Interleukin-6 in the prediction of primary cardiovascular events in diabetes patients: Results from the ESTHER study
Introduction
Inflammatory processes are major contributors to cardiovascular disease (CVD) [1]. The most frequently investigated immune mediators are C-reactive protein (CRP) and interleukin-6 (IL-6), its main inducer. Despite consistent reports on associations of both immune mediators with cardiovascular risk, a causal relationship appears more likely for chronic elevations of IL-6 than CRP in the circulation [2]. IL-6 may contribute to atherosclerotic plaque development and plaque instability by activation of leukocytes and endothelial cells, induction of other cytokines, chemokines, prothrombotic mediators and matrix metalloproteinases [1], [3].
Recent studies demonstrated associations of increased systemic IL-6 concentrations with incident coronary heart disease, stroke and cardiovascular mortality [4], [5]. However, most studies were conducted in the general population, whereas the relevance of IL-6 for the cardiovascular risk in diabetes patients has received little attention. Type 2 diabetes is a proinflammatory condition [6], and it is still unclear whether a further immune activation contributes to the increased cardiovascular risk in diabetes and whether immune mediators could improve prediction models.
Thus, we examined (i) the association between IL-6 serum concentrations and incidence of primary cardiovascular events and (ii) whether the addition of IL-6 to a model based on established risk factors improves risk prediction in a subsample of 1072 diabetes patients from the ESTHER study.
Section snippets
Methods
This investigation is based on the ESTHER study, an ongoing cohort study including 9953 subjects, aged 50–74 years, recruited by their general practitioners during a routine health check-up between 2000 and 2002 in Saarland, a federal state of Germany [7], [8]. All members of compulsory health insurances in Germany (≈90% of the German population) aged ≥35 years are entitled to have these health-screening examinations focusing on early detection of chronic diseases such as diabetes, CVD and renal
Results
The numbers of participants with incident primary myocardial infarction, stroke and cardiovascular death were 39 (3.6%), 36 (3.4%) and 37 (3.5%), respectively, leading to 84 individuals (7.8%) who reached the composite cardiovascular endpoint. Cases had higher IL-6 levels than controls (median [25th–75th percentile] 3.3 [2.0–7.0] versus 2.6 [1.5–5.1], p = 0.014). Both groups did not differ regarding BMI, systolic blood pressure, lipids, HbA1c, physical inactivity, chronic kidney disease or use of
Discussion
Our main findings are that the strength of association between IL-6 and incident primary cardiovascular events in a cohort of diabetes patients is similar to that found in non-diabetic populations [4], [5], [11] and that adding IL-6 to risk models based on traditional risk factors did not substantially improve prediction. The fact that we could not detect a substantial improvement of cardiovascular risk prediction by IL-6 in our diabetic population (change in AUC <0.01) is in line with previous
Conflict of interest
The authors have no conflicts of interest to disclose.
Acknowledgements
The ESTHER study was funded by the Ministry of Science, Research and Arts of the state Baden-Württemberg (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany) and the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany). Further support for this study was obtained from the Federal Ministry of Health (Berlin, Germany) and the Ministry of Innovation, Science, Research and Technology of the state North-Rhine Westphalia (Düsseldorf,
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