Based on the protective effect of GLP-1RA on the cardiovascular system in type 2 diabetics and our previous study showing that HDL could activate eNOS to produce NO using its receptor hSR-BI/CLA-1 in HUVECs, here we proved that GPL-1RA and exendin-4 increased the expression of hSR-BI/CLA-1 via the AMPK/FoxO1 pathway and enhanced the activation of eNOS in HUVECs. This evidence concerns the gene NOS3 and type 2 diabetes mellitus.