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

Abstract

BackgroundAlthough 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.MethodsRetrospective 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.Results16 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).ConclusionAlthough both drugs show comparable therapeutic efficacy, osilodrostat seems to reduce cortisol levels and to control blood pressure faster.

Medical Therapy of Endogenous Cushing’s Syndrome with Steroidogenesis Inhibitors: Treatment Rationale, Available Drugs, and Therapeutic Effects

“…Ketoconazole oral 200-1200 mg/day 45-93% [5,6,8,54,55] hirsutism (36%), hepatotoxicity (11-19%), adrenal insufficiency (5-19%), GI problems (4-19%), skin rash (4-6%), gynecomastia (new onset or worsening) (17-25%) [5,6,8,54,55] Levoketoconazole oral 300-1200 mg/day 31-81% [9,10] nausea (29-32%), headache (23-28%), hypokalemia (11-26%), hypertension (17-24%), QT prolongation (5-11%) [9,10] Metyrapone oral 250-6000 mg/day 45-100% [3,8,11,12,14,47] hirsutism (5-71%), nausea (5-33%), dizziness (10-44%), edema (6-20%), decreased appetite (18%), -fatigue (14%), headache (10%), hypokalemia (6%), hypertension (6-48%) [3,8,11,12,14,47] Osilodrostat oral 4-60 mg/day 66-100% [4,[14][15][16]39] fatigue (29-58%), nausea (32-42%), headache (25-34%), diarrhea (25-32%), adrenal insufficiency (28-32%), QT prolongation (4-13%), hypertension (12%) [4,[14][15][16]39] Mitotane oral mean drug dose 2500-3300 g/day (according to blood concentration) 76-91% [21,27,30] gastrointestinal tract problems (47-65%), neurological complications (26-36%), asthenia (68%), nausea (53%), hypercholesterolemia (54%), increased transaminases (36%), anorexia (36%) …”

“…Interestingly, as osilodrostat results in lower blood pressure, the number of antihypertensives may be decreased already within the first month of treatment [14,17]. Body weight, glucose metabolism, and quality of life were found to improve as well [3,15].…”

Clinical Utility of Osilodrostat in Cushing’s Disease: Review of Currently Available Literature

“…21,25 In the LINC 3 study, 4% of patients showed an increase in ALT or AST on osilodrostat treatment. 26 LINC 4 was a randomized, double-blind, placebo-controlled, multicenter study of 73 patients with CD treated with osilodrostat for 12 weeks, which was followed by open-label osilodrostat administration for 36 weeks; overall, the study lasted for a total of 48 weeks. 9 For the first 12 weeks, osilodrostat was compared to placebo, and then all subjects in the study received osilodrostat until week 48.…”

“… 21 , 25 In the LINC 3 study, 4% of patients showed an increase in ALT or AST on osilodrostat treatment. 26 …”

“…29 Some studies have shown that osilodrostat reduces cortisol levels and improves blood pressure more rapidly, when compared to metyrapone. 26 Decreased cortisol levels after the initiation of treatment may be associated with clinical signs and symptoms of adrenal insufficiency or glucocorticoid withdrawal symptoms, with a prevalence as high as 51% during the titration phase, decreasing to 6% in the osilodrostat group during the randomized withdrawal phase. 21 Patients should be educated about these symptoms and instructed on proper management.…”