Diabetes Core Update: Special Edition – Hypercortisolism

Release Date: May 12, 2025
Host: Dr. Neil Skolnick
Guest: Dr. John Buse
Length: ~22 minutes

Episode Overview

This special edition of the Diabetes Core Update explores the relationship between hypercortisolism and diabetes, focusing on newly published data that challenges conventional wisdom regarding the prevalence of hypercortisolism among individuals with uncontrolled type 2 diabetes. Dr. Neil Skolnick is joined by Dr. John Buse, an eminent endocrinologist and past President for Medicine and Science at the American Diabetes Association, to discuss pathophysiology, screening, recent trial findings, and evolving clinical implications for providers.

Key Discussion Points & Insights

1. Defining Hypercortisolism vs. Cushing's Syndrome

• Hypercortisolism means excess cortisol in the blood, whereas Cushing’s syndrome is defined by hypercortisolism plus characteristic clinical features (e.g., moon facies, buffalo hump, purple abdominal striae, hypertension, osteoporosis, and diabetes).
  • Quote [01:35]:

    "Hypercortisol technically means too much cortisol… Cushing's syndrome, which is the presence of hypercortisolism with other features." – Dr. Buse

2. Pathophysiology – Cortisol’s Impact on Glucose Control & Other Systems

• Cortisol impairs insulin secretion (pancreatic islet effect), induces insulin resistance (muscle, fat), increases hepatic glucose production (major contributor to fasting hyperglycemia), and promotes hypertriglyceridemia.
  • Quote [03:13]:

    "It has an effect in the islet to reduce insulin secretion, it has effect in muscle and fat to reduce insulin action or cause insulin resistance. In the liver, it causes excess hepatic glucose production." – Dr. Buse

• Broad systemic effects: neuropsychiatric (depression, irritability, anxiety), skin/morphologic changes, early CVD, hypertension, dyslipidemia, osteoporosis.
  • Quote [04:22]:

    "It basically affects all organ systems. ... neuropsychiatric consequences. Depression, anxiety, irritability, tremulousness... bone fractures, hypertension, dyslipidemia, early cardiovascular disease." – Dr. Buse

3. The Underrecognized Prevalence of Hypercortisolism

• Traditional teaching: Cushing’s syndrome is rare.
• New data suggest hypercortisolism alone is present in roughly 24% of people with poorly controlled diabetes.
  • Quote [05:13]:

    "Many of us very experienced clinical trialists... none of us thought that what we found was remotely possible. ... we've probably let hundreds of people with hypercortisolism slip by." – Dr. Buse

4. The Catalyst Trial – Rethinking Screening and Prevalence

• Background: Prior studies hinted at 10–25% prevalence of hypercortisolism among those with difficult-to-control diabetes, but these were small/obscure.
• Hypothesis: Hypercortisolism is underdiagnosed in diabetes outpatients.
• Attempt: Broader study design by recruiting people with poorly controlled type 2 diabetes not explained by classic Cushing’s features.
  • Quote [08:02]:

    "He talked to a number of us about was there a possibility of doing a broader study ... all of us said yeah, love to do that study. I think the person who guessed the highest number thought it might be 2 or 3%..." – Dr. Buse

5. Mifepristone (Korlym): Therapeutic and Diagnostic Role

• Mifepristone is both a cortisol receptor antagonist (used in hypercortisolism) and known in primary care for pregnancy termination.
• Clarification:
  • "It is exactly the same. ... It is a cortisol receptor antagonist and the primary effect is to reduce cortisol action." – Dr. Buse [08:25]
• Korlym is specifically indicated for hypercortisolism management in diabetes (300 mg, non-crushable tablets).

