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

Kieran F. Docherty; Kirsty McDowell; Paul Welsh; Mark C. Petrie; Inder Anand; David D. Berg; Rudolf A. de Boer; Lars Køber; Mikhail N. Kosiborod; Felipe A. Martinez; Eileen O'Meara; David A. Morrow; Piotr Ponikowski; Marc S. Sabatine; Naveed Sattar; Morten Schou; Ann Hammarstedt; Mikaela Sjöstrand; Anna Maria Langkilde; Pardeep S. Jhund; Scott D. Solomon; John J.V. McMurray

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

Kieran F. Docherty, Kirsty McDowell, Paul Welsh, Mark C. Petrie, Inder Anand, David D. Berg, Rudolf A. de Boer, Lars Køber, Mikhail N. Kosiborod, Felipe A. Martinez, Eileen O'Meara, David A. Morrow, Piotr Ponikowski, Marc S. Sabatine, Naveed Sattar, Morten Schou, Ann Hammarstedt, Mikaela Sjöstrand, Anna Maria Langkilde, Pardeep S. JhundScott D. Solomon, John J.V. McMurray^*

^*Corresponding author for this work

Cardiology

Research output: Contribution to journal › Article › Academic › peer-review

2 Citations (Scopus)

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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.

Original language	English
Article number	102393
Journal	JACC: Heart Failure
Volume	13
Issue number	7
DOIs	https://doi.org/10.1016/j.jchf.2024.12.012
Publication status	E-pub ahead of print - 12 Mar 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors

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10.1016/j.jchf.2024.12.012Licence: CC BY

Interleukin-6 in Heart Failure WithProof, 1.25 MBLicence: CC BY

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Docherty, K. F., McDowell, K., Welsh, P., Petrie, M. C., Anand, I., Berg, D. D., de Boer, R. A., Køber, L., Kosiborod, M. N., Martinez, F. A., O'Meara, E., Morrow, D. A., Ponikowski, P., Sabatine, M. S., Sattar, N., Schou, M., Hammarstedt, A., Sjöstrand, M., Langkilde, A. M., ... McMurray, J. J. V. (2025). 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. JACC: Heart Failure, 13(7), Article 102393. Advance online publication. https://doi.org/10.1016/j.jchf.2024.12.012

@article{52b29a52a7d04e659d76d68b84a69c65,

title = "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.",

author = "Docherty, \{Kieran F.\} and Kirsty McDowell and Paul Welsh and Petrie, \{Mark C.\} and Inder Anand and Berg, \{David D.\} and \{de Boer\}, \{Rudolf A.\} and Lars K{\o}ber and Kosiborod, \{Mikhail N.\} and Martinez, \{Felipe A.\} and Eileen O'Meara and Morrow, \{David A.\} and Piotr Ponikowski and Sabatine, \{Marc S.\} and Naveed Sattar and Morten Schou and Ann Hammarstedt and Mikaela Sj{\"o}strand and Langkilde, \{Anna Maria\} and Jhund, \{Pardeep S.\} and Solomon, \{Scott D.\} and McMurray, \{John J.V.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = mar,

day = "12",

doi = "10.1016/j.jchf.2024.12.012",

language = "English",

volume = "13",

journal = "JACC: Heart Failure",

issn = "2213-1779",

publisher = "Elsevier Inc.",

number = "7",

}

Docherty, KF, McDowell, K, Welsh, P, Petrie, MC, Anand, I, Berg, DD, de Boer, RA, Køber, L, Kosiborod, MN, Martinez, FA, O'Meara, E, Morrow, DA, Ponikowski, P, Sabatine, MS, Sattar, N, Schou, M, Hammarstedt, A, Sjöstrand, M, Langkilde, AM, Jhund, PS, Solomon, SD & McMurray, JJV 2025, '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', JACC: Heart Failure, vol. 13, no. 7, 102393. https://doi.org/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. / Docherty, Kieran F.; McDowell, Kirsty; Welsh, Paul et al.
In: JACC: Heart Failure, Vol. 13, No. 7, 102393, 12.03.2025.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Interleukin-6 in Heart Failure With Reduced Ejection Fraction and the Effect of Dapagliflozin

T2 - An Exploratory Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial

AU - Docherty, Kieran F.

AU - McDowell, Kirsty

AU - Welsh, Paul

AU - Petrie, Mark C.

AU - Anand, Inder

AU - Berg, David D.

AU - de Boer, Rudolf A.

AU - Køber, Lars

AU - Kosiborod, Mikhail N.

AU - Martinez, Felipe A.

AU - O'Meara, Eileen

AU - Morrow, David A.

AU - Ponikowski, Piotr

AU - Sabatine, Marc S.

AU - Sattar, Naveed

AU - Schou, Morten

AU - Hammarstedt, Ann

AU - Sjöstrand, Mikaela

AU - Langkilde, Anna Maria

AU - Jhund, Pardeep S.

AU - Solomon, Scott D.

AU - McMurray, John J.V.

PY - 2025/3/12

Y1 - 2025/3/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=86000788474&partnerID=8YFLogxK

U2 - 10.1016/j.jchf.2024.12.012

DO - 10.1016/j.jchf.2024.12.012

M3 - Article

C2 - 40088234

AN - SCOPUS:86000788474

SN - 2213-1779

VL - 13

JO - JACC: Heart Failure

JF - JACC: Heart Failure

IS - 7

M1 - 102393

ER -

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

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