11βHSD1 inhibition with AZD4017 improves lipid profiles and lean muscle mass in Idiopathic intracranial hypertension

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Abstract

Background The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines pre-receptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11β-HSD1 inhibitors. We examined the impact of the reversible competitive 11β-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension. Methods We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry (DXA). Results Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased HDL and cholesterol/HDL ratio), markers of hepatic function (decreased ALP and GGT) and increased lean muscle mass (1.8%, p<0.001). No changes in BMI, fat mass and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass. Conclusions These beneficial metabolic changes, represent a reduction in risk factors associated with raised intra-cranial pressure and represent further beneficial therapeutic outcomes of 11β-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia.

Details

Original languageEnglish
Article numberdgaa766
JournalJournal of Clinical Endocrinology and Metabolism
Early online date24 Oct 2020
Publication statusE-pub ahead of print - 24 Oct 2020