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ORLANDO, Florida — Almost a quarter of patients with poorly controlled type 2 diabetes enrolled in the prevalence-phase of a new study had hypercortisolism, suggesting there may need to be a shift in managing these individuals, said investigators.

Researchers participating in the CATALYST trial reported that 24% (253) of the 1055 patients being studied had hypercortisolism. They presented their findings at the 84th Scientific Sessions of the American Diabetes Association (ADA).

"The investigators were shocked that it was 24% in this study," lead author John Buse, MD, PhD, Verne S. Caviness Distinguished Professor and director of the Diabetes Center at the University of North Carolina School of Medicine, Chapel Hill, North Carolina, told reporters in a press briefing before the main presentation.

If that incidence was extrapolated, "we're talking more than a million people in the United States, theoretically have this condition, just from poorly controlled diabetes," Buse said at the briefing.

According to the ADA, 39%-77% of people with type 2 diabetes have uncontrolled diabetes.

Based on reports in the literature, the investigators expected the prevalence would be closer to 8%, he said. But the understanding of hypercortisolism prevalence, especially in the United States, has been limited. Symptoms of hypercortisolism — known as Cushing syndrome — can include weight gain, high blood pressure, muscle weakness, and mood changes, according to the ADA. Hypercortisolism is also a potential driver of type 2 diabetes.

Cushing has been thought to be relatively rare, at about 1.2-3.2 cases per million per year. As recently reported by Medscape Medical News, it may be more prevalent in the United States than previously thought.

Given CATALYST's prevalence findings, clinicians might want to rethink how they approach these patients, said Buse.

Currently, patients are typically only screened — usually following Endocrine Society guidelines — for hypercortisolism if there's a high suspicion. Patients with poorly controlled diabetes are rarely screened, said Buse.

However, most patients with hypercortisolism don't appears as if they have classic Cushing syndrome, Richard Auchus, MD, PhD, The James A. Shayman and Andrea S. Kevrick Professor of Translational Medicine at the University of Michigan Medical School, Ann Arbor, Michigan, said at the ADA meeting.

"As endocrinologists, we've gotten hung up with cutpoints," said Auchus. He urged clinicians to think of hypercortisolism "as a continuum." There should be a simple way to screen, "and we should think about doing that in the right clinical setting," he said.

Buse said he and other investigators "are sort of holding off on pushing the American Diabetes Association to say, everybody with inadequately controlled diabetes, despite good faith efforts — two, three drugs — really should be treated for hypercortisolism."

"We're not ready to say that yet," he said. Researchers may urge a change once data are in from the ongoing second phase of the study, which will randomize the CATALYST enrollees to placebo or mifepristone (Korlym, Corcept Therapeutics), said Buse.

Rigorous Screening of Hypercortisolism

To be eligible for the CATALYST trial, patients had to have an A1c of 7.5-11.5%, be taking three or more antihyperglycemic drugs, taking insulin plus another antihyperglycemic, taking two or more antihyperglycemics and have one or more micro- or macrovascular complications, or be taking two or more antihyperglycemics and two or more antihypertensive medications.

The mean age was 61 years. Forty-five percent of the enrollees were women, 71% were White individuals, 19% were Black individuals, the mean A1c was 8.8, and the mean body mass index was 33.5 kg/m².

Seventy percent were taking more than three antihyperglycemic medications. A third were taking insulin plus a sodium-glucose co-transporter-2 inhibitor, and about a third were taking insulin plus a glucagon-like peptide 1 (GLP-1) receptor agonist.

To ensure the exclusion of those with falsely elevated cortisol, the trial did not enroll patients using oral contraceptives, or anyone with excess alcohol consumption, severe psychiatric illness or severe untreated sleep apnea, type 1 diabetes, or night shift work.

Investigators used the 1-mg dexamethasone overnight suppression test to detect endogenous hypercortisolism. Positive results were verified with lab evaluation of adrenocorticotropic hormone, dehydroepiandrosterone sulfate, and cortisol and adrenal CT scans.

Interestingly, 66% of the enrollees with hypercortisolism had no abnormality on imaging. Twenty-three percent had a unilateral adrenal adenoma, and about 10% had another adrenal abnormality.

Multiple Medications, Higher Risk

The risk for hypercortisolism was highest in those taking two or more antihyperglycemic medications and two or more antihypertensives (odds ratio, 1.871; 95% CI, 1.406-2.491), reported investigator Vivian Fonseca, MD, professor of medicine and pharmacology, Tulane University Health Sciences Center, New Orleans, at the meeting.

The likelihood of having the condition also went up with overall medication burden. Those taking any cardiovascular medication, including antihypertensives, lipid medications, psychiatric drugs, and analgesics and opioids, all had a higher risk, said Fonseca.

Those taking three or more blood pressure-lowering medications seemed to be at special risk. Twenty-one percent of CATALYST enrollees were taking three or more antihypertensives. The odds of having hypercortisolism was two times as high for these patients. Some 35% of them were found to have the condition, Fonseca reported.

Other characteristics more strongly associated with hypercortisolism included non-Hispanic ethnicity, fibrates, and the dual glucose-dependent insulinotropic polypeptide/GLP-1 tirzepatide.

Too Early to Change Practice

Asked to comment on the study, Lynnette Nieman, MD, senior investigator with the Diabetes, Endocrine and Obesity Branch at the National Institute of Diabetes and Digestive and Kidney Diseases, said that it is "a very provocative study."

Nieman told Medscape Medical News that the 24% prevalence figure, "on the face of it at least, this is a surprising number, a surprisingly high percentage."

But she noted that the data presented is just in the screening phase. The full study aims to determine whether mifepristone, a glucocorticoid receptor antagonist, might help better control diabetes.

Glucocorticoid antagonists have the potential to cause adrenal insufficiency, which can be dangerous and even can cause death, said Nieman. "I would not change how I approach diabetic patients at this point," she said, adding that it's reasonable to look carefully for signs and symptoms of Cushing "in anybody who has difficult to control hypertension or diabetes."

"It will be very interesting to see the entirety of the data in published form," Nieman said, adding that she would "want to understand whether any of these patients had overt Cushing Syndrome or whether they have mild autonomous cortisol excess."

The results of the CATALYST trial "will be eagerly awaited to determine whether or not treatment is appropriate and safe in these patients," said Nieman.

The study was supported by Corcept Therapeutics. Buse made multiple disclosures, including that he is a paid consultant and receives research support from Corcept. Auchus did not receive support from Corcept but is a consultant for Lundbeck, Novo Nordisk, Sparrow Pharmaceuticals, and Xeris Pharmaceuticals. Fonseca is a consultant for Corcept and Abbott, Bayer, and Sun Pharmaceutical Industries. Nieman disclosed that National Institutes of Health receives research funding from Crinetics Pharmaceuticals, which makes a Cushing's treatment.

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in publications including JAMA and Smithsonian.com. You can find her on X @aliciaault.