What is the recommended treatment for Cushing's syndrome using Korlym (mifepristone)?

Mifepristone (Korlym) Treatment for Cushing's Syndrome

Mifepristone (Korlym) is specifically indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery. 1

Dosing and Administration

• Starting dose: 300 mg once daily with food
• Dose titration: Increase by 300 mg increments every 2-4 weeks based on clinical response
• Maximum dose: 1200 mg daily (not to exceed 20 mg/kg/day)
• Administration: Take tablets whole (do not split, crush, or chew)

Mechanism and Clinical Effects

Mifepristone works as a glucocorticoid receptor antagonist, directly blocking cortisol action rather than reducing cortisol levels. Key clinical benefits include:

• Significant improvement in glycemic control (60% of patients) 2
• Reduction in diastolic blood pressure (38% of patients) 2
• Improvements in insulin resistance, weight, waist circumference, and quality of life 2
• Rapid improvement in psychiatric symptoms, often within the first week 3

Monitoring Parameters

Unlike other medications for Cushing's syndrome, cortisol levels cannot be used to monitor treatment efficacy with mifepristone. Instead, monitor:

1. Clinical signs and symptoms:

   • Weight changes
   • Blood pressure
   • Cushingoid appearance
   • Psychiatric symptoms

2. Laboratory parameters:

   • Serum potassium (frequently)
   • Blood glucose levels
   • Thyroid function tests

3. Signs of adrenal insufficiency:

   • Fatigue, weakness, dizziness
   • Nausea, vomiting
   • Hypotension

Major Adverse Effects and Management

1. Hypokalemia (common and potentially severe):

   • Monitor potassium levels frequently
   • May require spironolactone treatment 2
   • Occurs due to mineralocorticoid receptor activation

2. Adrenal insufficiency:

   • Cannot be diagnosed by cortisol levels (remain elevated)
   • Diagnosis based solely on clinical features 2
   • Treat with dexamethasone (preferred) if symptoms develop 2

3. Endometrial effects in women:

   • Endometrial thickening
   • Irregular vaginal bleeding
   • Due to anti-progesterone activity 2

4. Drug interactions:

   • Significant CYP450 interactions
   • Avoid concomitant use with simvastatin, lovastatin, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus 1
   • Grapefruit juice should be avoided 1

5. Pregnancy:

   • Contraindicated in pregnancy (will cause pregnancy termination)
   • Women of reproductive potential must use non-hormonal contraception during and for 1 month after treatment 1

Clinical Considerations and Pitfalls

1. Challenging monitoring:

   • No laboratory markers of efficacy are available 2
   • Cortisol levels remain elevated or increase during treatment
   • ACTH levels typically increase ≥2-fold 2

2. Risk of tumor growth:

   • Monitor for tumor volume progression in patients with macroadenomas
   • Three cases of tumor progression were reported in patients with macroadenomas after 25 months of treatment 2

3. Thyroid function:

   • Close monitoring required
   • Thyroid hormone replacement may need adjustment 2

4. Specialized use:

   • Should be used only by clinicians with extensive experience in Cushing's syndrome 2
   • Patients require careful counseling about monitoring limitations

Place in Therapy

Mifepristone is generally not first-line therapy for Cushing's syndrome. According to guidelines 2:

1. First-line medical options for mild-moderate disease:

   • Adrenal steroidogenesis inhibitors (ketoconazole, osilodrostat, metyrapone)
   • Cabergoline for mild disease

2. Mifepristone is appropriate for:

   • Patients with hyperglycemia secondary to Cushing's syndrome
   • Those who have failed surgery or are not surgical candidates 1
   • Cases where other medical therapies have failed or are poorly tolerated
   • Situations requiring rapid improvement in psychiatric symptoms

3. Not appropriate for:

   • Type 2 diabetes unrelated to Cushing's syndrome 1
   • Pregnant patients or those planning pregnancy
   • Patients unable to undergo close monitoring

Mifepristone provides a valuable treatment option particularly for managing the metabolic complications of Cushing's syndrome, but requires vigilant monitoring due to its unique mechanism of action and potential for serious adverse effects.