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

Rowan S Hardy, Hannah Botfield, Keira Markey, James L Mitchell, Zerin Alimajstorovic, Connar S J Westgate, Michael Sagmeister, Rebecca J Fairclough, Ryan S Ottridge, Andreas Yiangou, Karl-Heinz H Storbeck, Angela E Taylor, Lorna C Gilligan, Wiebke Arlt, Paul M Stewart, Jeremy W Tomlinson, Susan P Mollan, Gareth G Lavery, Alexandra J Sinclair, Rowan S Hardy, Hannah Botfield, Keira Markey, James L Mitchell, Zerin Alimajstorovic, Connar S J Westgate, Michael Sagmeister, Rebecca J Fairclough, Ryan S Ottridge, Andreas Yiangou, Karl-Heinz H Storbeck, Angela E Taylor, Lorna C Gilligan, Wiebke Arlt, Paul M Stewart, Jeremy W Tomlinson, Susan P Mollan, Gareth G Lavery, Alexandra J Sinclair

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.

Trial registration: ClinicalTrials.gov NCT02017444.

Keywords: 11b-HSD1; 11b-HSD1 inhibitor; AZD4017; Idiopathic intracranial hypertension; cortisol.

© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.
Figure 1.
Trial design and participant numbers for double-blind, placebo-controlled, randomized controlled trial in IIH using the selective 11β-HSD1 inhibitor AZD4017.
Figure 2.
Figure 2.
Metabolic changes following 12 weeks of AZD4017 treatment in IIH patients. Histograms showing glucose (A), insulin (B), HOMA2-IR (C), HbA1c (D), triglycerides (E), cholesterol (F), HDL (G), and the cholesterol/HDL ratio (H) in IIH patients before and after 12 weeks of either placebo or AZD4017 treatment. Data presented as mean ± SD. *P < .05, **P < .01, ***P < .001.
Figure 3.
Figure 3.
Liver enzymes and kidney function changes following 12 weeks of AZD4017 treatment in IIH patients. Histograms showing (A) bilirubin, (B) AST, (C) ALT, (D) ALP, (E) GGT in IIH patients before and after 12 weeks of either placebo or AZD4017 treatment. ****P < .0001.
Figure 4.
Figure 4.
Alterations in (A) total lean mass, (B) proximal lean mass and (c) distal lean mass in grams, determined by DXA following 12 weeks treatments with either placebo (n = 10) or AZD4017 treatment (n = 12) in IIH patients. *P < .05; **P < .01.
Figure 5.
Figure 5.
Changes in the androgens (A) testosterone, (B) 11-ketoandrostenedione and (C) 11β-hydroxyandrostenedione in serum following 12 weeks of AZD4017 treatment in IIH patients. Correlations between changes in the androgens (D) testosterone, (E) 11β-hydroxyandrostenedione and (F) androstenedione changes in total lean muscle after treatment with AZD4017 for 12 weeks in IIH patients. Data presented as mean ± SD. **P < .01.

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