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In combination with vitamin K2, it refines mineral metabolism and supports vascular health, potentially modulating cardiometabolic risk via endocrine and paracrine mechanisms. Despite supplementation, vitamin D deficiency remains prevalent and correlates with hypertension, insulin resistance, heart failure, and cardiovascular mortality. Mechanistic pathways include renin–angiotensin–aldosterone modulation, anti-inflammatory and antifibrotic effects, and effects on endothelial and cardiomyocyte signaling. Yet large RCTs are inconsistent, suggesting efficacy depends on baseline deficiency and metabolic cofactors.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/modulation-of-cardiometabolic-risk-by-vitamin-d-and-k2-simple-supplementation-or-real-drug-uncovering-the-pharmacological-properties/465354/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/modulation-of-cardiometabolic-risk-by-vitamin-d-and-k2-simple-supplementation-or-real-drug-uncovering-the-pharmacological-properties/465354.png","ImageObject",300,407,{"name":92,"@type":93},"Mia  ","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why is vitamin D considered more than a nutrient in this review?","Question",{"text":113,"@type":114},"The review explains that vitamin D functions as a pharmacologically active secosteroid with pleiotropic effects that extend beyond calcium homeostasis and skeletal health.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does vitamin K2 relate to cardiometabolic risk modulation?",{"text":118,"@type":114},"Vitamin K2 is described as working alongside vitamin D to tune mineral metabolism and vascular health, with attention to pathways that may influence cardiometabolic risk.",{"name":120,"@type":111,"acceptedAnswer":121},"Why do randomized controlled trials (RCTs) show conflicting cardiovascular results?",{"text":122,"@type":114},"The abstract states that RCTs can yield neutral or inconsistent outcomes, and that clinical efficacy may depend on baseline vitamin D deficiency and metabolic cofactors rather than supplementation alone.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},465354,1790811963,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":31,"preview_page_count":4},687207024478,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Review  \nModulation of Cardiometabolic Risk by Vitamin D and K2: Simple Supplementation or Real Drug? Uncovering the Pharmacological Properties  \nSaverio D’Elia 1,2, Roberta Bottino 1, Andreina Carbone 1,3, Tiziana Formisano 1, Massimiliano Orlandi 1, Simona Sperlongano 1, Pasquale Castaldo 1, Daniele Molinari 1, Alberto Palladino 1, Mariarosaria Morello 4, Gisella Titolo 2, Francesco S. Loffredo 4,5, Francesco Natale 5,6, Plinio Cirillo 7 and Giovanni Cimmino 1,4, *  \nAcademic Editors: Francesco Visioli and Michele Correale  \nReceived: 15 October 2025  \nRevised: 21 November 2025  \nAccepted: 24 December 2025  \nPublished: 27 December 2025  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy;  \n[saverio.delia@unicampania.it](saverio.delia@unicampania.it) (S.D.); [ro-bottino@hotmail.com](ro-bottino@hotmail.com) (R.B.); [andr.carbone@gmail.com](andr.carbone@gmail.com) (A.C.);  \n[tiziana.formisano2019@gmail.com](tiziana.formisano2019@gmail.com) (T.F.); [massi.orlandi86@gmail.com](massi.orlandi86@gmail.com) (M.O.);  \n[simona.sperlongano@unicampania.it](simona.sperlongano@unicampania.it) (S.S.); [pasqualecast@gmail.com](pasqualecast@gmail.com) (P.C.);  \n[daniele.molinari@gmail.com](daniele.molinari@gmail.com) (D.M.); [alberto.palladino@policliniconapoli.it](alberto.palladino@policliniconapoli.it) (A.P.)  \n2 Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia, 2, 80138 Naples, Italy; [gisellatitolo@gmail.com](gisellatitolo@gmail.com)  \n3 Department of Public Health, University of Naples “Federico II”, 80131 Naples, Italy  \n4 Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy; [mariarosaria.morello@gmail.com](mariarosaria.morello@gmail.com) (M.M.); [francesco.loffredo@unicampania.it](francesco.loffredo@unicampania.it) (F.S.L.)  \n5 Vanvitelli Cardiology and Intensive Care Unit, Monaldi Hospital, 80131 Naples, Italy; [natalefrancesco@hotmail.com](natalefrancesco@hotmail.com)  \n6 Department of Life Science, Health, and Health Professions, Link Campus University, 00165 Rome, Italy  \n7 Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples “Federico II”, Via Pansini, 5, 80131 Naples, Italy; [plinio.cirillo@unina.it](plinio.cirillo@unina.it)  \n* Correspondence: [giovanni.cimmino@unicampania.it](giovanni.cimmino@unicampania.it); Tel.: +39-0815664269  \nAbstract  \nVitamin D, traditionally regarded as a nutrient, is increasingly recognized as a pharmacologically active secosteroid with pleiotropic effects extending beyond calcium homeostasis and bone integrity. Together with vitamin K2, it participates in the fine-tuning of mineral metabolism and vascular health, potentially modulating cardiometabolic risk through intertwined endocrine and paracrine pathways. Despite widespread fortification and supplementation, vitamin D deficiency remains a major global health concern, driven by limited sun exposure, obesity, and metabolic dysfunction. Observational and mechanistic studies consistently link low serum 25(OH)D concentrations with hypertension, insulin resistance, heart failure, and increased cardiovascular mortality. At the molecular level, vitamin D exerts pharmacological actions—modulating the renin–angiotensin–aldosterone system, exerting anti-inflammatory and antifibrotic effects, and influencing endothelialand cardiomyocyte signaling. While experimental and epidemiological evidence suggests potential cardiovascular benefits, large randomized controlled trials (RCTs) provide conflicting results, particularly regarding hypertension and heart failure. However, these often-neutral results do not preclude a targeted action. On the contrary, cl","cbCaipcToBcdzcRL","https://ap.wps.com/l/cbCaipcToBcdzcRL","pdf",1236457,"English","# Abstract\n# Keywords\n# 1. Introduction\n## Vitamin D receptor and tissue distribution\n## Links to inflammation and cardiovascular homeostasis\n## Interactions with renin–angiotensin–aldosterone system","[{\"question\":\"Why is vitamin D considered more than a nutrient in this review?\",\"answer\":\"The review explains that vitamin D functions as a pharmacologically active secosteroid with pleiotropic effects that extend beyond calcium homeostasis and skeletal health.\"},{\"question\":\"How does vitamin K2 relate to cardiometabolic risk modulation?\",\"answer\":\"Vitamin K2 is described as working alongside vitamin D to tune mineral metabolism and vascular health, with attention to pathways that may influence cardiometabolic risk.\"},{\"question\":\"Why do randomized controlled trials (RCTs) show conflicting cardiovascular results?\",\"answer\":\"The abstract states that RCTs can yield neutral or inconsistent outcomes, and that clinical efficacy may depend on baseline vitamin D deficiency and metabolic cofactors rather than supplementation alone.\"}]","Modulation of Cardiometabolic Risk by Vitamin D and K2 - Simple Supplementation or Real Drug? - Uncovering the Pharmacological Properties | PDF",1790769526]