Inflammatory markers and the risk of vascular complications and mortality in type 2 diabetes mellitus

Abstract

Purpose: There are few data assessing the relationship between circulating levels of C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) and the risk of vascular complications in individuals with type 2 diabetes mellitus (T2DM). We studied the associations between these inflammatory markers and the risk of major CV events (CV death, myocardial infarction or stroke), microvascular complications and death in patients T2DM who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Methods: Baseline high sensitivity CRP, fibrinogen and IL-6 levels were determined in a case-cohort study (n=3,865), nested within the ADVANCE trial. Results: During 5 years of follow-up, 709 patients suffered a major CV event, 439 a microvascular complication and 706 died. All 3 markers were associated with an increased risk of CV events and death in analyses adjusting for age, sex (Figure presented) and treatment groups. After further adjustment, for other potential confounders and for each other, only IL-6 was an independent predictor of these outcomes (hazard ratio [HR] for CV events 1.37 per 1 standard deviation [SD] increase in log IL-6, 95% confidence interval [CI] 1.24-1.51; HR for death 1.35, 95% CI 1.23-1.49). This increased hazard was seen in patients with and without prior CV disease (figure, HR per 1 SD increase in log IL-6). IL-6 significantly improved the prediction of CV events and death using reclassification statistics (net reclassification improvement in continuous models 23% for CV events and 30% for death). After adjustment, none of the markers predicted microvascular complications. Conclusions: IL-6, but not CRP or fibrinogen, levels add significantly to the prediction of CV events and mortality in individuals with T2DM.