Mifepristone as Bridge or Adjunct Therapy in the Management of Challenging Cushing Disease Cases.

Establishing a definitive diagnosis of Cushing disease (CD), given its clinical and biochemical heterogeneity, initiating effective treatment to control the effects of hypercortisolism, and managing recurrence are challenging disease aspects to address. Mifepristone is a competitive glucocorticoid receptor antagonist that is approved in the US by the Food and Drug Administration to control hyperglycemia secondary to endogenous hypercortisolism (Cushing syndrome) in patients who have glucose intolerance or type 2 diabetes mellitus and have failed surgery or are not candidates for surgery. Herein, we describe 6 patients with CD who received mifepristone as adjunct/bridge therapy in the following clinical settings: to assess clinical benefits of treatment for suspected recurrent disease, to control hypercortisolism preoperatively for severe disease, to control hypercortisolism during the COVID-19 pandemic, and to provide adjunctive treatment to radiation therapy. The patients were treated at multiple medical practice settings. Mifepristone treatment in each of the described cases was associated with clinical improvements, including improvements in overall glycemia, hypertension, and weight loss. In addition, in one case where biochemical and radiological evidence of disease recurrence was uncertain, clinical improvement with mifepristone pointed toward likely disease recurrence. Adverse events associated with mifepristone reported in the 6 cases were consistent with those previously reported in the pivotal trial and included cortisol withdrawal symptoms, antiprogesterone effects (vaginal bleeding), hypothyroidism (treated with levothyroxine), and hypokalemia (treated with spironolactone). These cases show how mifepristone can potentially be utilized as a therapeutic trial in equivocal cases of CD recurrence; as a presurgical treatment strategy, particularly during the COVID-19 pandemic; and as bridge therapy, while awaiting the effects of radiation.

Pasireotide: A Novel Treatment for Tumor-Induced Hypoglycemia Due to Insulinoma and Non-Islet Cell Tumor Hypoglycemia.

Tumor-induced hypoglycemia is a serious disorder most commonly caused by insulinoma or non-islet cell tumor hypoglycemia (NICTH). The hypoglycemia can be severe and refractory to conventional therapy, leading to significant morbidity and mortality. The objective of this work is to describe a series of challenging cases in which refractory, tumor-induced hypoglycemia was shown to respond to the use of pasireotide, a second-generation somatostatin receptor ligand. We describe the clinical and biochemical features of 3 patients with tumor-induced hypoglycemia due to an occult insulinoma, malignant insulinoma, and non-islet cell tumor hypoglycemia. In these 3 individuals, the hypoglycemia remained refractory to guideline-recommended medical therapy, such as diazoxide, nonpasireotide somatostatin analogues, and glucocorticoids. Pasireotide was substituted to attenuate the refractory hypoglycemia for each patient. The addition of pasireotide led to prompt improvement in the frequency and severity of hypoglycemic episodes for each tumor-induced hypoglycemia patient. We demonstrate the successful treatment of 3 individuals with refractory, tumor-induced hypoglycemia with pasireotide. We offer the first reported use of pasireotide for the successful treatment of nonmalignant insulinoma and non-islet cell tumor hypoglycemia.