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Supported by an unrestricted educational grant from Corcept Therapeutics.
Spotlight On
Hypercortisolism
in Resistant Hypertension and Difficult-to-Control Type 2 Diabetes
A non-classic, underrecognized form of hypercortisolism is increasingly documented in common cardiometabolic disease — with defined diagnostic criteria and a clear confirmatory workup
Prevalence
10–15 to ~40–49 cases per million person-years1
Classic Cushing's syndrome (overt form)
27.3% (MOMENTUM, 297/1,086 patients)2,3
Non-classic hypercortisolism — resistant hypertension
23.8% (CATALYST, 252/1,057 patients)4
Non-classic hypercortisolism — difficult-to-control T2D
Up to 21%5
Primary aldosteronism with concurrent autonomous cortisol secretion
Age of Onset
Typically during the fourth to fifth decades of life.
ICD-10
E24.9
(Cushing's syndrome, unspecified) — no dedicated code exists for non-classic/mild autonomous cortisol secretion.
No general-population prevalence exists for non-classic hypercortisolism — it's only been characterized within at-risk populations, which is itself diagnostically relevant: directed screening in the right population outperforms broad screening.
5 Facts you should know
FACT
‘Hypercortisolism’ is not synonymous with overt Cushing's syndrome; a milder, non-classic form is increasingly documented in common cardiometabolic disease and can be missed without directed screening
FACT
In a study of 1,057 U.S. adults with difficult-to-control type 2 diabetes, 23.8% met diagnostic criteria for hypercortisolism (1-mg overnight DST cortisol >1.8 µg/dL, confirmed by dexamethasone >140 ng/dL)
FACT
Up to 21% of patients with confirmed primary aldosteronism also have autonomous cortisol secretion, indicating meaningful pathophysiologic overlap between the two conditions
FACT
MOMENTUM, a large U.S. study using the same overnight DST methodology, found 27.3% prevalence of endogenous hypercortisolism in patients with resistant hypertension (297 of 1,086 screened), presented at ACC 2026
FACT
5
The overnight DST serves as the initial screen; confirmatory workup — including ACTH level and adrenal imaging — determines etiology and management
Interest over time
Google searches
Common signs & symptoms
Non-classic presentation often lacks overt Cushingoid features (moon face, striae, buffalo hump)
Presents through associated conditions: resistant hypertension, difficult-to-control T2D
May coexist with primary aldosteronism
A completed aldosteronism workup does not rule out concurrent hypercortisolism
Screening & Diagnosis
1-mg overnight DST
Cortisol >1.8 µg/dL, confirmed by dexamethasone >140 ng/dL to verify adequate suppression
Interfering factors
- CYP3A4 inducers can accelerate dexamethasone clearance and produce false positives
- Oral estrogens, obesity, and depression are established confounders worth ruling out
Localization after a positive screen
- ACTH level differentiates adrenal (suppressed/undetectable ACTH) from ACTH-dependent sources
- Adrenal imaging often shows normal or subtle findings in non-classic disease, unlike the more visible adenomas typical of classic Cushing's
Confirmatory workup is required
A single DST result is a screen, not a diagnosis
Management Approach
Etiology-directed
Management depends on whether the source is adrenal, pituitary, or ectopic, established via ACTH and imaging
Options span medical (adrenal-directed) and surgical approaches
Determined case-by-case
Endocrinology coordinates ongoing monitoring and management of cardiometabolic comorbidities alongside etiology-directed treatment
Clinical trials
| Title | Description | Phases | Status | Interventions | More Information |
|---|---|---|---|---|---|
| Study of the Prevalence of Endogenous Hypercortisolism in Patients With Resistant Hypertension (MOMENTUM) | This is a non-interventional study to assess the prevalence of endogenous hypercortisolism (eHC) in patients with resistant hypertension (rHTN) and will enroll approximately 1000 patients at approximately 45 sites in the United States (US). Each patient will have an initial visit for screening. Aft... | N/A | Completed | More Info | |
| Study to Determine the Prevalence of Hypercortisolism in Patients With Type 2 Diabetes and Treatment With Korlym® (Mifepristone) (CATALYST) | This is a Phase 4 study with 2 parts: Part 1 (Prevalence Phase) is non-interventional and will assess the prevalence of hypercortisolism in a population with difficult to control type 2 diabetes (T2D) (hemoglobin A1c ≥7.5%) despite receiving standard-of-care therapies. Part 2 (Treatment Phase) is a... | Phase 4 | Completed | Drug: Mifepristone 300 MG [Korlym] Drug: Placebo for mifepristone | More Info |
