Objective To investigate the effects of different doses of dapagliflozin on the progression of atherosclerotic plaque in ApoE -/- knockout mice. Methods We randomly assigned 30 ApoE -/- mice, which were fed high-fat diet for 8 weeks to establish AS model, into control group (placebo, n=10), Low-dose dapagliflozin group (0.5 mg/kg·d) and High-dose dapagliflozin group (1 mg/kg·d). Experimental sampling was started after 4 weeks of intervention. The aortic and frozen sections of aortic valve were stained with oil red O. The proportions of circulating monocyte subsets were analyzed by flow cytometry. The proportion of proliferating macrophages in the aortic valve plaque were detected by confocal microscopy after immunofluorescence staining. The serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were detected by ELISA kit.Results Compared with the control group, the different doses of dapagliflozin groups had the effect of relieve the aortic and aortic valve plaque load, significantly reduced the proportion of Ly6 Chi monocytes in the circulation, alleviate the proportion of proliferating macrophages in the aortic valve, restrain the release of inflammatory cytokines IL-1β, IL-6 and TNF-α, reduced the levels of TC and LDLC, increased the levels of HDLC. Compared with the low-dose dapagliflozin group, the high-dose dapagliflozin group had significant reductions in the proportion of proliferating macrophages in the plaque, inflammatory factors IL-1β, IL-6, TNF-α, blood lipids TC and LDLC. Conclusion There is no significant difference between low dose and high dose of dapagliflozin in inhibiting the occurrence and development of AS. This effect may be related to inhibition the inflammatory response and regulation the lipid metabolism. Meanwhile, high-dose dapagliflozin has a better effect in regulating lipid metabolism and inhibiting inflammatory response