Hypercortisolism in Refractory Diabetes, CATALYST Data

Experts examine the role of hypercortisolism in difficult-to-control diabetes, highlighting findings from the CATALYST trial and the practical implications of dexamethasone suppression testing in this population.

Here, Samson broadens the discussion from autoimmune etiologies to secondary endocrine causes of diabetes, focusing on hypercortisolism. She notes that diabetes can occur in the context of overt Cushing syndrome and acromegaly, in which treatment of the underlying endocrinopathy often leads to improved glycemic control and, in some cases, remission of diabetes.

Samson then turns to milder forms of cortisol excess, including so-called autonomous cortisol secretion from adrenal nodules, in which patients may lack classic Cushingoid features but still exhibit significant metabolic disturbances. She explains that the new 2026 AACE algorithm explicitly lists hypercortisolism among the conditions that warrant further evaluation when patients exhibit unexplained hyperglycemia or require unusually high insulin doses.

Umpierrez, who served as a principal investigator for the CATALYST trial, describes the study’s design and key findings. The trial enrolled more than 1000 adults with difficult-to-control type 2 diabetes, many of whom also had hypertension or required multiple glucose-lowering agents. Participants underwent an overnight 1‑mg dexamethasone suppression test, with morning cortisol levels measured the following day. A cortisol concentration greater than 1.8 μg/dL was considered indicative of nonsuppressible cortisol or hypercortisolism.

According to Umpierrez, approximately 23.8% of these patients met criteria for hypercortisolism, and the prevalence was even higher (around 36.6%) among those taking multiple antihypertensive medications. Subsequent adrenal imaging revealed that about one-third of patients with abnormal suppression tests had adrenal abnormalities, most commonly unilateral adrenal nodules.

Building on these data, Samson and Umpierrez discuss the therapeutic and practical implications of identifying hypercortisolism in patients with “type 2” diabetes that is refractory to standard management. Samson notes that in CATALYST, patients with hypercortisolism who entered a treatment phase with the glucocorticoid receptor antagonist mifepristone experienced improvements in weight, waist circumference, and hemoglobin A1c—on the order of a 1.5% reduction over 24 weeks. She cautions that while more research is needed to define screening strategies and long-term outcomes, the findings support a more active search for cortisol excess in patients with unexplained insulin resistance and metabolic instability.

Practically, Samson emphasizes that a positive dexamethasone suppression screen should prompt referral to an endocrinologist for comprehensive evaluation and management of hypercortisolism. Within the 2026 AACE algorithm, this approach reinforces the broader message that clinicians should consider endocrine comorbidities when glycemic control is unexpectedly difficult.