SUN-424 - Off-Label Use of Levoketoconazole in the Management of Mild Autonomous Cortisol Secretion

Background: Mild autonomous cortisol secretion (MACS) represents a form of mild adrenal cortisol excess causing partial hypothalamic-pituitary-adrenal axis dysregulation, resulting in attenuation of normal circadian rhythmicity in the absence of overt Cushing syndrome. It is increasingly recognized in patients with adrenal incidentalomas and is associated with increased comorbidities, including hypertension, type 2 diabetes mellitus, dyslipidemia, cardiovascular disease, and osteoporosis. Unilateral adrenalectomy is standard of care, and optimal medical management remains controversial, particularly in patients with bilateral adrenal disease for whom surgical intervention is not feasible. Levoketoconazole, a steroidogenesis inhibitor approved for treating Cushing syndrome, may represent a potential off-label therapeutic option to normalize cortisol circadian rhythm and improve associated cardiometabolic outcomes in MACS.

Case: A 51-year-old male with type 2 diabetes, hypertension, obesity, and severe coronary artery disease presented for evaluation of hypercortisolism with progressive weight gain, fatigue, and resistant hypertension (with average home readings of ~210/90-100 mmHg despite being on antihypertensive medications). Biochemical evaluation revealed three abnormal dexamethasone suppression tests (cortisol 2.5-2.8 µg/dL) with normal dexamethasone levels, borderline low ACTH ( 6.8 pg/mL), and low DHEA-S (36.4 µg/dL). Late-night salivary cortisol (x3) and 24-hour urinary free cortisol were normal. Primary hyperaldosteronism was excluded (renin 4.8 pg/mL, aldosterone 8.2 ng/dL). CT adrenals demonstrated bilateral adrenal thickening consistent with hyperplasia without discrete nodules. No characteristics of overt Cushing were seen on the physical exam. MACS was diagnosed.
Levoketoconazole was initiated following confirmation of normal baseline liver function tests and ECG. Within three months, home blood pressure readings improved to 110/70 -140/80 mmHg with subsequent de-escalation of antihypertensive therapy. Hemoglobin A1c improved from 6.8% to 5.5% with concomitant weight loss of 33 lbs within 4 months of treatment. At this time, tirzepatide was added, achieving further weight loss of 50 lbs over the next year. Serial monitoring demonstrated stable QTc and liver chemistries apart from mild hypokalemia (3.4 mmol/L). The patient did not develop any signs of adrenal insufficiency.

Conclusion: Evidence guiding non-surgical management of MACS remains limited, necessitating the need for further studies. This case supports the potential use of levoketoconazole as a therapeutic option for patients with MACS who cannot undergo surgery. Careful monitoring for hepatotoxicity, QTc prolongation, drug-drug interactions, and the development of adrenal insufficiency, are essential to optimize safety and clinical outcomes.

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