Effects of empaglifozin on collagen biomarkers in patients with heart failure. Results from the EMPEROR trials

Abstract

Abstract Background Extracellular matrix remodeling is one of the key pathways in progression of Heart Failure (HF). Clinical trials demonstrated that SGLT-2 inhibitors improved cardiovascular outcomes in HF patients, which may be partly explained by an effect on cardiac remodeling. Supporting data from preclinical studies suggested effects of SGLT-2 inhibitors on collagen synthesis and attenuation of fibrosis. However, the effect of SGLT-2 inhibitors on collagen turnover in HF patients is not fully elucidated. Purpose In patients of the EMPEROR-Preserved and EMPEROR-Reduced trials, across a wide spectrum of ejection fraction and renal function, the effect of empagliflozin on serum markers of collagen turnover was investigated. Methods 1084 patients (545 in empagliflozin and 539 in placebo) were included in the analysis. Biomarkers measured from serum samples at baseline, 12 and 52 weeks included PICP (a collagen type I formation marker; ELISA), PRO-C3 (a collagen type III formation marker; ECLIA), PINP (a collagen type I formation marker; ECLIA, Roche Diagnostics), PRO-C6 (a collagen type VI formation marker; ECLIA), C1M and C3M (markers of collagen type I and III degradation CLIA). A mixed model repeated measurements model (MMRM) was used to evaluate the treatment effects on the analysed biomarkers. Results Treatment with empagliflozin vs. placebo reduced PICP levels at week 12 and week 52, and reduced PRO-C3 at week 52. In contrast, no significant effect was observed on PINP, PRO-C6, C1M or C3M levels (Table 1). Conclusion Among patients with chronic HF, across a wide range of EF and of renal function, treatment with empagliflozin reduced the serum levels of PICP, a collagen type I formation marker, both at weeks 12 and 52 and PRO-C3, a collagen type III formation marker, at week 52. These results add support for an anti-fibrotic effect of empagliflozin and may help to explain the clinical effect of SGLT-2 inhibitors on cardiac remodeling.