Ferreira João Pedro, Anker Stefan D, Butler Javed, Filippatos Gerasimos, Januzzi James L, Schueler Elke, Panova-Noeva Marina, Wetzel Kristiane, Prochaska Juergen, Pocock Stuart J, Sattar Naveed, Sumin Mikhail, Zannad Faiez, Packer Milton
UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; Heart Failure Clinic, Internal Medicine Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal; Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, and INSERM U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
Department of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany; Institute of Heart Diseases, Wrocław Medical University, Wroclaw, Poland.
J Am Coll Cardiol. 2025 May 13;85(18):1757-1770. doi: 10.1016/j.jacc.2025.03.503.
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.
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.
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.
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.
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.
钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可刺激红细胞生成，但SGLT2抑制剂对心力衰竭患者全身铁代谢影响的机制及临床相关性尚不清楚。
作者试图在射血分数降低或保留的心力衰竭患者中，描述短期和长期使用恩格列净治疗前后心力衰竭患者一套全面的铁代谢生物标志物，特别是成红细胞信号分子促红细胞生成素铁调节蛋白。
在EMPEROR（慢性心力衰竭患者恩格列净结局试验）项目中，我们测量了1139例接受安慰剂或恩格列净治疗的患者在基线、12周和52周时的血清铁代谢生物标志物，并描述了这些生物标志物与临床状态以及恩格列净对红细胞生成和心力衰竭结局影响之间的相互关系。
铁生物标志物之间的相关性表明存在一条功能性促红细胞生成素-促红细胞生成素铁调节蛋白-转铁蛋白受体蛋白1（TfR1）-铁调素轴。随着心力衰竭进展，患者促红细胞生成素、促红细胞生成素铁调节蛋白和TfR1水平升高（P趋势<0.01），这些蛋白水平可预测心血管死亡或心力衰竭住院风险增加（所有P<0.01）。与安慰剂相比，在12周时，恩格列净使血红蛋白升高0.6至0.9 g/dL（P<0.001），这一效应伴随着促红细胞生成素-促红细胞生成素铁调节蛋白-TfR1轴的进一步激活和铁利用增加。恩格列净使促红细胞生成素铁调节蛋白血清水平升高>40%（同时促红细胞生成素和TfR1增加），同时降低铁调素水平，降低血清铁浓度和转铁蛋白饱和度（所有P<0.01）。基线时有缺铁证据的患者接受恩格列净治疗后，红细胞反应减弱（P趋势=0.04），但心力衰竭获益未减少。
随着心力衰竭进展，促红细胞生成素-促红细胞生成素铁调节蛋白-TfR1-铁调素轴在心力衰竭患者中被激活，SGLT2抑制剂可进一步增强该轴的活性，同时增强红细胞生成以及铁的动员和利用。这些变化对于理解SGLT2抑制剂的作用机制以及监测治疗反应具有重要意义。
