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Glucose-lowering agents and reduced risk of incident non-alcoholic fatty liver disease: new insights.

| https://dx.doi.org/10.21037/hbsn-2021-28 Non-alcoholic fatty liver disease (NAFLD) is classically defined as the hepatic manifestation of metabolic syndrome (1). Histologically, NAFLD covers a range of conditions, spanning from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis (2). At present, NAFLD is the most frequent chronic liver disease seen in clinical practice in high-income countries, as it affects nearly 30% of adults in the general population, up to 70% of patients with type 2 diabetes (T2DM) and almost all patients with obesity (2). Over the last decade, it has become evident that NAFLD is a “multisystemic” disease (2), which is not only associated with hepatic complications [i.e., hepatocellular carcinoma (HCC)], but also with a higher risk of extra-hepatic complications, including cardiovascular disease (CVD) and T2DM (2). In spite of the clinical burden of NAFLD, there are no pharmacological treatments for NAFLD/NASH approved by main national medicines agencies to date (3). However, based on the data provided by randomized controlled trials (RCTs) (Table 1), the EASL-EASD-EASO and AASLD practice guidelines for the NAFLD management now recommend the use of pioglitazone (which is a member of thiazolidinediones) in non-cirrhotic adults with biopsyconfirmed NASH (4,5). That said, several other drugs have been tested in phase-2 RCTs as potential therapy for NAFLD/NASH (3). Among these, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have received attention, as these agents are able to promote weight loss and to improve glycemic control and insulin resistance (3). In a 2021 metaanalysis, for instance, Mantovani et al. (6) reported that, compared to control therapy, treatment with GLP-1RAs was associated with reductions in the absolute percentage of liver fat content (as assessed by magnetic resonance-based techniques), as well as with histological resolution of NASH without worsening of liver fibrosis. However, to date, information on the association between the use of specific agents (including thiazolidinediones or GLP-1RAs) and the risk of developing NAFLD and its advanced forms is scarce. Notably, understanding this issue could help to create novel therapeutic strategies that may reduce the clinical burden of NAFLD, which is strongly associated with an excess of premature mortality (2). Recently, on Hepatology, van Dalem et al. (7) published the results of a large population-based cohort study collecting primary care data from the Clinical Practice Research Datalink database (2007–2018) with the aim to assess the potential role of different glucose-lowering agents on the risk of incident NAFLD. In this study involving 207,367 UK T2DM adults [median age: 61 years; 45% women; median body mass index (BMI): 31 kg/m] with an initial prescription of glucose-lowering agents, the investigators found that 2,526 patients had a new diagnosis of NAFLD (as assessed by Read codes) during Editorial