11βHSD1 Inhibition with AZD4017 Improves Lipid Profiles and Lean Muscle Mass in Idiopathic Intracranial Hypertension

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.

A randomised controlled pilot trial of oral 11β-HSD1 inhibitor AZD4017 for wound healing in adults with type 2 diabetes mellitus

“…Indeed conversely, we found evidence of improvements in some “metabolic” traits, notably high density lipoprotein, cholesterol and systolic blood pressure in the AZD4017 arm which were not present at baseline or after 7 days treatment washout (and despite ongoing treatment for these conditions). These improvements are consistent with results from other selective 11β-HSD1 inhibitor trials ( 33-36 ).…”

“…Our primary outcome measure failed to evidence 11β-HSD1 inhibition in skin. However, preliminary proof-of-concept was demonstrated though a reduction in [THF+alloTHF]/THE ratios (the gold-standard measure of systemic 11β-HSD1 activity) and elevated DHEAS consistent with other selective 11β-HSD1 inhibitor trials, including AZD4017 ( 34, 36-39 ). As anticipated, 11β-HSD2 activity was unaffected ( 40, 41 ).…”

Idiopathic Intracranial Hypertension: Evaluation of Admissions and Emergency Readmissions through the Hospital Episode Statistic Dataset between 2002–2020

“…New insights into the underlying pathophysiology have been discovered, including the role of the glucagon-like peptide 1 (GLP-1) receptor agonist in cerebrospinal fluid (CSF) secretion and intracranial pressure regulation, and the role of androgens in CSF dysregulation in IIH [ 11 , 12 , 13 , 14 , 15 ]. These have been translated into clinical trials, with the first phase 2 trial of a novel treatment recently reported [ 16 ].…”

The ratio of ursodeoxycholyltaurine to 7‐oxolithocholyltaurine serves as a biomarker of decreased 11β‐hydroxysteroid dehydrogenase 1 activity in mouse

“…Rodent studies and clinical investigations demonstrated an association between excessive 11β‐HSD1 activity and adverse health effects including insulin resistance and type II diabetes mellitus, osteoporosis, impaired wound healing, skin aging, cognitive impairment and glaucoma (Gathercole et al, 2013 ; Terao & Katayama, 2016 ; Wyrwoll et al, 2011 ). Therefore, 11β‐HSD1 attracted high attention for potential therapeutic applications and a variety of small molecule inhibitors have been developed in order to assess their effects in preclinical and clinical studies (Feig et al, 2011 ; Freude et al, 2016 ; Hardy et al, 2020 ; Markey et al, 2017 ; Rosenstock et al, 2010 ; Schwab et al, 2017 ; Scott et al, 2014 ; Tiganescu et al, 2018 ; Webster et al, 2017 ; Ye et al, 2017 ).…”