Once-daily osilodrostat restore cortisol rhythm in patients with Cushing syndrome

Treatment with osilodrostat once daily is safe and effective in patients with biochemically controlled Cushing syndrome (CS), improving circadian cortisol rhythm, a study has shown.

“By achieving lower evening cortisol exposures, this regimen improves sleep quality and overall quality of life,” the researchers said. “Over the long term, these changes may translate into potential cardiovascular benefits.”

Sixteen patients with well-controlled CS (mean age 53.3 years) were enrolled in this prospective, multicentre study. They were receiving twice-daily osilodrostat therapy before and 60 to 90 days after transitioning to a single equivalent daily dose at 19:00±1 h.

The researchers performed circadian steroid analysis on saliva, serum, and urine using ultra-high performance liquid chromatography–tandem mass spectrometry. They also carried out additional assessments, such as cardio-metabolic markers, quality of life, sleep function, and safety outcomes.

CS was well controlled at baseline, with a mean osilodrostat dose of 4.2 mg. After the transition, salivary cortisol exposure significantly decreased during the afternoon to early morning period (AUC_16:00-08:00, −6.1 ng/mL/h; p=0.029). [J Clin Endocrinol Metab 2025;110:3525-3537]

Both sleep (Pittsburgh Sleep Quality Index: –1.7; p=0.049) and quality of life (CushingQoL: 4.2; p=0.029) improved, while serum steroid precursors, including 11-deozycorticosterone (–3.1 ng/mL/h; p=0.008) and 11-deoxycortisol (–17.8 ng/mL/h; p=0.005), decreased.

Similar reductions were observed in eight patients who advanced dosing to 16:00±1 h, with phase shifts in acrophase and nadir. Notably, there was no incidence of adrenal insufficiency, liver toxicity, electrocardiogram abnormalities, or loss of disease control among the participants.

“Surprisingly, once-daily dosing also led to a significant reduction in steroid precursors and total testosterone levels in women despite stable day cortisol levels,” the researchers said. 

“This suggests that osilodrostat, when administered as a single dose, may exert a broader inhibition of the steroidogenic cascade, possibly through higher peak drug concentrations inhibiting enzymes upstream of CYP11B1, such as CYP11A1,” they added. [J Steroid Biochem Mol Biol 2023;231:106316; Eur J Endocrinol 2022;187:315‐322]

Kinetics

These findings are consistent with those of another study, which noted how osilodrostat exhibits dose-overproportional kinetics, “with higher single doses potentially affecting additional steroidogenic enzymes, usually unaffected at lower peak concentrations.” [J Am Coll Cardiol 2010;55:A61.E583]

“Furthermore, recent reports of prolonged adrenocortical blockade after treatment withdrawal suggest that osilodrostat's in vivo actions are more complex than observed in vitro,” the researchers said. 

A previous trial showed a delayed urinary free cortisol rebound following the switch from osilodrostat to placebo. [Lancet Diabetes Endocrinol 2020;8:748‐761]

Another study in 2023 found sustained adrenal insufficiency that lasted 6 weeks to 9 months in three patients who discontinued osilodrostat. Three additional cases were also reported in 2024 studies. [Eur J Endocrinol 2023;188:K29‐K32; Eur J Endocrinol 2024;190:L1‐L3; JCEM Case Rep 2024;2:luae088]

This “remnant” effect seemed to occur independently of osilodrostat dose, for an unpredictable duration, in some but not all patients, according to the researchers.

“Given these findings, we speculate that osilodrostat may act through two distinct mechanisms: a ‘canonical’, rapid, reversible CYP11B1 inhibition and a long-term effect, potentially involving broader upstream steroidogenesis inhibition or other yet-to-be-explored mechanisms, such as adrenal cytotoxicity,” they added. 

“The well-controlled, stable disease on low-dose osilodrostat, along with a long run-in period and extended observation in our cohort of CS, suggests that our circadian findings are primarily attributable to the canonical effect,” the researchers said.