Introduction and Objective: Hypercortisolism may reduce the efficacy of GLP-1 RAs or tirzepatide by disrupting the incretin system, impairing beta cell function, and inducing insulin resistance. The CATALYST trial studied the prevalence and medical treatment of hypercortisolism in people with difficult-to-treat T2D. This sub-analysis assessed treatment with mifepristone (mife) in participants on GLP-1 RAs or tirzepatide (“GLP-1/T group”). Methods: In the CATALYST treatment phase, 136 participants with T2D (HbA1c 7.5-11.5% on multiple glucose-lowering medications) and hypercortisolism (cortisol 1.8 μg/dL on 1-mg dexamethasone suppression test) were randomized 2:1 to mife 300-900 mg QD or placebo. The GLP-1/T group included those who took GLP-1 RAs or tirzepatide before and for ≥80% of the study. Results: See Table for results. Baseline HbA1c was similar across groups (~8.5%) while weight and waist circumference were higher in the GLP-1/T group. In all groups, HbA1c, weight, and waist circumference were significantly reduced with mife vs placebo, with the greatest improvements seen in the GLP-1/T group (difference from placebo -1.7%, -6.1 kg, -6.5 cm; all P0.05). Conclusion: Mife improved HbA1c, weight, and waist circumference in CATALYST participants, including those taking GLP-1 RAs or tirzepatide. These results suggest that individuals with poorly controlled T2D despite multiple therapies may need to be screened for hypercortisolism and considered for treatment. Disclosure L. Sloan: Speaker's Bureau; Current; Abbott, AstraZeneca. Advisory Panel; Current; Corcept Therapeutics. Speaker's Bureau; Current; Corcept Therapeutics, Boehringer Ingelheim International GmbH, Bayer AG, Eli Lilly and Company, Lilly. Advisory Panel; Current; Idorsia Pharmaceuticals Ltd. Speaker's Bureau; Current; Madrigal Pharmaceuticals, Inc. Advisory Panel; Current; Novo Nordisk. Advisory Panel; Ended; Xeris Pharmaceuticals, Inc. 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Sloan et al. (Sat,) studied this question.