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 ¹³ C cortisone to ¹³ 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.