Dapagliflozin preferentially reduces fibrosis biomarkers in chronic heart failure patients with high extracellular matrix remodeling activity
R Muniz-Anquela, E Angeli, A Riquelme-Perez, V Martinez-Pina, M T Perez-Martinez, C Anagnostopoulos, M Karsdal, F Genovese, M Domingo, H Morillas, J Nunez, M Cobos-Marcos, J A Noguera, A Bayes-Genis, D Pascual FigalAbstract
Introduction
Dapagliflozin improves clinical outcomes in patients with chronic heart failure (HF), irrespective of left ventricular ejection fraction (LVEF) [1]. However, its effects on circulating biomarkers of myocardial fibrosis such as PRO-C3 and PRO-C6, which reflect active collagen formation and chronic extracellular matrix remodeling – remain insufficiently characterized.
Methods
DAPA-MODA was a prospective, multicentre, single-arm study enrolling patients with stable chronic HF receiving optimized guideline-directed medical therapy, excluding sodium–glucose cotransporter 2 inhibitors (SGLT2i). In a previously defined substudy, circulating key fibrotic biomarkers PRO-C3 and PRO-C6 were measured at baseline, 30 days, 90 days and 180 days using validated assays. For PRO-C3, a substantial proportion of samples were above the upper limit of detection (ULOD = 131.40 ng/mL), precluding further dilution according to assay validation requirements. Biomarkers were log-transformed as appropriate. Associations were assessed using Spearman’s rank correlations based on baseline biomarker quartiles, and longitudinal changes were evaluated as percentage change from baseline using geometric mean ratios with 95% confidence intervals.
Results
a total of 131 patients (35.9 females, mean age 70.28±10.33 years) were included. Higher basal PRO-C3 levels were associated with elevated inflammatory biomarkers including GDF-15 (Spearman’s ρ≈0.15, p=0.08) and IL-6 (ρ≈0.20, p=0.030), as well as other fibrosis markers such as P1NP (ρ≈0.45, p<0.001) and neuro-endocrine stress marker (copeptin). Elevated baseline PRO-C6 levels were associated with impaired renal function (creatinine) (ρ≈0.40, p<0.001), congestion and inflammatory markers (CA-125) (ρ≈0.25, p=0.019) myocardial injury and stress biomarkers (NT-proBNP (ρ≈0.45, p<0.001), hs-TnT (ρ≈0.35, p<0.001), MR-proANP (ρ≈0.40, p<0.001)), fibrotic markers (P1NP, ρ≈0.50, p<0.001), and angiogenic markers (PlGF, sFlt-1) (ρ≈0.23, p=0.008 and ρ≈0.33, p<0.001, respectively). Patients were stratified into quartiles according to baseline geometric mean levels of PRO-C3 and PRO-C6. Dapagliflozin treatment resulted in significant reductions in both PRO-C3 and PRO-C6 in patients within the highest quartiles, already at 30 days (-79.9% [-87.8, -66.8] p<0.001 and -13.6 [-25.1, -0.2], p=0.045 respectively) and sustained through 180 days (-84.7% [-90.7, -74.8], p<0.001 and -15.9% [-27.1, -2.9], p=0.013 respectively).
Conclusions
In patients with chronic HF, dapagliflozin is associated with early and sustained reductions in circulating biomarkers of extracellular matrix remodeling, particularly among those with a high fibrotic burden. These findings support a potential antifibrotic effect of dapagliflozin and highlight the utility of PRO-C3 and PRO-C6 for fibrotic phenotyping in HF.Longitudinal PRO-C3 and PRO-C6 changesFor image description, please refer to the figure legend and surrounding text.