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

Hardy, Rowan S, Botfield, Hannah, Markey, Keira, Mitchell, James L, Alimajstorovic, Zerin, Westgate, Connar S J, Sagmeister, Michael, Fairclough, Rebecca J, Ottridge, Ryan S, Yiangou, Andreas, H Storbeck, Karl-Heinz, Taylor, Angela E, Gilligan, Lorna C, Arlt, Wiebke, Stewart, Paul M, Tomlinson, Jeremy W, Mollan, Susan P, Lavery, Gareth G and Sinclair, Alexandra J (2020) 11βHSD1 inhibition with AZD4017 improves lipid profiles and lean muscle mass in Idiopathic intracranial hypertension. The Journal of clinical endocrinology and metabolism. ISSN 1945-7197. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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Official URL: https://academic.oup.com/jcem

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.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: QU Biochemistry
WK Endocrine system. Endocrinology
WL Nervous system. Neurology
WT Geriatrics. Elderly care
Divisions: Ambulatory Care > Endocrinology
Related URLs:
Depositing User: Jamie Edgar
Date Deposited: 09 Nov 2020 13:49
Last Modified: 09 Nov 2020 13:49
URI: http://www.repository.uhblibrary.co.uk/id/eprint/3631

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