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

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).