Empagliflozin effects on iron metabolism as a possible mechanism for improved clinical outcomes in non-diabetic patients with systolic heart failure

Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve clinical outcomes in patients with heart failure (HF), but mechanisms of action are incompletely understood. In the EMPATROPISM trial, empagliflozin reversed cardiac remodeling and increased physical capacity in stable non-diabetic patients with systolic HF. EMPATROPISM-FE explored post hoc in this cohort, who had a high prevalence of iron deficiency, whether treatment effects were related to changes in iron metabolism. Here we show that myocardial iron content estimated by cardiac magnetic resonance T2* quantification increased after initiation of empagliflozin, but not placebo (between-group difference p = 0.01). T2* changes were significantly correlated with changes in left ventricular volumes, mass and ejection fraction, peak oxygen consumption and 6-minute walking distance; concomitant changes in red blood cell indices were consistent with augmented hematopoiesis. Our findings suggest that effects of empagliflozin on iron metabolism may be a potential mechanism mediating its beneficial clinical effects in patients with HF. Clinical Trial Registration: www.clinicaltrials.gov; NCT03485222