Hypercortisolism Affects 1 in 4 Patients with Difficult-to-Control Type 2 Diabetes: Study Finds

Despite the use of various glucose-lowering medications, many individuals with type 2 diabetes still fail to achieve their glycemic targets. Cortisol, known as the "stress hormone," plays a key role in regulating metabolism, blood pressure, and the body’s response to stress. However, chronic elevation of cortisol levels can have detrimental effects, particularly in individuals with type 2 diabetes, where it can worsen hyperglycemia.

In the prospective, observational study, John B. Buse, University of North Carolina School of Medicine, Chapel Hill, NC, and colleagues evaluated the prevalence of hypercortisolism as a potential factor contributing to poor glucose control.

For this purpose, the researchers screened individuals with type 2 diabetes and HbA1c levels ranging from 7.5% to 11.5% (58–102 mmol/mol) who were on two or more glucose-lowering medications, with or without micro-/macrovascular complications, or those taking multiple blood pressure–lowering medications. A 1-mg dexamethasone suppression test (DST) was conducted, excluding common causes of false-positive results.

The primary endpoint was the prevalence of hypercortisolism, defined as post-DST cortisol levels exceeding 1.8 μg/dL (50 nmol/L). The researchers also used multiple logistic regression to assess the characteristics associated with hypercortisolism and evaluated the percentage of participants with hypercortisolism and adrenal imaging abnormalities.

Key Findings:

• Post-DST cortisol was unsuppressed in 252 of 1,057 participants, with a prevalence of 23.8%.

• The prevalence of hypercortisolism was 33.3% among participants with cardiac disorders.

• Among those taking three or more blood pressure–lowering medications, the prevalence of hypercortisolism was 36.6%.

• 34.7% of participants with hypercortisolism had adrenal imaging abnormalities.

• Factors associated with a higher prevalence of hypercortisolism included:

• Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558).

 • Use of maximum-dose glucagon-like peptide 1 receptor agonists (odds ratio 1.544).

• Use of tirzepatide (odds ratio 1.981).

• A higher number of blood pressure–lowering medications (odds ratio 1.390).

• Older age (odds ratio 1.316).

• BMI <30 kg/m2 (odds ratio 1.639).

• Non-Latino/Hispanic ethnicity (odds ratio 3.718).

• Use of fibrates (odds ratio 2.676) or analgesics (odds ratio 1.457).

• All associations were statistically significant.

The authors revealed that hypercortisolism was identified in approximately 23.8% of individuals with difficult-to-control type 2 diabetes, despite the use of multiple medications. They discovered that this condition was associated with several factors, including older age, lower body mass index (BMI), non-Latino/Hispanic ethnicity, a higher burden of hypertension medications, and the use of fibrates, analgesics, or newer glucose-lowering treatments. These findings emphasize the role of hypercortisolism in exacerbating hyperglycemia in individuals with inadequately controlled type 2 diabetes.

The authors also suggest that screening for hypercortisolism could be beneficial for patients who are not meeting glycemic targets despite treatment with multiple medications, providing valuable insights into the challenges of managing type 2 diabetes.

Reference:

John B. Buse, Steven E. Kahn, Vanita R. Aroda, Richard J. Auchus, Timothy Bailey, Irina Bancos, Robert S. Busch, Elena A. Christofides, Ralph A. DeFronzo, Bradley Eilerman, James W. Findling, Vivian Fonseca, Oksana Hamidi, Yehuda Handelsman, Harold J. Miller, Jonathan G. Ownby, John C. Parker, Athena Philis-Tsimikas, Richard Pratley, Julio Rosenstock, Michael H. Shanik, Lance L. Sloan, Guillermo Umpierrez, Iulia Cristina Tudor, Tina K. Schlafly, Daniel Einhorn, CATALYST Investigators; Prevalence of Hypercortisolism in Difficult-to-Control Type 2 Diabetes. Diabetes Care 2025; dc242841. https://doi.org/10.2337/dc24-2841