Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease

Abstract

As biologic, epidemiologic, and clinical trial data have demonstrated, inflammation is a key driver of atherosclerosis. Circulating biomarkers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), are associated with increased risk of cardiovascular events independent of cholesterol and other traditional risk factors. Randomized trials have shown that statins reduce hsCRP, and the magnitude of hsCRP reduction is proportional to the reduction in cardiovascular risk. Additionally, these trials have demonstrated that many individuals remain at increased risk due to persistent elevations in hsCRP despite significant reductions in low-density lipoprotein cholesterol (LDL-C) levels. This "residual inflammatory risk" has increasingly become a viable pharmacologic target. In this review, we summarize the data linking inflammation to atherosclerosis with a particular focus on residual inflammatory risk. Additionally, we detail the results of Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), which showed that directly reducing inflammation with an IL-1β antagonist reduces cardiovascular event rates independent of LDL-C. These positive data are contrasted with neutral evidence from CIRT in which low-dose methotrexate neither reduced the critical IL-1β to IL-6 to CRP pathway of innate immunity, nor reduced cardiovascular event rates.

Keywords: atherosclerosis; prevention; randomized trials; residual risk; vascular inflammation.

Figure 1

Patient laboratory panels demonstrating various types of residual risk. (A) After myocardial infarction, this patient exhibits blood concentrations of LDL-C, hsCRP, triglycerides, and lipoprotein(a) above target concentrations. Following initiation of a high-intensity statin, this individual's LDL-C concentration remains above target, demonstrating residual LDL-C risk. (B) After myocardial infarction, this patient also exhibits blood concentrations of LDL-C, hsCRP, triglycerides, and lipoprotein(a) above target concentrations. Following initiation of a high-intensity statin, this individual's hsCRP concentration remains above target, demonstrating residual inflammatory risk. (C) After myocardial infarction, this patient also exhibits blood concentrations of LDL-C, hsCRP, triglycerides, and lipoprotein(a) above target concentrations as well as an HDL-C concentration below target. Following initiation of a high-intensity statin, concentrations of HDL-C, triglycerides, and lipoprotein(a) are still not adequately controlled, demonstrating residual risk from these pathways.

Figure 2

Median percentage change in hsCRP with different cardiovascular drugs. Median percentage change in hsCRP is displayed for several drugs from trials of patients either with established cardiovascular disease or at high risk for cardiovascular events. Drugs are ordered by their impact on hsCRP. PCSK9 indicates proprotein convertase subtilisin-kexin type 9; CCR2, CC-chemokine ligand 2 receptor. *Mean, rather than median, percentage change.