Identifying Hypercortisolism as a Major Contributing Cause of Metabolic Derangement

1. The patients who have difficult to control diabetes, obesity, coronary artery disease, fatty liver, hyperinsulinemia, excessive visceral fat, positive Kraft study, resistant hypertension, are candidates for workup for this disorder.
2. This is disorder is totally under recognized
3. It is now treatable using Korlym.

Exclusions:  Pregnancy and therefore you have to do a pregnancy test on females if they are in the age group.  Adrenal insufficiency and HIV medications, hypokalemia.

• 1 mg overnight dexamethasone suppression test. Takes the night before going to bed, and measure the serum cortisol level at 8AM.
• This test is not done at CVI
• This test should be done through Quest or LabCorp.
• Dexamethasone is only available by prescription. Ask your doctor if you are a candidate for this test.

A level that is greater than 1.8 mcg/dL suggests that this patient has hypercortisolism

CT scan of the abdomen and pelvis should be done to make sure that this patient does not have an adrenal adenoma.  If this is negative, therapy can be initiated.

ACTH level:  This will help determine whether the cortisol is coming from the pituitary gland with the adrenal gland.

300 mg:  Korlym daily.  Titrate slowly every 3 to 4 weeks to a maximum dose of 1200 mg.  Keep the maximum dose to less than 600 mg in patients who have chronic renal failure.

Monitor with BNP for hypokalemia and your doctor should adjust medications appropriately.

Monitor blood pressure carefully because it can go in both directions. The use of spironolactone or Inspra is recommended if there is fluid retention or high blood pressure or low potassium levels.  This is because this medication can sometimes stimulate the mineralocorticoid receptors.

The efficacy of Korlym (mifepristone) in the management of hypercortisolism (Cushing’s syndrome) is primarily demonstrated in the pivotal SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome) trial, an open-label, uncontrolled Phase III study. 
The main references used to show efficacy are:
Pivotal Phase III Study: The primary data for FDA approval came from a 24-week, open-label, multicenter study of 50 adults with endogenous Cushing’s syndrome who had type 2 diabetes mellitus or glucose intolerance and for whom surgery had failed or was not an option.
Key Finding: 60% of patients in the glucose-intolerant group demonstrated a greater than 25% reduction in the area under the curve in the oral glucose tolerance test.
Key Finding: Mean hemoglobin A1C (HbA1c) in the glucose-intolerant group decreased from 7.4% to 6.3%.
Key Finding: An independent review board assessed overall clinical improvement and determined that 87% of patients showed evidence of improvement at any post-baseline visit. Peer-Reviewed Publication of Phase III Results: The results of this pivotal trial were published in the peer-reviewed journal Clinical Endocrinology (Oxf):
Katznelson L, Loriaux DL, Feldman D, Braunstein GD, Schteingart DE, Gross C. Global clinical response in Cushing’s syndrome patients treated with mifepristone. Clin Endocrinol (Oxf). 2014;80(4):562-569. doi:10.1111/cen.12332.

CATALYST Study: A more recent Phase 4 study (CATALYST) further evaluated Korlym in patients with difficult-to-control type 2 diabetes and hypercortisolism. This study confirmed that Korlym produced a significant reduction in HbA1c compared to placebo.
Key Publication: DeFronzo RA, Auchus RJ, Bancos I, et al. Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone. BMJ Open. 2024;14(7):e081121. doi:10.1136/bmjopen-2023-081121.

These studies demonstrate Korlym’s effectiveness in controlling hyperglycemia and improving other clinical signs and symptoms of hypercortisolism by blocking the cortisol receptor, rather than reducing cortisol production itself.