Effects of Empagliflozin on Erythropoiesis in Patients with Type 2 Diabetes - data from a randomized, placebo controlled study.

Abstract

BACKGROUND\nSodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to significantly reduce heart failure hospitalization (HHF) and cardiovascular (CV) mortality in various cardiovascular outcome trials in patients with and without type 2 diabetes mellitus (T2D). SGLT2 inhibition further increased haemoglobin concentration and hematocrit by a yet unknown mechanism and this increase proved as an independent predictor for the CV benefit of these agents e.g. in the EMPA-REG OUTCOME trial.\n\n\nAIM\nThis analysis of the EMPA hemodynamic study examined early and delayed effects of empagliflozin treatment on haemoglobin concentrations and hematocrit in addition to parameters of erythropoiesis and iron metabolism to better understand the underlying mechanisms.\n\n\nMETHODS\nIn this prospective, placebo-controlled, double blind, randomized, 2-arm parallel, interventional and exploratory study 44 patients with T2D were randomized into 2 groups and received empagliflozin 10\xa0mg or placebo for a period of 3\xa0months in addition to their concomitant medication. Blood and urin was collected at baseline, day 1, day 3 and after 3\xa0months of treatment to investigate effects on haematological parameters, erythropoietin concentrations and indices of iron stores.\n\n\nRESULTS\nBaseline characteristics were comparable in the empagliflozin (n\xa0=\xa020) and placebo (n\xa0=\xa022) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3\xa0±\u200922.7\xa0g/24\xa0hrs; day 1: 48.4\xa0±\u200934.7\xa0g/24\xa0hrs, p\xa0<\u20090.001) as well as urinary volume (baseline: 1740\xa0±\u2009601\xa0mL/24\xa0hrs; day 1: 2112\xa0±\u2009837\xa0mL/24\xa0hrs, p\xa0=\xa00.011) already after one day and throughout the 3\xa0months study period while hematocrit and hemoglobin were only increased after 3\xa0months of treatment (hematocrit: baseline: 41.0\xa0±\u20094.5%; month 3: 43.3\xa0±\u20095.6%, p\xa0<\u20090.001; hemoglobin: baseline: 13.7\xa0±\u20091.8\xa0g/dL; month 3: 14.2\xa0±\u20092.4\xa0g/dL, p\xa0=\xa00.005). In addition, after 3\xa0months, empagliflozin further increased red blood cell count (p\xa0<\u20090.001) and transferrin concentrations (p\xa0=\xa00.063) and a trend toward increased erythropoietin levels (p\xa0=\xa00.117) while ferritin (p\xa0=\xa00.017), total iron (p\xa0=\xa00.053) and transferrin saturation (p\xa0=\xa00.030) decreased. Interestingly, the increase in urinary glucose excretion significantly correlated with the induction of erythropoietin in empagliflozin treated patients at the 3\xa0month timepoint (Spearman rho 0.64, p\xa0=\xa00.008).\n\n\nCONCLUSION\nEmpagliflozin increased hemoglobin concentrations and hematocrit with a delayed time kinetic which was most likely attributable to increased erythropoiesis with augmented iron utilization and not hemoconcentration. This might be attributable to reduced tubular glucose reabsorption in response to SGLT2 inhibition possibly resulting in diminished cellular stress as a mechanism for increased renal erythropoietin secretion.