Direct effects of empagliflozin on erythropoiesis in heart failure: data from the Empire HF trial

Abstract

Background Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a newly recommended treatment of heart failure with reduced ejection fraction (HFrEF). The consistently observed increase in haematocrit with SGLT2 inhibition is associated with a large proportion of the observed clinical benefit in different type 2 diabetes (T2D) populations. Whether the increase in haematocrit is caused by diuresis-associated haemoconcentration or is due to a direct effect on erythropoiesis is unknown. We have previously observed a decrease in ferritin alongside increases in haematocrit and haemoglobin with empagliflozin, thus indicating a direct effect on erythropoiesis. Purpose To investigate the effect of the SGLT2 inhibitor empagliflozin on erythropoiesis in patients with HFrEF. Methods The Empire HF trial was an investigator-initiated, double-blind, randomised, placebo-controlled trial conducted at two Danish university hospitals with enrolment of 190 patients from five outpatient heart failure clinics. Patients with a left ventricular ejection fraction (LVEF) of 40% or lower, with New York Heart Association (NYHA) Class I, II, or III symptoms, and on stable doses of guideline-directed HFrEF therapy were randomly assigned (1:1) to receive empagliflozin 10 mg or matching placebo once daily for 12 weeks. The present biomarker endpoints were analysed according to the intention-to-treat principle in analyses of covariance models with baseline adjustments. Results A minimum of 91 patients (96%) in each group had complete data and were included in the present analyses. Baseline characteristics were well-balanced between the allocated groups [mean age: 64 (SD 11) years; male: 85%; mean LVEF: 29 (SD 8) %; NYHA Class II: 78%; T2D: 13%; anaemia: 28%]. Serum-erythropoietin increased in the empagliflozin group compared to placebo from baseline to 12 weeks [adjusted mean difference 2.6 IU/L (95% CI 0.8–4.4; P=0.0052)]. Moreover, plasma-hepcidin decreased [adjusted ratio of change 0.68 (95% CI 0.22–1.02; P=0.067)], and mean corpuscular volume increased [adjusted ratio of change 1.01 (95% CI 1.00–1.02; P=0.0033)] compared to placebo, while no changes were observed for mean corpuscular haemoglobin concentration or plasma-iron (P>0.05). Conclusion The consistently observed increase in haematocrit with SGLT2 inhibitor treatment may not exclusively be due to diuresis-associated haemoconcentration as previously suspected. The present analyses suggest that empagliflozin increases erythropoiesis and induces changes in iron metabolism in a population of patients with HFrEF, primarily without diabetes. The observed decrease in hepcidin, and in ferritin as we have previously reported, further implies an anti-inflammatory effect, all of which may contribute to the cardioprotective properties of empagliflozin. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Danish Heart Foundation;The A.P. Møller Foundation for the Advancement of Medical Science, Copenhagen, Denmark

February 2023 at a glance: focus on pathophysiology and treatment

“…Overall, 190 patients were randomized 1:1 to empagliflozin or placebo for 12 weeks. Increased erythropoietin and reduced hepcidin were reported in the treated group, consistent with an anti‐inflammatory effect, while no changes in erythroferrone were observed 30 …”

“…Increased erythropoietin and reduced hepcidin were reported in the treated group, consistent with an anti-inflammatory effect, while no changes in erythroferrone were observed. 30 The efficacy of the selective cardiac myosin activator omecamtiv mecarbil seems to be greater in patients with more severe systolic HF. [31][32][33][34] examined as a continuous variable, with greater effect of omecamtiv mecarbil on the primary outcome in patients with a higher baseline NT-proBNP.…”

Little at a time: trying to understand the battery of benefits of sodium–glucose contransporter 2 inhibitors in heart failure

“…12 A total of 190 outpatients with HFrEF were randomly assigned to receive empagliflozin 10 mg once daily or placebo for 12 weeks. In this issue of the Journal, Fuchs Andersen et al 13 present a post hoc analysis of outcomes reflecting changes in erythropoiesis and iron metabolism. They report that empagliflozin significantly increases serum EPO levels compared to placebo from baseline to 12 weeks.…”