Mechanistic Insights of Empagliflozin-Mediated Cardiac Benefits: Nearing the Starting Line

Excerpt

Type 2 diabetes mellitus (T2DM), which affects 29 million Americans, is a major risk factor for the development of cardiovascular diseases (CVD) such as myocardial infarction and heart failure (HF). In the last decade, empagliflozin, a sodium glucose co-transporter 2 (SGLT-2) inhibitor, has emerged as a novel and promising drug for T2DM patients with benefits extending beyond its glucose-lowering action [1]. These comprise weight loss, blood pressure reduction, lessening arterial stiffness, and a remarkable drop in cardiovascular death [2‐5]. This drug elicits its glucose-lowering effect by inhibiting SGLT-2, thereby decreasing glucose reabsorption in the proximal tubule and increasing glucose excretion in the urine [6]. While the glucose-lowering effect of empagliflozin is well recognized, the cardiovascular benefits were unexpected. The first study that reported the protective role of empagliflozin on cardiovascular outcomes was the EMPA-REG OUTCOME trial, which included 7020 T2DM patients from 42 countries with a high risk of cardiovascular events [3]. Enrolled subjects received either empagliflozin once daily (10 or 25 mg) or placebo in addition to standard care. Surprisingly, a significant reduction in death from cardiovascular cause, hospitalization from heart failure, and percent of death from any cause were noticed in the case of patients receiving empagliflozin. Subsequently, several other clinical trials confirmed the cardiac benefits of empagliflozin in patients with or without baseline heart failure [4, 5]. Kaku et al. [5] investigated the potential cardiovascular benefits of empagliflozin treatment in the Asian population. Indeed, T2DM patients receiving empagliflozin showed significantly reduced cardiovascular associated events. While the available data provide a strong evidence of empagliflozin benefits in reducing cardiac mortality and morbidity, the mechanism through which empagliflozin exerts its cardiac benefits is unknown. Therefore, an important challenge remaining is to elucidate the molecular mechanism of empagliflozin-mediated cardiac benefits. …