Xinrong Zhang1,2,3, Grace Lai-Hung Wong1,2,3, Terry Cheuk-Fung Yip1,2,3, Yee-Kit Tse1,2,3, Lilian Yan Liang1,2,3, Vicki Wing-Ki Hui1,2,3, Huapeng Lin1,2,3, Guan-Lin Li1,2,3, Jimmy Che-To Lai1,2,3, Henry Lik-Yuen Chan1,2,3, Vincent Wai-Sun Wong1,2,3

1Department of Medicine and Therapeutics, The Chinese University of Hong Kong; Hong Kong SAR, , 2Medical Data Analytic Centre (MDAC), The Chinese University of Hong Kong; Hong Kong SAR, and 3Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong; Hong Kong SAR, China

Background/Aims: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to inhibit liver fibrogenesis in animal models. However, data from clinical studies are limited and inconclusive. We aimed to evaluate the impact of ACEI/ARB use on the risk of hepatocellular carcinoma (HCC) and cirrhotic complications in patients with nonalcoholic fatty liver disease (NAFLD).

Methods: We conducted a retrospective, territory-wide cohort study of adult NAFLD patients with baseline date between January 1, 2000 and December 31, 2014 to allow for at least 5 years of follow-up. ACEI/ARB users were defined as patients who started ACEI/ARB treatment at least six months before last visit or primary endpoint. Primary endpoint was liver-related events, defined as a composite endpoint of HCC and cirrhotic complications.

Results: We analysed data from 12,494 NAFLD patients (mean age 54.4±14.5 years; 6,301 men [50.4%]); 7,428 (59.5%) received ACEI/ARB. At a median (interquartile range) follow-up of 9.9 (5.4-14.2) years, 268 (3.6%) ACEI/ARB users and 173 (3.4%) non-users developed liver-related events. After propensity score weighting, ACEI/ARB treatment was associated with a lower risk of liver-related events (weighted subdistribution hazard ratio (SHR) 0.44, 95% confidence interval (CI) 0.33-0.59, P < 0.001), HCC (weighted SHR 0.46, 95% CI 0.30-0.72, P < 0.001), and cirrhotic complications (weighted SHR 0.42, 95% CI 0.29-0.61, P < 0.001). In subgroup analysis, ACEI/ARB treatment was associated with greater reduction in liver-related events in patients with chronic kidney diseases (CKD) than those without (CKD weighted SHR 0.12, 95% CI 0.06-0.26, P < 0.001; non-CKD weighted SHR 0.67, 95% CI 0.49-0.93, P = 0.02).

Conclusion: ACEI/ARB treatment is associated with a lower risk of HCC and cirrhotic complications in NAFLD patients, especially among those with CKD.

Keywords: nonalcoholic fatty liver disease, ACEI/ARB, hepatocellular carcinoma, cirrhotic complications, chronic kidney diseases