By recognizing subclinical presentations of hypercortisolism, Diabetes Care and Education Specialists (DCESs) and primary care clinicians can help initiate screening, diagnosis, prompt referral, and effective management, transforming care for patients with difficult-to-manage Type 2 diabetes (T2D).

The following content is made possible due to educational grant support from Corcept Therapeutics. Content was developed independently by ADCES. 

Hypercortisolism and T2D: Why Awareness Matters Now

Achieving glucose targets remains a persistent challenge for many people with Type 2 diabetes (T2D), even with the introduction of SGLT2 inhibitors and GLP-1 receptor agonists. In the US today, approximately 1 in 4 people with T2D have persistently high blood glucose levels despite the use of multiple standard-of-care medications.

Hypercortisolism is a multisystemic endocrine disorder that can have serious consequences, increasing risks of heart disease, diabetes, osteoporosis, and more. Emerging evidence from the CATALYST study reveals a high prevalence of hypercortisolism - approximately 24% - in individuals with difficult-to-manage T2D (defined as individuals with HbA1c between 7.5% and 11.5% despite multiple standard-of-care therapies).

Inadequate outcomes are both frustrating and dangerous for people with difficult-to-manage T2D, and signal a substantial unmet need for screening, diagnosis, and prompt treatment of hypercortisolism as an underlying cause in these individuals. Furthermore, the availability of targeted, cortisol-directed medical therapies, makes early recognition of hypercortisolism and appropriate intervention especially critical for improving long-term outcomes in people with difficult-to-manage T2D.

Identifying Hypercortisolism in the At-Risk Individual

As mentioned in previous modules, hypercortisolism occurs in a broad spectrum of individuals, including those who may not exhibit classic physical features, such as buffalo hump, moon face, and abdominal striae. Some people with hypercortisolism may present with features that are considered subclinical or unusual for their age, such as osteoporosis, or with multiple and progressive features, such as T2D or hypertension. However, there are some “red flags” that should trigger a high index of clinical suspicion for hypercortisolism including:

• T2D, including difficult-to-manage T2D despite multiple medications
• Hypertension, especially if difficult-to-manage despite the use of multiple blood pressure medications
• Weight gain, or the presence of central obesity
• Osteoporosis or fractures, especially if unusual for the patient’s age

By looking beyond classic overt features to incorporate non-specific presentations, it becomes easier to identify patients who may benefit from formal screening for hypercortisolism.

DST: One Simple Step to Revealing Hidden Risk

When hypercortisolism is suspected as an underlying driver of difficult-to-manage T2D, it is important to use an accessible screening tool to confirm or rule out a diagnosis. While there are several available tests, the 1-mg overnight dexamethasone suppression test (DST) is recommended because it is highly sensitive, easy to administer, and practical for use in primary care and diabetes clinic settings.

Performing the DST is a straightforward, 3-step process:

1. The individual takes 1 mg of oral dexamethasone at approximately 11:00 PM.
2. A blood sample is drawn the next morning, ideally between 8:00 AM and 9:00 AM, to measure serum cortisol and dexamethasone levels.
3. A post-DST serum cortisol level >1.8 μg/dL is indicative of hypercortisolism in this high-risk population, suggesting the need for further specialized evaluation. A dexamethasone level ≥140 ng/dL confirms that an adequate amount was absorbed for accurate suppression testing.

What a Positive Finding Means for Patient Care.

Following a positive screening result from the 1-mg overnight DST, the individual should be referred to an endocrinology practitioner for further evaluation (i.e., biochemical testing and imaging) that can facilitate a definitive diagnosis of hypercortisolism. To support further evaluation, ensure the referral includes the patient’s relevant medical history, specific reasons for suspicion, and the complete results of initial screening tests.

A confirmed diagnosis of hypercortisolism could prove consequential, as recent evidence suggests that cortisol-directed treatment may improve specific outcomes in patients with difficult-to-manage T2D.

In the clinical phase of the CATALYST study, mean HbA1c decreased by 1.47% (from 8.62% to 7.12%) after 24 weeks of treatment with mifepristone in subjects with difficult-to-manage T2D. By comparison, the mean HbA1c among placebo-treated patients decreased by 0.15% (from 8.41% to 8.36%). Investigators also reported numerical improvements in body weight, BMI, waist circumference, and medication burden with mifepristone treatment.

Key Takeaways

The prevalence of endogenous hypercortisolism in people with difficult-to-manage T2D is substantially higher than generally recognized. Hypercortisolism often goes underrecognized, leading to negative consequences, including unnecessary morbidity and increased mortality risks. DCESs and primary care clinicians can play a key role in implementing targeted screening, ensuring early detection and prompt referrals that are instrumental in improving patient outcomes:

• Recognize the At-Risk Clinical Profile: Look beyond the overt clinical features usually associated with Cushing syndrome. Maintain a high index of suspicion for non-specific symptoms, such as osteoporosis at younger age than expected or obesity, or those that may point toward hypercortisolism, particularly in individuals with difficult-to-manage T2D and hypertension.
• Incorporate Simple Testing into Routine Evaluation: Initiate first-line screening using the 1-mg overnight DST, which is highly sensitive and accessible for non-specialists. A post-DST serum cortisol level >1.8 μg/dL along with adequate dexamethasone levels supports the presence of hypercortisolism and warrants further investigation.
• Engage Patients and Colleagues for Effective Management: Facilitate a successful referral to endocrinology practitioner by communicating the patient’s complete medical history, clinical findings, reasons for suspicion and full results of the initial screening tests.
• Elevate the Urgency of Early Identification: Patients and clinicians alike need to recognize that hypercortisolism is associated with cardiometabolic risks that increase with disease severity and duration. Pharmacologic management of comorbidities alone, without treating the cortisol excess, is inadequate in reducing cardiovascular morbidities and mortality over the long term.
  

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