In a 37-year-old patient with difficult-to-control type 2 diabetes (T2D), despite treatment with metformin, an SGLT2 inhibitor, and a GLP-1 agonist, A1c remains persistently elevated at 7.8%-8.5%. The patient also has central obesity and severe hypertension requiring three or more antihypertensive medications. Recent evidence suggests that this constellation of findings should raise suspicion for an often-overlooked underlying cause of poor glycemic control: occult hypercortisolism.

This warning stems from the prevalence analysis of the CATALYST study, a multicenter clinical trial published in 2025 in the journal Diabetes Care: Among more than 1000 patients with poorly controlled T2D, nearly 24% with the described profile had occult hypercortisolism, identified through a 1-mg dexamethasone suppression test performed at night (cut-off values: serum cortisol > 1.8 µg/dL; dexamethasone ≥ 140 ng/dL the following morning).

“These findings don’t usually occur by chance. If we’re looking for a disorder that could be driving diabetes, hypercortisolism is one that’s important to keep in mind,” said Richard Joseph Auchus, MD, PhD, professor of internal medicine in the Division of Metabolism, Endocrinology, and Diabetes at the University of Michigan, Ann Arbor, and a study author. Auchus presented the findings at the 37th Brazilian Congress of Endocrinology and Metabology, held August 26-29 in Rio de Janeiro, Brazil.

The study’s findings underscore the importance of checking cortisol levels when type 2 diabetes remains uncontrolled — with A1c between 7.5% and 11.5% — despite treatment with multiple medications, particularly if the patient also has comorbidities such as hypertension or cardiovascular disease, along with clinical signs suggestive of hypercortisolism, including central fat accumulation in the abdomen, trunk, and neck, moon facies, and abdominal stretch marks.

If hypercortisolism is suspected, the recommended approach is to obtain at least two tests using different methods to confirm endogenous cortisol excess. One option is the standard overnight dexamethasone suppression test: The patient takes 1 mg of dexamethasone at 11:00 PM, and a cortisol level above 1.8 µg/dL indicates inadequate suppression and is consistent with hypercortisolism. While the sample is ideally collected between 8:00 AM and 10:00 AM, any draw time is acceptable. The other option is a 24-hour urinary free cortisol test.

Once hypercortisolism has been identified, the next step is to measure plasma adrenocorticotropic hormone (ACTH) levels, which will determine whether the cause of the problem is ACTH-dependent or ACTH-independent.

Surgery is indicated for both types, but with very different degrees of complexity. In ACTH-independent cases, the excess cortisol usually originates from an adrenal tumor, which can be addressed surgically in a more straightforward manner. In ACTH-dependent cases, however, the source is typically a pituitary tumor — a highly complex surgical procedure that is inoperable in some cases.

“If it is ACTH-independent, the recommendation is to perform a CT scan of the abdomen to look for an adrenal tumor. If there is no tumor, it may be non-neoplastic hypercortisolism. In ACTH-independent hypercortisolism, this is quite straightforward, since in most places there are urologists or surgeons specializing in the surgical treatment of endocrine glands who can perform adrenal surgery,” commented Auchus.

For patients who are not eligible for surgery or who did not respond adequately to the procedure, pharmacologic treatment is the alternative. The CATALYST treatment phase evaluated mifepristone in 136 patients with T2D and confirmed hypercortisolism and observed a 1.3% reduction in A1c over a 24-week period, as well as an average weight loss of 5 kg and reduced need for insulin and sulfonylureas.

Mifepristone does not reduce cortisol production, but it blocks cortisol’s binding to glucocorticoid receptors, thereby preventing its effects on insulin resistance and weight gain. However, the drug is not registered with the Brazilian Health Regulatory Agency and is not available for sale or use in Brazil. In the US, the drug was approved by the FDA for the management of hyperglycemia secondary to endogenous hypercortisolism in adults with Cushing syndrome and T2D or glucose intolerance who are not eligible for surgery or have not responded adequately to the procedure.

Although the metabolic results are promising, the medical community continues to debate the widespread use of mifepristone due to certain factors observed during patient follow-up. In the study, treatment was discontinued by 46% of participants in the mifepristone group compared with 18% in the placebo group, primarily due to adverse events. The most common were hypokalemia, nausea, fatigue, and symptoms of low cortisol. There was also a mean increase of 10.1 mm Hg in systolic blood pressure compared to the placebo — a relevant finding given the hypertensive profile of patients eligible for the trial.

“Although there are some treatments available, none of them are perfect. Many of them are very expensive and have side effects. It’s not like spironolactone for primary hyperaldosteronism, which is an inexpensive medication that we’ve been using for 60 years,” concluded Auchus in an interview with Medscape’s Portuguese edition.

According to Auchus, the difficulty of finding an appropriate treatment increases when lifelong care is required. “If a patient has, for example, an ACTH-dependent condition caused by an inoperable pituitary tumor, they will need treatment for the rest of their life. In that case, we can perform an adrenalectomy and remove the source of cortisol, but then we’ll have to treat them for adrenal insufficiency. So, in that case, any treatment will be for life.”

This story was translated from Medscape’s Portuguese edition.