The New and Evolving Roles of Sodium Glucose Co-Transporter 2 Inhibitors

Abstract

In 2013 the Food and Drug Administration (FDA) approved the first sodium glucose cotransporter 2 inhibitor (SGLT2i), canagliflozin, for the treatment of hyperglycemia in patients with type 2 diabetes (T2D). This was followed a year later by the approvals of two other SGLT2is, empagliflozin and dapagliflozin. The last currently FDA approved agent in this class, ertugliflozin, was approved in late 2017. Following approval each agent had to also undergo further evaluation of their cardiovascular safety as mandated by the FDA at that time for all new agents used in the treatment of T2D hyperglycemia. The first cardiovascular outcome trial (CVOT) appeared in 2015 and showed that empagliflozin not only showed no increased cardiovascular risk but actually decreased cardiovascular and all-cause mortality in patients with both diabetes and established cardiovascular disease [1]. Subsequently in 2017 the CVOT of canagliflozin showed a 14% relative risk reduction in the combined outcome of nonfatal stroke, myocardial infarction (MI), or cardiovascular death in subjects with established cardiovascular disease or at high risk for such but did not show a reduction in cardiovascular mortality [2]. Last year, dapagliflozin’s CVOT failed to demonstrate a cardiovascular benefit in the same combined outcome as the canagliflozin study [3]. No CVOT of these agents showed a significant reduction in MI or stroke but each showed a significant reduction in hospital admissions for heart failure. The CVOT for ertugliflozin was completed in late 2019 and results should be published in the near future. As a result of the CVOT for empagliflozin the FDA approved a new indication for the agent late in 2016 for the reduction of cardiovascular death in patients with T2D and cardiovascular disease. In the fall of 2018, the FDA approved dapagliflozin with a new indication to reduce MI, stroke, or cardiovascular death in patients with T2D and cardiovascular disease. The CVOTs have also led to updates in clinical practice guidelines recommending the use of agents within this class that have demonstrated reduced cardiovascular outcomes in patients with T2D and cardiovascular disease [4,5].