Physicians' Academy for Cardiovascular Education

High CV risk in atherosclerosis patients with highest levels of inflammatory biomarkers and LDL-c

Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial

Literature - Ridker PM, MacFadyen JG, Glynn RJ, et al. - Eur Heart J 2020, doi:10.1093/eurheartj/ehaa160

Introduction and methods

The inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL-6) are independent predictors of CV events, as was demonstrated in primary prevention cohorts that were started >30 years ago. The magnitude of prediction is similar to that of LDL-c [1-5]. For this reason high-sensitivity CRP (hsCRP) is commonly used in North America as a validated biomarker of inflammatory risk [6], but use in Europe is limited.

Polymorphism in the IL-6 pathway are associated with hsCRP levels and vascular risk, as demonstrated in Mendelian randomization studies [7,8]. Intervention trials, such as CANTOS and more recently COLCOT, showed that anti-inflammatory therapy reduces ischemic events [9-12].

In clinical practice, IL-6 may be the preferred inflammatory biomarker compared to hsCRP, as it may give an improved signal to noise ratio - IL-6 is a central inflammatory cytokine and hsCRP a downstream inflammatory biomarker. But translational evidence comparing the use of IL-6, hsCRP and LDL-c in prediction of CV risk is limited and comparative data among secondary prevention patients taking statins, which has concomitant anti-inflammatory effects are scarce. In addition, it is unknown whether aggressive adjunctive therapies beyond statins have an effect on the relationship between inflammation, lipids and vascular risk.

These issues were examined in a prospective cohort of 4168 North American patients with atherosclerotic disease (MI or multivessel coronary disease and T2DM or the metabolic syndrome). Data of the Cardiovascular Inflammation Reduction Trial (CIRT) [13] were used and contained baseline measurements of IL-6, hsCRP and LDL-c. The CIRT trial, which evaluated the effect of methotrexate in the prevention of recurrent CV events, showed no effect of methotrexate on IL-6, hsCRP and LDL-c levels, nor on CV events. Participants were followed up to 5 years for MACE (nonfatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina requiring urgent revascularization, CV death) and all-cause mortality.

Main results


Despite contemporary aggressive therapy, levels of LDL-c, IL-6 and hsCRP all still predict future CV events in a cohort of North American atherosclerosis patients. Those with highest quartiles of IL-6 or hsCRP and highest quartile of LDL-c had highest risk of MACE, suggesting that future combination therapies targeting both pathways could improve outcomes in atherosclerosis patients.


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