I’m returning from the 2025 American Association of Clinical Endocrinology meeting held in Orlando Florida over this past weekend. I make my way through the very long security line filled with grandparents and grandchildren with Mickey Mouse ears and I’m thinking about what I learned and what was a “hot topic” at this meeting.
I’ll highlight three areas that I consider new and may possibly change how we practice medicine:
- The role of hypercortisolism in uncontrolled type 2 diabetes.
- A new therapy designed to minimize the adverse consequences of long-term steroid use to suppress ACTH in the rare condition of classical congenital adrenal hyperplasia.
- The utility of a novel new drug for the treatment of hepatic steatosis.
Diabetes and difficult to treat hyperglycemia are common and sometimes frustrating clinical challenges for the internist, family practitioners, and others. Additionally, there has also been a growing consensus that mild autonomous cortisol secretion, sometimes seen in adrenal nodules, increases morbidity and mortality. The confluence of these two problems partially resulted in the construction of the CATALYST trial. The first part of the trial has been completed, which looked at the prevalence of excess cortisol secretion in persons with uncontrolled type 2 diabetes. One thousand subjects were screened with a 1 mg dexamethasone suppression test. Those subjects that “escaped” dexamethasone suppression with a morning cortisol of greater than 1.8 µg /dL then had further evaluation for ACTH independent hypercortisolism associated with an adrenal nodule. This defined approximately 40% of participants who then moved on to part two of the study. CATALYST part 2 examines the efficacy of reducing cortisol levels by treatment with mifepristone.
The results of this study are to be presented at the upcoming American Diabetes Association meeting in Chicago late June 2025. If positive results are seen in this selected population then our perspective on poorly controlled type 2 diabetes and its management will dramatically change. I think it is important to point out that escaping from dexamethasone suppression testing does not completely define the presence of subclinical Cushing’s syndrome and may have many alternative explanations. Hopefully part two of this trial will be able to provide us with the information to potentially have another pathway for people with difficult to control type 2 diabetes.
Classic congenital adrenal hyperplasia (CAH) most commonly is due to a deficiency in the 21 hydroxylase enzyme, a key regulatory step in adrenal steroid production (90 to 95% of cases). One result of the disruption of adrenal steroid synthesis is adrenal androgen excess, which can lead to shortened adult height and infertility. Until recently traditional therapy utilized supra-physiologic doses of glucocorticoids to suppress ACTH and lower the androgens. This treatment approach, in a sense, results in trading illnesses: androgen excess versus long-term over treatment with glucocorticoids. The recent approval of crinecerfont, which is a corticotropin-releasing hormone (CRH) antagonist that inhibits ACTH release by blocking CRH action to signal ACTH, offers a new option for CAH patients. Lowering ACTH by an alternative pathway can lower the dosage of large glucocorticoid doses. Adding crinecerfont has been shown to reduce ACTH levels by more than 50% which allowed for clinically meaningful steroid dose reductions. Minimizing glucocorticoid doses is an exciting management option and is expected to minimize or reduce the long-term complication of treating this patient group with long term supra-physiologic doses of glucocorticoids.
Hepatic steatosis has had many names. Now it is currently referred to as metabolic associated liver disease (MASLD) and when there’s evidence of inflammation and fibrosis, metabolic dysfunction-associated steatohepatitis (MASH). When I began training, “fatty liver“ was assumed to be a normal finding in persons with type 2 diabetes or obesity. We now know that early identification and intervention can prevent the development of fibrosis, scarring, and ultimately cirrhosis. The worldwide prevalence is increasing, and what was previously considered benign could possibly become the most common cause of non-drug related hepatic cirrhosis.
Another recently approved drug, that again works through a novel pathway, resmetirom has been approved for use in persons with MASH. Results published in the New England Journal of Medicine in February 2024 demonstrated an improvement in liver fibrosis score one class or resolution of fibrosis. Resmetirom is an oral thyroid hormone receptor, beta activator; this pathway in the liver is responsible for mobilization of fatty acids. In MASH, thyroid hormone receptor beta function is altered, leading to an increase in liver fibrosis. The activity of thyroid hormone in normal human physiology is modulated by its receptor, which has both an alpha and a beta form. The alpha receptor largely acts on the cardiac system and the beta has significantly greater action at the liver, making this medication a targeted approach to a key altered pathway in the affected organ.
Overall, I think it’s an exciting and important time for the development of drugs utilizing what we know about physiology and using this information to develop novel approaches to diseases. I’m anxious to learn more and, in particular, see the updates of the CATALYST trial results at the American Diabetes Association meeting in a few weeks.
Dr. Joseph A. Aloi, M.D. is Chief of Endocrinology at the Wake Forest School of Medicine in Winston Salem, North Carolina. His interests include connecting persons with diabetes to technology designed to help improve their glucose control and improve quality of life. Dr. Aloi reports no COI with any of the topics mentioned.
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