CATALYST Trial: Mifepristone Improves Glycemic Control in Type 2 Diabetes with Hypercortisolism

Results of the phase 4 CATALYST trial indicate mifepristone (Korlym) significantly improved glycemic control, reduced body weight, and decreased waist circumference in patients with hypercortisolism and type 2 diabetes—offering a promising new strategy for a population with limited therapeutic success.

“I have been doing these kinds of trials for about 30 years, and this is about the most exciting thing I've ever done,” said study investigator John Buse, MD, PhD, from the University of North Carolina School of Medicine, in an episode of Diabetes Dialogue.

A 2-part, phase 4 trial, the first part of the CATALYST trial sought to define the prevalence of hypercortisolism. A total of 1055 patients from 36 study sites were included in the study. For inclusion in the study, patients needed to have an HbA1c greater than 7.5% despite receiving optimal therapies. Once identified, patients were required to complete a dexamethasone suppression test. If the values from this test were greater than 1.8 µg/dL and dexamethasone levels were greater than 140 ng/dL, these patients were considered as having hypercortisolism.

The results of part 1 from CATALYST were presented at ADA 2024 and suggested the true prevalence of hypercortisolism among patients with difficult-to-control type 2 diabetes was 24% (n=253 of 1055; 95% CI, 21.4 to 26.7).

In part 2 of the trial, which was presented at the 85th Scientific Sessions of the American Diabetes Association and published concurrently in Diabetes Care, investigators sought to determine whether use of mifepristone, a glucocorticoid receptor antagonist, might help improve glycemic control among patients with hypercortisolism. With this in mind, the randomized, prospective, placebo-controlled, double-blind, multicenter trial enrolled 136 patients meeting the same criteria from part 1 and randomized them 2:1 to mifepristone or placebo for 24 weeks.

The primary outcome of interest for the study was change in HbA1c from baseline to 24 weeks. The trial also included multiple secondary endpoints of interest, such as changes in glucose-lowering medications, weight, and waist circumference.

Results for the primary endpoint analysis, which Corcept Therapeutics announced in December 2024, use of mifepristone was associated with a least squares mean (LSM) difference from placebo in HbA1c was -1.3% (95% CI, -1.81 to -0.83; P <.001). Secondary outcome analysis suggested use was associated with reductions in body weight (LSM, -5.12 kg; 95% CI, -8.20 to -2.03) and waist circumference (LSM, -5.1 cm; 95% CI, -8.23 to -1.99) relative to placebo therapy.

Investigators pointed out that 49% of patients on mifepristone discontinued therapy compared to only 18% in the placebo group. Safety data suggested the most common adverse events observed with mifepristone included hypokalemia, fatigue, nausea, vomiting, headache, diarrhea, peripheral edema, and dizziness. Investigators also called attention to increase in blood pressure observed during the trial.
References:

Defronzo RA, Fonseca V, Auchus RJ, et al. Inadequately Controlled Type 2 Diabetes and Hypercortisolism: Improved Glycemia with Mifepristone. Dibetes Care. Published online June 23, 2025. doi: 10.2337/dc25-1055

Campbell P. CATALYST Proves Hypercortisolism More Common than Previously Known in Type 2 Diabetes. HCP Live. Published June 24, 2024. Accessed June 23, 2025. https://www.hcplive.com/view/catalyst-proves-hypercortisolism-more-common-than-previously-known-in-type-2-diabetes

Corcept Therapeutics. Corcept Announces Positive Results in Treatment Phase of CATALYST Trial in Patients With Hypercortisolism (Cushing’s Syndrome) and Difficult-to-Control Diabetes – Corcept Therapeutics, Incorporated. Corcept Therapeutics, Incorporated. Published December 12, 2024. Accessed June 23, 2025. https://ir.corcept.com/news-releases/news-release-details/corcept-announces-positive-results-treatment-phase-catalyst