What is the recommended starting dose, titration schedule, monitoring parameters, and contraindications for oral mifepristone in an adult with Cushing syndrome and type 2 diabetes mellitus or impaired glucose tolerance?

Mifepristone for Hypercortisolism in Diabetes

Recommended Starting Dose and Titration

Begin mifepristone at 300 mg orally once daily with food, and increase by 300 mg increments every 2-4 weeks based on clinical response, up to a maximum of 1200 mg daily (not exceeding 20 mg/kg/day). 1

• Patients must swallow tablets whole—do not split, crush, or chew 1
• Dose increases should be guided by clinical assessment of tolerability and improvement in Cushing's manifestations, not cortisol levels 1
• Early response indicators (within 6 weeks) include changes in glucose control, anti-diabetic medication requirements, insulin levels, and psychiatric symptoms 1
• Later indicators (beyond 2 months) include improvements in cushingoid appearance, acne, hirsutism, striae, and body weight 1

Dose Adjustments for Special Populations

• Renal impairment: No change in starting dose, but maximum dose limited to 600 mg 1
• Hepatic impairment (mild-moderate): No change in starting dose, but maximum dose limited to 600 mg 1
• Severe hepatic impairment: Mifepristone should not be used 1
• Concomitant strong CYP3A inhibitors: Start at 300 mg with maximum of 900 mg; if already on mifepristone, reduce dose according to current level (600 mg→300 mg, 900 mg→600 mg) 1

Critical Monitoring Parameters

Pre-Treatment Requirements

Exclude pregnancy with a negative pregnancy test before initiating treatment—mifepristone will terminate pregnancy due to its potent antiprogestational effects. 1

• Confirm hypercortisolism with at least 2-3 measurements of late-night salivary cortisol, 24-hour urinary free cortisol, or 1 mg dexamethasone suppression test 2
• For premenopausal women, use late-night salivary cortisol or urinary free cortisol rather than dexamethasone suppression test (oral estrogen causes false-positives) 2

During Treatment Monitoring

Monitor clinical features exclusively—cortisol levels cannot be used to assess treatment response or adrenal insufficiency because mifepristone blocks the glucocorticoid receptor, causing paradoxical cortisol elevation. 3, 4

Critical parameters to monitor:

• Hypokalemia: Check potassium levels regularly; occurred in 55% of patients in clinical trials 5, 6
• Hypertension: Monitor blood pressure closely; mifepristone can paradoxically increase blood pressure despite treating hypercortisolism 3, 5
• Adrenal insufficiency: Assess only by clinical signs (fatigue, weakness, nausea, hypotension); occurred in <5% of patients but requires immediate dexamethasone treatment 7, 6
• Endometrial hyperplasia: Monitor in women during long-term treatment due to antiprogestational effects 7, 8, 6
• Metabolic parameters: Track HbA1c, fasting glucose, weight, waist circumference, and liver enzymes every 3 months 2
• Pregnancy testing: Repeat if treatment interrupted >14 days in women of reproductive potential 1

Management of Adverse Effects

• Hypokalemia: Add spironolactone or eplerenone as first-line treatment (also addresses mineralocorticoid receptor overstimulation) 2
• Hypertension: Use mineralocorticoid receptor antagonists first-line, then ACE inhibitors or ARBs as second-line 2
• Adrenal insufficiency: Treat with dexamethasone (preferred over other glucocorticoids due to mifepristone's long half-life requiring several days of stress-dose replacement) 3

Absolute Contraindications

Mifepristone is absolutely contraindicated in pregnancy—it will terminate pregnancy. 1

Additional contraindications and precautions:

• Severe hepatic impairment 1
• Concurrent use of hormonal contraception: Mifepristone blocks progesterone receptors; require non-hormonal contraception (barrier methods, IUD) throughout treatment and for one month after stopping 1
• Treatment interruption >14 days: Requires repeat pregnancy testing before resuming 1

Position in Treatment Algorithm

Mifepristone is specifically indicated for patients with Cushing's syndrome who have type 2 diabetes or glucose intolerance AND have failed surgery or are not surgical candidates—it should not be used for general diabetes management. 1, 2

• The Endocrine Society recommends adrenal steroidogenesis inhibitors (ketoconazole, osilodrostat, metyrapone) as usual first-line medical therapy because they allow biochemical monitoring of cortisol levels 4
• Mifepristone is preferred specifically when severe hyperglycemia is the dominant clinical problem, as 60% of patients achieved ≥25% reduction in glucose area under the curve after 24 weeks 2, 6
• Consider mifepristone as bridge therapy while awaiting surgery or radiation effects, or when other medical therapies have failed 4, 9

Clinical Expertise Requirement

Mifepristone should only be prescribed by clinicians with extensive experience in Cushing's disease management, as the inability to use biochemical markers for monitoring creates significant risk of unrecognized adrenal insufficiency. 3, 4

• The Endocrine Society emphasizes that careful evaluation of drug interactions is essential before prescribing, particularly in patients with multiple medications 3
• The American College of Endocrinology recommends mifepristone only be used by expert pituitary endocrinologists who can properly monitor for interactions and complications 3

Common Pitfalls to Avoid

• Do not use cortisol measurements to guide dosing or assess adrenal insufficiency—rely entirely on clinical assessment 3, 4
• Do not overlook comprehensive medication review before initiating—significant CYP3A interactions exist with ketoconazole, itraconazole, ritonavir, clarithromycin, and many others 3, 1
• Do not prescribe without experience in Cushing's disease management—this medication requires specialized expertise 3, 4
• Do not use in pediatric patients—not currently approved for children 4