Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

Abstract

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular-kidney-metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone.

Keywords: biomarkers; cardiovascular risk; liver biopsy; metabolic dysfunction; natural history.

Figure 1

Multifactorial pathogenesis of NAFLD and its progression to NASH. A combination of environmental, inflammatory, genetic, and epigenetic factors promote the development of insulin resistance. Through different mechanisms, insulin resistance is closely associated with increased FFA influx to the liver and increased hepatic de novo lipogenesis. In turn, lipid excess leads to compensatory (and over-compensatory) responses, including hepatic triglyceride accumulation (steatosis), VLDL secretion (high plasma triglyceride levels), and increased hepatic fat oxidation with generation of inflammatory lipid intermediates and reactive oxygen species. Abbreviations: CHO: carbohydrates; FFA: free fatty acids; DNL: de novo lipogenesis; TG: triglycerides; VLDL: very low-density lipoproteins; Cer: ceramides; DAG: diacylglycerols; ROS: reactive oxygen species.

Figure 2

Multiple reasons may explain the high rate of unsuccessful phase 2 and phase 3 NASH clinical trials. The lack of success in phase 2 and phase 3 clinical trials in patients with NASH ± liver fibrosis can be explained by multiple factors, which can be schematically divided into biopsy-related, intervention-related, population-related, and drug-related factors.