Growth differentiation factor‐15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program

Abstract

BackgroundGrowth differentiation factor 15 (GDF‐15) is upregulated in part in response to cardiomyocyte stretch and stress, and it exerts a protective role that is mediated by its action to suppress signaling through insulin‐like growth factor (IGF) and enhance signaling through adenosine monophosphate‐activated protein kinase (AMPK). Sodium glucose co‐transporter 2 (SGLT2) inhibitors improve outcomes in heart failure, which has been experimentally linked to AMPK.AimsTo study the associations of GDF‐15 with baseline characteristics, the prognostic significance of GDF‐15, and the effect of empagliflozin on GDF‐15 in patients with heart failure with a reduced and preserved ejection fraction.MethodsGDF‐15 was determined in serum samples from the EMPEROR‐Reduced and EMPEROR‐Preserved trials. Cox regression and mixed models for repeated measures were used to study the association with outcomes and the effect of empagliflozin on GDF‐15, respectively.ResultsWe studied 1124 patients (560 placebo and 564 empagliflozin) with median GDF‐15 levels at baseline of 2442 (IQR 1603‐3780) pg/mL. Patients with higher GDF‐15 levels were typically older men with more severe symptoms, higher NT‐proBNP levels, worse kidney function and who were prescribed metformin. Baseline levels of GDF‐15 were well correlated with levels of insulin‐like binding protein 7 (IGFBP‐7; rho=0.64). Higher levels of GDF‐15 were independently associated with an increased risk of cardiovascular death, heart failure hospitalizations, and worse kidney outcomes. When considered as a continuous variable, for each doubling in GDF‐15, the adjusted hazard ratio for cardiovascular death or HF hospitalization was 1.40 (95%CI 1.15,1.71; P<0.001). The relative effect of empagliflozin on cardiovascular death and hospitalization for heart failure was most pronounced in patients with higher baseline levels of GDF‐15 (interaction P‐trend=0.031). At week 52, when compared with placebo, empagliflozin increased GDF‐15 by an additional 8% (P=0.020), an effect that was primarily seen in patients not receiving metformin, a known AMPK activator.ConclusionsGDF‐15 is a marker of worse heart failure severity, is an independent predictor of major heart failure outcomes and may be associated with more pronounced benefits of empagliflozin. GDF‐15 is increased among metformin users, and empagliflozin was associated with an increase in GDF‐15 levels, primarily in patients not receiving metformin.This article is protected by copyright. All rights reserved.

Insulin‐like growth factor binding protein‐7 concentrations in chronic heart failure: Results from the EMPEROR programme

“…[18][19][20][21] Additional adjustment was performed on GDF-15, another important prognostic marker in the EMPEROR programme. 22 Week 12 landmark analysis were performed to study the associations between IGFBP7 changes and the subsequent occurrence of the primary outcome. Heterogeneity of treatment effect on major HF outcomes across the groups defined by the tertiles of GDF-15 was investigated by fitting Cox regression and negative binomial models, as appropriate, adjusted by the pre-specified covariates except for hs-cTnT and NT-proBNP and including a IGFBP7 group by treatment interaction.…”

“…FABP3 has been implicated in metabolic syndrome and mitochondrial dysfunction. 39,40 The implication of GDF-15 in the EMPEROR programme has been thoroughly discussed, 22 however the correlation with IGFBP7 and additive value for prognosis of these two biomarkers is noteworthy. The investigation into the relationship between IGFBP7 and myocardial disease processes requires additional research.…”

“…Multivariable models included age, sex, geographical region, diabetes, LVEF, eGFR, and trial (EMPEROR‐Reduced or EMPEROR‐Preserved) as covariates, and were additionally adjusted for log‐transformed baseline hs‐cTnT and NT‐proBNP, the most important biomarker predictors of the primary outcome in the EMPEROR studies 18–21 . Additional adjustment was performed on GDF‐15, another important prognostic marker in the EMPEROR programme 22 . Week 12 landmark analysis were performed to study the associations between IGFBP7 changes and the subsequent occurrence of the primary outcome.…”

Growth differentiation factor‐15 in sodium–glucose cotransporter 2 inhibition: Mechanistic insights from the EMPEROR program

“…6 In this issue of the Journal, Ferreira and colleagues report an exploratory analysis from the EMPEROR (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure) program focusing on the prognostic implications of growth differentiation factor-15 (GDF-15) and the effect of empagliflozin on GDF-15 levels in patients with HF. 7 The study cohort comprised 1124 patients recruited from the EMPEROR-Reduced and EMPEROR-Preserved trials who received either empagliflozin 10 mg once daily (n = 564) or placebo (n = 560) in addition to standard HF medication. Patients with the highest baseline levels of GDF-15 (3rd tertile) were significantly older, had longer duration of HF and a greater comorbidity burden including T2DM, hypertension, atrial fibrillation and chronic kidney disease.…”