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

Abstract

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 ClinicalTrials.gov, NCT03198585.

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

Conflict of interest statement

MO reports grant from the Danish Heart Foundation, grants from The Steno Diabetes Center Odense (SDCO), Odense University Hospital Denmark, grants from A.P. Møller Foundation for the Advancement of Medical Science, Denmark related to present study, and personal fees from scientific advisory board from AstraZeneca, outside the submitted work. JJ reports grants from the Research Council at Herlev and Gentofte University Hospital, Denmark, grants from the Research and Innovation Foundation of the Department of Cardiology (FUHAS; formerly FUKAP), Herlev and Gentofte University Hospital, Denmark, grants from the A.P. Møller Foundation for the Advancement of Medical Science, Denmark, during the conduction of the study, and personal fees from scientific advisory board from AstraZeneca, outside the submitted work. CK reports personal fees from scientific advisory panels and speaker fees from Boehringer Ingelheim, Merck, Sharp & Dohme, AstraZeneca, Amgen, Novartis, Novo Nordisk, and Shire, outside the submitted work. KH, LV, JHL, and CFA have nothing to disclose. CT reports personal fees from scientific advisory panels and speaker fees from Orion Pharma and Bayer outside the submitted work. FG reports personal fees from Boehringer Ingelheim during the conduction of the study, personal fees from Novartis, grants and personal fees from Pfizer, and personal fees from Orion Pharma Abbott, Bayer, AstraZeneca, and Carmat, outside the submitted work. LK reports personal fees from speaker honorarium from Novartis, AstraZeneca, Novo Nordisk, and Boehringer Ingelheim, outside the submitted work. MS reports grants from The Capital Region of Denmark and grants from the Danish Heart Foundation, during the conduction of the study; personal fees and non-financial support from AstraZeneca, and personal fees from Novo Nordisk and Boehringer Ingelheim, outside the submitted work. JEM reports grant from Roche to perform GDF-15 analyses, research grant from Abiomed outside submitted work, and speaker honorarium from Abiomed, Novartis, Abbott, Boehringer Ingelheim and Orion Pharma, outside the submitted work.

© 2022. The Author(s).

Figures

Fig. 1

Trial profile

Fig. 2

Values at baseline and follow-up by group for each variable and Treatment effects. Unadjusted values at baseline and 12 weeks follow-up, and the unadjusted treatment effect in the empagliflozin and placebo group with the adjusted p value. The box represents median with IQR, and whiskers represent 1.5 times the IQR. GDF-15 growth differentiation factor 15, HsCRP high-sensitivity C-reactive protein, HsTNT high-sensitivity Troponin T

Fig. 3

Subgroup analyses of GDF-15. Mean (95% CI) change in the empagliflozin group versus the placebo group. For continuous variables, the cut-off value is illustrated in the figure. GDF-15 growth differentiation factor 15, HF heart failure, ARNi angiotensin receptor-neprilysin inhibitor, MRA mineralocorticoid receptor antagonist, NT-proBNP N-terminal pro-B-type natriuretic peptide