Mice

Direct associations between hyperglycemia and atherosclerosis remain unclear. We inves-tigated the association between the amelioration of glycemia by sodium-glucose cotran-sporter 2 inhibitors (SGLT2is) and macrophage-driven atherosclerosis in diabetic mice. We administered dapagliflozin or ipragliflozin (1.0 mg/kg/day) for 4-weeks to apolipoprotein E-null (Apoe−/−) mice, streptozotocin-induced diabetic Apoe−/−mice, and diabetic db/db mice. We then determined aortic atherosclerosis, oxidized low-density lipoprotein (LDL)-induced foam cell formation, and related gene expression in exudate peritoneal macro-phages. Dapagliflozin substantially decreased glycated hemoglobin (HbA1c) and glucose tolerance without affecting body weight, blood pressure, plasma insulin, and lipids in dia-betic Apoe−/−mice. Aortic atherosclerotic lesions, atheromatous plaque size, and macro-phage infiltration in the aortic root increased in diabetic Apoe−/−mice; dapagliflozin attenuated these changes by 33%, 27%, and 20%, respectively. Atherosclerotic lesions or foam cell formation highly correlated with HbA1c. Dapagliflozin did not affect atherosclero-sis or plasma parameters in non-diabetic Apoe−/−mice. In db/dbmice, foam cell formatio