Diabetes mellitus is a substantial global health threat due to its high prevalence and its serious complications. The hyperglycemic state causes damage to vascular endothelial cells and disturbance of lipid metabolism, thus contributing to the development of vascular disorders, especially atherosclerotic diseases. Aggressive glycemic control combined with vascular intervention is critical to the prevention and treatment of diabetes-associated atherosclerosis. It is suggested that metformin should be combined with hypoglycemic agents with proven vascular benefits for treating type 2 diabetes (T2DM) complicated with atherosclerotic diseases. Clinical studies indicates that the preferred combination is metformin with either glucagon-like peptide-1 receptor agonist or sodium/glucose cotransporter-2 inhibitor, which could offer additional vascular benefits and reduce the risk of atherosclerotic complications. Likewise, combination therapy with metformin and hypolipidemic agents has also shown additive effects on glucose control and lipid-lowering in patients with both diabetes and dyslipidemia, whereas extensive clinical trials using atherosclerotic-associated outcomes are required to support the vascular benefits. Moreover, co-administration of metformin with systemic antioxidant or anti-inflammatory therapy may also provide additional vascular benefits as indicated by several animal studies. For instance, a recent study found that additional supplementation of cholecalciferol and taurine enhanced metformin efficacy in controlling diabetes while reducing the risk of associated atherosclerotic complications. However, these potential benefits remain need validation by the evidence from clinical studies. Despite the limitations, such as heterogeneity across different patient populations, and deficiency in long-term outcomes, such efforts can contribute to finding optimal drug combinations to improve the management of T2DM and reduce its atherosclerotic complications.