IL-6, hs-CRP, LDL and Residual Risk in Contemporary Practice

Study Questions:

Are markers of inflammation, interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and low-density lipoprotein cholesterol (LDL) levels, associated with cardiovascular (CVD) events in high-risk patients on contemporary medical therapy for CVD?


This study is a secondary analysis of CIRT (Cardiovascular Inflammation Reduction Trial), in which 4,168 patients with known coronary artery disease at high risk of CVD events were randomized to either methotrexate or placebo. The authors measured IL-6, hs-CRP, and LDL levels at enrollment, and examined their association with major CVD events (MACE) and all-cause death during a maximal follow-up period of 5 years.


Enrolled patients had a mean age of 65 years and were mostly male (82%). One third were diabetics, and two thirds had a history of myocardial infarction. The majority of patients were on statins (85%). Patients with elevated IL-6, hs-CRP, and LDL were more likely to be women, obese, and have elevated triglycerides. IL-6 and hs-CRP were correlated (r = 0.47). There was a total of 341 MACE (of which 186 were nonfatal myocardial infarctions) and 154 deaths during the follow-up period. Baseline IL-6, hs-CRP, and LDL were all predictive of MACE in a stepwise fashion. Patients with elevated levels of all three markers had the highest incidence of MACE. hs-CRP and LDL were, however, not associated with an increased risk of all-cause death. The associations were similar across subgroups, notably across randomization arms. Of note, methotrexate had no effect on IL-6, hs-CRP, and LDL levels in the CIRT trial.


Markers of inflammation, hs-CRP, IL-6, and LDL, are not reduced by methotrexate and remain associated with MACE in this large cohort on contemporary medical therapy.


The CIRT trial showed no improvement in outcomes with methotrexate and no reduction in inflammation, as measured by IL-6 and hs-CRP. In this trial of high-risk patients with coronary artery disease on high rates of contemporary medical therapy, these markers remained associated with outcomes; with associations similar to those reported 30 years ago. Essentially, the findings suggest that the progress in the management of CVD over the past decades had no significant impact on the underlying inflammatory process. The lack of effectiveness of methotrexate in reducing markers of inflammation and improving outcomes should not be a nail in the coffin of immunosuppressive therapies for CVD, but rather a call to better understand underlying mechanisms and expanding the search for strategies targeting inflammation.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Hypertriglyceridemia, Lipid Metabolism, Nonstatins

Keywords: acc20, ACC Annual Scientific Session, Cholesterol, LDL, Coronary Artery Disease, C-Reactive Protein, Diabetes Mellitus, Dyslipidemias, Inflammation, Interleukins, Methotrexate, Myocardial Infarction, Obesity, Primary Prevention, Risk, Triglycerides

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