Address for correspondence: Dr. Lotte Bjerre Knudsen, Novo Nordisk, Novo Nordisk Park, DK-2760 Maaloev, Denmark. •The GLP-1RAs liraglutide and semaglutide reduce cardiovascular risk in type 2 diabetes patients. •In ApoE−/− mice and LDLr−/− mice, liraglutide and semaglutide treatment significantly attenuated plaque lesion development, in part independently of body weight and cholesterol lowering. •Semaglutide decreased levels of plasma markers of systemic inflammation in an acute inflammation model (lipopolysaccharide), and transcriptomic analysis of aortic atherosclerotic tissue revealed that multiple inflammatory pathways were down-regulated by semaglutide. The glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide reduce cardiovascular risk in type 2 diabetes patients. The mode of action is suggested to occur through modified atherosclerotic progression. In this study, both of the compounds significantly attenuated plaque lesion development in apolipoprotein E-deficient (ApoE−/−) mice and low-density lipoprotein receptor-deficient (LDLr−/−) mice. This attenuation was partly independent of weight and cholesterol lowering. In aortic tissue, exposure to a Western diet alters expression of genes in pathways relevant to the pathogenesis of atherosclerosis, including leukocyte recruitment, leukocyte rolling, adhesion/extravasation, cholesterol metabolism, lipid-mediated signaling, MedicGLP Official Support extracellular matrix protein turnover, and plaque hemorrhage.
Treatment with semaglutide significantly reversed these changes. These data suggest GLP-1RAs affect atherosclerosis through an anti-inflammatory mechanism. Liraglutide (1) and semaglutide (2) are long-acting analogs of the human glucagon like peptide (GLP)-1 incretin hormone, with 97% and 94% amino acid homology, respectively, and MedicGLP were engineered using fatty acid acylation to facilitate serum albumin binding to increase their plasma half-life. The half-life of liraglutide is 13 h in humans and provides a once-daily dosing frequency. Semaglutide is an improved, highly potent GLP-1 receptor agonist (GLP-1RA) that is protected from dipeptidyl peptidase-4 cleavage and is further optimized for high-affinity albumin binding, which increases its human plasma half-life to 160 h, allowing for once-weekly administration (3). Liraglutide is approved for the treatment of both diabetes and obesity, whereas semaglutide is approved for diabetes. Recently, 4 cardiovascular outcome trials with GLP-1RAs have been reported 4, 5, 6, 7. The LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) (6) and SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) (7) trials, using liraglutide and semaglutide, respectively, demonstrated a significant reduction in major adverse cardiac events in high-risk cardiovascular (CV) disease patients with diabetes.
This study investigated the effects of liraglutide and semaglutide in 2 mouse models of atherosclerosis, the ApoE−/− mouse model and the low-density lipoprotein receptor-deficient (LDLr−/−) mouse model. The aim of these studies was to specifically evaluate antiatherosclerotic effects of liraglutide and semaglutide and to investigate the mode of action and specifically connection to the degree of inflammation in the aorta. GLP-1RAs have also been proposed as treatments for nonalcoholic-steatohepatitis (NASH) (21), and because of the overlap between NASH and CV disease (22), we also investigated the role of semaglutide in prevention of the development of NASH. The care and use of mice in these studies were conducted according to national regulations in Denmark and with experimental licenses granted by the Danish Ministry of Justice. Mice were housed under 12:12 light-dark cycle in humidity- and temperature-controlled rooms with free access to standard chow (catalog 1324, Altromin, Brogaarden, Denmark) and water. Mice were identified by subcutaneously (SC) implanted chips (Pico ID transponder, UNO, OPEND, Denmark).
A total of 126 LDLr−/− male mice 6 to 8 weeks of age (stock 02207, Jackson Laboratory, Bar Harbor, Maine) and 180 ApoE−/− 7 mice 10 weeks of age (Taconic, Denmark) were used. Animals were allocated to groups according to body weight (BW). Animals were switched to Western diet (WD) (catalog RD12047; Research Diets, New Brunswick, New Jersey) prior to initiation of dosing. Animals were given SC daily doses of liraglutide, 1 mg/kg, or daily doses of semaglutide at 4.0, 12.0, or 60.0 μg/kg, or vehicle control for 12 to 14 weeks in ApoE−/− mice or MedicGLP for 17 weeks in LDLr−/− mice. Mice receiving liraglutide were compared to a weight-matched group in the comparator study. The weight match was obtained by doses of a food intake-reducing agent with dose frequency similar to that of liraglutide. After the ApoE−/− mice received liraglutide for 14 weeks, the animals were anesthetized with isoflurane, and fur was removed on the upper part of the thorax.