Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease
Authors: C. David Mazer, Gregory M.T. Hare, Philip W. Connelly, Richard E. Gilbert, Nadine Shehata, Adrian Quan, Hwee Teoh, Lawrence A. Leiter, Bernard Zinman, Peter Jüni, Fei Zuo, Nikhil Mistry, Kevin E. Thorpe, Ronald M. Goldenberg, Andrew T. Yan, Kim A. Connelly, Subodh Verma
Journal: Circulation (2019)

empagliflozin ◼ erythrocytes ◼ erythropoietin ◼ iron ◼ sodium-glucose transporter 2 inhibitors S odium-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 mellitus. 1,2The mechanisms underlying this benefit remain unclear.Although several hypotheses have been suggested (including SGLT2 inhibitormediated 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 (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) suggests that an increase in hematocrit may account for more than half of the mortality benefit observed.The consistent observation of an increase in hematocrit, even in those without diabetes mellitus, has led to the hypothesis that SGLT2 inhibitors may increase erythropoiesis via enhanced erythropoietin secretion by the kidney. 4This SGLT2 inhibitor-mediated increase in erythropoietin 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 erythropoietin-induced hematocrit may improve myocardial function by directly enhancing myocardial and systemic tissue oxygen delivery.In this substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes) CardioLink-6 randomized clinical trial in which 6 months of empagliflozin treatment was associated with significant reduction in left ventricular mass index, 5 we measured erythropoietin levels, red blood cell (RBC) morphology, and indices of iron stores in individuals with type 2 diabetes mellitus and stable coronary artery disease who were randomized to either empagliflozin 10 mg daily or placebo for 6 months.The St Michael's Hospital Research Ethics Board approved the study, and all subjects gave informed consent.Blood samples were collected at baseline, after 1 month of treatment, and at the end of the study (6 months).Erythropoietin levels were measured from frozen sera with a 2-site immunoenzymatic chemiluminescent assay, and the data were analyzed with a linear mixed-effects model that included treatment group, visit, and treatment-by-visit interaction, and baseline values as fixed effects.Iron indices, ferritin, and complete blood counts were measured at baseline and at 6 months with standard spectrophotometric, 2-site immunoenzymatic, and flow cytometric techniques, with data analyzed using ANCOVA adjusted for baseline values.Values of P<0.05 were considered significant.