, Houston, Texas, US; 3. Fellowship Program Director, Department of Endocrinology, Baylor College of Medicine, Houston, Texas, US Abstract Until recently, there have been few options for the treatment of patients with Cushing’s disease who have failed surgery or have recurred. With the approval of US Food and Drug Administration (FDA) and European Medicines Agency (EMA) of mifepristone and pasireotide, endocrinologists now have additional therapies they can consider for their Cushing’s disease patients. Each of these medications has its own positive characteristics and adverse effects so that patient-specific characteristics must be taken into account when deciding on a suitable medical therapy. Keywords Cushing’s disease, mifepristone, pasireotide Disclosure: Susan L Samson, MD, PhD, FRCPC, FACE, has served on the advisory boards of Corcept Therapeutics and Novartis Pharmaceuticals and has been a site principal investigator for the SOM230 and LCI699 trials and has an investigator-initiated research grant from Novartis Pharmaceuticals. No funding was received for the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: October 4, 2015 Published Online: October 25, 2015 Citation: US Endocrinology, 2015;11(2):95–6 Correspondence: Susan L Samson, MD, PhD, FRCPC, FACE, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, ABBR R615, Houston TX 77030, US. E: ssamson@bcm.edu In 1932, Dr Harvey Cushing published his findings on a series of patients with what he called the “killing disease,” revealing that the median survival for most of his patients was less than 5 years from diagnosis. 1 With advances in surgical techniques and medical management of comorbidities, the standardized mortality ratio for patients with Cushing’s disease still is elevated two- to fivefold. The surgical remission rates for corticotroph adenomas are approximately 75% for microadenomas and <50% for macroadenomas, although this is dependent on the surgical center. 2 Further, recurrence rates are substantial. Endocrinologists have been left with few options for the treatment of patients who have failed surgery or have recurred. Ketoconazole inhibits multiple steps in cortisol synthesis, but has been subject to a black box warning from the US Food and Drug Administration (FDA) regarding potential for liver damage. Off- label use of the dopamine agonist, cabergoline, has been shown to lower cortisol levels, but only in a subset of patients and, even then, some responders will escape from control and manifest elevated cortisol. 3 At the extreme, adrenalectomy is an option but requires that there is good control of the pituitary adenoma, usually by prior treatment with radiotherapy, or there is risk of unchecked growth of the residual tumor cells, resulting in Nelson’s disease. Three years ago, our armoury against Cushing’s disease was expanded with the regulatory approval of two pharmaceutical agents. Mifepristone (Korlym, Corcept Therapeutics) (previously known as RU486) is a glucocorticoid receptor antagonist that blocks the effects of cortisol at the tissue level. It was approved by the European Medicines Agency (EMA) in 2011 as an orphan drug for the treatment of endogenous hypercortisolemia. Shortly after, the FDA approved mifepristone for the treatment of hyperglycemia associated with hypercortisolemia. The second addition was pasireotide (Signifor, Novartis Pharmaceuticals), TOU CH MED ICA L MEDIA which is a somatostatin receptor agonist (SRA) approved by the EMA and FDA in 2012. Pasireotide has a strong affinity for somatostatin receptor 5, which enables it to inhibit adrenocorticotropic hormone (ACTH) secretion from corticotroph adenoma cells, unlike its predecessors octreotide and lanreotide. For Cushing’s disease patients who are out of options, both therapies have potential. However, the choice of the right therapy must take into account patient-specific characteristics and the positive features and adverse effects of both drugs. Mifepristone Mifepristone is capable of rapid improvement in the clinical signs and symptoms of hypercortisolemia. The SEISMIC trial included subjects with Cushing’s syndrome of many etiologies: adrenocortical carcinoma, ectopic ACTH, bilateral adrenal hyperplasia, and corticotroph adenomas. 4 After 24  weeks of therapy, those subjects with a previous diagnosis of diabetes had improved glucose levels, including lowered fasting glucose, glycated hemoglobin, and glucose excursions during glucose tolerance testing. Thus, the FDA approval was for the treatment of hypercortisolemia accompanied by hyperglycemia. Weight decreased and there were improvements in the scores of questionnaires designed to test for depression, cognition, and quality of life. As mifepristone blocks cortisol feedback at the level of the corticotroph adenoma, the ACTH and cortisol levels rise two- to threefold, 5 so determining clinical efficacy for dose titration can be challenging, and the clinician has to rely on surrogate markers, such as improvement in Cushing’s syndrome-related symptoms and signs as well as indirect laboratory markers, such as lowered glycated hemoglobin. Mifepristone can be so effective in blocking the glucocorticoid receptor that patients can present with symptoms reminiscent of adrenal insufficiency, 61