Investigating a biomarker-driven approach to target collagen turnover in diabetic heart failure with preserved ejection fraction patients. Effect of torasemide versus furosemide on serum C-terminal propeptide of procollagen type I (DROP-PIP trial)

Abstract

Aim: Heart failure with preserved ejection fraction (HFpEF) is associated with myocardial remodelling including severe pro-fibrotic changes contributing to an increase in left ventricular stiffness and diastolic dysfunction. Serum C-terminal propeptide of procollagen type I (PIP) strongly correlates with the turnover of extracellular cardiac matrix proteins and fibrosis. Torasemide, but not furosemide, was described to reduce collagen type I synthesis in clinically unstable patients with heart failure with reduced ejection fraction. We evaluated whether its effect translated to HFpEF patients with type 2 diabetes mellitus (T2DM) and abnormal basal PIP levels.

Methods and results: We performed a relatively small, single-centre, randomised, double-blind, two-arm parallel-group, active controlled clinical trial in 35 HFpEF patients with T2DM to determine the effects of a 9-month treatment with torasemide vs. furosemide on changes of serum PIP levels. Patients with increased PIP levels (≥110 ng/mL), or evidence of structural changes with a left atrial volume index (LAVI) >29 mL/m² and abnormal PIP levels (≥70 ng/mL), were eligible to participate. Fifteen patients were female (42%), mean age was 69 years, body mass index was 34.7 kg/m² , 83% were in New York Heart Association class II/III. Echocardiographic characteristics showed a mean left ventricular ejection fraction of >60%, a left ventricular mass index >120 g/m² , an E/e' ratio of 14, and a LAVI of 40 mL/m² with a NT-proBNP of 174 ng/L and a 6-minute walk distance of 421 m. Mean per cent change in PIP was 2.63 ± 5.68% (±SEM) in torasemide vs. 2.74 ± 6.49% in furosemide (P = 0.9898) treated patients. Torasemide was not superior to furosemide in improving functional capacity, diastolic function, quality of life, or neuroendocrine activation.

Conclusion: In this hypothesis-generating, mechanistic trial in stable HFpEF patients with T2DM, neither long-term administration of torasemide nor furosemide was associated with a significant effect on myocardial fibrosis, as assessed by serum PIP. Further studies are urgently needed in this field. More specific diuretic and anti-fibrotic treatment strategies in T2DM and/or HFpEF are warranted.

Keywords: C-terminal propeptide of procollagen type I; Diabetes mellitus; Diuretics; Fibrosis; Furosemide; Heart failure with preserved ejection fraction; PIP; Torasemide.