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. 2022 Jun 13:13:903545.
doi: 10.3389/fendo.2022.903545. eCollection 2022.

Metyrapone Versus Osilodrostat in the Short-Term Therapy of Endogenous Cushing's Syndrome: Results From a Single Center Cohort Study

Mario Detomas  1 , Barbara Altieri  1 , Timo Deutschbein  1   2 , Martin Fassnacht  1   3 , Ulrich Dischinger  1
Affiliations

Metyrapone Versus Osilodrostat in the Short-Term Therapy of Endogenous Cushing's Syndrome: Results From a Single Center Cohort Study

Mario Detomas et al. Front Endocrinol (Lausanne). .

Abstract

Background: Although surgery is considered the first-line treatment for patients with endogenous Cushing's syndrome (CS), medical therapy is often required to control severe hypercortisolism. Metyrapone and osilodrostat are both steroidogenic inhibitors targeting the 11β-hydroxylase, however, their therapeutic effectiveness has not yet been directly compared. This study aimed to evaluate metyrapone and osilodrostat in the short-term therapy of CS.

Methods: Retrospective analysis of patients with endogenous CS treated with metyrapone or osilodrostat as monotherapy for at least 4 weeks. Main outcome measures were serum cortisol and 24h urinary free cortisol (UFC) at baseline (T0) and after 2 (T1), 4 (T2), and 12 weeks (T3) of therapy.

Results: 16 patients with endogenous CS were identified (pituitary n=7, adrenal n=4, ectopic CS n=5). Each 8 patients were treated with metyrapone and osilodrostat. Despite heterogeneity, both groups showed comparable mean UFC levels at T0 (metyrapone: 758 µg/24h vs osilodrostat: 817 µg/24h; p=0.93). From T0 to T1, the decrease of UFC was less pronounced under metyrapone than osilodrostat (-21.3% vs -68.4%; median daily drug dose: 1000 mg vs 4 mg). This tendency persisted at T2 (-37.3% vs -50.1%; median drug dose: 1250 mg vs 6 mg) while at T3 a decrease in UFC from T0 was more pronounced in the metyrapone group (-71.5% vs -51.5%; median dose 1250 mg vs 7 mg). Under osilodrostat, a QTc-interval prolongation was identified at T3 (mean 432 ms vs 455 ms). From T0 to T2, the number of antihypertensive drugs remained comparable under metyrapone and decreased under osilodrostat (n= -0.3 vs n= -1.0).

Conclusion: Although both drugs show comparable therapeutic efficacy, osilodrostat seems to reduce cortisol levels and to control blood pressure faster.

Keywords: Cushing’s syndrome; blood pressure; efficacy; hypercortisolism; isturisa; medical therapy; metyrapone; osilodrostat.

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Conflict of interest statement

UD received honoraria from Recordati Rare Diseases for scientific board activities. TD received honoraria from Recordati Rare Diseases and HRA Pharma for scientific board activities. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Timeline of the study with description of follow-up visit. The data analysis was performed at baseline (T0), after 2 weeks (T1), after 4 weeks (T2) and after 12 weeks (T3). ALT, alanine transaminase; AST, aspartate aminotransferase; Crea, creatinine; ECG, electrocardiography; GGT, gamma-glutamyltransferase; K, potassium; LDL, low density lipoprotein; UFC, urinary free cortisol.
Figure 2
Figure 2
Changes of basal serum cortisol and 24h-urinary free cortisol during the follow-up in patients treated with metyrapone or osilodrostat. Changes in absolute values (A) and delta percentage (B) of morning basal serum cortisol during metyrapone or osilodrostad treatment from T0 (baseline) to 2 weeks (T1), 4 weeks (T2) and 12 weeks (T3) of therapy. Changes in absolute values (C) and delta percentage (D) of 24h-urinary free cortisol during metyrapone or osilodrostad treatment from T0 (baseline) to 2 weeks (T1), 4 weeks (T2) and 12 weeks (T3) of therapy. Absolute values are reported with mean and standard error of mean (SEM). Normal range of serum cortisol and 24h-urinary free cortisol is reported within the dotted lines in (A, B).
Figure 3
Figure 3
Delta percentage of systolic and diastolic blood pressure and change in number of antihypertensive drugs under metyrapone or osilodrostat treatment during follow-up compared with baseline. Changes in percentage from T0 (baseline) of (A) systolic, (B) diastolic blood pressure after 4 weeks (T2) of metyrapone or osilodrostat therapy compared with baseline (T0). (C) Changes in number of anti-hypertensive drugs after two weeks (T1) and 4 weeks (T2) of treatment in comparison to baseline.
Figure 4
Figure 4
QTc-interval at baseline and during follow-up under metyrapone or osilodrostat treatment. Changes in absolute values of QTc-interval in electrocardiography under metyrapone or osilodrostat treatment. Electrocardiogram and QTc-interval analysis was performed at 4 weeks (T2) and at 12 weeks (T3). Values are reported with mean and standard error of mean (SEM).
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