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

## TL;DR

This paper reviews how vitamins D and K2 may act as drugs to reduce heart and metabolic risks, rather than just supplements, especially when used together in specific cases.

## Contribution

The paper proposes reclassifying vitamin D as a pharmacological agent for cardiometabolic risk, emphasizing personalized dosing with K2.

## Key findings

- Low vitamin D levels are linked to hypertension, insulin resistance, and cardiovascular mortality.
- Vitamin D modulates the renin–angiotensin–aldosterone system and has anti-inflammatory effects.
- Combining high-dose vitamin D with K2 may prevent vascular calcification and act as a targeted therapy.

## 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.