Mifepristone Reduced HbA1c, Body Weight in Adults with Hypercortisolism and Inadequately Controlled T2D: CATALYST Trial Treatment Phase

John Buse, MD, PhD

Photo courtesy of UNC School of Medicine

In people with hypercortisolism and inadequately controlled type 2 diabetes (T2D), mifepristone lowered HbA_1c levels by about 1.5% over 24 weeks compared with placebo, according to the final results of the phase 4 CATALYST clinical trial.¹

In part 1 of the CATALYST trial, researchers found that the prevalence of hypercortisolism was 24% in a cohort of patients with an HbA_1c of 7.5% to 11.5% despite being on multiple medications.² For part 2, investigators enrolled 136 patients with hypercortisolism from part 1 who underwent random assignment to mifepristone (Korlym, Corcept Therapeutics), a glucocorticoid receptor antagonist, or placebo. The final results of part two were presented at the American Diabetes Association Scientific Sessions and simultaneously published in Diabetes Care.

“Approximately one-quarter of people with type 2 diabetes who do not meet glycemic targets despite treatment with multiple medications may have endogenous hypercortisolism. We wanted to understand whether mifepristone treatment may lower HbA_1c in these individuals,” researchers wrote.¹

Participants were randomized in a 2:1 ratio to receive mifepristone (300–900 mg daily) or placebo for 24 weeks. The primary endpoint was change in HbA_1c from baseline at week 24. The results showed that mifepristone reduced HbA_1c by a least squares mean (LSM) difference of -1.32% (95% CI, –1.81 to –0.83; P < .001) compared with placebo. Baseline HbA_1c was 8.55% on average, and the reduction was consistent across subgroups with and without adrenal imaging abnormalities.¹

Secondary outcomes included reductions in body weight and waist circumference, with mifepristone-treated participants experiencing a decrease of approximately 1.5 kg/m² and 5.2 cm, respectively (both P < .05) vs placebo.¹

“Many people with type 2 diabetes do not respond adequately to conventional glucose-lowering therapies,” coauthor John Buse, MD, PhD, director of the University of North Carolina’s Diabetes Center, said in a press release. “CATALYST shows that these patients should be screened for hypercortisolism and that treatment with a cortisol-directed therapy can confer significant clinical benefits, including meaningful reductions in HbA1c, body weight and waist circumference. These powerful findings provide important guidance for physicians treating patients with difficult-to-control type 2 diabetes.”³

Adverse events were common but manageable; over 90% of participants on mifepristone experienced treatment-emergent adverse events, chiefly hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness. Notably, hypokalemia occurred in 29.7% of mifepristone-treated participants and was defined as potassium <3.6 mmol/L. Blood pressure increases were also observed, consistent with known effects.¹

The tolerability profile was acceptable, although discontinuation rate was higher in the mifepristone group (46%) versus placebo (18%). Despite some adverse effects, the findings suggest mifepristone as a potentially effective therapy for a subset of patients with difficult-to-control T2D associated with biochemical hypercortisolism.¹

The authors conclude that screening for hypercortisolism in patients resistant to conventional glucose-lowering regimens is warranted, as cortisol-directed therapy offers a new avenue to improve glycemic control in this population. Longer-term studies are required to further evaluate safety and efficacy.¹

References:

1. Buse JB, DeFronzo RA, Fonseca V, et al. Inadequately controlled type 2 diabetes and hypercortisolism: Improved glycemia with mifepristone treatment. Diabetes Care. Published online July 23, 2025. doi:10.2337/dc25-1055

2. Jennings S. One-Quarter of Adults with Difficult-to-Control T2D have Hypercortisolism, According to New Data. Patient Care Online. June 26, 2024. https://www.patientcareonline.com/view/one-quarter-of-adults-with-difficult-to-control-t2d-have-hypercortisolism-according-to-new-data

3. Corcept presents data from treatment phase of CATALYST trial at American Diabetes Association’s 85th Scientific Sessions with simultaneous publication in Diabetes Care. Corcept Therapeutics. News release. June 23, 2025. Accessed June 24, 2025. https://ir.corcept.com/news-releases/news-release-details/corcept-presents-data-treatment-phase-catalyst-trial-american