Treatment of heart failure (HF) with the SGLT2 inhibitor empagliflozin was accompanied by further activation of the erythropoietin-erythroferrone-transferrin-receptor-protein-1 (TfR1)-hepcidin axis, but systemic inflammation may limit the ability of erythroferrone to suppress hepcidin and mobilize delivery of iron, according to results from the EMPEROR trial program published May 5 in JACC.

João Pedro Ferreira, MD, PhD, et al., analyzed outcomes of 1,139 patients who were treated with placebo or empagliflozin in the EMPEROR-Reduced and EMPEROR-Preserved trials. The authors measured serum iron metabolism biomarkers at baseline, 12 weeks and 52 weeks to characterize the inter-relationships of these biomarkers with clinical status and with the effect of empagliflozin on erythropoiesis and HF outcomes.

Compared with placebo, results showed that at 12 weeks, treatment with empagliflozin increased hemoglobin by 0.6 to 0.9 g/dL (p<0.001). This effect was accompanied by further activation of the erythropoietin-erythroferrone-TfR1-hepcidin axis and increased iron use. Correlations among iron biomarkers indicated the presence of a functional erythropoietin-erythroferrone-TfR1-hepcidin axis. The authors note that as HF advanced, patients showed higher levels of erythropoietin, erythroferrone and TfR1 (p for trend <0.01). Levels of these proteins predicted a heightened risk of cardiovascular death or HF hospitalization (p< 0.01 for all).

Patients with evidence of iron deficiency at baseline and treated with empagliflozin showed attenuation of the erythrocytic response (p for trend 0.04), but no diminution of HF benefits.

Noting the further activation of the axis with empagliflozin and that systemic inflammation may limit the ability of erythroferrone to suppress hepcidin and mobilize the delivery of iron, the authors write, "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."

In an accompanying editorial comment, Kieran F. Docherty, MB, ChB, writes, "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."