The effect of empagliflozin on growth differentiation factor 15 in patients with heart failure: a randomized controlled trial (Empire HF Biomarker)

Cardiovasc Diabetol. 2022 Feb 27;21(1):34. doi: 10.1186/s12933-022-01463-2.


Background: Plasma growth differentiation factor-15 (GDF-15) biomarker levels increase in response to inflammation and tissue injury, and increased levels of GDF-15 are associated with increased risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which improve outcome in HFrEF, have been shown to increase plasma GDF-15 in diabetic patients. We aimed to investigate the effect of empagliflozin on GDF-15 in HFrEF patients.

Methods: This Empire HF Biomarker substudy was from the multicentre, randomized, double-blind, placebo-controlled Empire HF trial that included 190 patients from June 29, 2017, to September 10, 2019. Stable ambulatory HFrEF patients with ejection fraction of ≤ 40% were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo for 12 weeks. Changes from baseline to 12 weeks in plasma levels of GDF-15, high-sensitive C-reactive protein (hsCRP), and high-sensitive troponin T (hsTNT) were assessed.

Results: A total of 187 patients who were included in this study, mean age was 64 ± 11 years; 85% male, 12% with type 2 diabetes, mean ejection fraction 29 ± 8, with no differences between the groups. Baseline median plasma GDF-15 was 1189 (918-1720) pg/mL with empagliflozin, and 1299 (952-1823) pg/mL for placebo. Empagliflozin increased plasma GDF-15 compared to placebo (adjusted between-groups treatment effect; ratio of change (1·09 [95% confidence interval (CI), 1.03-1.15]: p = 0.0040). The increase in plasma GDF15 was inversely associated with a decrease in left ventricular end-systolic (R = - 0.23, p = 0.031), and end-diastolic volume (R = - 0.29, p = 0.0066). There was no change in plasma hsCRP (1.09 [95%CI, 0.86-1.38]: p = 0.48) or plasma hsTNT (1.07 [95%CI, 0.97-1.19]: p = 0.18) compared to placebo. Patients with diabetes and treated with metformin demonstrated no increase in plasma GDF-15 with empagliflozin, p for interaction = 0·01.

Conclusion: Empagliflozin increased plasma levels of GDF-15 in patients with HFrEF, with no concomitant increase in hsTNT nor hsCRP.

Trial registration: The Empire HF trial is registered with, NCT03198585.

Keywords: GDF15; HFrEF; SGLT2 inhibitors; hsCRP; hsTNT.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Benzhydryl Compounds / adverse effects
  • Biomarkers
  • Diabetes Mellitus, Type 2* / chemically induced
  • Diabetes Mellitus, Type 2* / diagnosis
  • Diabetes Mellitus, Type 2* / drug therapy
  • Double-Blind Method
  • Female
  • Glucosides
  • Growth Differentiation Factor 15
  • Heart Failure* / diagnosis
  • Heart Failure* / drug therapy
  • Humans
  • Male
  • Middle Aged
  • Sodium-Glucose Transporter 2 Inhibitors* / adverse effects
  • Stroke Volume


  • Benzhydryl Compounds
  • Biomarkers
  • Glucosides
  • Growth Differentiation Factor 15
  • Sodium-Glucose Transporter 2 Inhibitors
  • empagliflozin

Associated data