Nonalcoholic Steatohepatitis Drug Development Pipeline: An Update

Abstract

Non-alcoholic steatohepatitis (NASH) is a burgeoning global health crisis that mirrors the obesity pandemic. This global health crisis has stimulated active research to develop novel NASH pharmacotherapies targeting dysregulated inflammatory, cellular stress and fibrogenetic processes that include: 1) metabolic pathways to improve insulin sensitivity, de-novo lipogenesis, and mitochondrial utilization of fatty acids, 2) cellular injury or inflammatory targets that reduce inflammatory cell recruitment and signalling, 3) liver-gut axis targets that influence bile acid enterohepatic circulation and signalling, and 4) anti-fibrotic targets. In this review, we summarize several of the therapeutic agents that have been studied in phase 2 and 3 randomized trials. In addition to reviewing novel therapeutic drugs targeting nuclear receptor pathways, liver chemokine receptors, liver lipid metabolism, lipotoxicity or cell death, and glucagon-like peptide-1 receptors, we also discuss the rationale behind the use of combination therapy and the lessons learned from unsuccessful or negative clinical trials.

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

“…The epidemic of obesity is associated with a steady rise in drug consumption in order to treat several associated diseases such as type 2 diabetes mellitus (T2DM), hypertension, atherosclerosis, dyslipidemia and osteoarthritis [ 1 , 2 ]. In addition, numerous drugs are currently being developed in order to specifically treat nonalcoholic fatty liver disease (NAFLD), which is frequently associated with obesity and overweight [ 3 , 4 ]. This implies increased polypharmacy among obese patients, which can augment the risk of adverse events including drug-induced liver injury (DILI) [ 5 , 6 ].…”

Hepatic steatosis and advanced hepatic fibrosis are independent predictors of long‐term mortality in acute myocardial infarction

“…Liver disease is defined as a spectrum from simple hepatic steatosis to a more advanced disease form of non-alcoholic steatohepatitis, which may progress to advanced fibrosis and cirrhosis. 17,18 Our data reveal that more than 40% of patients with hepatic steatosis were determined to have the more severe form of advanced hepatic fibrosis. Those with advanced fibrosis had a substantially higher mortality risk compared with those with hepatic steatosis alone.…”

Hepatic steatosis and advanced fibrosis are independent predictors of mortality in acute myocardial infarction without standard modifiable risk factors

“…Future interventional studies examining the effects of newer pharmacological treatment, such as antidiabetic or antiinflammatory agents, on nontraditional risk factors such as hepatic steatosis and cardiovascular outcomes in the SMuRF-less AMI population will be the next important step. 16 Our data provide unique insights into the association of hepatic steatosis and AMI outcomes in the absence of cardiovascular risk factors. However, this study is not without its limitations.…”

“…Previous findings on the improvement of insulin resistance and the associated reduction of major adverse cardiac events through sustained virological response by direct‐acting antivirals in the population with hepatitis C infection, 13‐15 lends indirect support to the hypothesis that improvement of the underlying liver disease may translate to favourable cardiovascular outcomes. Future interventional studies examining the effects of newer pharmacological treatment, such as antidiabetic or anti‐inflammatory agents, on nontraditional risk factors such as hepatic steatosis and cardiovascular outcomes in the SMuRF‐less AMI population will be the next important step 16 …”