2033-LB: Dulaglutide Improves Metabolic Dysfunction–Associated Steatohepatitis (MASH), but Not Atherosclerosis, Independent of Weight Loss in Middle-Age LDLR-/- Mice

Clinical trials have demonstrated that glucagon-like peptide-1 receptor agonist (GLP-1 RA) reduces atherosclerosis risk in individuals with obesity independent of their diabetes status and is currently under investigation as a treatment for metabolic dysfunction-associated steatohepatitis (MASH). Several studies have associated weight loss with improvements in metabolic comorbidities, such as metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes (T2D). To determine the contribution of weight loss to the effect of dulaglutide; a GLP-1 RA, on atherosclerosis and MASH, we pair-fed western high-fat diet (WHFD) to middle-aged low-density lipoprotein receptor knockout (LDLR-/-) mice which develop accelerated atherosclerosis and MASH, compared to fatty streaks and simple steatosis in younger LDLR-/- mice. We administered dulaglutide and a placebo twice a week for the last 6 weeks of 12 weeks of WHFD. As a result, both dulaglutide and placebo-treated mice gained weight equally which was maintained throughout the study. Atherosclerosis extent measured with en-face analysis was similar between dulaglutide vs. placebo (18± 5% vs.14± 4% aorta covered by plaque), but dulaglutide-treated mice showed reduced liver fat by 50% (p