Hypercortisolism prevalent among 24% of adults with difficult-to-control type 2 diabetes
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Key takeaways:
- The percentage of adults with hypercortisolism and difficult-to-control type 2 diabetes was higher than researchers expected.
- Adults using more antihypertensive medications had higher odds for hypercortisolism.
ORLANDO — Nearly one-quarter of adults with difficult-to-control type 2 diabetes also have hypercortisolism, and treating hypercortisolism may also benefit glycemic control in those with both conditions, according to speakers.
Researchers presented findings from part one of the two-part phase 4 CATALYST trial at the American Diabetes Association Scientific Sessions. The first part of the trial examined the prevalence of hypercortisolism among adults with difficult-to-control type 2 diabetes. As Healio previously reported, researchers reported that 24% of participants in part one had hypercortisolism. The figure far exceeded what the trial investigators expected, according to John B. Buse, MD, PhD, the Verne S. Caviness Distinguished Professor, director of the UNC Diabetes Center and co-director of the NC Translational and Clinical Sciences Institute at the University of North Carolina School of Medicine.
“Nobody guessed the number [would be] higher than 8%,” Buse told Healio during a press conference. “When each of us was approached by [Corcept Therapeutics] to design the study and then execute it, I was extremely skeptical. ... I didn’t think there was any chance we would identify a big problem like this.”
Buse said the higher than expected prevalence of hypercortisolism could indicate treating the condition may lead to improvements in glycemic control for people with type 2 diabetes not responding to other medications.
Assessing hypercortisolism prevalence
Previously published research on hypercortisolism prevalence among adults with type 2 diabetes has been limited and most studies have been conducted outside the U.S., according to Athena Philis-Tsimikas, MD, corporate vice president of Scripps Whittier Diabetes Institute in San Diego. The prevalence of hypercortisolism has also varied widely in past studies, ranging from 8% to 33%.
“This is what drove the need for a robust study, to look at what is the prevalence of hypercortisolism in difficult-to-control or manage diabetes,” Philis-Tsimikas said during a presentation.
Part one of the CATALYST trial enrolled 1,055 adults aged 18 to 80 years with type 2 diabetes who had an HbA1c between 7.5% and 11.5% and were taking three or more antihyperglycemic drugs, insulin and any other antihyperglycemic drug, two antihyperglycemic drugs with the presence of at least one microvascular or macrovascular complication, or at least two antihyperglycemic drugs and at least two antihypertensive drugs (mean age, 60.7 years; 45.1% women).
Participants underwent a 1 mg overnight dexamethasone suppression test (DST). Adults were defined as having endogenous hypercortisolism if they had a post-DST cortisol level of more than 1.8 µg/dL with dexamethasone level of 140 ng/dL or higher. Adults with hypercortisolism underwent further laboratory tests and an adrenal CT scan. The primary endpoint of the trial was the percentage of adults with endogenous hypercortisolism.
Prevalence higher than expected
Of the study group, 24% had endogenous hypercortisolism. The mean post-DST cortisol level was 3.5 µg/dL, and the mean dexamethasone level was 412.7 ng/dL.
“Twenty-four percent is a lot of people,” Buse told Healio. “Theoretically, more than 1 million people in the U.S. have this condition just from poorly controlled diabetes.”
Buse noted part of the reason for the higher than expected prevalence is screening for hypercortisolism is not routinely done for people with diabetes.
“[Screening is] done when we’re evaluating patients for hypercortisolism,” Buse told Healio. “It’s not done when we’re evaluating patients with poorly controlled diabetes. We always knew that Cushing’s disease would make someone’s diabetes worse. It’s called a secondary cause of diabetes. But a [1 mg DST] is not very commonly done.”
In univariate logistic regression analysis, adults who took at least two antihyperglycemic and at least two antihypertension drugs (OR = 1.871; 95% CI, 1.406-2.491) and those taking at least two antihyperglycemic drugs with one microvascular or macrovascular complication (OR = 1.654; 95% CI, 1.242-2.202) were more likely to have hypercortisolism. The odds for hypercortisolism was increased for adults taking tirzepatide (Mounjaro, Eli Lilly; OR = 1.82; 95% CI, 1.187-2.79) or an SGLT2 inhibitor (OR = 1.687; 95% CI, 1.265-2.251). Hypercortisolism odds increased with each additional antihyperglycemic medication class a person was taking (OR = 1.211; 95% CI, 1.046-1.402).
Ties to cardiovascular disease
Adults taking antihypertensive medications has increased odds for hypercortisolism (OR = 2.109; 95% CI, 1.383-3.216) and the odds for hypercortisolism were increased for all types of antihypertensive medications assessed except for angiotensin-converting enzyme inhibitors. Increased odds for hypercortisolism were also observed for adults taking lipid medications (OR = 1.771; 95% CI, 1.171-2.679), psychiatric medications (OR = 1.526; 95% CI, 1.126-2.069) and analgesics (OR = 1.55; 95% CI, 1.145-2.097) compared with adults not taking those medication types.
The prevalence of any cardiac disorder was higher among adults with hypercortisolism than those without hypercortisolism (33.2% vs. 20.6%; P < .0001). Vivian Fonseca, MD, FRCP, professor of medicine, assistant dean for clinical research, Tullis-Tulane Alumni Chair in Diabetes and chief of the section of endocrinology and metabolism at Tulane University School of Medicine, also noted adults taking three or more hypertension medications had higher odds for hypercortisolism as adults taking fewer than three hypertension medications (OR = 2.078; 95% CI, 1.509-2.861).
“The odds of having hypercortisolism was twice as high in those taking at least three antihypertensive drugs,” Fonseca said during a presentation. “The overall prevalence of hypercortisolism in these patients, which reflect the kind of patients I see in my clinic, was 35%.”
Of adults with hypercortisolism, 66% had no imaging abnormality found on a CT scan, whereas 23.2% had a unilateral adrenal adenoma, making them potential candidates for surgery, according to Fonseca.
“People normally come in with an adrenal adenoma and then we do the DST,” Fonseca said. “We’ve done it the other way around, not knowing that 23% of them had an adrenal adenoma.”
The odds of having an abnormal adrenal CT scan were higher in men vs. women and for adults with a higher medication burden.
Potentially ‘paradigm changing’
After identifying adults with hypercortisolism, researchers will assess the efficacy of medical therapy in part two of the CATALYST trial. The trial’s second part is ongoing and scheduled to be completed in the fourth quarter. In part two, 136 adults diagnosed with hypercortisolism in part one were randomly assigned, 2:1, to mifepristone (Korlym, Corcept Therapeutics), a cortisol receptor blocker, or placebo for 24 weeks. The primary outcome of part two is change in HbA1c from baseline to week 24.
The findings from part two of the trial could have enormous implications on the treatment of type 2 diabetes and potentially other cardiometabolic diseases in the future, according to Buse. He said if mifepristone demonstrates efficacy, it could lead to a new pathway for treating diabetes among adults not responding to other medications.
Buse added the study could have implications beyond medical therapy. The higher than expected prevalence of hypercortisolism could call for changes in screening guidance. However, Buse said part two of the CATALYST study needs to be completed to see whether treating adults with hypercortisolism and poorly controlled type 2 diabetes with mifepristone shows a benefit.
“If the second half of the study is positive ... I would push very hard [for guideline changes],” Buse told Healio. “I think this is paradigm-changing data, but we need the second part of the experiment to push.”
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Auchus R, et al. Symposium – Prevalence of hypercortisolism in difficult-to-control type 2 diabetes. Presented at: American Diabetes Association Scientific Sessions; June 21-24, 2024; Orlando.
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