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Inhibition of 11ß-Hydroxysteroid dehydrogenase-1 with AZD4017 in patients with
nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized,
double-blind, placebo-controlled, phase II study.
Authors Yadav Y, Dunagan K, Khot R, Venkatesh SK, Port J, Galderisi A, Cobelli C, Wegner
C, Basu A, Carter R, Basu R
Submitted By Submitted Externally on 3/9/2022
Status Published
Journal Diabetes, obesity & metabolism, REFERENCES
Year 2022
Date Published 1/1/2022
Volume : Pages Not Specified : Not Specified
PubMed Reference 35014156
Abstract To evaluate whether short-term treatment with a selective 11ß-Hydroxysteroid
dehydrogenase-1 (11ß-HSD1) inhibitor, AZD4017, would block hepatic cortisol
production and thereby decrease hepatic fat in patients with nonalcoholic fatty
liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type
2 diabetes (T2D)., This was a randomized, double-blind, placebo-controlled,
phase 2 study conducted at two sites. Key inclusion criteria were the presence
of NAFLD or NASH on magnetic resonance imaging (MRI) or recent biopsy positive
for NASH. Enrolled patients were randomly assigned (1:1) to AZD4017 or placebo
for 12?weeks. Primary outcomes were between-group differences in mean change
from baseline to week 12 in liver fat fraction (LFF) and conversion of 13 C
cortisone to 13 C cortisol in the liver., A total of 93 patients were
randomized; 85 patients completed treatment. The mean (standard deviation [SD])
change in LFF was -0.667 (5.246) and 0.139 (4.323) in the AZD4017 and placebo
groups (P = 0.441). For patients with NASH and T2D, the mean (SD) change in LFF
was significantly improved in the AZD4017 versus the placebo group (-1.087
[5.374] vs. 1.675 [3.318]; P = 0.033). Conversion of 13 C cortisone to 13 C
cortisol was blocked in all patients in the AZD4017 group. There were no
significant between-group differences (AZD4017 vs. placebo) in changes in
fibrosis, weight, levels of liver enzymes or lipids, or insulin sensitivity.,
Although the study did not meet one of the primary outcomes, AZD4017 blocked the
conversion of 13 C cortisone to 13 C cortisol in the liver in all patients who
received the drug. In patients with NASH and T2D, AZD4017 improved liver
steatosis versus placebo.


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