Effects of empagliflozin on collagen biomarkers in patients with heart failure: Findings from the EMPEROR trials

Abstract

AimsExtracellular matrix remodelling is one of the key pathways involved in heart failure (HF) progression. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) may have a role in attenuating myocardial fibrosis. The impact of SGLT2i on blood markers of collagen turnover in humans is not fully elucidated. This study aimed to investigate the effect of empagliflozin on serum markers of collagen turnover in patients enrolled in the EMPEROR‐Preserved and EMPEROR‐Reduced trials.Methods and resultsOverall, 1084 patients (545 in empagliflozin and 539 in placebo) were included in the analysis. Procollagen type I carboxy‐terminal propeptide (PICP), a fragment of N‐terminal type III collagen (PRO‐C3), procollagen type I amino‐terminal peptide (PINP), a fragment of C‐terminal type VIa3 collagen (PRO‐C6), a fragment of type I collagen (C1M), and a fragment of type III collagen (C3M) were measured in serum at baseline, 12 and 52 weeks. A mixed model repeated measurements model was used to evaluate the effect of empagliflozin versus placebo on the analysed biomarkers. Higher baseline PICP, PRO‐C6 and PINP levels were associated with older age, a more severe HF presentation, higher levels of natriuretic peptides and high‐sensitivity troponin T, and the presence of comorbid conditions such as chronic kidney disease and atrial fibrillation. Higher PICP levels were associated with the occurrence of the study primary endpoint (a composite of HF hospitalization or cardiovascular death), and PRO‐C6 and PINP were associated with the occurrence of sustained worsening of kidney function. On the other hand, PRO‐C3, C1M, and C3M were not associated with worse HF severity or study outcomes. Compared to placebo, empagliflozin reduced PICP at week 12 by 5% and at week 52 by 8% (week 12: geometric mean ratio = 0.95, 95% confidence interval [CI] 0.91–0.99, p = 0.012; week 52: geometric mean ratio = 0.92, 95% CI 0.88–0.97, p = 0.003). Additionally, empagliflozin reduced PRO‐C3 at week 52 by 7% (week 12: geometric mean ratio = 0.98, 95% CI 0.95–1.02, p = 0.42; week 52: geometric mean ratio = 0.93, 95% CI 0.89–0.98, p = 0.003), without impact on other collagen markers.ConclusionOur observations are consistent with experimental observations that empagliflozin down‐regulates profibrotic signalling. The importance of such an effect for the clinical benefits of SGLT2i in HF remains to be elucidated.

Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial

“…26 Furthermore, non-steroidal MR antagonists and sodium-glucose co-transporter-2 inhibitors have potent anti-inflammatory and antifibrotic properties. 27 Given the present findings, UPP analysis combined with measurement of circulating fibrosis biomarkers offers novel perspectives in documenting the antifibrotic properties of novel drug classes. Of note, the serum PICP decrease produced by empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure (EMPEROR) was of the same order of magnitude as in the current study: 5% at 12 weeks and 8% at 52 weeks.…”

Advancing the fight against fibrosis in patients with heart failure: The contribution of sodium–glucose cotransporter 2 inhibition

“…The authors found that, compared to placebo (n = 539), empagliflozin (n = 545) significantly reduced PICP at weeks 12 and 52, and PIIINP at week 52. 6 All other fibrosis biomarkers were not significantly modified by empagliflozin. 6 Furthermore, they found that higher levels of PICP were associated with the occurrence of the primary endpoint, while higher levels of PINP and endotrophin mortality Figure 1 Proposed sequence of participating elements (top) and attending events (bottom) to explain how the antifibrotic effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin is possibly involved in the clinical benefits observed in patients with heart failure.…”

“…6 All other fibrosis biomarkers were not significantly modified by empagliflozin. 6 Furthermore, they found that higher levels of PICP were associated with the occurrence of the primary endpoint, while higher levels of PINP and endotrophin mortality Figure 1 Proposed sequence of participating elements (top) and attending events (bottom) to explain how the antifibrotic effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin is possibly involved in the clinical benefits observed in patients with heart failure. PICP, carboxy-terminal propeptide of type I procollagen; PINP, amino-terminal propeptide of type I procollagen; PIIICP, carboxy-terminal propeptide of type III procollagen; PIIINP, amino-terminal propeptide of type III procollagen.…”

“…were associated with the occurrence of the secondary endpoint. 6 From these findings, the authors conclude that empagliflozin down-regulates profibrotic signalling, particularly biomarkers of type I and type III synthesis. Although the study is a secondary analysis of two randomized trials, it does potentially contribute to the understanding of the clinical benefits of SGLT2 inhibition in HF.…”

“…5 The results of the analysis suggested an antifibrotic effect of empagliflozin in patients with and without diabetes and with and without HF. 5 In this issue of the Journal, a new study carried out by Ferreira et al 6 explores for the first time the effects of empagliflozin on circulating biomarkers of fibrosis. The authors investigated the effects of empagliflozin on serum levels of a panel of collagen-related biomarkers (i.e.…”