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
Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Fonden Background Cardiogenic shock (CS) is seen in up to 10% of patients with ST-elevation myocardial infarction (STEMI) and is associated with a high mortality rate of up to 50%. Approximately 1/3 of STEMI-patients developing CS are not in overt shock at time of hospital admission but will develop hemodynamical instability within the following hours to days. Patients at risk of CS development may be clinically stable but with normal lactate levels (Society for Cardiovascular Angiography and Interventions classification, SCAI A/B). The Observatoire Régional Breton sur l'Infarctus (ORBI) clinical risk score has recently been developed and validated for predicting the risk of in-hospital (late) CS. STEMI-patients with an ORBI score >=10 have a risk of in-hospital CS development of more than 8-10%. NTproBNP is a biomarker released from the myocardium reflecting neurohormonal activation which is strongly correlated with hemodynamic parameters. Neurohormonal activation as well as a systemic inflammatory response are present acutely at hospital admission in STEMI patients developing late CS compared to non-CS patients suggesting an early subclinical hemodynamic deterioration. Dobutamine induces significant positive inotropic- and dose-dependent chronotropic effects and decreases afterload by peripheral vasodilatation, which increases cardiac output and organ perfusion. The interleukin-6 receptor antagonist Tocilizumab has been shown to reduce troponin leakage and increase myocardial salvage in acute MI patients. The effects of Dobutamine and Tocilizumab in a high-risk population have not previously been investigated. Methods DOBERMANN is an investigator-initiated, double blinded randomized clinical trial. Consecutive patients with acute MI admitted for acute coronary angiography and treated with percutaneous coronary intervention are screened with the ORBI risk score in the catheterization laboratory. One hundred adult patients presenting without CS at hospital admission with an intermediate-high risk of CS development (ORBI risk score of >=10) will be randomized 2x2 to receive a continuous intravenous infusion of dobutamine (5 micrograms/kg/minute, 24h) vs. placebo, and a single dose of Tocilizumab (280 mg, 1h) vs. placebo. NTproBNP as a proxy for development of CS and hemodynamic instability will be sampled for primary endpoint analysis. Effects on clinical parameters, mortality, morbidity as well as specific indicators of inflammation, cardiac function, and infarct size will secondarily be assessed noninvasively at 48h and at three months follow-up. Enrollment began in March 2022 and is commencing as planned. Discussion We hypothesize that inflammatory and neurohormonal responses are associated with subclinical hemodynamic instability in patients with AMI with intermediate/high risk of CS. The potentially unstable condition may be targeted pharmacologically as an add-on to existing therapy.
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