Pharmacologic approach to metabolic dysfunction and related diseases: focus on liver aspects

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly 1.5 billion adults worldwide. It is closely associated with type 2 diabetes mellitus and obesity. Longer duration of MASLD increases risk of progression to metabolic dysfunction-associated steatohepatitis (MASH, the progressive form of MASLD that requires pharmacological therapy), cirrhosis and hepatocellular carcinoma, as well as development of cardiovascular complications. Despite the need for MASH pharmacologic intervention, several studies on new investigational compounds have failed, with only Resmetirom and Semaglutide recently conditionally approved by the Food and Drug Administration (FDA). The role of incretins may be more critical in the early phase of MASH development, but integration with drugs that directly target the liver may represent the winning strategy. The armamentarium of drugs for MASH is rapidly expanding, and several promising drugs are under investigation in phase 2 of development. Integrating fibrosis stage-specific combination therapies targeting different steps of the complex pathogenic mechanism of MASLD/MASH may lead to successful treatment rates larger than the currently obtained 25%-30%. The effects of both FDA-approved compounds (Resmetirom and Semaglutide) on clinical outcomes remain to be shown and will not be available before the conclusion of the respective outcome studies in 2027 and 2028.