Effect of Empagliflozin on Erythropoietin Levels, Iron Stores and Red Blood Cell Morphology in Patients with Type 2 Diabetes and Coronary Artery Disease.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to improve cardiovascular outcomes including hospitalization for heart failure and mortality in people with and without diabetes.1, 2 The mechanism(s) underlying this benefit remain unclear. While several hypotheses have been suggested (including SGLT2 inhibitor mediated diuresis and natriuresis, reduction in blood pressure and afterload, direct effects on myocardial sodium and calcium handling, alterations in myocardial energetics, reduction in left ventricular mass and improved progenitor cell response),3 a mediation analysis from the EMPA-REG OUTCOME trial suggests that an increase in hematocrit may account for over half of the mortality benefit observed. The consistent observation of an increase in hematocrit, even in those without diabetes, has led to the hypothesis that SGLT2 inhibitors may increase erythropoiesis via enhanced erythropoietin (EPO) secretion by the kidney.4 This SGLT2 inhibitor mediated increase in EPO production (and resultant rise in hematocrit) could lead to systemic organ protection by virtue of its capacity as a circulating pleiotropic cytokine, known to favorably influence cardiomyocyte mitochondrial function, angiogenesis, cell proliferation and inflammation. In addition, an increase in EPO-induced hematocrit may also improve myocardial function by directly enhancing myocardial and systemic tissue oxygen delivery.