Pleiotropic effects of SGLT2 inhibitors beyond the effect on glycemic control

The risk cardiovascular disease is markedly increased in patients with type 2 diabetes mellitus (T2DM). Recently, the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in T2DM Patients-Removing Excess Glucose) trial showed, for the first time, that a glucose lowering drug, the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin decreased cardiovascular events, cardiovascular mortality, and overall mortality in patients with T2DM at establish cardiovascular disease. Following to EMPA-REG OUTCOME trial, the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program also showed that the SGLT2 inhibitor canagliflozin decreased cardiovascular events in patients with T2DM at high cardiovascular risk. These results suggest the class effects rather than drug-specific effects on cardiovascular risk. In addition, these two clinical trials showed that empagliflozin and canagliflozin improved renal outcomes. With regard to adverse events, the rate of urinary tract infection and genital infection significantly increased in patients receiving SGLT2 inhibitor such as empagliflozin or canagliflozin. Notably, the lower limb amputation significantly increased in the only canagliflozin group. However, the possibility that increased amputation risk might be a class effect remains open and in need of further research. This report discusses the results of cardiovascular and renal outcomes from the two landmark trials.