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Atherosclerotic is one of the leading causes of death worldwide. Although lowering low-density lipoprotein cholesterol (LDL-C) levels reduces cardiovascular risk, studies have shown that even when LDL-C is well controlled, patients may still develop atherosclerotic cardiovascular disease, a phenomenon known as residual risk. This review synthesizes current research on the definition, pathogenesis, and therapeutic strategies of residual risk, aiming to provide a theoretical basis for future advances in its diagnosis and management. Evidence derived exclusively from human clinical trials, cohort studies, and meta-analyses is summarized, excluding data from animal or in vitro experiments to maintain clinical relevance. We focus on lipid and inflammatory biomarkers beyond LDL-C, including non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B, lipoprotein(a), triglycerides, triglyceride-rich lipoproteins, HDL dysfunction, and systemic inflammatory markers. Therapeutic interventions encompassing lifestyle modification, lipid-lowering agents, anti-inflammatory therapies, and novel gene-silencing approaches are reviewed. Evidence indicates that in patients receiving statin therapy, non-HDL-cholesterol and apolipoprotein B provide superior assessment of residual risk compared with LDL-C. Lipoprotein(a) remains predictive of cardiovascular events even when LDL-C levels are well controlled, while elevated triglycerides and triglyceride-rich lipoproteins consistently associate with higher cardiovascular risk. Inflammatory biomarkers such as high-sensitivity C-reactive protein and interleukin-6 serve as indicators of residual inflammatory risk. Persistent residual risk despite LDL-C control underscores the need for integrated, multi-target strategies to achieve comprehensive cardiovascular protection.
Tan et al. (Mon,) studied this question.