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ORLANDO -- A surprisingly high prevalence of hypercortisolism was found in people with uncontrolled diabetes, according to the two-part, phase IV study.

Of 1,055 patients with difficult-to-treat type 2 diabetes, 24% (253) were found to have endogenous hypercortisolism upon screening, reported John Buse, MD, PhD, of the University of North Carolina School of Medicine in Chapel Hill, at the American Diabetes Association (ADA) annual meeting.

Prevalence was even higher -- 35.4% -- among patients taking three or more antihypertensives (OR 2.079, 95% CI 1.509-2.861).

"This is potentially paradigm-shifting data," Buse said. He told MedPage Today that "the investigators were shocked [prevalence] was 24% in this study."

"Among the steering committee, the highest guess, based on our review of the literature beforehand, was 8%," he said. "I didn't think there was any chance we'd identify a big problem like this. We're talking more than a million people in the U.S. theoretically have this condition just from poorly controlled diabetes."

"And the signal around three drugs for hypertension makes us think we should do this study again in people with poorly controlled hypertension, and maybe people who are obese and don't respond to drugs like tirzepatide [Mounjaro] and semaglutide [Ozempic]," he said.

Hypercortisolism was defined as post-dexamethasone suppression test (DST) cortisol greater than 1.8 μg/dL with dexamethasone of 140 ng/dL or higher. Buse explained patients take a 1-mg tablet of the corticosteroid dexamethasone by mouth at 11 p.m. and then have a blood draw at 8 a.m. The average post-DST cortisol was 3.5 μg/dL and average dexamethasone was 412.7 ng/dL in those with hypercortisolism, far exceeding the diagnostic thresholds.

"The way we did the test really excludes patients with known causes of false-positive results," he added.

All patients enrolled in the 36-site study were already receiving standard-of-care therapy for their diabetes, but had an HbA1c between 7.5-11.5% on some combination of antihyperglycemic agents, insulin, and/or antihypertensives. Certain groups had a significantly higher likelihood of hypercortisolism based on baseline hypertension and micro- or macro-vascular complications:

• On 2+ antihyperglycemics and 2+ antihypertensives: OR 1.871 (95% CI 1.406-2.491)
• On 2+ antihyperglycemics with 1+ micro/macrovascular complication: OR 1.654 (95% CI 1.242-2.202)

When stratified by classes of antihyperglycemic medications, patients taking newer drug classes tended to be more likely to have hypercortisolism:

• Tirzepatide: OR 1.820 (95% CI 1.187-2.790)
• SGLT2 inhibitors: OR 1.687 (95% CI 1.265-2.251)
• GLP-1 receptor agonists and SGLT2 inhibitors: OR 1.467 (95% CI 1.080-1.992)
• Insulin and SGLT2 inhibitors: OR 1.448 (95% CI 1.082-1.938)

Beyond diabetic agents, several other medications were tied with significantly higher odds of hypercortisolism in the uncontrolled diabetes population. This included all hypertensives besides angiotensin-converting-enzyme (ACE) inhibitors -- including beta-blockers (OR 2.275), diuretics (OR 1.882), calcium channel blockers (OR 1.621), and angiotensin II receptor blockers (ARBs; OR 1.392) -- lipid medications (OR 1.771), psychiatric medications (OR 1.526), opioids (OR 1.984), and other cardiovascular medications (OR 1.929).

People with diabetes already have an increased risk for cardiovascular disease, but those with concomitant hypercortisolism appeared to have an even higher rate. This was reported for overall cardiac disorders (33.2% of hypercortisolism vs 20.6% without), coronary artery disease (16.6% vs 9.7%), atrial fibrillation (8.3% vs 3.0%), and congestive cardiac failure (6.7% vs 1.4%).

Other characteristics were also more common in diabetes patients with hypercortisolism, including being white, non-Hispanic, older, or on fibrates, having a BMI under 30, or having higher HbA1c. Among the patients enrolled, the average age was 60.7, 45% were female, mean BMI was 33.5, and mean HbA1c was 8.8%.

After the DST, patients had further evaluation with adrenal CT scans and labs for adrenocorticotropic hormone (ACTH), dehydroepiandrosterone (DHEAS), and cortisol. While most had no imaging abnormalities (66%), a third had adrenal abnormalities.

About a quarter had a unilateral adrenal adenoma, which Buse called "potentially surgically amenable." Another 3.9% had bilateral adrenal adenomas, 3.4% had unilateral/bilateral adrenal enlargement, and 3.4% had other adrenal abnormalities. Women were more likely to have an abnormal adrenal CT scan.

Uncovering hypercortisolism prevalence in this population was part one of the CATALYST study. Concluding by the end of this year, the second part will evaluate (Korlym), a cortisol receptor blocker, as a treatment of high cortisol in these diabetes patients.

Those with hypercortisolism will be randomized 2:1 with placebo, stratified by abnormal adrenal CT scans. Mifepristone will be administered as 300 mg/day titrated up to 600 mg/day for 24 weeks.

"If that is successful in improving glycemic control and provides other meaningful benefits, we will have established a new paradigm where people with poorly controlled diabetes -- and perhaps, in the future, poorly controlled hypertension or poorly controlled obesity, those kinds of features -- would be routinely screened for hypercortisolism and then treated if indicated," Buse said.

"I think most clinicians, given the opportunity to treat [hypercortisolism], would do so," he noted.

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