Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic steatohepatitis: new insights from subcutaneous semaglutide

Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease globally. It affects around 25% of the adult population, and up to 70-80% of patients, who are obese or have type 2 diabetes mellitus (T2DM) (1, 2). Over the past decades, it has become increasingly clear that NAFLD is a “multisystem” disease, requiring a multidisciplinary and holistic approach (3). Indeed, this common liver disease is not only associated with liver-related complications, but also with an increased risk of incident extra-hepatic diseases, such as T2DM, cardiovascular disease, chronic kidney disease, and extra-hepatic malignancies (4-7). There is currently no approved therapy for NAFLD or nonalcoholic steatohepatitis (NASH). General therapeutic strategies have been proposed to treat this liver condition, including lifestyle modifications to lose body weight; correction of modifiable cardiometabolic risk factors implicated in the progression from simple steatosis to NASH and cirrhosis; and prevention of NAFLD-related extra-hepatic manifestations (8). However, in the last years, several agents have been investigated in phase 2 randomized controlled trials (RCTs) as possible treatment options for NAFLD or NASH. Among these agents, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have received a lot of attention. Experimentally, it has been reported that activation of GLP-1 receptors may reduce liver fat content by improving insulin sensitivity, de novo lipogenesis, mitochondrial function and lipotoxicity (8). Treatment with GLP-1RAs promotes a significant weight reduction (on average 4-5 kg), mostly by improved appetite control and reduced energy intake, thereby resulting in improvement of hepatic and systemic insulin resistance (8). Some preclinical NASH studies also suggested that GLP-1RAs reduce hepatic inflammation, independent of weight loss (8). In addition, given that cardiovascular disease is the predominant cause of death in people with NAFLD (1, 7), it is also important to remember that large RCTs on GLP-1RAs have shown that these drugs reduce all-cause mortality and exert cardioprotective and nephroprotective effects in patients with T2DM (9), thereby representing an attractive bonus for their long-term use in people with T2DM and NAFLD.