| A Study to Evaluate the Safety and PK of CRN04894 for the Treatment of Cushing's Syndrome | A Phase 1b/2a, first-in-disease, open-label, multiple-ascending dose exploratory study to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamic biomarker responses associated with CRN04894 (an adrenocorticotropic hormone \[ACTH\] receptor antagonist) in participants with ACTH-dep... | Phase 1, Phase 2 | Recruiting | Drug: atumelnant | More Info |
| A Block-and-Replace Therapy With Osilodrostat and Concomitant Glucocorticoid Replacement | The major goal of this study is to determine the incidence of adrenal insufficiency in patients with endogenous Cushing syndrome receiving osilodrostat treatment combined with a replacement of glucocorticoid (block-and-replace approach). The investigators are also evaluating new biomarker steroids... | Recruiting | Drug: Osilodrostat | More Info | |
| Combination Osilodrostat and Cabergoline in Cushing's Disease | Cushing disease remains a challenging endocrine disorder in which persistent or recurrent hypercortisolism often requires medical therapy after surgery or when surgery is not feasible. Combination medical therapy has emerged as a rational strategy to improve biochemical control through complementary... | Phase 4 | Enrolling by invitation | Drug: osilodrostat Drug: osilodrostat and cabergoline | More Info |
| Isturisa Treatment in Mild Autonomous Cortisol Secretion( MACS) | To characterize the impact of Isturisa on clinical features and comorbidities associated with MACS. The investigators hypothesize that patients treated with Isturisa will exhibit significantly better metabolic indicators (such as fasting glucose, HbA1c, and lipid profile), blood pressure, weight, bo... | Phase 4 | Recruiting | Drug: Osilodrostat (Isturisa) | More Info |
| Extension Study to Evaluate the Safety of Long-Term Use of Relacorilant in Patients With Cushing Syndrome | This is an open-label extension study to evaluate the long-term safety of relacorilant in patients with endogenous Cushing syndrome who successfully completed participation in a Corcept-sponsored study of relacorilant and may benefit from continuing treatment. | Phase 2 | Active | Drug: relacorilant | More Info |
| Effect of Metyrapone on Cardiovascular Risk Factors in Patients With Adrenal Incidentalomas and Cushing's Syndrome | Drug interventional, controlled, randomized open-label, parallel-group, multicenter study in patients with bilateral adrenal incidentalomas associated with subclinical Cushing's syndrome | Phase 4 | Recruiting | Drug: Metarapone Drug: Standardized antihypertensive therapy | More Info |
| Metyrapone for Mild Autonomous Cortisol Secretion (MACS) | The purpose of this study is to find out whether the study drug, metyrapone, is safe and effective in treating participants with Mild Autonomous Cortisol Secretion (MACS). | Phase 2 | Active | Drug: Metyrapone | More Info |
| Desmopressin Stimulation Test Performance in ACTH-Dependent Cushing Syndrome | Background: Cushing syndrome (CS) is a set of diseases that develop when the body produces too much adrenocorticotropic hormone (ACTH). ACTH stimulates the production of a hormone called cortisol. Excess cortisol can cause serious issues, such as diabetes, high blood pressure, weight gain, and mood... | Phase 2 | Recruiting | Drug: Desmopressin Drug: Dexamethasone | More Info |
| Diagnostic Value of CXCR4-targeted PET/CT in ACTH-dependent and Independent Cushing's Syndrome | In previous clinical practice, 68Ga-Pentixafor PET/CT has demonstrated promising diagnostic utility in various neuroendocrine tumors by targeting CXCR4, a chemokine receptor overexpressed in several ACTH-secreting neoplasms. Building on this, and leveraging the Nuclear Medicine expertise at Peking U... | Phase 1, Phase 2 | Recruiting | Drug: 68Ga-Pentixafor | More Info |
| Long-Term Follow-Up of Survivors of Pediatric Cushing Disease | Background: The pituitary gland produces hormones. A tumor in this gland can cause it to produce too much of the hormone cortisol. Too much cortisol in the body causes Cushing disease. This disease causes many problems. Some of these problems might persist after the disease is cured. Objective: T... | Recruiting | More Info |