EMPA-REG OUTCOME and CANVAS trials were designed to study the cardiovascular safety of empagliflozin and canagliflozin, respectively. Both studies were sufficiently powered to study the non-inferiority for cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus (DM) and showed superiority for major adverse cardiovascular events and composite renal outcomes independent of glycemic control. Further, all patients in EMPA-REG had prior CV events (secondary prevention), compared to CANVAS that also included subjects with no prior CV events, indicating the beneficial effects of canagliflozin in primary prevention of CV events as well. Moreover, there seems to be ethnic variations in response to sodium-glucose cotransporter 2 inhibitors (SGLT2i) regarding CV benefits, as Blacks fared better with canagliflozin and Asians with empagliflozin. Increases in lower extremity amputation and fracture incidence were observed with canagliflozin in CANVAS and this needs further substantiation, though these events were not systematically captured in the EMPA-REG study.
Keywords: CANVAS; Canagliflozin; Cardiovascular mortality; Cardiovascular outcome trials; Diabetes mellitus; EMPA-REG; Empagliflozin; Hazard ratio (HR); Major adverse cardiovascular events (MACE); Sodium-glucose linked cotransporter inhibitors (SGLT2i).