Therapy Combining Glucagon-Like Peptide-1 Receptor Agonist with Sodium-Glucose Cotransporter 2 Inhibitor Suppresses Atherosclerosis in Diabetic ApoE-Deficient Mice

Abstract

Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have beneficial effects on cardiovascular disease in addition to their glucose-lowering effects. We directly compared the effects of these drugs when used individually or in combination on cardiovascular atherosclerotic lesion development using diabetic ApoE-deficient hyperlipidemic mice. Methods We treated ApoE-deficient mice with streptozotocin and nicotinamide, generating a type 2 diabetes model. The mice were randomly divided into four groups: vehicle-treated (Untreated), liraglutide (LIRA), ipragliflozin (IPRA), and combination therapy (Combo). These mice as well as non-diabetic controls were fed a high-fat diet. After 8 weeks of drug administration, the heart and aorta were removed and analyzed. Results Atherosclerotic lesions evaluated by oil red O (ORO) staining were significantly larger in the Untreated group (13.4 ± 0.8% of total aortic area) than in the non-diabetic controls (4.4 ± 0.5%, p < 0.01), while being reduced in the Combo (6.0 ± 1.0%, p < 0.01) as compared with the Untreated group. The ORO stain-positive area in the LIRA and IPRA groups tended to be reduced but their differences failed to reach statistical significance. Transcript levels of Mcp1 and Sirt1 were significantly reduced and increased, respectively, in the Combo as compared with the Untreated group, while no significant changes were observed in the monotherapy groups. Conclusions Our data suggest that combination therapy with liraglutide and ipragliflozin may be an efficient regimen for preventing the development of atherosclerosis in diabetic ApoE-deficient mice.