Rowan S Hardy1,2,3, Hannah Botfield2, Keira Markey1, James L Mitchell1,4,5, Zerin Alimajstorovic1,4, Connar S J Westgate1, Michael Sagmeister1, Rebecca J Fairclough6, Ryan S Ottridge7, Andreas Yiangou1,4,5, Karl-Heinz H Storbeck1,8, Angela E Taylor1,4, Lorna C Gilligan1,4, Wiebke Arlt1,4,9, Paul M Stewart10, Jeremy W Tomlinson11, Susan P Mollan1,4, Gareth G Lavery1,4, Alexandra J Sinclair1,4,5. 1. Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. 2. Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. 3. Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, UK. 4. Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK. 5. Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK. 6. Emerging Innovations Unit, Discovery Sciences. BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. 7. Birmingham Clinical Trials Unit, Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. 8. Department of Biochemistry, Stellenbosch University, Stellenbosch, Matieland, South Africa. 9. NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. 10. Medical School, University of Leeds, Leeds, UK. 11. Oxford Centre for Diabetes, Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.
Abstract
BACKGROUND: The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor 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 (IIH). 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. RESULTS: Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, 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 intracranial 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.
BACKGROUND: The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor 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 (IIH). 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. RESULTS: Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, 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 intracranial 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.
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