Non-Neoplastic Hypercortisolism, CATALYST Data, and Expanding the Concept of Cushing Syndrome

In this segment, Richard Auchus, MD, and Ralph DeFronzo, MD, delve into findings from the CATALYST trial to clarify the spectrum of hypercortisolism in difficult-to-control type 2 diabetes. Dr DeFronzo explains that entry criteria included hemoglobin A1c levels around 7.5% or higher plus evidence of treatment resistance—such as three oral agents, insulin plus oral therapy, or significant comorbidities including microvascular and macrovascular complications or hypertension. Within this enriched cohort, approximately 25% of participants—and as many as 39% in Dr DeFronzo’s own center—failed the overnight DST, indicating biochemically demonstrable hypercortisolism despite largely “typical” type 2 diabetes phenotypes.

Dr Auchus notes that these abnormalities occurred in patients with and without adrenal tumors, reinforcing the significance of non-neoplastic hypercortisolism. Previously labeled “pseudo-Cushing,” this state reflects cortisol dysregulation and impaired suppressibility due to chronic illness, psychiatric disease, or other stressors. In CATALYST, whether patients had adrenal adenomas, pituitary lesions, or no identifiable tumor, those with hypercortisolism responded to treatment with mifepristone, a glucocorticoid receptor antagonist. This observation underscores that cortisol excess is pathologic and therapeutically actionable regardless of the underlying structural etiology.

Dr DeFronzo emphasizes that the CATALYST protocol excluded obvious confounders—night-shift work, obstructive sleep apnea (OSA), and medications that disrupt ACTH secretion—to clarify primary hypercortisolism. However, both he and Dr Auchus stress that when hypercortisolism is secondary to conditions such as OSA, it should not be dismissed as benign. Cortisol excess in that setting still promotes adverse cardiovascular outcomes, including atrial fibrillation, stroke, and myocardial infarction. Treating the upstream driver (eg, OSA) is the appropriate focus, but recognizing the presence of cortisol excess helps explain why patients remain refractory to otherwise potent therapies. This segment reframes non-neoplastic hypercortisolism as a meaningful clinical target, not a diagnostic curiosity.