Interleukin-6 in Heart Failure With Reduced Ejection Fraction and the Effect of Dapagliflozin: An Exploratory Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial
- PMID: 40088234
- DOI: 10.1016/j.jchf.2024.12.012
Interleukin-6 in Heart Failure With Reduced Ejection Fraction and the Effect of Dapagliflozin: An Exploratory Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial
Abstract
Background: Inflammation may play an important pathophysiological role in the development and progression of heart failure (HF). Interleukin (IL)-6 is a circulating cytokine and is the main regulator of the release of C-reactive protein (CRP).
Objectives: The authors examined the association between IL-6 and high-sensitivity (hs)-CRP and outcomes in patients with HFrEF in the DAPA-HF trial and their relationship with the effect of dapagliflozin.
Methods: Inclusion criteria included: 1) NYHA functional class II-IV; 2) left ventricular ejection fraction ≤40%; 3) elevated N-terminal pro-B-type natriuretic peptide; and 4) estimated glomerular filtration rate ≥30 mL/min/1.73 m2. The primary outcome was a composite of a worsening HF event or cardiovascular death. IL-6 and hs-CRP were measured at baseline and 12 months (Roche Diagnostics). The associations between IL-6 and hs-CRP and outcomes were adjusted for known prognostic variables, including NT-proBNP.
Results: Among 2,940 patients, median IL-6 and hs-CRP at baseline were 6.01 pg/mL (Q1-Q3: 4.18-9.28 pg/mL) and 2.05 mg/L (Q1-Q3: 0.83-4.9 mg/L), respectively. Baseline IL-6 tertiles (T) were: T1 ≤4.72 pg/mL; T2 4.73-7.89 pg/mL; and T3 ≥7.90 pg/mL. The adjusted risks of the primary outcome relative to T1 were as follows: T2 = HR 1.34 (95% CI: 1.04-1.73) and T3 = HR 1.80 (95% CI: 1.41-2.31). A rise in IL-6 between baseline and 12 months was associated with worse outcomes. The beneficial effect of dapagliflozin on the primary outcome was consistent regardless of IL-6 concentration (continuous interaction P = 0.57), with similar results for hs-CRP. Dapagliflozin did not reduce IL-6 or hs-CRP at 12 months.
Conclusions: In DAPA-HF, elevated IL-6 and hs-CRP levels were each associated with the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of adverse outcomes regardless of baseline IL-6 or hs-CRP. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).
Keywords: SGLT2i; heart failure; inflammation; interleukin-6.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Funding Support and Author Disclosures The DAPA-HF trial was funded by AstraZeneca. Roche Diagnostics supported this study through provision of IL-6 tests, free of charge. Drs Jhund, Petrie, and McMurray were supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund. Dr Docherty’s employer, the University of Glasgow, has been remunerated by AstraZeneca for his work on clinical trials. Dr Docherty has received speaker fees from AstraZeneca, Boehringer Ingelheim, Pharmacosmos, Translational Medical Academy, and Radcliffe Cardiology; has served on an advisory board for Us2.ai; has served on an advisory board and served on a clinical endpoint committee for Bayer AG; has served on an advisory board for FIRE-1; and has received research grant support (paid to his institution) from AstraZeneca, Roche, Novartis and Boehringer Ingelheim. Dr Welsh has received grant income from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; and has received speaker fees from Novo Nordisk outside of the submitted work. Dr Petrie was supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund; has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novo Nordisk, Novartis, Pharmacosmos, Roche, and SQ Innovations; and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. Dr Anand has served as a consultant for Novartis, Amgen, Cyberonics, and Zensun. Dr Berg is a member of the TIMI Study Group, which receives institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Intarcia, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, Roche Diagnostics, Siemens Healthcare Diagnostics Inc, and Zora Biosciences; has received research grant support to his institution from AstraZeneca and Pfizer; has received consulting fees from AstraZeneca, Mobility Bio Inc, and Youngene Therapeutics; has received honoraria from the Medical Education Speakers Network (MESN) and USV Private Limited; and has participated on clinical endpoint committees for studies sponsored by Kowa Pharmaceuticals. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; has had speaker engagements with and/or received fees from and/or served on an advisory board for Abbott, AstraZeneca, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, NovoNordisk, and Roche; and has received travel support from Abbott, Cardior Pharmaceuticals GmbH, and NovoNordisk. Dr Køber has received compensation from Novartis for other services; has received compensation from Novo Nordisk for other services; and has received compensation from AstraZeneca for other services. Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Martinez has received personal fees from AstraZeneca. Dr O’Meara has received research funds (paid to her institution) for clinical trials from American Regent, Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, and Pfizer; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, and Janssen; and has received speaker fees from AstraZeneca, Bayer, and Boehringer Ingelheim. Dr Morrow is a member of the TIMI Study Group, which receives institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Intarcia, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, Roche Diagnostics, Siemens Healthcare Diagnostics Inc, and Zora Biosciences; and has received consulting fees from Abbott Laboratories, ARCA Biopharma, Inflammatix, Merck and Co, Novartis, Regeneron, and Roche Diagnostics. Dr Ponikowski has received consulting fees from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Amgen, Servier, Novartis, Bayer, Merck Sharp & Dohme, Pfizer, Cibiem, Impulse Dynamics, Renal Guard Solutions, and BMS; has received honoraria from Boehringer Ingelheim, AstraZeneca, Vifor Pharma, Amgen, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, Impulse Dynamics, Renal Guard Solutions, BMS, and Abbott Vascular for lectures, presentations, Speakers Bureaus, manuscript writing, or educational events. Dr Sabatine is a member of the TIMI Study Group, which receives institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Intarcia, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, Roche Diagnostics, Siemens Healthcare Diagnostics Inc, and Zora Biosciences; has received research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Accumetrics, Amgen, Anthos Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Ionis, Merck, Nanosphere, Novartis, Pfizer, Roche Diagnostics, Sanofi-Aventis, and Takeda; and has done consulting for Aegerion, Alnylam, Amgen, AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Cubist, CVS Caremark, Fibrogen, Intarcia, Merck, MyoKardia, Novo Nordisk, Pfizer, Precision BioSciences, Quest Diagnostics, Sanofi-Aventis, Silence Therapeutics, Vertex, and Zeus Scientific. Dr Sattar has consulted for Affimune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi; and has received grant support from Boehringer Ingelheim. Dr Sattar was supported by a British Heart Foundation Centre of Research Excellence grant RE/18/6/34217. Dr Schou has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. Drs Hammarstedt, Sjöstrand, and Langkilde are employees of AstraZeneca. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, Intas Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; and is a director of Global Clinical Trial Partners. Dr Jhund’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and NovoNordisk. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals and Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and is a director of Global Clinical Trial Partners Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Publication types
MeSH terms
Substances
Associated data
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous
