Incretin Receptor Agonists Offer Promising Therapeutic Avenue for Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly NAFLD, is a prevalent liver condition intrinsically linked to components of metabolic syndrome, including type 2 diabetes mellitus (T2DM), visceral obesity, and dyslipidemia. A central pathogenic mechanism is insulin resistance, which drives increased hepatic glucose production, reduced glucose uptake, and enhanced hepatic de novo lipogenesis. This leads to elevated circulating free fatty acids (FFAs) and subsequent hepatic lipid accumulation, exacerbating steatosis and creating a self-perpetuating cycle of metabolic derangement. Current interventions primarily focus on weight loss, highlighting a critical need for targeted pharmacological approaches.

This comprehensive review synthesized current evidence on the evolving role of incretin receptor agonists in managing Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). It explored the mechanistic links between incretin action, insulin resistance, and hepatic lipid metabolism, drawing from a wide range of preclinical and clinical studies. The authors analyzed the progression of incretin-based therapies, from early DPP-4 inhibitors to advanced GLP-1 receptor agonists (GLP-1RAs) and next-generation dual and triple agonists, focusing on their impact on MASLD pathophysiology and progression. The review aimed to position incretin pharmacology as a metabolic strategy to halt liver disease progression.

The review highlights that incretin receptor agonists effectively target the core metabolic dysfunctions underlying MASLD, particularly insulin resistance and hepatic steatosis. These agents improve glucose homeostasis, reduce visceral obesity, and mitigate dyslipidemia, thereby disrupting the vicious cycle of FFA accumulation and insulin resistance in the liver. Specifically, GLP-1R activation has been shown to reduce hepatic fat content, inflammation, and fibrosis markers, while dual GLP-1/GIP agonists demonstrate even greater efficacy in weight loss and metabolic improvements. The synthesis suggests that these therapies not only manage associated comorbidities like type 2 diabetes mellitus but also directly impact liver disease progression by reducing de novo lipogenesis and promoting beta-oxidation. This comprehensive metabolic approach offers a promising strategy to halt MASLD progression.

Incretin receptor agonists, especially dual GLP-1/GIP agonists, represent a significant advancement in addressing the multifaceted pathology of MASLD by improving insulin sensitivity, reducing hepatic fat, and mitigating inflammation.