TY - JOUR

T1 - Effects of empagliflozin on erythropoiesis in heart failure

T2 - data from the Empire HF trial

AU - Fuchs Andersen, Camilla

AU - Omar, Massar

AU - Glenthøj, Andreas

AU - El Fassi, Daniel

AU - Møller, Holger J.

AU - Lindholm Kurtzhals, Jørgen A.

AU - Styrishave, Bjarne

AU - Kistorp, Caroline

AU - Tuxen, Christian

AU - Poulsen, Mikael K.

AU - Faber, Jens

AU - Køber, Lars

AU - Gustafsson, Finn

AU - Møller, Jacob E.

AU - Schou, Morten

AU - Jensen, Jesper

N1 - Funding Information: This work was supported by The Danish Heart Foundation [grant numbers 17‐R116‐A7714‐22076, 18‐R124‐A8573‐22107, 21‐R150‐A9936‐22197]; The Research Council at Herlev and Gentofte University Hospital, Denmark [institutional research grant]; The Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Denmark [institutional research grant]; The A.P. Møller Foundation for the Advancement of Medical Science, Copenhagen, Denmark [grant number 17‐L‐0002]; The Capital Region of Denmark [grant number A6058]. The manufacturer of empagliflozin had no part in funding or conduction of the study. Funding Information: C.F.A. reports grants from the Danish Heart Foundation, Toyota‐Fonden Denmark, Arvid Nilsson's Foundation, Aase & Ejnar Danielsen's Foundation, Fru Asta Florida Bolding's Memorial Grant, KV Foundation and The Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Herlev, Denmark; personal fees from AstraZeneca, all outside the submitted work. J.J. reports grants from The Danish Heart Foundation, Denmark, and The CARDIOHGH at the Department of Cardiology, Herlev and Gentofte University Hospital, Denmark, during the conduct of the submitted work; personal fees from scientific advisory board from AstraZeneca and Boehringer Ingelheim, outside the submitted work; grants from The Research Council at Herlev and Gentofte University Hospital, Denmark, grants from The CARDIOHGH (formerly FUHAS), Herlev and Gentofte University Hospital, Denmark, and grants from The A.P. Møller Foundation for the Advancement of Medical Science, Denmark [as sub‐investigator of the Empire HF trial]. Funding organizations had no role in the trial design, data collection, writing of the article or decision to submit the paper. M.A.O reports grants from the Danish Heart Foundation, grants from The Steno Diabetes Center Odense, Denmark and grants from A.P. Møller Foundation during the conduct of the study. C.T. reports speaker fees from Orion Pharma, personal fees for advisory board participation from Boehringer Ingelheim, all outside the submitted work. F.G. reports speaker fees from Orion Pharma, Vifor Pharma and Novartis, and personal fees for advisory board participation from Abbott, Pfizer, AstraZeneca, Ionis, Alnylam and Bayer, all outside the submitted work. J.E.M. reports speaker fees from Novartis, Boehringer Ingelheim, Abiomed, Orion and Abbott, advisory board from Orion and Boehringer Ingelheim, and research grant Abiomed and Roche, all outside submitted work. Conflict of interest:

PY - 2023

Y1 - 2023

N2 - 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 (pinteraction >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.

AB - 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 (pinteraction >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.

KW - Erythropoiesis

KW - Heart failure

KW - Pharmacotherapy

KW - SGLT2 inhibitor

U2 - 10.1002/ejhf.2735

DO - 10.1002/ejhf.2735

M3 - Journal article

C2 - 36377106

AN - SCOPUS:85144130941

VL - 25

SP - 226

EP - 234

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

SN - 1567-4215

IS - 2

ER -