Type 2 diabetes mellitus (T2DM) is associated with a substantially increased cardiovascular (CV) risk, and several international guidelines statements addressing the management of T2DM underscore the need to prevent and reduce CV complications. Although, it is conceivable that glycemic control plays an important role in this process, as suggested by epidemiological studies, there remains great controversy concerning the impact of glucose lowering on CV outcomes from intensive glycemic control trials. This chapter covers the role of the kidney in glucose metabolism, sodium-glucose cotransporter-2 inhibitors mode of action and glucose lowering properties (EHJ), effects of sodium-glucose cotransporter-2 inhibitors beyond glucose control, clinical landmark trials of sodium–glucose cotransporter type-2 inhibitors and cardiovascular risk, and canagliflozin cardiovascular assessment study trial with canagliflozin.