Modulation of Cardiometabolic Risk by Vitamin D and K2: Simple Supplementation or Real Drug? Uncovering the Pharmacological Properties.
| Title: | Modulation of Cardiometabolic Risk by Vitamin D and K2: Simple Supplementation or Real Drug? Uncovering the Pharmacological Properties. |
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| Authors: | D'Elia S; Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy.; Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia, 2, 80138 Naples, Italy.; Bottino R; Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy.; Carbone A; Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy.; Department of Public Health, University of Naples 'Federico II', 80131 Naples, Italy.; Formisano T; Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy.; Orlandi M; Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy.; Sperlongano S; Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy.; Castaldo P; Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy.; Molinari D; Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy.; Palladino A; Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy.; Morello M; Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy.; Titolo G; Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia, 2, 80138 Naples, Italy.; Loffredo FS; Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy.; Vanvitelli Cardiology and Intensive Care Unit, Monaldi Hospital, 80131 Naples, Italy.; Natale F; Vanvitelli Cardiology and Intensive Care Unit, Monaldi Hospital, 80131 Naples, Italy.; Department of Life Science, Health, and Health Professions, Link Campus University, 00165 Rome, Italy.; Cirillo P; Department of Advanced Biomedical Sciences, Division of Cardiology, University of Naples 'Federico II', Via Pansini, 5, 80131 Naples, Italy.; Cimmino G; Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy.; Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy. |
| Source: | International journal of molecular sciences [Int J Mol Sci] 2025 Dec 27; Vol. 27 (1). Date of Electronic Publication: 2025 Dec 27. |
| Publication Type: | Journal Article; Review |
| Language: | English |
| Journal Info: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel, Switzerland : MDPI, [2000- |
| MeSH Terms: | Vitamin D*/therapeutic use ; Vitamin D*/pharmacology ; Vitamin D*/administration & dosage ; Cardiovascular Diseases*/prevention & control ; Cardiovascular Diseases*/metabolism ; Cardiovascular Diseases*/drug therapy ; Vitamin K 2*/therapeutic use ; Vitamin K 2*/pharmacology ; Dietary Supplements*; Vitamin D Deficiency/drug therapy ; Vitamin D Deficiency/complications ; Humans ; Animals |
| Abstract: | Vitamin 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 endothelial and 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, clinical efficacy is strongly dependent on baseline deficiency status and the presence of metabolic cofactors. In this context, high-dose supplementation of Vitamin D, in combination with Vitamin K2 to prevent vascular calcification, elevates the supplement to a genuine pharmacological agent, with a distinct therapeutic potential for modulating cardiometabolic risk in selected patient subgroups. Emerging evidence supports the concept that vitamin D, when appropriately dosed and combined with K2, may act more as a low-potency pharmacological modulator than a simple nutritional supplement. This review synthesizes current mechanistic, observational, and interventional evidence, aiming to clarify whether vitamin D should be reclassified-from a micronutrient to a pharmacologically relevant agent-in cardiometabolic prevention and therapy, proposing a paradigm shift toward personalized and targeted dosing strategies, characteristic of precision pharmacology. |
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| Contributed Indexing: | Keywords: 25-hydroxyvitamin D; bone-vascular crosstalk; cardiovascular disease; diabetes; heart failure; hypertension; renin–angiotensin–aldosterone system; supplementation; vitamin D; vitamin K2 |
| Substance Nomenclature: | 1406-16-2 (Vitamin D); 11032-49-8 (Vitamin K 2) |
| Entry Date(s): | Date Created: 20260110 Date Completed: 20260110 Latest Revision: 20260113 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12785717 |
| DOI: | 10.3390/ijms27010298 |
| PMID: | 41516172 |
| Database: | MEDLINE |
Journal Article; Review