Summary: In a prespecified biomarker substudy of the placebo-controlled EMPEROR program (1,139 patients with heart failure), empagliflozin raised haemoglobin by 0.6 to 0.9 g/dL at 12 weeks (P<0.001) and further activated the erythropoietin-erythroferrone-TfR1-hepcidin axis, increasing erythroferrone by more than 40% while lowering hepcidin, serum iron and transferrin saturation. The work characterises a mechanism of action; it does not test a new clinical endpoint.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,139 patients with chronic heart failure (reduced or preserved ejection fraction) from the EMPEROR program; randomised, double-blind, placebo-controlled, multicentre design. |
| Intervention | Empagliflozin (an SGLT2 inhibitor), with serum iron-metabolism biomarkers measured at baseline, 12 weeks and 52 weeks. |
| Comparison | Placebo, within the same randomised EMPEROR cohort. |
| Outcome | At 12 weeks versus placebo, empagliflozin increased haemoglobin by 0.6 to 0.9 g/dL (P<0.001), raised erythroferrone by more than 40% alongside higher erythropoietin and TfR1, and lowered hepcidin, serum iron and transferrin saturation (all P<0.01). Patients with baseline iron deficiency showed an attenuated erythrocytic response (P trend = 0.04) but no diminution of heart-failure benefit. As heart failure advanced, higher erythropoietin, erythroferrone and TfR1 predicted greater risk of cardiovascular death or heart-failure hospitalisation (all P<0.01). No new clinical efficacy endpoint, absolute risk reduction or NNT was reported in this mechanistic analysis. |
Expert Commentary
This prespecified biomarker substudy is best read as a mechanistic explanation rather than a new efficacy result. Within a randomised, double-blind, placebo-controlled cohort, empagliflozin was shown to engage a coherent erythropoietin-erythroferrone-TfR1-hepcidin axis: erythropoietin and erythroferrone rose, hepcidin fell, and iron was mobilised toward the marrow, with a consistent 0.6 to 0.9 g/dL haemoglobin gain at 12 weeks. The internal consistency of the biomarker changes, the placebo control and the large sample lend the findings credibility. Two cautions temper enthusiasm. First, the trans-disease-stage associations linking erythropoietin, erythroferrone and TfR1 to worse outcomes are observational and prognostic, not causal, so these proteins are markers of advancing disease rather than validated treatment targets. Second, the analysis was funded by the manufacturer and several authors are company employees, which warrants the usual scrutiny even though the underlying randomised data are robust. Can I use this with my patients? Not as a reason to start or stop empagliflozin, but it reassures prescribers that the familiar rise in haemoglobin reflects active erythropoiesis and iron use rather than haemoconcentration, and that iron-deficient patients still derive heart-failure benefit. Clinicians should interpret a haemoglobin rise on therapy as expected physiology, and future work should test whether these biomarkers usefully guide iron repletion.
References
Ferreira JP, Anker SD, Butler J, Filippatos G, Januzzi JL, Schueler E, et al. Effect of empagliflozin on the mechanisms driving erythropoiesis and iron mobilization in patients with heart failure: the EMPEROR program. J Am Coll Cardiol. 2025;85(18):1757-1770. doi:10.1016/j.jacc.2025.03.503