Incretin-based therapies in MASLD/MASH: from GLP-1 receptor agonists to dual and triple agonists - mechanisms, clinical evidence, and therapeutic perspectives

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), constitute an escalating worldwide health challenge, with prevalence estimates reaching one-quarter of adults globally. The pathophysiology of MASLD/MASH encompasses complex interactions among genetic background, impaired insulin signaling, hepatic lipid accumulation, inflammatory cascades, and progressive fibrosis. Until recently, therapeutic strategies remained limited to lifestyle interventions, with few pharmacological options demonstrating meaningful clinical benefit. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have garnered recognition as potentially revolutionary therapeutic modalities for MASLD/MASH management, offering multifaceted benefits extending beyond glycemic regulation. These medications exert (in)direct hepatic actions by reducing steatosis, attenuating inflammation, and potentially reversing fibrosis, while simultaneously addressing systemic metabolic abnormalities including excessive obesity, insulin resistance, and cardiovascular risk. Recent phase 2 and phase 3 clinical trials have established the therapeutic value of various GLP-1 RAs in improving liver histology and metabolic parameters in patients with MASH. Furthermore, dual-action compounds engaging GLP-1 combined with glucose-dependent insulinotropic polypeptide (GIP) or glucagon pathways, alongside triple agonists incorporating all three receptors activation, have exhibited enhanced therapeutic potential. This review examines the biological mechanisms underlying GLP-1 RA therapy in MASLD/MASH, analyzes the mechanistic distinctions between mono-, dual-, and triple agonists, and synthesizes current clinical evidence supporting their utilization in individuals with this condition.

Keywords

MASLD / MASH / GLP-1 receptor agonists / hepatic steatosis / metabolic dysfunction / tirzepatide / semaglutide / survodutide

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