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 - Funding Information:
We are deeply indebted to the research participants. We thank Dr Vinaya Simha for providing regulatory support with institutional review board submissions after Dr Basu transitioned her programme from the Mayo Clinic to UVA, and Dr Robert Rizza for his wisdom during the planning of this work at the Mayo Clinic, and we are grateful to Supraja Gururaj MD for assistance with manuscript submission. We also sincerely thank Barbara Norby, RN (nurse coordinator, Mayo Clinic); and Safia Sawleh, MD (coordinator, UVA) for assistance with the conduct and recruitment of patients for the study. In addition, we thank Michael Slama (Senior Research Technologist, Mayo Clinic), Prestin Schwichtenberg (Research Technologist, Mayo Clinic), Ben Gran (Research Technologist, UVA), Nirmal Bhandari (Research Technologist, UVA), and the UVA radiology imaging core staff. The study was funded in part by Astra Zeneca. Additional support was provided by DK 029953 (RB), DK 085516 (AB), VUMC Hormone Assay and Analytical Services Core supported by DK059637 and DK020593 and UL1 TR000135 from the National Centre for Advancing Translational Science awarded to Mayo Clinic.
Funding Information:
We are deeply indebted to the research participants. We thank Dr Vinaya Simha for providing regulatory support with institutional review board submissions after Dr Basu transitioned her programme from the Mayo Clinic to UVA, and Dr Robert Rizza for his wisdom during the planning of this work at the Mayo Clinic, and we are grateful to Supraja Gururaj MD for assistance with manuscript submission. We also sincerely thank Barbara Norby, RN (nurse coordinator, Mayo Clinic); and Safia Sawleh, MD (coordinator, UVA) for assistance with the conduct and recruitment of patients for the study. In addition, we thank Michael Slama (Senior Research Technologist, Mayo Clinic), Prestin Schwichtenberg (Research Technologist, Mayo Clinic), Ben Gran (Research Technologist, UVA), Nirmal Bhandari (Research Technologist, UVA), and the UVA radiology imaging core staff. The study was funded in part by Astra Zeneca. Additional support was provided by DK 029953 (RB), DK 085516 (AB), VUMC Hormone Assay and Analytical Services Core supported by DK059637 and DK020593 and UL1 TR000135 from the National Centre for Advancing Translational Science awarded to Mayo Clinic.
Funding Information:
: The study was funded in part by Astra Zeneca. Additional support was provided by DK 029953 (R.B.), DK 085516 (A.B.), the VUMC Hormone Assay and Analytical Services Core, supported by DK059637 and DK020593 and UL1 TR000135 from the National Centre for Advancing Translational Science awarded to the Mayo Clinic. Funding information
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
VL - 24
SP - 881
EP - 890
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
SN - 1462-8902
IS - 5
ER -