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Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease
1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, TN, United States.
Insights
Inflammation drives atherosclerosis, posing residual inflammatory risk even with statin therapy. Targeting inflammation, like with IL-1β antagonists, can reduce cardiovascular events independently of cholesterol levels.
Area of Science:
- Cardiovascular Science
- Immunology
- Pharmacology
Background:
- Inflammation is a critical factor in atherosclerosis development and progression.
- Biomarkers like high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) indicate cardiovascular event risk.
- Residual inflammatory risk persists despite statin therapy and low-density lipoprotein cholesterol (LDL-C) reduction.
Purpose of the Study:
- To review the link between inflammation and atherosclerosis.
- To focus on residual inflammatory risk as a therapeutic target.
- To evaluate the efficacy of anti-inflammatory agents in reducing cardiovascular events.
Main Methods:
- Review of biologic, epidemiologic, and clinical trial data.
- Analysis of statin trial results regarding hsCRP reduction and cardiovascular risk.
- Examination of Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) and Cardiovascular Inflammation Reduction Trial (CIRT) data.
Main Results:
- Statins reduce hsCRP, with greater reduction correlating to decreased cardiovascular risk.
- Canakinumab (IL-1β antagonist) significantly reduced cardiovascular event rates independent of LDL-C.
- Low-dose methotrexate in CIRT did not impact the IL-1β to IL-6 to CRP pathway or cardiovascular event rates.
Conclusions:
- Residual inflammatory risk is a valid pharmacologic target for cardiovascular disease.
- Targeting specific inflammatory pathways, such as IL-1β, can effectively reduce cardiovascular events.
- Not all anti-inflammatory approaches are effective; pathway specificity is crucial.
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.
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