An Open-label Phase I/IIa Clinical Trial of 11[beta]-HSD1 Inhibitor for Cushing's Syndrome and Autonomous Cortisol Secretion

Context: 11[beta]-hydroxysteroid dehydrogenase type 1 (11[beta]-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients. Objective: To confirm the efficacy and safety of S-707106 (11[beta]-HSD1 inhibitor)...

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Published in:The journal of clinical endocrinology and metabolism 2021-10, Vol.106 (10), p.e3865
Main Authors: Oda, Satoko, Ashida, Kenji, Uchiyama, Makiko, Sakamoto, Shohei, Hasuzawa, Nao, Nagayama, Ayako, Wang, Lixiang, Nagata, Hiromi, Sakamoto, Ryuichi, Kishimoto, Junji, Todaka, Koji, Ogawa, Yoshihiro, Nakanishi, Yoichi, Nomura, Masatoshi
Format: Article
Language:English
Subjects:
Clinical trials
Corticosteroids
Dextrose
Glucose
Glucose tolerance tests
Type 2 diabetes
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Summary:Context: 11[beta]-hydroxysteroid dehydrogenase type 1 (11[beta]-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients. Objective: To confirm the efficacy and safety of S-707106 (11[beta]-HSD1 inhibitor) administered to CS and ACS patients. Design: A 24-week single-center, open-label, single-arm, dose-escalation, investigatorinitiated clinical trial on a database. Setting: Kyushu University Hospital, Kurume University Hospital, and related facilities. Patients: Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance. Intervention: Oral administration of 200 mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200 mg twice daily) was administered for the residual 12 weeks. Main Outcome Measures: The rate of participants responding to glucose tolerance impairment, defined as those showing a 25% reduction in the area under the curve (AUC) of plasma glucose during the 75-g oral glucose tolerance test at 24 weeks. Results: S-707106 administration could not achieve the primary endpoint of this clinical trial (>20% of responsive participants). AUC glucose decreased by -7.1% [SD, 14.8 (90% CI -14.8 to -1.0), P = 0.033] and -2.7% [14.5 (-10.2 to 3.4), P = 0.18] at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by -2.5% [1.7 (-3.3 to -1.8), P < 0.001] and body muscle percentage increased by 2.4% [1.6 (1.7 to 3.1), P < 0.001]. Conclusions: S-707106 is an effective insulin sensitizer and antisarcopenic and antiobesity medication for these patients. Key Words: 11[beta]-hydroxysteroid dehydrogenase type 1, Cushing's syndrome, diabetes mellitus, cortisol, obesity, sarcopenia
ISSN:0021-972X
1945-7197
DOI:10.1210/clinem/dgab450