Mifepristone Improves HbA1c, Weight in Poorly Controlled T2D, Regardless of GLP-1 Treatment

Mifepristone has successfully improved HbA1c, weight, and waist circumference in patients with poorly controlled type 2 diabetes (T2D) regardless of prior treatment with GLP-1 RAs, according to a subanalysis of the CATALYST trial.1

These data were presented at the American Diabetes Association (ADA) Scientific Sessions 2026 in New Orleans, Louisiana, by Lance Sloan, MD, the president of the Texas Institute for Kidney and Endocrine Disorders. The analysis was based on the potential of hypercortisolism to reduce the efficacy of GLP-1 RAs or tirzepatide through inducing insulin resistance.1

“We have a lot of people with type 2 diabetes that we’re treating, and we’re adding more and more medications at higher and higher doses,” Sloan told HCPLive in an exclusive interview. “Sometimes, we feel like we’re just burning rubber – nothing’s happening, we’re not moving very far or very fast.”

The original CATALYST study was a prospective, multicenter, double-blind study including 136 patients with T2D and hypercortisolism. These patients were randomly assigned in a 2:1 ratio to either the glucocorticoid receptor antagonist mifepristone 300-900 mg once daily (n = 91) or placebo (n = 45) for 24 weeks. Patients were stratified by the presence or absence of an adrenal imaging abnormality. The trial’s primary endpoint was the change in HbA1c, with secondary endpoints including changes in weight, waist circumference, and glucose-lowering medications.2

Mean HbA1c was 8.55% at baseline in the study cohort. By 24 weeks, the least squares mean (LSM) difference from placebo was -1.32% (95% CI, -1.81 to -0.83; P <.001). Those receiving mifepristone also saw reductions in body weight and waist circumference (placebo-adjusted LSM differences of -5.12 kg [95% CI, -8.2 to -2.03] and -5.1 cm [-8.23 to -1.99], respectively).2

Among the mifepristone arm, 46% of patients discontinued therapy during the trial versus 18% of placebo recipients. Adverse events occurred in >10% of mifepristone recipients, including hypokalemia, fatigue, vomiting, diarrhea, peripheral edema, dizziness, nausea, and headache. These were consistent with mifepristone’s known tolerability profile.2

The present analysis specifically highlighted patients who were on GLP-1 RAs or tirzepatide – Sloan and colleagues noted that the most significant improvements in HbA1c, weight, and waist circumference were among the GLP-1/tirzepatide group (difference from placebo -1.7%, -6.1 kg, -6.5 cm, all P <.05). According to the team, these results may suggest that patients with poorly controlled T2D despite multiple therapies may require hypercortisolism screening.1

Sloan also discusses potential next steps for this patient population, highlighting upcoming therapies and treatments in the pipeline that may reduce the burden of hypercortisolism and allow for easier disease management.

“We do, of course, have newer medicines coming out that may be able to work around that by hitting other receptors,” Sloan said. “We’re getting more sophisticated all the time, and we’re now trying to figure out different things causing resistance to treatment. The good thing is that we have so many different things coming down the road – we’ll have different options for different patients.”

Editors’ Note: Abbott, AstraZeneca, Corcept Therapeutics, Boehringer Ingelheim, Bayer AG, Eli Lilly, and others.

References

1. Sloan L, Aroda V, Busch R, et al. Effects of Mifepristone in People with Difficult-to-Control T2D and Hypercortisolism on GLP-1RAs. Abstract presented at the American Diabetes Association (ADA) Scientific Sessions 2026, New Orleans, LA. June 5-8, 2026.

2. DeFronzo RA, Fonseca V, Aroda VR, et al. Inadequately controlled type 2 diabetes and hypercortisolism: Improved glycemia with mifepristone treatment. Diabetes Care. 2025;48(12):2036-2044. doi:10.2337/dc25-1055