Higher plasma high-mobility group box 1 levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12 year follow-up study

Abstract

Aims/hypothesis: This study aimed to investigate the associations of plasma levels of the pro-inflammatory cytokine high-mobility group box 1 (HMGB1) with incident cardiovascular disease (CVD) and all-cause mortality in patients with type 1 diabetes.

Methods: We prospectively followed 165 individuals with diabetic nephropathy and 168 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of HMGB1 and other cardiovascular risk factors were measured at baseline.

Results: During the course of follow-up (median, 12.3 years [interquartile range, 7.8-12.5]), 80 patients died, 82 suffered a fatal (n = 46) and/or non-fatal (n = 53) CVD event. After adjustment for age, sex, case-control status and other risk factors, patients with higher levels of log(e) HMGB1 had a higher incidence of fatal and non-fatal CVD and all-cause mortality: HR 1.55 (95% CI 0.94, 2.48) and HR 1.86 (95% CI 1.18, 2.93), respectively. Further adjustments for differences in markers of low-grade inflammation, endothelial and renal dysfunction and arterial stiffness did not attenuate these associations because plasma levels of HMGB1 were not independently associated with these variables.

Conclusions/interpretation: In patients with type 1 diabetes, higher levels of plasma HMGB1 are independently associated with a higher risk of all-cause mortality and, to a lesser extent, with a higher incidence of CVD. Larger studies are needed to ascertain more definitely the role of HMGB1 in the development of vascular complications in diabetes.

Fig. 1

Cumulative hazard for fatal and non-fatal CVD (a) and all-cause mortality (b) across tertiles of plasma HMGB1. Data are adjusted for age, sex, case–control status, duration of diabetes, HbA_1c, smoking status, MAP, BMI, total cholesterol, use of anti-hypertensive treatment and continuation of medication use at baseline examination. Compared with patients in the lowest tertile of HMGB1 (grey line), those in the middle (dotted line) and highest (black line) tertiles had increased risk for fatal and non-fatal CVD (HR 1.18 [95% CI 0.68, 2.05] and HR 1.29 [0.73, 2.28]), respectively, p for trend = 0.337 and all-cause mortality (HR 1.28 [95% CI 0.70, 2.33] and 2.05 [1.14, 3.67], respectively, p for trend = 0.018)