Randomized placebo-controlled trial of losartan for pediatric NAFLD

• Type of Material: Article
• Authors: Miriam Vos, Emory University; Mark L Van Natta, Johns Hopkins Bloomberg Sch Publ Hlth; Niviann M Blondet, University of Washington; Srinivasan Dasarathy, Cleveland Clinic; Mark Fishbein, Northwestern University; Paula Hertel, Texas Childrens Hospital; Ajay K Jain, St Louis University; Saul Karpen, Emory University; Joel E Lavine, Columbia University; Saeed Mohammad, Northwestern University; Laura A Miriel, Johns Hopkins Bloomberg School of Public Health; Jean P Molleston, Indiana University School of Medicine; Marialena Mouzaki, University of Cincinnati; Arun Sanyal, Virginia Commonwealth University; Emily P Sharkey, Johns Hopkins Bloomberg School of Public Health; Jeffrey B Schwimmer, University of California San Diego; James Tonascia, Johns Hopkins Bloomberg School of Public Health; Laura A Wilson, Johns Hopkins Bloomberg School of Public Health; Stavra A Xanthakos, University of Cincinnati
• Language: English
• Date: 2022-02-28
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/hep.32403
• Title of Journal or Parent Work: HEPATOLOGY
• Volume: 76
• Issue: 2
• Start Page: 429
• End Page: 444
• Grant/Funding Information: NASH CRN, which is supported by the NIDDK (U01DK061713, U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, and U24DK061730); National Center for Advancing Translational Sciences (UL1TR000077, UL1TR000150, UL1TR000424, UL1TR000006, UL1TR000448, UL1TR000040, UL1TR000100, UL1TR000004, UL1TR000423, and UL1TR000454); and the Intramural Research Program of the National Institutes of Health, National Cancer Institute
• Keywords: Life Sciences & Biomedicine; RESISTANCE; RECEPTOR BLOCKERS; VITAMIN-E; Science & Technology; CHILDREN; FIBROSIS; RENIN-ANGIOTENSIN SYSTEM; FATTY LIVER-DISEASE; OSTEOPOROSIS; HYPERTENSIVE PATIENTS; Gastroenterology & Hepatology; INSULIN SENSITIVITY
• Research Categories: Health Sciences, Nutrition

Abstract

Background and Aims: To date, no pharmacotherapy exists for pediatric NAFLD. Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its antifibrotic effects. Approach and Results: The Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double-masked, placebo-controlled, randomized clinical trial in children with histologically confirmed NAFLD at 10 sites (September 2018 to April 2020). Inclusion criteria were age 8–17 years, histologic NAFLD activity score ≥ 3, and serum alanine aminotransferase (ALT) ≥ 50 U/l. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks, and the preset sample size was n = 110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. Eighty-three participants (81% male, 80% Hispanic) were randomized to losartan (n = 43) or placebo (n = 40). During an enrollment pause, necessitated by the 2019 coronavirus pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; 95% CI = −30.6, 32.7; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: −23.4 U/l; 95% CI = −41.5, −5.3; p = 0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: −7.5 mm Hg; 95% CI = −12.2, −2.8; p = 0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group. Conclusions: Losartan did not significantly reduce ALT in children with NAFLD when compared with placebo.