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Once-daily evening osilodrostat improved cortisol rhythms, sleep, and quality of life in Cushing syndrome without compromising disease control or safety.

Once-daily osilodrostat administered in the evening is safe, effective, and restores circadian cortisol rhythms in patients with biochemically controlled Cushing syndrome (CS), according to results published in the Journal of Clinical Endocrinology & Metabolism.

“By achieving lower evening cortisol exposures, this regimen improves sleep quality and overall quality of life. Over the long term, these changes may translate into potential cardiovascular benefits,” wrote corresponding author Andrea M. Isidori, MD, PhD, and colleagues.

A loss of circadian cortisol rhythm is a hallmark of CS and contributes to systemic adverse effects, the authors explained. The prospective pilot study assessed chronotherapy with once-daily osilodrostat and its effect on circadian cortisol profiles in 16 patients with well-controlled CS who transitioned from twice-daily osilodrostat therapy.

Researchers used ultra-high performance liquid chromatography–tandem mass spectrometry on saliva, serum, and urine samples to analyze circadian steroid hormones at baseline, when patients were taking twice-daily osilodrostat, and 60 to 90 days after they switched to a single equivalent daily dose at 19:00 ±1 hour. Investigators also assessed cardiometabolic markers, quality of life, sleep function, and safety outcomes.

At baseline, most patients had mild CS; the mean osilodrostat dose was 4.2 ±1.3 mg.

“Compared to the standard twice-daily regimen, once-daily dosing resulted in significantly reduced late afternoon to early morning cortisol exposure…without altering morning peak levels, reflecting an improved alignment with the natural circadian rhythm of glucocorticoids,” the researchers reported.

With the transition to dosing at 19:00 ±1 hour, salivary cortisol exposure decreased 6.1 ng/mL/h during the afternoon to early morning period, according to the study. Additionally, scores on the CushingQoL questionnaire increased 4.2 points, while scores on the Pittsburgh Sleep Quality Index decreased 1.7 points. The serum steroid precursors 11-deoxycorticosterone and 11-deoxycortisol also decreased.

“Eight patients advancing dosing to 16:00 ±1 hour showed comparable reductions,” the authors wrote, “with phase shifts in acrophase and nadir.”

No patients experienced adrenal insufficiency, liver toxicity, electrocardiogram abnormalities, or loss of disease control with the transition. Moreover, blood pressure, lipid profile, and glucose metabolism trended toward improvement.

“These results lay the groundwork for future large-scale, long-term studies to fully explore the potential of chronotherapy approach in the management of CS,” the researchers wrote.