6. Study Methodology and Definitions

• Inclusion criteria:
  • Type 2 diabetes (not type 1/secondary), A1C 7.5–11%, on 3 diabetes meds, or 2 with insulin, or 2 meds + micro/macrovascular complication, or 2+2 diabetes/antihypertensives.
• Sites: High-functioning, diabetes-focused centers.
• Quote [09:33]:

  “They didn't have to be horribly controlled, but they had to have some elevation in glucose despite a good faith effort…” – Dr. Buse

7. Major Findings

• Prevalence: ~24% of the screened cohort had positive dexamethasone suppression tests indicating hypercortisolism.
  • Quote [12:15]:

    “What we found was that 25 or 24% of them actually flunked this dexamethasone suppression test and thus, by definition… have hypercortisolism.” – Dr. Buse

• About 1/3 of positives had a solitary adrenal nodule on CT scan (potentially surgically curable); 2/3 had no visible adrenal abnormality.

8. Clinical Implications and Next Steps

• Most with mild, isolated findings aren’t currently treated unless further features or abnormal tests develop.

• Ongoing trial: mifepristone vs. placebo in those with hypercortisolism. Preliminary results: ~1.4% reduction in A1C with mifepristone.

  • Quote [14:35]:

    “The top line result is that there was about a 1.4% reduction in hemoglobin A1C with mifepristone and with placebo there was none or essentially none.” – Dr. Buse

• Referral is recommended: Treatment and monitoring for hypercortisolism can be challenging and should be managed by experienced endocrinologists.

9. Pathophysiologic Parallels: Hyperaldosteronism

• Similarities between current underrecognition of hypercortisolism in diabetes and long-standing gaps in recognizing hyperaldosteronism in hypertension.
  • Quote [18:44]:

    “We need to do a better job on both.” – Dr. Buse

10. Case Story – Clinical Impact

• A real-life patient with neuropsychiatric symptoms and recently developed diabetes was found to have hypercortisolism and responded well to treatment.
• Quote [19:26]:

  “The benefit of the therapy went far beyond the glucose management. It was actually the sort of neuropsychiatric part... a real opportunity to make a huge difference in people's lives.” – Dr. Buse

11. Practical Screening Approach

• Screening test: 1 mg overnight dexamethasone suppression test at 11pm, with 8am serum cortisol. Positive if >1.8 µg/dL. Also check dexamethasone levels to confirm medication was taken and absorbed.
  • Quote [21:13]:

    “The 1mg overnight dexamethasone suppression test… a serum sample for cortisol at 8am… with a reflex that if it’s greater than 1.8 that you would then also measure dexamethasone levels…” – Dr. Buse

Notable Quotes & Memorable Moments

• On missed opportunities:

  “…frankly embarrassed that we've been practicing for 30 years and have probably let hundreds of people with hypercortisolism slip by.” – Dr. Buse [05:13]

• Clinical paradigm shift:

  “We're talking millions of people.” – Dr. Skolnick on national prevalence [11:20]

• On the impact of diagnosis:

  “…It's a real opportunity to make a huge difference in people's lives.” – Dr. Buse [19:26]

Important Timestamps

• [00:02] – Introduction & new evidence on hypercortisolism prevalence in diabetes
• [01:35] – Defining hypercortisolism vs. Cushing’s syndrome
• [03:13] – Cortisol’s effects on metabolism
• [05:13] – Investigators reflect on underdiagnosis
• [08:02] – Study background & rationale
• [09:33] – Study methodology and inclusion criteria
• [12:15] – Results: Prevalence and follow-up imaging
• [14:35] – Treatment trial (mifepristone/placebo) & initial efficacy
• [17:42] – Pathophysiology & parallels with hyperaldosteronism
• [19:26] – Case study illustrating real-world impact
• [21:13] – Summary of recommended screening strategy

Take-home Points for Clinicians

• Hypercortisolism is substantially more common in difficult-to-control type 2 diabetes than previously thought—consider screening in appropriate patients.
• The recommended and feasible screening method is the overnight dexamethasone suppression test.
• Treatment can have marked benefits—not just for glycemia, but also quality of life—yet should involve specialists due to medication complexity.
• This emerging recognition could signal a paradigm shift in diabetes care, akin to trends seen in resistant hypertension and hyperaldosteronism.
• Look for more results in upcoming ADA meetings and future episodes.

(Episode sponsored by Corcept; summary excludes all advertising content and sponsor acknowledgments outside of direct clinical/research context)