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The prevalence of hypercortisolism in persons with difficult-to-control type 2 diabetes (T2D) may be higher than currently appreciated, particularly in persons who require a greater number of antihyperglycemic agents and/or have more comorbidities. To better understand the prevalence and whether treatment of hypercortisolism may result in better control of diabetes and other hypercortisolism-associated comorbidities, we have designed CATALYST, a prospective phase 4 study in adults with difficult-to-control T2D (HbA1c 7.5–11.5%) despite receiving multiple antihyperglycemic agents. CATALYST is being conducted at about 30 sites in the United States. In Part 1, about 1000 persons with difficult-to-control T2D will be screened with a 1-mg dexamethasone suppression test (cutoff: serum cortisol >1.8 µg/dL; dexamethasone ≥140 ng/dL). Patients with ACTH-dependent hypercortisolism will be referred out of the study. The primary study endpoint—the prevalence of ACTH-independent hypercortisolism—will be evaluated in Part 1. Patients with ACTH-independent hypercortisolism may advance to Part 2, a prospective, 2:1 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of treatment with the competitive glucocorticoid receptor antagonist mifepristone. Patients will be randomized (stratified by the presence/absence of adrenal adenomas on CT) and receive treatment for 24 weeks. The mifepristone dose will be 300 mg QD for 4 weeks, then increased to 600 mg QD for 20 weeks based on glycemic efficacy and tolerability (option to increase to mifepristone 900 mg). Secondary endpoints include changes in HbA1c from baseline to 24 weeks and changes in hypercortisolism-related comorbidities (e.g., blood pressure, weight, waist circumference, quality of life). [ABSTRACT FROM AUTHOR]