The once-daily GLP-1 receptor (GLP-1R) agonist, liraglutide, has been approved as a treatment for type 2 diabetes. Liraglutide improves glycaemic control, lowers body weight and is the subject of ongoing clinical trials to evaluate effects on cardiovascular disease progression.

The presence of a GLP-1R on vascular endothelial cells suggests a potential role for GLP-1R in atherogenesis. We have previously demonstrated liraglutide-mediated attenuation of induced plasminogen activator inhibitor-1 (PAI-1) and vascular cell adhesion molecule expression in human vascular endothelial cells (hVEC's) in vitro and significant liraglutide-mediated improvement in endothelial function in vivo in the ApoE^-/- mouse model. The aim of our current study was to determine the in vivo effect of liraglutide on atherosclerotic plaque formation and stability in the ApoE^-/- mouse model.

In vivo experiments utilised two protocols. (1) 17-week-old ApoE^-/- mice on normal chow diet were commenced on a high-fat diet and treated with either saline (vehicle), liraglutide (300 μg/kg twice daily, s.c.) or liraglutide + exendin-9 (150 pmol/kg/min s.c., osmotic mini-pump) for 4 weeks; or (2) 18-week-old ApoE^-/- mice on a high-fat diet for 12 weeks were treated with a regimen identical to protocol 1 for 4 weeks. Vascular reactivity studies identified improvement in endothelial function in liraglutide-treated mice from protocol 2 only. Interestingly oil red O staining and intima:media ratio (IMR) analysis of atherosclerotic plaques from the aorta and brachiocephalic artery (BCA) identified a significant reduction in staining and IMR in liraglutide-treated mice from protocol 1. A significant increase in vascular smooth muscle cell content of BCA atherosclerotic lesions in liraglutide-treated mice from protocol 1 was also identified, suggesting a plaque-stabilising effect associated with liraglutide treatment.

Together these results suggest a potential therapeutic benefit of GLP-1R activation by liraglutide in the attenuation of atherogenesis and stabilisation of existing atherosclerotic disease.