Impact of dapagliflozin on key pathophysiological pathways underlying chronic heart failure progression: the DAPA-MODA biomarker study.

Abstract

Dapagliflozin improves clinical outcomes in patients with chronic heart failure (HF), irrespective of left ventricular ejection fraction. However, its effects on circulating biomarkers that reflect distinct pathophysiological pathways remain incompletely understood. DAPA-MODA is a prospective, multicenter, single-arm study that enrolled patients with stable chronic HF receiving optimized guideline-directed medical therapy, excluding sodium-glucose cotransporter-2 inhibitors. In a predefined biomarker substudy (n=156; 63.5% men; age 70.5±10.6 years; 67.9% with left ventricular ejection fraction > 40%), 11 biomarkers representing 5 key biological pathways (cardiac stress, inflammation, neurohormonal activation, congestion, and fibrosis) were measured at baseline, 1 month, and 6 months. At baseline, markers of myocardial stress were frequently elevated (NT-proBNP [95.5%] and MR-proANP [34.8%]), as was troponin for myocardial injury (73.5%). Inflammatory (IL-6 [40%], CRP [35%], GDF-15 [56%]) and neuro-endocrine stress (copeptin [43%]) markers were also commonly raised. In contrast, elevations in congestion (MR-proADM, CA-125) and fibrosis markers (ST2, PINP) were less frequent, reflecting diverse pathophysiological involvement. Dapagliflozin led to significant reductions in NT-proBNP and MR-proADM levels by 6 months. Reductions in MR-proANP, CRP, IL-6, copeptin, and PINP were confined to patients with elevated baseline levels. ST2 and CA-125 remained unchanged, while GDF-15 levels increased modestly. Dapagliflozin favorably modulates several key pathophysiological pathways involved in chronic HF progression, with differential effects among biomarkers by acting particularly on those that are elevated at baseline.