Hypercortisolism in Patients with Treatment-Resistant Type 2 Diabetes, with Richard Auchus, MD, PhD

At the 2025 Endocrine Society Conference, Richard Auchus, MD, PhD, presented the results of his deeper examination of the participants of the CATALYST trial for management of type 2 diabetes (T2D) in patients with hypercortisolism.

CATALYST was a phase 4, 2-part, multicenter trial; part 1 examined the prevalence of hypercortisolism in a population of roughly 1000 patients over 36 sites across the US. Each patient had hemoglobin A1c >7.5%, despite using several glucose-lowering therapies such as glucagon-like peptide-1 receptor agonists (GPL-1 RAs). Investigators administered a 1 mg dexamethasone suppression test, the results of which indicated 24% of participants had hypercortisolism.1,2

Part 2 of CATALYST was a randomized, double-blind, placebo-controlled study of mifepristone (Korlym) in select patients from part 1. Patients were randomized to either mifepristone or placebo; the former cohort exhibited a salutary response on glucose, with A1c lowering by roughly 1.5% and roughly 1.3% relative to placebo.1,2

Auchus and colleagues conducted a deeper examination of the patient characteristics highlighted in CATALYST, who had an A1c between 7.5% and 11.5%. Investigating the results from the dexamethasone suppression test, the team stratified patients into 3 major categories: cortisol <1.2, cortisol 1.2-1.8, and cortisol >1.8 after dexamethasone. Auchus and colleagues found substantial worsening of disease, disease control, and comorbidities associated with greater amounts of cortisol after dexamethasone.

“We found that 25% of them failed the dexamethasone suppression test, indicating some form of hypercortisolemia,” Auchus said. “And ‘failed’ conventionally is 1.8 mcg/dL or higher of serum cortisol after the 1mg test. But if you take truly normal people, their cortisol normally suppresses to zero. A couple of groups have looked at what the normal range is for dexamethasone suppression tests in people who are at low suspicion of hypercortisolism, and it turns out that the +2 standard deviation is about 1.2 mcg/dL.”

“Now, we didn’t test the 1.2 to 1.8 people,” Auchus told HCPLive. “So what would happen if we treated those people? And you could also take this one step further and say, ‘What would happen if we treated the people who were less than 1.2?’ I think these are the sort of questions that we need to address.”

Auchus spoke to the lack of variance in response between cohorts. He addressed the alternative approach taken when studying mifepristone and hypercortisolism’s impact on T2D.

“I think it’s comforting but vexing in that the test is an easy way to find people who should respond well, but the reason they respond and the underlying reason that their cortisol doesn’t suppress completely doesn’t seem to matter,” Auchus said. “And it’s a little different than the way we’ve normally thought about it.”

Auchus also mentioned barriers to implementation, chiefly the lack of comfort in drugs like mifepristone and cortisol-directed therapy at large.

“They’ve generally been boutique drugs that only a few endocrinologists use, who specialize in Cushing’s and pituitary centers, adrenal centers,” Auchus said. “I think a barrier to implementation is the comfort level of the average endocrinologist in using cortisol-directed therapy.”

Auchus advised clinicians to keep the possibility of secondary causes in mind when investigating a patient’s treatment-resistant diabetes or high blood pressure. He encouraged broader screening and earlier consideration of alternative causes.

“When the usual things don’t work, don’t keep banging your head against the wall,” Auchus said. “Think about secondary causes. Cortisol and aldosterone are two of the first things you should be thinking of.”

References

1. DeFronzo RA, Auchus RJ, Bancos I, et al. Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone. BMJ Open. 2024;14(7):e081121. Published 2024 Jul 16. doi:10.1136/bmjopen-2023-081121

2. Diabetes Care Publishes Results from Prevalence Phase of Corcept’s CATALYST Trial in People with Difficult-to-Control Type 2 Diabetes. Corcept Therapeutics. April 21, 2025. Accessed July 14, 2025. https://ir.corcept.com/news-releases/news-release-details/diabetes-care-publishes-results-prevalence-phase-corcepts