What is the management approach for a patient with pseudo Cushing's syndrome taking Osilodrostat (LCI699)?

Management of Pseudo-Cushing's Syndrome in a Patient Taking Osilodrostat

Osilodrostat should be immediately discontinued in patients with pseudo-Cushing's syndrome, as this medication is indicated only for true endogenous Cushing's syndrome and will cause iatrogenic adrenal insufficiency in patients without pathologic hypercortisolism.

Critical Distinction: Pseudo-Cushing's vs. True Cushing's Syndrome

Pseudo-Cushing's syndrome represents a state of physiologic hypercortisolism (from conditions like depression, alcoholism, or obesity) rather than autonomous cortisol production. Osilodrostat, as an 11β-hydroxylase inhibitor, blocks cortisol synthesis and is FDA-approved only for endogenous Cushing's syndrome 1. Using this medication in pseudo-Cushing's will:

• Suppress already-normal HPA axis regulation, leading to adrenal insufficiency 2, 1
• Create unnecessary risk of hypocortisolism-related adverse events (reported in 27-50% of patients with true Cushing's disease) 2
• Expose patients to medication-specific risks including hypokalemia (17%), hypertension (14%), QT prolongation (4%), and hyperandrogenic effects in women (11-12% hirsutism) 2, 1

Immediate Management Steps

1. Discontinue Osilodrostat

• Stop the medication immediately to prevent iatrogenic adrenal insufficiency 2, 1
• Monitor for withdrawal symptoms, as hypocortisolism-related adverse events occurred in 28.6% of patients in real-world practice 3
• Consider stress-dose glucocorticoid coverage if the patient has been on osilodrostat long enough to suppress the HPA axis 2

2. Reassess the Diagnosis

• Re-evaluate whether this is truly pseudo-Cushing's or undiagnosed endogenous Cushing's syndrome 2
• Measure urinary free cortisol (UFC), late-night salivary cortisol (LNSC), and morning cortisol to confirm the absence of autonomous hypercortisolism 2
• If diagnostic uncertainty exists, perform a dexamethasone suppression test or CRH stimulation test to differentiate 2

3. Address Underlying Causes of Pseudo-Cushing's

• Treat depression with appropriate psychiatric management
• Address alcohol use disorder if present
• Implement weight loss strategies for obesity-related pseudo-Cushing's
• Manage poorly controlled diabetes or other metabolic conditions

Monitoring After Discontinuation

Assess for adrenal insufficiency symptoms including:

• Fatigue, weakness, nausea (reported in 8-11% during osilodrostat treatment) 2
• Hypotension and electrolyte abnormalities
• Morning cortisol levels to confirm HPA axis recovery 2

Monitor for rebound effects from:

• Accumulated adrenal steroid precursors (occurred in 42% of treated patients) 2
• Hypokalemia requiring potassium supplementation 2, 1
• QT interval changes if baseline ECG showed prolongation 1

Common Pitfall to Avoid

The most critical error is continuing osilodrostat in pseudo-Cushing's syndrome. This medication has no therapeutic role in physiologic hypercortisolism and will only cause harm. In phase III trials, 36% of patients with true Cushing's disease required glucocorticoid replacement for hypocortisolism-related adverse events 2. In pseudo-Cushing's patients with normal HPA axis feedback, this risk would be substantially higher.

If there was diagnostic uncertainty that led to osilodrostat initiation, prioritize definitive testing before considering any cortisol-lowering therapy. Osilodrostat demonstrated 77.1% efficacy in achieving UFC normalization in true Cushing's disease 2, but this efficacy is irrelevant and potentially dangerous in pseudo-Cushing's syndrome where cortisol levels should normalize with treatment of the underlying condition rather than pharmacologic suppression.