Erik Swain , 2025-06-23 20:24:00
Key takeaways:
- Mifepristone reduced HbA1c and weight in patients with hypercortisolism and difficult-to-control type 2 diabetes.
- Screening patients with difficult-to-control diabetes for hypercortisolism is a viable strategy.
CHICAGO — In patients with hypercortisolism and inadequately controlled type 2 diabetes, mifepristone lowered HbA1c levels by about 1.5% over 24 weeks compared with placebo, according to the final results of the CATALYST trial.
As Healio previously reported, in part one of the CATALYST trial, researchers determined that the prevalence of hypercortisolism was 24% in a cohort of patients with an HbA1c of 7.5% to 11.5% despite being on multiple medications. For part two, the researchers 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.
The discovery that so many patients in part one had hypercortisolism “was extremely exciting, because to my knowledge, there has never been anything that we thought might account for 24% of people that are challenging to manage in diabetes care,” John B. Buse, MD, PhD, the Verne S. Caviness Distinguished Professor of Medicine and director of the UNC Diabetes Center at University of North Carolina School of Medicine, told Healio. “What was unknown was whether we could do anything about it. So part two involved taking those people with difficult-to-control type 2 diabetes who had evidence of hypercortisolism, doing some additional screening to determine the cause of hypercortisolism, and then randomizing them to mifepristone or placebo to see if the drug would improve their glycemic control.”
The cohort had a mean age of 63.2 years, 61% were men and mean baseline HbA1c was 8.55%. All were on multiple glucose-lowering medications; some were on multiple blood pressure medications and also had evidence of a microvascular or macrovascular complication at baseline.
Improvements at 24 weeks
At 24 weeks, HbA1c declined from 8.62% to 7.12% in the mifepristone group (least squares mean change, –1.47 percentage points; 95% CI, –1.79 to –1.14) compared with a decline from 8.41% to 8.36% in the placebo group (least squares mean change, –0.15 percentage points; 95% CI, –0.56 to 0.27). The mean difference in HbA1c between the groups was –1.32 percentage points (95% CI, –1.81 to –0.83; P < .001), according to the researchers.
The difference in HbA1c reduction occurred despite the fact that participants in the mifepristone group “reduced one or more of their antidiabetes medications,” Buse told Healio. “In some ways, a 1.5 [percentage point] reduction in HbA1c is an underestimate of what the potential effect really is.”
Compared with the placebo group, the mifepristone group at 24 weeks also had reductions in body weight (– 4.4 kg; 95% CI, –6.275 to –2.525 vs. gain of 0.72 kg; 95% CI, –1.838 to 3.272; placebo-adjusted least squares mean change, –5.12 kg; 95% CI, –8.203 to –2.031), BMI (–1.47 kg/m2; 95% CI, –2.096 to –0.841 vs. gain of 0.28 kg/m2; 95% CI, –0.577 to 1.131; placebo-adjusted least squares mean change, –1.75 kg/m2; 95% CI, –2.799 to –0.713) and waist circumference (–5.2 cm; 95% CI, –7.25 to –3.21 vs. –0.1 cm; 95% CI, –2.74 to 2.51; placebo-adjusted least squares mean change, –5.1 cm; 95% CI, –8.23 to –1.99), according to the researchers.
Safety of mifepristone
Mifepristone was associated with an increase in blood pressure. At 24 weeks, systolic BP rose 8 mm Hg in the mifepristone group (95% CI, 3.82-12.18) compared with a drop of –2.1 mm Hg in the placebo group (95% CI, –7.47 to 3.27; placebo-adjusted least squares mean change, 10.1 mm Hg; 95% CI, 3.62-16.59), the researchers found.
The rate of treatment discontinuation was 46% in the mifepristone group compared with 18% in the placebo group.
Buse said the safety profile was consistent with what is already known about mifepristone. Hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea and dizziness each occurred in at least 10% of participants in the mifepristone group.
“This drug requires attention to potassium and clinical symptom, but nothing new or surprising came up,” he said.
The results suggest that “we should be screening for hypercortisolism with the 1 mg overnight dexamethasone suppression test in a large proportion of our patients with type 2 diabetes, namely, people that seem to have multimorbidity disease and are on multiple drugs,” Buse told Healio. “More patients that screened positive in our study had cardiovascular disease, as well as depression or other neuropsychiatric conditions. More patients had pain and were taking analgesics. They were not doing well in their diabetes control. If hypercortisolism is identified … treatment directed at cortisol can dramatically improve not only glycemic control but weight. We felt it was very likely that mifepristone created those improvements in the setting of hypercortisolism. But what this really proves is that that using the DST as an initial screening strategy is adequate. That’s probably the most important point for the endocrine community.”
Reference:
For more information:
John B. Buse, MD, PhD, can be reached at jbuse@med.unc.edu.
Sources/Disclosures
Collapse
Buse JB, et al. Symposium – Treatment of hypercortisolism in people with difficult-to-control type 2 diabetes — Final results of the CATALYST trial. Presented at: American Diabetes Association Scientific Sessions; June 20-23, 2025; Chicago.
Disclosures:
The CATALYST study was funded by Corcept Therapeutics. Buse reports consulting or serving on an advisory panel for Altimmune, Antag Therapeutics, Aqua Medical, AstraZeneca, Boehringer Ingelheim, CeQur, Corcept Therapeutics, Dexcom, Eli Lilly, Embecta, GentiBio, Glyscend, Insulet, Medtronic MiniMed, Mellitus Health, Metsera, Novo Nordisk, Pendulum Therapeutics, Pratego, Stability Health, Tandem Diabetes Care, Terns, Vertex and Zealand; receiving research support from Corcept Therapeutics, Dexcom and Novo Nordisk; and holding equity in Glyscend, Mellitus Health, Metsera, Pendulum Therapeutics, Pratego and Stability Health. Please see the study for all other authors’ relevant financial disclosures.
