Modulation of Cardiometabolic Risk by Vitamin D and K2 - Simple Supplementation or Real Drug? - Uncovering the Pharmacological Properties

Sep 30, 2026

Uploaded by Mia

Vitamin D is increasingly understood as a pharmacologically active secosteroid with pleiotropic actions beyond calcium homeostasis and bone integrity. 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.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages20

Reading Time50 min

AccessFree to download

Abstract

Keywords

1. Introduction

Vitamin D receptor and tissue distribution

Links to inflammation and cardiovascular homeostasis

Interactions with renin–angiotensin–aldosterone system

Review Modulation of Cardiometabolic Risk by Vitamin D and K2: Simple Supplementation or Real Drug? Uncovering the Pharmacological Properties Saverio 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, * Academic Editors: Francesco Visioli and Michele Correale Received: 15 October 2025 Revised: 21 November 2025 Accepted: 24 December 2025 Published: 27 December 2025 Copyright: © 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. 1 Cardiology Unit, University Hospital Luigi Vanvitelli, 80138 Naples, Italy; [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.); [tiziana.formisano2019@gmail.com](tiziana.formisano2019@gmail.com) (T.F.); [massi.orlandi86@gmail.com](massi.orlandi86@gmail.com) (M.O.); [simona.sperlongano@unicampania.it](simona.sperlongano@unicampania.it) (S.S.); [pasqualecast@gmail.com](pasqualecast@gmail.com) (P.C.); [daniele.molinari@gmail.com](daniele.molinari@gmail.com) (D.M.); [alberto.palladino@policliniconapoli.it](alberto.palladino@policliniconapoli.it) (A.P.) 2 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) 3 Department of Public Health, University of Naples “Federico II”, 80131 Naples, Italy 4 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.) 5 Vanvitelli Cardiology and Intensive Care Unit, Monaldi Hospital, 80131 Naples, Italy; [natalefrancesco@hotmail.com](natalefrancesco@hotmail.com) 6 Department of Life Science, Health, and Health Professions, Link Campus University, 00165 Rome, Italy 7 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) * Correspondence: [giovanni.cimmino@unicampania.it](giovanni.cimmino@unicampania.it); Tel.: +39-0815664269 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 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

FAQs

Why is vitamin D considered more than a nutrient in this review?

The review explains that vitamin D functions as a pharmacologically active secosteroid with pleiotropic effects that extend beyond calcium homeostasis and skeletal health.

How does vitamin K2 relate to cardiometabolic risk modulation?

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.

Why do randomized controlled trials (RCTs) show conflicting cardiovascular results?

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.

Sep 30, 2026

Uploaded by Mia