3c659e947276bd36bd0c08c26e71d8a9 335916.pdf 75cd1bca7f2e3024a03509965438070310ebfe0e 335916.pdf 6fd46f22841340c2cd25c49c1620482f68aabf03ed68d8c01077e159f177b524 335916.pdf Title: Targeting Atherosclerosis: Cholesterol-Lowering Therapies with a New Immunometabolic Dress for an Old Disease Subject: Atherosclerotic cardiovascular disease (ASCVD) persists as the foremost cause of global morbidity and mortality. Central to its pathogenesis, atherosclerosis emerges as a chronic inflammatory disorder fueled by the intricate interplay between dysregulated lipid metabolism and immune cell activation. Recent insights reveal that inflammatory cues within atherosclerotic plaques or ischemic tissues orchestrate metabolic reprogramming in immune cells, thereby modulating disease trajectories. While cholesterol-lowering agents such as statins and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have long been recognized for their lipid-modulating properties, accumulating evidence now underscores their pleiotropic anti-inflammatory effects mediated through immune cell modulation. For instance, recent clinical observations reveal that PCSK9 inhibitors not only substantially reduce low-density lipoprotein cholesterol (LDL-C) and triglycerides but also appear to reduce advanced glycoprotein signals, emerging composite biomarkers of systemic inflammation. This highlights a novel and more nuanced dimension of inflammation modulation by PCSK9 inhibitors, although current evidence remains limited and requires further confirmation. Moreover, this dual immune-metabolic influence reshapes our understanding of therapeutic mechanisms and calls for a reassessment of treatment paradigms in ASCVD management. Here, we present a synthesis of current findings that emphasize how both established and novel therapies transcend lipid-lowering to exert profound immunomodulatory actions, offering promising avenues to attenuate cardiovascular disease progression through integrated metabolic and inflammatory control. Keywords: lipids; lipoprotein metabolism; cardiovascular disease; PCSK9; statins; inflammation; diabetes; immune cells; glycoproteins; plaque; clinical studies Author: Josep Julve, Ricardo Rodriguez-Calvo, Bertrand Perret, Laurent O. Martinez and Didac Mauricio Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Thu Dec 11 14:55:06 2025 CET ModDate: Thu Dec 11 14:57:49 2025 CET Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 816652 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- IFBGRA+URWPalladioL-Bold Type 1 Custom yes yes yes 96 0 OXLQAP+URWPalladioL-Roma Type 1 Custom yes yes yes 97 0 WRIRDB+URWPalladioL-Ital Type 1 Custom yes yes yes 98 0 ZAPTTN+CMSY10 Type 1 Builtin yes yes yes 167 0 QDULQU+EURM10 Type 1 Builtin yes yes yes 168 0 IIGABH+Calibri TrueType WinAnsi yes yes no 133 0 IIGABG+Calibri CID TrueType Identity-H yes yes yes 134 0 IIFPCF+PalatinoLinotype TrueType WinAnsi yes yes no 135 0 IIFPBE+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 136 0 IIGGAF+Symbol Type 1C Custom yes yes yes 137 0 IIGABJ+Calibri,Bold TrueType WinAnsi yes yes no 138 0 IIFPNG+TimesNewRoman TrueType WinAnsi yes yes no 139 0 IIGABH+Calibri TrueType WinAnsi yes yes no 207 0 IIFPCF+PalatinoLinotype TrueType WinAnsi yes yes no 208 0 IIGABJ+Calibri,Bold TrueType WinAnsi yes yes no 209 0 IIFPNG+TimesNewRoman TrueType WinAnsi yes yes no 210 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-09-18 04:27:14 CEST RepresentationInformation: 335916.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-09-17 12:31:11 CEST Size: 816652 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 497 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Item: Title: Towards the Immune-Metabolic Hypothesis of Atherosclerosis Item: Title: Cholesterol-Lowering Drugs Also Anti-Inflammatory Children: Item: Title: Cholesterol Synthesis Inhibitors Item: Title: PCSK9 Inhibitors Item: Title: Ezetimibe Item: Title: Direct Anti-Inflammatory Therapy: Canakinumab (CANTOS) Item: Title: Conclusions and Perspectives Item: Title: Future Directions Item: Title: References Info: Title: Targeting Atherosclerosis: Cholesterol-Lowering Therapies with a New Immunometabolic Dress for an Old Disease Author: Josep Julve, Ricardo Rodriguez-Calvo, Bertrand Perret, Laurent O. Martinez and Didac Mauricio Subject: Atherosclerotic cardiovascular disease (ASCVD) persists as the foremost cause of global morbidity and mortality. Central to its pathogenesis, atherosclerosis emerges as a chronic inflammatory disorder fueled by the intricate interplay between dysregulated lipid metabolism and immune cell activation. Recent insights reveal that inflammatory cues within atherosclerotic plaques or ischemic tissues orchestrate metabolic reprogramming in immune cells, thereby modulating disease trajectories. While cholesterol-lowering agents such as statins and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have long been recognized for their lipid-modulating properties, accumulating evidence now underscores their pleiotropic anti-inflammatory effects mediated through immune cell modulation. For instance, recent clinical observations reveal that PCSK9 inhibitors not only substantially reduce low-density lipoprotein cholesterol (LDL-C) and triglycerides but also appear to reduce advanced glycoprotein signals, emerging composite biomarkers of systemic inflammation. This highlights a novel and more nuanced dimension of inflammation modulation by PCSK9 inhibitors, although current evidence remains limited and requires further confirmation. Moreover, this dual immune-metabolic influence reshapes our understanding of therapeutic mechanisms and calls for a reassessment of treatment paradigms in ASCVD management. Here, we present a synthesis of current findings that emphasize how both established and novel therapies transcend lipid-lowering to exert profound immunomodulatory actions, offering promising avenues to attenuate cardiovascular disease progression through integrated metabolic and inflammatory control. 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