Richard Auchus, MD, and Ralph DeFronzo, MD, reframe hypercortisolism, including classic Cushing syndrome, adrenal adenoma–related cortisol excess, and non-neoplastic forms, as an under-recognized yet common driver of refractory metabolic disease, emphasizing practical clinical red flags and the simple, high-yield use of the overnight 1-mg dexamethasone suppression test to identify high-risk patients and guide further diagnostic evaluation and treatment.
In this introductory segment, Richard Auchus, MD, and Ralph DeFronzo, MD, frame hypercortisolism as an underrecognized driver of difficult-to-control type 2 diabetes, hypertension, and osteoporosis, challenging the traditional view of Cushing syndrome as a rare disorder.
Auchus and DeFronzo describe the underuse of hypercortisolism screening in primary care and outline a straightforward, clinically pragmatic approach to the overnight 1-mg dexamethasone suppression test and subsequent workup.
Auchus and DeFronzo use the CATALYST trial to illustrate that both tumor-related and non-neoplastic hypercortisolism are common in refractory diabetes and respond to glucocorticoid receptor blockade, redefining “pseudo-Cushing” as a clinically important disease state.
Auchus and DeFronzo review mifepristone (RU-486) as a glucocorticoid receptor antagonist for Cushing syndrome and refractory hypercortisolism, detailing its effects on glycemic control, weight, and safety considerations from the SEISMIC and CATALYST trials.
DeFronzo and Auchus underscore the magnitude of metabolic benefit with mifepristone, the complexity of managing withdrawal and electrolyte issues, and the importance of specialist support and education for primary care physicians.
Auchus and DeFronzo survey the broader pharmacologic armamentarium for Cushing syndrome and hypercortisolism, including metyrapone, osilodrostat, ketoconazole, levoketoconazole, pasireotide, and investigational agents such as relacorilant and ACTH receptor antagonists.
In their closing remarks, Auchus and DeFronzo emphasize routine screening of high-risk patients, the persistent cardiovascular burden of hypercortisolism despite risk-factor treatment, and the necessity of targeting cortisol excess itself.
