Emerging roles of sodium-glucose cotransporter 2 inhibitors in cardiology

The ultimate goal of treatment in people with diabetes mellitus is to prevent development of cardiovascular (CV) disease, resulting in prolongation of healthy life expectancy. Although impaired glycemic metabolism has a central role in its pathology, a number of studies have demonstrated that remedy for its imbalance cannot necessarily be accomplished as a therapeutic goal. A comprehensive medical approach against multi-factorial pathologies in diabetes, such as insulin resistance, obesity, hypertension, and dyslipidemia, in addition to diet and exercise therapy should be rather performed in the routine clinical setting. Along with such conceptual transition, what is required in anti-diabetes agents has also changed, and several anti-diabetes agents have been newly placed on the market in this decade. Such agents are required to undergo global pre- or post-marketing clinical trials assessing CV safety. A growing body of clinical evidence from those trials is now accumulating, and empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has first demonstrated significant risk reduction, relative to placebo, in CV death, overall mortality, and hospitalization for worsened heart failure in high-risk patients with diabetes mellitus. An SGLT2 inhibitor is a unique glucose-lowering agent and at the same time has multifaceted effects on hemodynamic and metabolic parameters beyond glycemic control. A major mode of action of SGLT2 inhibitors appears to be 'glycosuria' and 'natriuresis,' leading to amelioration of systemic glycemic homeostasis and potential cardio-renal protection. However, the precise mechanisms by which SGLT2 inhibitors affect benefits on the CV systems are yet to be fully elucidated. Thus, although we are now facing several unanswered concerns lurking behind the successful trial, SGLT2 inhibitors surely play several important roles in high-quality management of not only diabetes, but also CV medicine. This review summarizes our current understandings and future perspectives of SGLT2 inhibitors in CV medicine.