Effects of empagliflozin on erythropoiesis in heart failure: data from the Empire HF trial

Camilla Fuchs Andersen, Massar Omar, Andreas Glenthoj, Daniel El Fassi, Holger J. Moller, Jorgen A. Lindholm Kurtzhals, Bjarne Styrishave, Caroline Kistorp, Christian Tuxen, Mikael K. Poulsen, Jens Faber, Lars Køber, Finn Gustafsson, Jacob E. Moller, Morten Schou, Jesper Jensen

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Aims: It remains unknown whether the consistently observed increase in haematocrit with sodium–glucose cotransporter 2 inhibitors is caused by diuresis-associated haemoconcentration or increased erythropoiesis. We aimed to investigate the early effect of empagliflozin on erythropoiesis and iron metabolism in patients with heart failure with reduced ejection fraction (HFrEF). Methods and results: The Empire HF was a double-blind, randomized, placebo-controlled trial. Patients with a left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association (NYHA) class I–III symptoms, and on stable guideline-directed HFrEF therapy were randomly assigned (1:1) to empagliflozin or matching placebo once daily for 12 weeks. Exploratory outcomes reflecting changes in erythropoiesis and iron metabolism were analysed. In total, 190 patients were randomized. Baseline characteristics were well-balanced between the groups (age: mean 64 [± 11] years; male: 85%; LVEF: mean 29 [± 8)%; NYHA class II: 78%; type 2 diabetes: 13%; anaemia: 28%; chronic kidney disease: 13%). In this post hoc analysis, erythropoietin was increased with empagliflozin compared to placebo from baseline to 12 weeks (adjusted mean difference 2.6 IU/L, 95% confidence interval [CI] 0.8–4.4; p = 0.0046). Moreover, hepcidin was reduced (adjusted ratio of change 0.76, 95% CI 0.59–0.97; p = 0.031), with no change observed for erythroferrone (adjusted ratio of change 1.17, 95% CI 0.86–1.60; p = 0.31) compared to placebo. No significant treatment-by-subgroup interactions were observed regarding baseline type 2 diabetes, anaemia, or chronic kidney disease (p interaction >0.05). Conclusion: These findings suggest that empagliflozin increases erythropoiesis and augments early iron utilization in patients with HFrEF. These mechanisms may contribute to the cardioprotective properties of empagliflozin.

Original languageEnglish
JournalEuropean Journal of Heart Failure
Issue number2
Pages (from-to)226-234
Publication statusPublished - Feb 2023


  • SGLT2 inhibitor
  • Heart failure
  • Pharmacotherapy
  • Erythropoiesis
  • Renal Insufficiency, Chronic
  • Ventricular Function, Left
  • Humans
  • Male
  • Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
  • Stroke Volume
  • Diabetes Mellitus, Type 2/drug therapy
  • Heart Failure
  • Ventricular Dysfunction, Left/drug therapy


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