In this editorial, we comment on Yin's recently published Letter to the editor. In particular, we focus on the potential use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) alone, but even more so in combination therapy, as one of the most promising therapies in metabolic dysfunction-associated steatotic liver disease (MASLD), the new definition of an old condition, non-alcoholic fatty liver disease, which aims to better define the spectrum of steatotic pathology. It is well known that GLP-1RAs, having shown outstanding performance in fat loss, weight loss, and improvement of insulin resistance, could play a role in protecting the liver from progressive damage. Several clinical trials have shown that, among GLP-1RAs, semaglutide is a safe, well-studied therapeutic choice for MASLD patients; however, most studies demonstrate that, while semaglutide can reduce steatosis, including steatohepatitis histological signs (in terms of inflammatory cell infiltration and hepatocyte ballooning), it does not improve fibrosis. Combinations of therapies with different but complementary mechanisms of action are considered the best way to improve efficiency and slow disease progression due to the complex pathophysiology of the disease. In particular, GLP-1RAs associated with antifibrotic drug therapy, dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA or GLP-1 and glucagon RAs have promoted greater improvement in hepatic steatosis, liver biochemistry, and non-invasive fibrosis tests than monotherapy. Therefore, although to date there are no definitive indications from international drug agencies, there is the hope that soon the therapeutic lines in the most advanced phase of study will be able to provide a therapy for MASLD, one that will certainly include the use of GLP-1RAs as combination therapy. et al
