Circulating Inflammatory Markers and the Risk of Vascular Complications and Mortality in People With Type 2 Diabetes and Cardiovascular Disease or Risk Factors: The ADVANCE Study

Gordon Lowe; Mark Woodward; Graham Hillis; Ann Rumley; Qiang Li; Stephen Harrap; Michel Marre; Pavel Hamet, Anushka Patel; Neil Poulterl; John Chalmers


Diabetes. 2014;63(3):1115-1123. 

In This Article

Abstract and Introduction


C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) are associated with cardiovascular disease (CVD) and death in general populations. However, studies of these factors in type 2 diabetes are limited. We studied their associations with the risk of major macrovascular events, microvascular complications, and mortality in patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Study. Plasma CRP, fibrinogen, and IL-6 levels were determined in a case-cohort study (n = 3,865) nested within the 11,140 men and women with type 2 diabetes and baseline CVD or risk factors in the ADVANCE Study. All three biomarkers of inflammation were associated with an increased risk of macrovascular events and death in analyses adjusted for age, sex, and treatment groups. After further adjustment, only IL-6 was an independent predictor of macrovascular events (hazard ratio per SD increase 1.37 [95% CI 1.24–1.51]) and death (1.35 [1.23–1.49]). IL-6 significantly improved the prediction of macrovascular events and death. After adjustment, none of the markers predicted microvascular complications. We conclude that IL-6 levels, but not CRP or fibrinogen levels, add significantly to the prediction of macrovascular events and mortality in individuals with type 2 diabetes who have baseline CVD or risk factors.


Type 2 diabetes mellitus (T2DM) is a major and growing health problem worldwide, increasing the risk of both macrovascular and microvascular disease, as well as nonvascular mortality.[1] Although control of blood pressure, lipid, and blood glucose levels are proven strategies in reducing the risk of cardiovascular complications,[2,3] other less classical risk factors contribute to the cardiovascular risk associated with T2DM.[1] Inflammation plays a role in atherothrombosis and its clinical complications,[4] and prospective studies of generally healthy persons (and meta-analyses of such studies) have established that circulating levels of inflammatory markers including C-reactive protein (CRP), fibrinogen, leukocytes, and albumin are associated with risks of macrovascular disease and total mortality.[5–7] Persons with diabetes have higher levels of CRP[7] and fibrinogen[6] compared with those without diabetes, but limited numbers of individuals with diabetes have been included in published prospective studies of general populations;[6,7] there are only three previous studies of cohorts with T2DM and CRP[8–10] or fibrinogen[11] levels. These previous reports studied only mortality[9–11] or cardiovascular events only in men.[8] Hence, there is a need for studies to evaluate these associations in large cohorts of people with diabetes.

While they have several potential pathogenic roles, the causality of increased CRP and fibrinogen levels in individuals with cardiovascular disease (CVD) has not yet been established.[6,7] They may be downstream markers of the expression of proinflammatory cytokines[12] such as the key "messenger" cytokine interleukin-6 (IL-6). A meta-analysis[13] of prospective studies of IL-6 in generally healthy persons has reported a stronger association of long-term IL-6 levels with risk of coronary heart disease (CHD) compared with CRP or fibrinogen levels; and (in contrast to CRP or fibrinogen) a recent meta-analysis[14] of genetic studies has suggested a causal role for IL-6 in the condition. Proinflammatory cytokines, including IL-6, may play a role in the pathogenesis of obesity and insulin resistance,[15] and in the cardiovascular complications of obesity and T2DM.[16,17] However, there is only one previous prospective study of IL-6 and complications in T2DM: the ESTHER Study (Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung),[18,19] in which 161 subjects experienced a primary cardiovascular event, and IL-6 was associated only with the risk of cardiovascular events in those with renal dysfunction.[19]

We therefore performed a nested case-cohort study of the associations of baseline circulating levels of CRP, fibrinogen, and IL-6 and risk of major macrovascular and microvascular complications and death from any cause in men and women with T2DM who had either baseline CVD or risk factors and who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Study (clinical trial reg. no. NCT00145925,[2,3] Our aims were 1) to assess their potential clinical utility as predictors of vascular events and mortality; and 2) to discuss their potential causal significance, which is currently being evaluated in other studies of functional genotypes and specific drug antagonists.[6,7,14]