Empagliflozin Reduces the Risk of Mortality, Macro- and Microvascular Events in Patients with Type 2 Diabetes and Established Cardiovascular Disease

Patients with type 2 diabetes mellitus face an increased risk of cardiovascular events, even under conditions of optimal lipid reduction, blood pressure and blood glucose control. To ensure cardiovascular safety of novel antidiabetic drugs, FDA and EMA regulations require evidence of non-inferiority compared to placebo in cardiovascular outcome studies for approval. Previously, cardiovascular safety of various newer antidiabetic drugs was observed in dedicated non-inferiority trials. In contrast, the EMPA-REG OUTCOME (R) study was the first trial to demonstrate for empagliflozin, followed by the LEADER trial for liraglutide, prespecified cardiovascular superiority of an individual antidiabetic medication versus placebo. Subsequently, semaglutide showed a significant reduction in cardiovascular events in the SUSTAIN 6 trial. Administration of empagliflozin, a sodium glucose-linked cotransporter (SGLT-2) inhibitor, in addition to antidiabetic and cardiovascular standard of care medication led to a significant relative risk reduction by 14 % of the primary composite endpoint composed of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke as compared to placebo. This overall risk reduction was mainly driven by a significant 38 % reduction in cardiovascular death. Furthermore, empagliflozin reduced the relative risk of hospitalisations for heart failure, or incident or worsening nephropathy by 35 % and 39 %, respectively. Empagliflozin reduced the relative risk of all-cause mortality by 32 %. The underlying mechanisms for the observed risk reductions are not yet completely understood. Specifically, relieving the heart from excess glucose, sodium and water, effects on renal hemodynamics and restored tubuloglomerular feedback as well as a substrate shift towards ketone bodies resulting in better energy consumption in the diabetic heart are considered. Empagliflozin was well tolerated but associated with an increased incidence of genital infections, which are generally associated with the mode of action of SGLT-2 inhibitors.