What is the role of aldosterone synthetase inhibitors, such as osilodrostat (osilodrostat), in treating patients with Cushing's syndrome or hypertension?

Role of Aldosterone Synthase Inhibitors in Cushing's Syndrome and Hypertension

Osilodrostat, an aldosterone synthase inhibitor, is highly effective for treating Cushing's disease in patients for whom pituitary surgery is not an option or has not been curative, with 86% of patients maintaining normal urinary free cortisol levels compared to 29% with placebo. 1, 2

Mechanism of Action and Indications

Osilodrostat (Isturisa) is a potent cortisol synthesis inhibitor that works by:

• Inhibiting 11β-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland 2
• Also inhibiting aldosterone synthase (CYP11B2), which was its initial development target for hypertension before its efficacy in Cushing's syndrome was discovered 3
• Reducing cortisol levels with an IC50 value of 2.5 ± 0.1 nM 2

FDA-approved specifically for:

• Treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative 2

Efficacy in Cushing's Disease

Osilodrostat has demonstrated superior efficacy compared to other steroidogenesis inhibitors:

• In phase 3 clinical trials, 86% of patients randomized to osilodrostat maintained normal urinary free cortisol (UFC) versus only 29% of those on placebo (OR 13.7 [95% CI: 3.7,53.4]; p<0.0001) 1
• In another large prospective phase 3 study, 77.1% of patients receiving osilodrostat achieved mean UFC ≤ ULN after 12 weeks versus 8.0% with placebo 1
• It is the only steroidogenesis inhibitor to have been assessed in prospective randomized controlled trials and approved for Cushing's disease by the FDA 4

Clinical Benefits Beyond Cortisol Control

Treatment with osilodrostat provides significant improvements in comorbidities:

• Significant decreases in body weight, blood pressure, total and LDL cholesterol
• Decreased fasting serum glucose and HbA1c levels
• Improved quality of life and depression scores 1
• Rapid onset of action compared to some other treatments like mitotane 5

Dosing and Administration

• Starting dose: Generally 2-7 mg/day 6
• Administered twice daily due to its approximately 4-hour half-life 2, 5
• Can be taken with or without food (high-fat meals reduce AUC by 11% and Cmax by 21%, but this is not clinically significant) 2
• Dose titration should be individualized based on cortisol levels and tolerability
• No dosage adjustment required for mild hepatic impairment or renal impairment, but dose adjustments needed for moderate to severe hepatic impairment 2

Adverse Effects and Monitoring

Common adverse effects include:

• Hypocortisolism-related adverse events (27.4-50% of patients) 1
• Nausea, anemia, and headache (8-11% of patients) 1
• Hypokalemia and hypertension (due to increased levels of adrenal steroid precursors) in 42% of treated patients 1
• Hirsutism in 11% of women due to hyperandrogenic effects 1, 5
• QT interval prolongation (dose-dependent) 2

Monitoring recommendations:

• Regular assessment of cortisol levels
• Electrolyte monitoring, particularly potassium
• ECG monitoring, especially in patients on other medications that may prolong QT interval
• Liver function tests
• Clinical assessment for signs of hypocortisolism or hyperandrogenism

Role in Hypertension Management

While initially developed for hypertension, osilodrostat's primary clinical application has shifted to Cushing's syndrome:

• Hypertension is present in 70-90% of patients with Cushing's syndrome 6
• Mineralocorticoid receptor antagonists (spironolactone, eplerenone) remain first-line antihypertensives for Cushing's-related hypertension 6
• Osilodrostat can improve blood pressure as part of its overall effect on Cushing's syndrome 1, 6
• For primary hypertension without Cushing's syndrome, there is insufficient evidence to recommend aldosterone synthase inhibitors over established antihypertensives 1

Special Considerations

1. Off-label use: While approved for Cushing's disease, osilodrostat has been used successfully off-label in cases of adrenocortical carcinoma causing Cushing's syndrome 7

2. Block-and-replace strategy: In cases of adrenal insufficiency during osilodrostat treatment, a block-and-replace strategy with hydrocortisone can be employed 7

3. Drug interactions: Multiple CYP enzymes (CYP3A4, CYP2B6, CYP2D6) and UDP-glucuronosyltransferases contribute to osilodrostat metabolism, requiring careful assessment of concomitant medications 2, 5

Practical Algorithm for Use

1. Patient selection:

   • Patients with Cushing's disease who failed surgery or are not surgical candidates
   • Consider in patients with severe hypercortisolism who cannot tolerate first-line therapies

2. Pre-treatment assessment:

   • Baseline cortisol levels (UFC, serum)
   • Electrolytes, particularly potassium
   • ECG to assess QT interval
   • Concomitant medications review for potential interactions

3. Treatment initiation and monitoring:

   • Start at low dose (2 mg/day)
   • Titrate gradually based on cortisol levels and tolerability
   • Monitor for hypocortisolism, electrolyte abnormalities, and hyperandrogenism
   • Assess for clinical improvement in Cushing's features including blood pressure

4. Long-term management:

   • Continue regular monitoring of cortisol levels and electrolytes
   • Periodic ECG assessment
   • Adjust dose as needed to maintain normal cortisol levels while minimizing side effects

In conclusion, osilodrostat represents a significant advancement in the medical management of Cushing's disease with demonstrated efficacy in normalizing cortisol levels and improving clinical outcomes including hypertension, but its role as a primary treatment for hypertension without Cushing's syndrome is not established.