Relationship between endothelin-1, heart failure with reduced ejection fraction and dapagliflozin: findings from DAPA-HF
Authors: Yeoh S E , Docherty K F , Jhund P S , Hammarstedt A , Inzucchi S E , Kober L , Kosiborod M N , Martinez F A , Ponikowski P , Solomon S D , Sattar N , Welsh P , Sabatine M S , Morrow D A , McMurray J J V 
Published: October 2022

Abstract

Background
Circulating Endothelin-1 (ET-1) is associated with heart failure (HF) severity and has also been widely implicated in the pathophysiology of renal disease. However, its prognostic importance and relationship with kidney function in patients with HFrEF receiving contemporary treatment is uncertain.

Purpose
To investigate the association of ET-1 with heart failure outcomes, as well as change in kidney function; and the efficacy of dapagliflozin according to baseline serum ET-1 in the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure trial (DAPA-HF).

Methods
Serum ET-1 was measured at randomization and at 12 months and analysed using a Microfluidics immunoassay. We investigated the incidence of the primary outcome (cardiovascular death or worsening HF), and analysed change in kidney function according to tertile of baseline ET-1 concentration. Additionally, we assessed whether baseline ET-1 modified the treatment effect of dapagliflozin.

Results
Of 4744 randomized participants, 3048 (64.2%) had a baseline ET-1 measurement: tertile 1 (≤3.28 pg/mL, n=1016), tertile 2 (&gt;3.28 to 4.41 pg/mL, n=1022), and tertile 3 (&gt;4.41 pg/mL, n=1010). Patients with higher baseline ET-1 concentrations were more likely male, obese and to have lower LVEF, lower eGFR, worse functional status, and elevated NT-proBNP and high-sensitivity troponin-T.
Adjusting for other predictive variables including NT-proBNP, higher baseline ET-1 was independently associated with worse outcomes and steeper decline in kidney function: adjusted hazard ratio (aHR) for the primary outcome of 1.95 (1.53–2.50) for tertile 3 and 1.36 (95% CI 1.06–1.75) for tertile 2; aHR for worsening HF of 2.54 (1.82–3.53) for tertile 3 and 1.54 (1.10–2.18) for tertile 2; aHR for cardiovascular death of 1.39 (1.01–1.92) for tertile 3 and 1.13 (0.82–1.57) for tertile 2; and eGFR slope −3.19 (95% CI −3.66 to −2.72) mL/min/1.73 m2 per year in tertile 3 versus −2.06 (−2.51 to −1.62) in tertile 2 and −2.35 (−2.79 to −1.91) in tertile 1, p for difference (eGFR slope)=0.002.
The benefit of dapagliflozin was consistent regardless of baseline ET-1, whether analysed according to tertiles or as a continuous variable, with p-interaction for primary outcome 0.47 and 0.10 respectively. Compared to placebo, there was a trend to reduction in ET-1 level at 12 months with dapagliflozin (difference −0.12 pg/mL, p-value=0.07).

Conclusions
Baseline ET-1 concentration was independently associated with clinical outcomes and with more rapid decline in kidney function. The benefit of dapagliflozin was consistent across the range of ET-1 concentrations measured.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): The DAPA-HF trial was funded by AstraZeneca. Professor John McMurray is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217.