Prognostic value of soluble ST2, high-sensitivity cardiac troponin, and NT-proBNP in type 2 diabetes: a 15-year retrospective study

Abstract

Background: Patients with type 2 diabetes (T2DM) present an increased risk of cardiovascular (CV) disease and excess CV-related mortality. Beyond the established role of brain natriuretic peptide (BNP) and cardiac troponins (cTn), other non-cardiac-specific biomarkers are emerging as predictors of CV outcomes in T2DM.

Methods: Serum levels of soluble suppression of tumorigenesis 2 (sST2), high-sensitivity (hs)-cTnI, and N-terminal (NT)-proBNP were assessed in 568 patients with T2DM and 115 healthy controls (CTR). Their association with all-cause mortality and the development of diabetic complications was tested in T2DM patients over a median follow-up of 16.8 years using Cox models and logistic regressions.

Results: sST2 followed an increasing trend from CTR to uncomplicated T2DM patients (T2DM-NC) to patients with at least one complication (T2DM-C), while hs-cTnI was significantly higher in T2DM-C compared to CTR but not to T2DM-NC. A graded association was found between sST2 (HR 2.76 [95% CI 1.20-6.33] for ≥ 32.0 ng/mL and 2.00 [1.02-3.94] for 16.5-32.0 ng/mL compared to < 16.5 ng/mL, C-statistic = 0.729), NT-proBNP (HR 2.04 [1.90-4.55] for ≥ 337 ng/L and 1.48 [1.05-2.10] for 89-337 ng/L compared to < 89 ng/L, C-statistic = 0.741), and 15-year mortality in T2DM, whereas increased mortality was observed in patients with hs-cTnI ≥ 7.8 ng/L (HR 1.63 [1.01-2.62]). A 'cardiac score' based on the combination of sST2, hs-cTnI, and NT-proBNP was significantly associated with all-cause mortality (HR 1.35 [1.19-1.53], C-statistic = 0.739) and development of CV events.

Conclusions: sST2, hs-cTnI, and NT-proBNP are associated with 15-year mortality and onset of CV events in T2DM. The long-term prognostic value of sST2 and its ability to track variables related to insulin resistance and associated metabolic disorders support its implementation into routine clinical practice.

Keywords: Cardiovascular risk; Natriuretic peptides; Soluble ST2; Troponin; Type 2 diabetes.

Fig. 1

A Comparison of serum sST2, Dimension Vista hs-cTnI, and NT-proBNP between healthy controls (CTR) and patients with type 2 diabetes (T2DM). Data are median and IQR. P-values for Mann–Whitney U test. B Distribution of log-transformed sST2, hs-cTnI, and NT-proBNP among CTR and patients with uncomplicated (T2DM-NC) or complicated (T2DM-C) diabetes. P-values for Dunn’s post-hoc tests. C Log-transformed sST2, hs-cTnI, and NT-proBNP in CTR, T2DM-NC, and T2DM-C grouped according to sex. P-values for post-hoc Tukey test following two-way ANOVA.

Fig. 2

Spearman’s correlation plots for CTR subjects and patients with T2DM. The intensity of the color depends on the magnitude of the correlation. Non-significant correlations are crossed.

Fig. 3

Kaplan–Meier survival estimates for A sST2, B Dimension Vista hs-cTnI, C NT-proBNP, D ‘Cardiac score’. Models adjusted for sex, age, smoking status, hypertension, T2DM duration, BMI, HbA1c, blood lipids, eGFR, and hs-CRP

Fig. 4

A Marginal means plot showing the probability of developing the composite endpoint death or MACE in T2DM patients based on the logistic regression model including ‘cardiac score’ as predictor (95% CI in gray). B ROC curve for the logistic regression model.

Fig. 5

A Nomogram for predicting overall survival in patients with type 2 diabetes. The points assigned to each variable are summed up to obtain the total score and a vertical line can be drawn to obtain the corresponding survival probability. B Performance of the model based on the external validation dataset. Model areas under the curve (AUCs) at each year are displayed. C Kaplan–Meier survival function for patients with type 2 diabetes according to quartiles of the nomogram-based mortality risk score