Effect of Empagliflozin on the Mechanisms Driving Erythropoiesis and Iron Mobilization in Patients With Heart Failure
Key result
Empagliflozin raises hemoglobin by ~0.8 g/dL while increasing erythroferrone and decreasing hepcidin and serum iron.
- 0.6 to 0.9 g/dL increase
- P<0.001
- n=1,139
Why the study?
SGLT2 inhibitors stimulate erythropoiesis, but the mechanisms and clinical relevance of their effect on systemic iron metabolism in heart failure were not well understood.
Does empagliflozin alter iron metabolism biomarkers and erythropoiesis in patients with heart failure?
Key Points
- To characterize circulating iron metabolism biomarkers, focusing on erythroferrone, in patients with heart failure receiving empagliflozin.
- Measured serum iron metabolism biomarkers at baseline, 12 weeks, and 52 weeks in 1,139 patients treated with empagliflozin or placebo in the EMPEROR program.
- Evaluated correlations among biomarkers (erythropoietin, erythroferrone, TfR1, and hepcidin) and their relationship with clinical status and heart failure outcomes.
- At 12 weeks, empagliflozin increased hemoglobin by 0.6 to 0.9 g/dL compared with placebo (P < 0.001), boosted erythroferrone by >40%, elevated erythropoietin and TfR1, and reduced hepcidin, serum iron, and transferrin saturation (all P < 0.01).
- Higher baseline levels of erythropoietin, erythroferrone, and TfR1 correlated with more advanced heart failure (P trend < 0.01) and predicted an increased risk of cardiovascular death or heart failure hospitalization (all P < 0.01).
- Baseline iron deficiency blunted the erythrocytic response to empagliflozin (P trend = 0.04) without diminishing its clinical heart failure benefits.
Study Design
Type
RCT (n=1,139)
Structured PICO
Does empagliflozin alter iron metabolism biomarkers and erythropoiesis in patients with heart failure?
P
Population
1,139 patients with heart failure and a reduced or preserved ejection fraction treated with empagliflozin or placebo, with biomarker follow-up at 12 and 52 weeks.
I
Intervention
Empagliflozin
C
Comparator
Placebo
O
Outcome
Serum iron metabolism biomarkers (including erythroferrone, erythropoietin, TfR1, hepcidin, serum iron, transferrin saturation) and hemoglobin at 12 weeks and 52 weekssurrogate
Main Result
Effect estimate: 0.6 to 0.9 g/dL increase
p-value: p=<0.001
Empagliflozin enhances erythropoiesis and iron mobilization in heart failure patients by activating the erythropoietin-erythroferrone-TfR1-hepcidin axis.
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Consequently, in patients with iron deficiency before treatment, the resulting hypoferremia may be sufficient to limit the erythrocytic response but not the [HF] benefits of SGLT2 inhibitors.”
KFKieran F. DochertyCardiovascular researcher, University of Glasgow
“It is clear that SGLT2 inhibitors and iron utilization are intricately linked, and we are only beginning to unravel the diverse mechanisms contributing to the clinical benefits of this drug class in cardiovascular-kidney-metabolic disease. Reassuringly, the presence of iron deficiency does not attenuate the clinical benefits of SGLT2 inhibitors in HF, and efforts should continue to ensure their widespread implementation in clinical practice.”
Implication
Empagliflozin activates the EPO-erythroferrone-TfR1-hepcidin axis to enhance erythropoiesis and iron use in HF; extends mechanistic understanding of SGLT2 inhibitor effects.
Abstract
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors stimulate erythropoiesis, but the mechanisms and clinical relevance of the effect of SGLT2 inhibitors on systemic iron metabolism in patients with heart failure is not well understood. OBJECTIVES: The authors sought to characterize a comprehensive suite of iron metabolism biomarkers-particularly the erythroblast signaling molecule, erythroferrone-in patients with heart failure before and after short- and long-term treatment with empagliflozin in patients with heart failure and a reduced or preserved ejection fraction. METHODS: We measured serum iron metabolism biomarkers at baseline, 12 weeks, and 52 weeks in 1,139 patients who were treated with placebo or empagliflozin in the EMPEROR (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure) program, and we characterized the inter-relationships of these biomarkers with clinical status and with the effect of empagliflozin on erythropoiesis and heart failure outcomes. RESULTS: Correlations among iron biomarkers indicated the presence of a functional erythropoietin-erythroferrone-transferrin-receptor-protein-1 (TfR1)-hepcidin axis. As heart failure advanced, patients showed higher levels of erythropoietin, erythroferrone, and TfR1 (P trend <0.01), and levels of these proteins predicted a heightened risk of cardiovascular death or heart failure hospitalization (all P < 0.01). Compared with placebo, at 12 weeks, empagliflozin increased hemoglobin by 0.6 to 0.9 g/dL (P < 0.001), an effect that was accompanied by further activation of the erythropoietin-erythroferrone-TfR1 axis and increased iron use. Empagliflozin increased serum levels of erythroferrone by >40% (along with increases in erythropoietin and TfR1), while simultaneously decreasing hepcidin levels and reducing serum iron concentrations and transferrin saturation (all P < 0.01). When treated with empagliflozin, patients with evidence of iron deficiency at baseline showed attenuation of the erythrocytic response (P trend = 0.04) but no diminution of the heart failure benefits. CONCLUSIONS: The erythropoietin-erythroferrone-TfR1-hepcidin axis is activated in patients with heart failure as the disease advances and is further heightened by SGLT2 inhibitors, in parallel with their effect to enhance erythropoiesis and iron mobilization and use. These changes have important implications for understanding the mechanism of action of SGLT2 inhibitors and for monitoring the response to treatment.
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Cite This Study
Ferreira et al. (2025) conducted an RCT in Heart failure (n=1,139). Empagliflozin vs. Placebo was evaluated on Change in hemoglobin at 12 weeks (0.6 to 0.9 g/dL increase, p=<0.001). Empagliflozin increased hemoglobin by 0.6 to 0.9 g/dL at 12 weeks (P<0.001) and increased serum erythroferrone by >40% while decreasing hepcidin levels and serum iron concentrations.