Don’t Overlook the Diagnosis of Hypercortisolism

Hypercortisolism is more common than previously appreciated in at-risk populations, including individuals with difficult-to-manage Type 2 diabetes (T2D) despite use of standard medications. Unfortunately, the diagnosis of hypercortisolism is often overlooked, delaying appropriate treatment that could reduce the risk of cardiometabolic morbidity and mortality while improving quality of life.

For these reasons, hypercortisolism screening is a critical intervention that should be more commonly utilized in clinical practice. Yet to date, screening is not routinely provided for people with difficult-to-manage T2D, in part due to a misperception that hypercortisolism is rare and challenging to diagnose. In fact, diagnosis is straightforward when screening tests are employed according to clinical practice recommendations when elevated cortisol is suspected as a cause for concern.

Diabetes Care and Education Specialists (DCESs) and other clinicians can play a critical role in identifying high-risk individuals, ensuring that they receive biochemical testing, imaging studies, and referral to an endocrinology practitioner who can provide further evaluation and a personalized management plan. This module provides practical guidance on identifying at-risk patients, use of recommended screening tests, and interpretation of results to determine the next best course of action.

Who Should be Screened for Hypercortisolism? Identifying High-Risk Patients

Today, the importance of uncovering hypercortisolism in people with T2D is more important than ever before. We have learned recently from the CATALYST study that the prevalence of hypercortisolism is unexpectedly high (approximately 24%) in people with T2D that is difficult to manage (i.e., not meeting glycemic targets despite appropriate use of multiple medications). The prevalence is even higher (almost 37%) in those individuals with difficult-to-manage T2D who are taking three or more blood pressure medications. Based on these findings, it makes sense to screen for hypercortisolism in people who have difficult-to-manage T2D, especially if they are also having trouble achieving blood pressure targets despite appropriate therapy.

Screening for hypercortisolism in people with difficult-to-manage T2D is consistent with principles established in 2008 guidelines from the Endocrine Society. According to guidelines, people often exhibit features such as diabetes, hypertension, and obesity that are common in the general population, yet may be caused by cortisol excess. The guidelines encourage clinicians to consider these features as a potential cause of hypercortisolism, particularly if additional features of the condition are present.

It is important to emphasize that screening is most effective when directed toward people with a high pre-screening probability of hypercortisolism. By focusing on high-risk groups, screening can be prioritized for people most likely to have hypercortisolism, ensuring that resources are used efficiently for those who are most likely to benefit from further evaluation.

Quantifying Hypercortisolism: Prevalence in At-Risk Populations

By applying specific criteria to prioritize screening, we can effectively identify patients at high risk for hypercortisolism and ensure that appropriate diagnostic testing is performed.

This approach is supported by evidence from the landmark CATALYST study, including more than 1,000 people with difficult-to-manage T2D (i.e., not meeting A1c targets despite multiple standard-of-care therapies) that showed the prevalence of hypercortisolism was 24%, as discussed in earlier modules in this guide.

These findings are corroborated by results of a systemic review and meta-analysis demonstrating a ~3.5-fold increased risk of hypercortisolism in people with T2D with complications, and ~2-fold increased risk in people with T2D and hypertension or requiring insulin.

Screening for Hypercortisolism: Strategies for Initial Evaluation

Use of a highly sensitive screening test is essential in the initial evaluation of suspected hypercortisolism. Although several different tests are available, the 1-mg overnight dexamethasone suppression test (DST) is recommended as the first-line screening test due to its high sensitivity (sensitivity: up to 95% using a post-DST serum cortisol cutoff of >1.8 μg/dL).

Other commonly available tests include the late-night salivary cortisol (LNSC) test and urine-free cortisol (UFC). LNSC and UFC may be less sensitive in patients with adrenal hypercortisolism; in the CATALYST study of patients with difficult-to-manage T2D, nearly 35% of participants with hypercortisolism had adrenal imaging abnormalities on imaging, i.e., computed tomography (CT).

DST: Using it Correctly

The 1-mg overnight DST is sensitive, inexpensive, and easy to employ. The DST assesses an individual’s responsiveness to glucocorticoids. The patient should be prescribed 1 mg of dexamethasone, with the instruction to take the pill at approximately 11:00 PM. Two lab tests should be ordered: one to measure serum cortisol and one to confirm dexamethasone levels. A blood draw should be scheduled between 8:00 AM and 9:00 AM the next morning to measure the body's reaction to dexamethasone. A post-DST cortisol level >1.8 µg/dL suggests hypercortisolism. A morning dexamethasone level ≥140 ng/dL confirms adequate HPA axis suppression occurred and verifies the DST result.

Before performing the DST, common causes of false-positive results should be excluded, such as chronic glucocorticoid use, estrogen-containing medication use, chronic renal disease, pregnancy, and circadian disruption due to night-shift work.

Positive DST: What Comes Next

If the result of the screening test is positive for hypercortisolism, referral to an endocrinology practitioner is recommended for further evaluation, including additional biochemical testing or imaging needed to determine the underlying cause.

Once biochemical and imaging results are obtained, they need to be interpreted in the context of the individual’s medical history and current clinical presentation, including the presence of comorbidities such as T2D, hypertension, and obesity. This clinical assessment may include history of difficult-to-manage diabetes, difficult-to-manage high blood pressure, renal impairment, and obesity, particularly obesity that persists despite use of GLP-1 receptor agonist-based medications.

Key Takeaways

• Screening for hypercortisolism begins with identifying people likely to be at risk for hypercortisolism based on clinical features and comorbidities.
• The probability of identifying hypercortisolism is higher in specific at-risk populations, such as people with difficult-to-manage T2D, especially if they are also having trouble achieving blood pressure targets despite appropriate therapy.
• The 1-mg overnight dexamethasone suppression test (DST) is simple to use and recommended for initial screening due to its high sensitivity.
• Before performing a DST, common causes of false-positive results need to be excluded, including chronic administration of glucocorticoids or use of estrogen-containing medications.
• If DST results are positive, referral to an endocrinology practitioner is recommended for further evaluation, including additional biochemical testing or imaging needed to determine the underlying cause.
• Screening results should always be interpreted in the context of a person’s medical history, comorbidities, and current clinical presentation.