Podcast Summary: Endocrine News Podcast – ENP110: Hypercortisolism and T2D

Date: January 21, 2026
Host: Aaron Lohr (A)
Guests:

• Dr. Vivian Fonseca (B), Professor of Medicine, Tulane University
• Dr. James Findling (C), Professor of Medicine and Surgery, Medical College of Wisconsin

Overview

This episode focuses on the relationship between inadequately controlled type 2 diabetes (T2D) and hypercortisolism, exploring prevalence, causes, and how emerging therapies like mifepristone may offer better glycemic control. The discussion is anchored in results from the Catalyst trial recently published in Diabetes Care, shedding new light on what clinicians should consider when treating difficult-to-control diabetes.

Key Discussion Points & Insights

1. Defining Inadequately Controlled T2D

[01:28]

• Study’s Definition:
  • Adults aged 18–80 with HbA1c between 7.5 and 11.5%
  • Must be on extensive anti-hyperglycemic therapy—at least three drugs, or insulin plus another agent, or two drugs with a micro/macrovascular complication, or two drugs and two antihypertensives.
• Quote:
  “Somewhat broad, but there are a lot of people around who are uncontrolled like this, taking this type of medication.” —Dr. Fonseca [01:34]

2. Causes and Prevalence of Hypercortisolism

[02:17]

• Classic causes: Pituitary or ectopic ACTH-secreting neoplasms (Cushing’s syndrome); adrenal nodular disease.

• Growing recognition of non-neoplastic hypercortisolism: HPA axis activation independent of tumors, often seen in chronic conditions like poorly controlled T2D.

• Critique of the term "pseudo Cushing’s syndrome": Need for precise terminology.

• Quote:
  “Non-neoplastic hypercortisolism…may have activation of the HPA axis because of their underlying condition... One of those categories is poorly controlled type 2 diabetes.” —Dr. Findling [02:23]

3. T2D and Hypercortisolism: The Clinical Relationship

[03:15]

• Steroid-induced diabetes: Well-known; exogenous steroids quickly worsen glycemic control, especially in T2D.
• Diagnosing hypercortisolism in practice: Importance of correct testing, excluding confounders (e.g., oral contraceptives, shift work, kidney failure).
• Quote:
  “We see this in practice with people taking modest doses of prednisone. If they have diabetes, it gets worse. So this is analogous to that in some way.” —Dr. Fonseca [06:15]

4. Why Mifepristone?

[04:29]

• Only approved drug for hypercortisolism, with proven efficacy in improving glycemic control (Seismic trial, 2012).

• Particularly useful in diabetic populations, as recognized in its FDA approval.

• Discovery in Catalyst: Prevalence of abnormal dexamethasone suppression test (DST) was much higher than expected (24%), aligning with mild autonomous cortisol secretion (MACS).

• Quote:
  “It's becoming more and more clear that even patients with mild degrees of cortisol excess...may benefit from some cortisol-directed therapy.” —Dr. Findling [04:37]

5. Study Design & Methods

[06:08]

• Part 1: Determine hypercortisolism prevalence using overnight DST (1 mg dex, cortisol ≥1.8 mcg/dL, confirming dex taken).

  • Excluded known confounders.
  • Further evaluated positive cases with labs and adrenal CT.

• Part 2: Randomized patients with confirmed hypercortisolism to mifepristone vs placebo (only those with no surgical indication/willingness).

  • Endpoint: Change in HbA1c.

• Quote:
  “We did our best to exclude pseudo Cushing's, yet find such a high prevalence, which was surprising to us because we haven't really thought this through before.” —Dr. Fonseca [08:30]

6. Results

[08:25]

Patient Demographics:

• Mean age: 60; balanced sex distribution.
• Moderate obesity (BMI 33, waist 44 inches).
• Racial makeup: 71% white, 19% black, ~24% Hispanic.
• Mean baseline HbA1c: 8.8%.
• Heavy medication usage: 69% ≥3 diabetes drugs, 71% on insulin, 50%+ on SGLT2 inhibitors and GLP1RAs, many on combinations.

Key Findings:

• Prevalence: 24% with abnormal DST; mean post-DST cortisol 3.5 mcg/dL.
• Correlation: More anti-diabetic and antihypertensive drugs taken, higher chance for hypercortisolism (up to 35% in high-med groups).
• Imaging: 66% with no adrenal abnormality; of those with findings, most had unilateral adenomas, indicating missed surgical opportunities.

