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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.