Inhibition of 11β-Hydroxysteroid dehydrogenase-1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled, phase II study
Diabetes, Obesity and Metabolism Jan 28, 2022
In patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type 2 diabetes (T2D), it was investigated if short-term therapy with a selective 11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, AZD4017, would block hepatic cortisol generation and thereby reduce hepatic fat.
This randomized, double-blind, placebo-controlled, phase 2 study included 93 patients with NAFLD or NASH who were randomized (1:1) to AZD4017 or placebo for 12 weeks; 85 patients completed treatment.
In the AZD4017 and placebo groups, mean (standard deviation [SD]) alteration in liver fat fraction (LFF) was −0.667 (5.246) and 0.139 (4.323), respectively.
In both the groups, mean (SD) change in LFF was significantly improved for those with NASH and T2D (−1.087 [5.374] vs 1.675 [3.318]).
No significant between-group differences (AZD4017 vs placebo) were observed in changes in fibrosis, weight, levels of liver enzymes or lipids, or insulin sensitivity.
In this study, one of the primary outcomes was not met, conversion of <sup>13</sup> C cortisone to <sup>13</sup> C cortisol in the liver was blocked by AZD4017 in all patients who received the drug.
Treatment with AZD4017 led to liver steatosis improvement in patients with NASH and T2D, compared with placebo.
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