Introduction: Growth differentiation factor 15 (GDF-15) is considered as a biomarker of inflammatory and myocardial tissue injury. However, metformin increases plasma GDF-15, and may be responsible for the metabolic benefits (e.g. weight loss, decrease in Hemoglobin A1c and systolic blood pressure, and improvement in insulin resistance) effects in type 2 diabetes (T2D). Recently, sodium-glucose cotransporter-2 inhibitors (SGLT2i) demonstrated increment in GDF-15 in a proteomic analysis in T2D patients. Hypothesis: To examine SGLT2i’s effect on GDF-15 in HFrEF patients. Methods: This multicenter, randomized, double-blind, placebo-controlled exploratory sub-study enrolled 190 stable HFrEF patients with an ejection fraction of 40% or below. Patients were randomized (1:1) to empagliflozin 10 mg once daily or matching placebo for 12 weeks. Outcome measures were changes from baseline in GDF-15, high sensitive C-reactive protein (hsCRP), and high sensitive troponin T (hsTNT) adjusted for age, sex, BMI, T2D. Results: Mean age was 64 (SD, 11) years; 85% male, 13% with T2D, mean ejection fraction 29 (SD, 8)). Empagliflozin significantly increased GDF-15 compared to placebo [Empagliflozin: baseline, median (interquartile range (IQR)) 1177 (899-1720) pg/mL, follow-up, 1394 (970-1942) pg/mL: Placebo: baseline 1299 (915-1849) pg/mL, follow-up, 1276 (879-1924) pg/mL, adjusted ratio of change (1.10 [95% confidence interval (CI), 1.04-1.17]: p=0.002). There was no significant change in hsCRP (1.13 [95%CI, 0.89-1.43]: p=0.31), nor in hsTNT (1.09 [95%CI, 0.98-1.20]: p=0.12) (Figure 1). Conclusions: Empagliflozin significantly increased GDF-15 in predominantly non-diabetic HFrEF patients regardless of HF etiology, without a concomitant increase in hsCRP, or hsTNT compared to placebo. These results might explain the link between empagliflozin and the metabolic benefits seen in this population.