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

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@article{7413bd735b4a4044924ff28209f0f5d8,
title = "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.",
author = "Rowan Hardy and Hannah Botfield and Keira Markey and James Mitchell and Zerin Alimajstorovic and Connar Westgate and Michael Sagmeister and Rebecca Fairclough and Ryan Ottridge and Andreas Yiangou and Karl-Heinz Storbeck and Angela Taylor and Lorna Gilligan and Wiebke Arlt and Paul Stewart and Jeremy Tomlinson and Susan Mollan and Gareth Lavery and Alex Sinclair",
year = "2020",
month = oct,
day = "24",
doi = "10.1210/clinem/dgaa766",
language = "English",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "Endocrine Society",

}

RIS

TY - JOUR

T1 - 11βHSD1 inhibition with AZD4017 improves lipid profiles and lean muscle mass in Idiopathic intracranial hypertension

AU - Hardy, Rowan

AU - Botfield, Hannah

AU - Markey, Keira

AU - Mitchell, James

AU - Alimajstorovic, Zerin

AU - Westgate, Connar

AU - Sagmeister, Michael

AU - Fairclough, Rebecca

AU - Ottridge, Ryan

AU - Yiangou, Andreas

AU - Storbeck, Karl-Heinz

AU - Taylor, Angela

AU - Gilligan, Lorna

AU - Arlt, Wiebke

AU - Stewart, Paul

AU - Tomlinson, Jeremy

AU - Mollan, Susan

AU - Lavery, Gareth

AU - Sinclair, Alex

PY - 2020/10/24

Y1 - 2020/10/24

N2 - 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.

AB - 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.

U2 - 10.1210/clinem/dgaa766

DO - 10.1210/clinem/dgaa766

M3 - Review article

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

M1 - dgaa766

ER -