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Background and Aims <p>Despite substantial statin-induced low-density lipoprotein cholesterol (LDL-C) lowering, residual cardiovascular risk remains a major clinical challenge. A mechanistic synthesis of preclinical and clinical evidence was undertaken to explain why inflammation and risk persist despite optimal lipid control.</p> Methods <p>Literature from preclinical models, clinical trial data, mechanistic modeling, and biomarker trajectories was reviewed and integrated to construct a unified framework linking lipid lowering with persistent immunometabolic activity.</p> Results <p>Long-term, high-dose statin exposure has been associated with paradoxical effects in arterial macrophages, including activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, impaired resolution pathways, and promotion of elevated blood glucose and insulin resistance, including via reduction of circulating glucagon-like peptide-1 (GLP-1) in a microbiota-dependent manner. These local effects may coexist with systemic anti-inflammatory benefits, creating a lower bound beyond which arterial inflammation does not regress. Adaptive immune feedback, Lipoprotein(a)-driven amplification, and vascular remodeling further contribute to inter-individual variability. Temporal biomarker evolution defines three mechanistic phases that may assist in stratifying patient response and guiding therapy design.</p> Conclusions <p>Residual cardiovascular risk can be reframed as an unintended but potentially modifiable immunometabolic plateau. By integrating established lipid-lowering outcomes with emerging insights into inflammation and metabolism, this framework provides a testable model to support biomarker-driven precision strategies and the earlier adoption of complementary therapies, thereby improving outcomes.</p>

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The Statin Floor Effect: a Mechanistic Framework for Residual Cardiovascular Risk

  • 期刊论文

  • 发表日期：

    2026年1月24日

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  • Evan J. Peacock

摘要

Background and Aims

Despite substantial statin-induced low-density lipoprotein cholesterol (LDL-C) lowering, residual cardiovascular risk remains a major clinical challenge. A mechanistic synthesis of preclinical and clinical evidence was undertaken to explain why inflammation and risk persist despite optimal lipid control.

Methods

Literature from preclinical models, clinical trial data, mechanistic modeling, and biomarker trajectories was reviewed and integrated to construct a unified framework linking lipid lowering with persistent immunometabolic activity.

Results

Long-term, high-dose statin exposure has been associated with paradoxical effects in arterial macrophages, including activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, impaired resolution pathways, and promotion of elevated blood glucose and insulin resistance, including via reduction of circulating glucagon-like peptide-1 (GLP-1) in a microbiota-dependent manner. These local effects may coexist with systemic anti-inflammatory benefits, creating a lower bound beyond which arterial inflammation does not regress. Adaptive immune feedback, Lipoprotein(a)-driven amplification, and vascular remodeling further contribute to inter-individual variability. Temporal biomarker evolution defines three mechanistic phases that may assist in stratifying patient response and guiding therapy design.

Conclusions

Residual cardiovascular risk can be reframed as an unintended but potentially modifiable immunometabolic plateau. By integrating established lipid-lowering outcomes with emerging insights into inflammation and metabolism, this framework provides a testable model to support biomarker-driven precision strategies and the earlier adoption of complementary therapies, thereby improving outcomes.