Editorial: Treatment with Dual Incretin Receptor Agonists to Maintain Normal Glucose Levels May Also Maintain Normal Weight and Control Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)

Abstract

Worldwide, metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease. MAFLD is associated with insulin resistance, type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Early diagnosis and management are vital to improving hepatic and cardiometabolic outcomes. Dietary change, weight loss, and structured exercise are the main treatment approaches for fatty liver disease. Since 2010, several investigational drug treatments failed to achieve regulatory approval due to mixed and unsatisfactory results. Although glucagon-like peptide 1 receptor agonists (GLP1-RAs) showed initial promise as therapeutic agents, metabolic liver damage can recur after monotherapy cessation. Dual incretin receptor agonists target the receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP). Importantly, on May 13, 2022, the US Food and Drug Administration (FDA) approved tirzepatide as the first dual GLP-1 and GIP receptor agonist for the treatment of T2DM. Dual incretin receptor agonists induce weight loss and enhance hepatic lipid metabolism and systemic insulin sensitivity. Insulin resistance and hepatic steatosis are the main contributors to the development of MAFLD. Treatment with dual incretin analogs reduces hepatic steatosis, lobular inflammation, liver cell damage, fibrosis, and total liver triglyceride levels. The availability of dual incretin receptor agonists for patients with MAFLD may result in weight control, normalizing insulin sensitivity, and reducing or even reversing metabolic dysfunction and liver damage. This Editorial aims to provide an update and discuss how treatment with dual incretin receptor agonists may maintain normal glucose levels and weight and control MAFLD.

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

“…In healthy individuals with stable insulin and glucagon concentrations, GLP-1 inhibits EGP, mediated by a direct effect of GLP-1 on the liver or by a neuro-mediated inhibitory reflex. Thus, in patients with insulin resistance, the administration of Exenatide, a GLP-1 receptor agonist drug, reduces liver fat and liver enzymes, favoring the treatment of MAFLD [119,120]. Thus, this hormonal response is suppressed through a neuro-mediated inhibitory reflex in EGP, leading to a reduction in liver fat among individuals with insulin resistance.…”

Gut–Liver–Pancreas Axis Crosstalk in Health and Disease: From the Role of Microbial Metabolites to Innovative Microbiota Manipulating Strategies

“…GLP-1-GIP dual agonists (tirzepatide), GLP-glucagon receptor dual agonists (cotadutide), or triple agonists against GLP-1-GIP-glucagon receptors have gained much attention as novel hypoglycemic agents capable of better controlling blood glucose levels and body weight, improving hepatic lipid metabolism and systemic insulin sensitivity [135]. Importantly, in May 2022, the US FDA approved tirzepatide as the first dual GLP-1 and GIP receptor agonists for the T2D treatment [136]. Due to their numerous effects, dual incretin receptor agonists could also represent a potential treatment for patients with MAFLD [136].…”

“…Importantly, in May 2022, the US FDA approved tirzepatide as the first dual GLP-1 and GIP receptor agonists for the T2D treatment [136]. Due to their numerous effects, dual incretin receptor agonists could also represent a potential treatment for patients with MAFLD [136].…”