Safety Choice Drivers of the Coming Treatment Options for Non-Cirrhotic Metabolic Steatohepatitis

Metabolic dysfunction associated steatohepatitis (MASH), formerly known as NASH, represents one of the leading causes of chronic liver disease worldwide. Its high prevalence is driven by insulin resistance, obesity and type 2 diabetes (T2D) and is associated with cardiovascular disease. The main driver of liver damage is fat accumulation in hepatocytes leading to inflammation and fibrosis development. People with MASH and clinically significant fibrosis (stage F2/F3) are 'at risk' of progressing to cirrhosis and hepatocellular carcinoma and are considered in need of treatment. Metabolic drivers of MASH originating outside the liver, for example, from the adipose tissue and the gut, and genetic heterogeneity contribute to making the prevalent pathogenetic factor difficult to dissect at an individual level. In this scenario, the Food and Drug Administration's conditional approval of the liver-directed thyroid hormone receptor beta agonist Resmetirom as the first pharmacological treatment for MASH last March 2024 and the expected extension of the glucagon-like protein-1 receptor agonist Semaglutide indication from diabetes and obesity to MASH mark a key milestone. Both drugs are also under evaluation by the European Medicines Agency. The proven efficacy of these compounds in clinical trials needs to be balanced against safety profiles and patient preferences. To investigate future trajectories and possible uses as mono-therapy or in combination, we examined available results of clinical trials and real-life studies. Despite the need to await the final results of outcome studies to exclude any possible challenges for both compounds, safety profiles and external factors including reimbursement policies or supply limitations may currently guide the individual choice.