Sodium-
glucose cotransporter-2 (
SGLT2) inhibitors have been shown to significantly reduce hospitalization for
heart failure (HHF) and cardiovascular (CV) mortality in various CV outcome trials in patients with and without
type 2 diabetes mellitus (T2D). SGLT2 inhibition further increased haemoglobin and haematocrit levels by an as yet unknown mechanism, and this increase has been shown to be an independent predictor of the CV benefit of these agents, for example, in the EMPA-REG OUTCOME trial. The present analysis of the EMPA haemodynamic study examined the early and delayed effects of
empagliflozin treatment on haemoglobin and haematocrit levels, in addition to measures of erythropoiesis and
iron metabolism, to better understand the underlying mechanisms. In this prospective, placebo-controlled, double-blind, randomized, two-arm parallel, interventional and exploratory study, 44 patients with T2D were randomized into two groups and received
empagliflozin 10 mg or placebo for a period of 3 months in addition to their concomitant medication. Blood and urine was collected at baseline, on Day 1, on Day 3 and after 3 months of treatment to investigate effects on haematological variables,
erythropoietin concentrations and indices of
iron stores. 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 h; Day 1: 48.4 ± 34.7 g/24 h; P < 0.001) as well as urinary volume (baseline: 1740 ± 601 mL/24 h; Day 1: 2112 ± 837 mL/24 h; P = 0.011) already after 1 day and throughout the 3-month study period, while haematocrit and haemoglobin were only increased after 3 months of treatment (haematocrit: baseline: 40.6% ± 4.6%; Month 3: 42.2% ± 4.8%, P < 0.001; haemoglobin: baseline: 136 ± 19 g/L; Month 3: 142 ± 25 g/L; P = 0.008). In addition, after 3 months,
empagliflozin further increased red blood cell count (P < 0.001) and
transferrin concentrations (P = 0.063) and there was a trend toward increased
erythropoietin levels (P = 0.117), while
ferritin (P = 0.017), total
iron (P = 0.053) and
transferrin saturation levels (P = 0.030) decreased. Interestingly, the increase in urinary
glucose excretion significantly correlated with the induction of
erythropoietin in
empagliflozin-treated patients at the 3-month timepoint (Spearman rho 0.64; P = 0.008).
Empagliflozin increased haemoglobin concentrations and haematocrit with a delayed time kinetic, which was most likely attributable to increased erythropoiesis with augmented
iron utilization and not haemoconcentration. 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.