Glycemic Outcomes:

• HbA1c reduction: Mifepristone lowered HbA1c by ~1.5% vs 0.15% on placebo (Δ = –1.3%).
  • Faster onset (within 12 weeks), sustained through 24 weeks.
  • Many reduced or discontinued diabetes medications during the study, including insulin, yet glycemic control still improved.
  • Benefit seen regardless of presence of adrenal adenoma.
  • Modest weight and waist circumference reduction.
• Quote:
  “The difference between the two was minus 1.3, which is better than many of the diabetes drugs that we have in clinical practice.” —Dr. Fonseca [08:30]

7. Safety and Adverse Effects

[13:53]

• Expected withdrawal symptoms: Nausea, muscle aches, fatigue.
• Most significant: Hypokalemia due to cortisol receptor blockade and resultant physiological compensations.
  • Increased potassium wasting, sometimes mild blood pressure rise.
  • Standard of care: Use spironolactone and potassium supplementation in real-world practice.
• Special notes: Progesterone antagonism—concerns around menstrual changes and pregnancy, mostly moot in this (older) population.
• Quote:
  “When this drug is used, I almost routinely give patients spironolactone and sometimes potassium replacement if necessary.” —Dr. Findling [13:57]

8. The Clinical Meaning of Cortisol in Diabetes

[15:44]

• Proof of concept: Modest cortisol elevations materially contribute to difficult-to-control diabetes.
  • “Blocking that cortisol…could be done through some other ways…So this is the first one and it provides, as I said, proof of principle.” —Dr. Fonseca [15:51]
• Opportunities for new management strategies; mechanism still not fully understood.

9. Practitioner Awareness & Implications for Screening

[16:44]

• General practitioners recognize steroid-induced hyperglycemia, but underappreciate cortisol’s role in endogenous T2D.
• Recommendation for broader screening of dysregulated cortisol secretion in diabetes clinics, not just for rare "classic" Cushing’s.
  • “The more broad screening should be done in this patient population to identify those who have dysregulated cortisol hypersecretion and who may benefit from either surgical or pharmacotherapy.” —Dr. Findling [16:56]
• Chronic, hard-to-manage diabetes should prompt consideration of hypercortisolism, not just noncompliance or poor diet.

10. Take-Home Messages for Providers

[17:46]

• Even without classic Cushing’s physical traits, patients with highly refractory diabetes/hypertension may be experiencing cortisol excess.

• Failing to investigate can miss significant, treatable contributors—some surgical.

• Patients often grateful for identification of a new, actionable diagnosis.

• Quote:
  “Their abnormalities being manifest in difficult to control diabetes...That's not a happy situation for the patient...identifying an abnormality you could possibly treat really contributes a great deal towards them being accepting of what's going on and looking for a treatment solution.” —Dr. Fonseca [17:55]

Notable Quotes & Memorable Moments

• Dr. Findling:
  “Non-neoplastic hypercortisolism…may have activation of the HPA axis because of their underlying condition...One of those categories is poorly controlled type 2 diabetes.” [02:23]
• Dr. Fonseca:
  “The difference between [mifepristone] and placebo was minus 1.3, which is better than many of the diabetes drugs that we have in clinical practice.” [08:30]
• Dr. Findling (on screening):
  “The more broad screening should be done in this patient population to identify those who have dysregulated cortisol hypersecretion and who may benefit from either surgical or pharmacotherapy.” [16:56]
• Dr. Fonseca (on clinical changes):
  “If you're confronted with a challenging patient where you don't have an easy answer, we shouldn't just dismiss it as being related to lack of compliance or lack of dieting and so on...identifying an abnormality that you could possibly treat really contributes a great deal...” [17:55]

Timestamps for Important Segments

• 00:00–01:24 – Introduction and expert backgrounds
• 01:28 – Defining suboptimal diabetes control for the study
• 02:17–03:15 – Causes and prevalence of hypercortisolism
• 04:29 – Why mifepristone and insights on DST
• 06:08–08:25 – Study design and detailed patient stats
• 08:25–13:53 – Results: Prevalence, demographics, imaging, treatment outcomes
• 13:53–15:44 – Adverse effects and management implications
• 15:44–16:44 – Study’s implications on the role of cortisol in diabetes
• 16:44–17:46 – Practitioner awareness and call for broader screening
• 17:46–19:09 – Key takeaways and closing thoughts

Conclusion

This episode delivers key insights for any clinician managing challenging T2D: a significant subset of these patients likely have undiagnosed hypercortisolism, often without classic Cushingoid features. Mifepristone offers a promising new tool for improving glycemic control in this population. The data encourages more routine screening for occult cortisol excess in refractory diabetes—reframing difficult cases not as patient failure, but as a potential missed diagnosis with real therapeutic potential.

For further episodes or to suggest topics, reach out to the Endocrine News Podcast team at podcast@endocrine.org.