SGLT2 inhibitors

Three cardiovascular (CV) outcome trials (CVOTs) with SGLT2 inhibitors have reported primary outcome results thus far. Though designed as CV safety trials according to the FDA mandate, they consistently showed CV benefit for the primary 3 point MACE (major adverse cardiovascular event) outcome which comprises a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke in studies with empagliflozin (EMPAREG OUTCOME) and  canagliflozin (CANVAS program). In contrast, the DECLARE TIMI 58 trial investigating a third SGLT2 inhibitor, dapagliflozin, demonstrated – besides CV safety – superiority only for the co-primary composite endpoint of hospitalization for heart failure and CV death, whilst the other co-primary 3 point MACE outcome fell short of significance. So, along differences of study populations and trial concepts studied, there clearly are differences, but also similarities between the available study results of CVOTs with SGLT2 inhibitors, especially since hospitalization for heart failure as a pre-defined outcome of interest showed also a significant reduction with trial use of empagliflozin and canagliflozin in EMPAREG OUTCOME and the CANVAS program. On the other hand, a significant reduction of all-cause mortality was only found with empagliflozin in EMPAREG OUTCOME. In terms of unexpected downsides, increased rates of amputations at the lower limb have only been seen with canagliflozin in the CANVAS program. Conversely, however, renal benefits as a secondary outcome, have been established with all SGLT2 inhibitors, with positive topline primary outcome results (renal protection by evaluating the risk reduction of the composite endpoint of time to dialysis or kidney transplantation, doubling of serum creatinine, and renal or cardiovascular death) already in the public domain for the CREDENCE renal outcomes trial with canagliflozin which especially looked at participants with chronic kidney disease and was stopped early because of superior benefit with this SGLT2 inhibitor. Pending ongoing trials with a fourth SGLT 2 inhibitor, ertugliflozin, and at least five dedicated trials with SGLT2 inhibitors in primary heart failure populations, the discussion over class or individual medication effects will remain timely.