TY - JOUR
T1 - Inhibition of 11β-Hydroxysteroid dehydrogenase-1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease
T2 - A randomized, double-blind, placebo-controlled, phase II study
AU - Yadav, Yogesh
AU - Dunagan, Kelly
AU - Khot, Rachita
AU - Venkatesh, Sudhakar K.
AU - Port, John
AU - Galderisi, Alfonso
AU - Cobelli, Claudio
AU - Wegner, Craig
AU - Basu, Ananda
AU - Carter, Rickey
AU - Basu, Rita
N1 - Publisher Copyright:
© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
PY - 2022/5
Y1 - 2022/5
N2 - Aim: To evaluate whether short-term treatment with a selective 11β-Hydroxysteroid dehydrogenase-1 (11β-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). Materials and Methods: 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 13C cortisone to 13C cortisol in the liver. Results: 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 13C cortisone to 13C 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. Conclusion: Although the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of 13C cortisone to 13C cortisol in the liver in all patients who received the drug. In patients with NASH and T2D, AZD4017 improved liver steatosis versus placebo.
AB - Aim: To evaluate whether short-term treatment with a selective 11β-Hydroxysteroid dehydrogenase-1 (11β-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). Materials and Methods: 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 13C cortisone to 13C cortisol in the liver. Results: 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 13C cortisone to 13C 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. Conclusion: Although the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of 13C cortisone to 13C 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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U2 - 10.1111/dom.14646
DO - 10.1111/dom.14646
M3 - Article
C2 - 35014156
AN - SCOPUS:85123590893
SN - 1462-8902
VL - 24
SP - 881
EP - 890
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
IS - 5
ER -