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<0.01), MASH pathology grade by 30% (p<0.05), and liver function testing by 50% (p<0.05). Furthermore, dulaglutide improved glucose tolerance but did not impact insulin sensitivity between the two groups. In addition, dulaglutide treatment substantially reduced the expression of de novo lipogenesis and inflammation genes in the liver. Together, these results reveal that weight loss contributes to the anti-atherosclerosis effects of GLP-1 RAs, but reduced liver fat accumulation and MASH are independent of weight loss.