Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitor have been shown to significantly reduce heart failure hospitalization (HHF) and cardiovascular (CV) mortality in various cardiovascular outcome trials in patients with 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 CV mortality e.g. in the EMPA-REG OUTCOME trial.

Aim: This 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. 

Methods: In 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 mg or placebo for a period of 3 months in addition to their concomitant medication. Blood and urin was collected at baseline, day 1, day 3 and after 3 months of treatment to investigate effects on haematological parameters, erythropoietin concentrations and indices of iron stores. 

Results: Baseline characteristics were comparable in the empagliflozin (n=20) and placebo (n=22) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 hrs; day 1: 48.4 ± 34.7 g/24 hrs, p<0.001) as well as urinary volume (baseline: 1740 ± 601 mL/24 hrs; day 1: 2112 ± 837 mL/24 hrs, p=0.011) already after one day and throughout the study while hematocrit and hemoglobin was only found to be increased after 3 months of treatment (hematocrit: baseline: 41.0 ± 4.5 %; month 3: 43.3 ± 5.6 %, p<0.001; hemoglobin: baseline: 13.7 ± 1.8 g/dl; month 3: 14.2 ± 2.4 g/dl, p=0.005). Empagliflozin further increased red blood cell count (p<0.001), erythropoietin levels (p=0.087) and transferrin concentrations (p=0.021) while decreasing ferritin (p=0.006), total iron (p=0.035) and transferrin saturation (p=0.022) only after 3 month of treatment. As a possible mechanism we importantly found strong correlation between the induction of  urinary glucose excretion and the induction of erythropoietin in empagliflozin treated patients at the 3 month timepoint (Spearman rho 0.64, p=0.008). 

Conclusion: Empagliflozin 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.