A randomized, controlled, crossover pilot study of losartan for pediatric nonalcoholic fatty liver disease

Abstract

BackgroundNonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children, and currently, there are no FDA-approved therapies. Plasminogen activator inhibitor-1 (PAI-1) is elevated in children with NAFLD and associated with increased disease severity. Losartan potassium (losartan) is an angiotensin II receptor blocker (ARB) that reduces PAI-1 production and improves insulin sensitivity that has been proposed as a treatment for pediatric NAFLD but has not previously been tested.MethodsThis was an 8-week randomized, double-blind, placebo-controlled, phase 2a, crossover study (with a 6-week washout between conditions) for safety and preliminary efficacy of losartan 50 mg a day taken orally in 12 normotensive children with biopsy proven nonalcoholic steatohepatitis (NASH).ResultsTwelve children enrolled in the study, and nine completed all visits. No changes in blood pressure or serious adverse events occurred during the study. Trends in improvement in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and homeostatic model assessment insulin resistance (HOMA-IR) were seen with losartan treatment compared to the placebo time-period. More participants decreased ALT on losartan as compared to placebo (89% [8 out 9] vs. 56% [5 out of 9], respectively).ConclusionsThis data provides preliminary evidence that losartan treatment is safe over 8 weeks in children with NAFLD and supports consideration of larger studies to test its efficacy.Trial registrationURL and trial identification number: https://clinicaltrials.gov/show/NCT01913470, NCT01913470.Date registered: August 1, 2013.

Metabolic Fatty Liver Disease in Children: A Growing Public Health Problem

“…This molecule has been proposed as a novel treatment of MAFLD by improving steatosis and fibrosis. Preliminary evidence (phase II) suggests that losartan treatment is safe over 8 weeks in children with MAFLD and supports consideration of larger studies to test its efficacy [ 73 ]. A clinical trial evaluating the antagonist of SGLT-2 has been initiated in children, but data are still lacking due to the difficulties of recruiting patients during the COVID-19 pandemic (NCT03867487).…”

Non-alcoholic fatty liver disease and childhood obesity

“…Losartan is currently being compared to placebo in 8 to 17 year olds with histological evidence of NAFLD. Losartan is thought to reduce plasminogen activator inhibitor-1 (PAI-1), which is elevated in children with NAFLD and associated with increased disease severity [72].…”

Relationship of Nonalcoholic Fatty Liver Disease and Heart Failure With Preserved Ejection Fraction

“…Although there is paucity of data on the effect of RAAS inhibitors on NAFLD in humans, a recent study suggested that RAAS inhibitors can decrease the risk for NAFLD development and progression in obese patients ( 106 ). In a randomized, double-blind, placebo-controlled, phase 2a trial that included 12 children with NASH, losartan improved ALT and AST levels ( 107 ). In this context, the RELIEF-NAFLD (Role of Lisinopril in Preventing the Progression of Non-Alcoholic Fatty Liver Disease; NCT04550481 ) trial is an ongoing study to examine the effect of lisinopril on the prevention and progression of NAFLD.…”