The effect of menaquinone-7 supplementation on vascular calcification in patients with diabetes: a randomized, double-blind, placebo-controlled trial

S R Zwakenberg, P A de Jong, J W Bartstra, R van Asperen, J Westerink, H de Valk, R H J A Slart, G Luurtsema, J M Wolterink, G J de Borst, J A van Herwaarden, M A van de Ree, L J Schurgers, Y T van der Schouw, J W J Beulens, S R Zwakenberg, P A de Jong, J W Bartstra, R van Asperen, J Westerink, H de Valk, R H J A Slart, G Luurtsema, J M Wolterink, G J de Borst, J A van Herwaarden, M A van de Ree, L J Schurgers, Y T van der Schouw, J W J Beulens

Abstract

Background: Vitamin K occurs in the diet as phylloquinone and menaquinones. Observational studies have shown that both phylloquinone and menaquinone intake might reduce cardiovascular disease (CVD) risk. However, the effect of vitamin K on vascular calcification is unknown.

Objectives: The aim of this study was to assess if menaquinone supplementation, compared to placebo, decreases vascular calcification in people with type 2 diabetes and known CVD.

Methods: In this double-blind, randomized, placebo-controlled trial, we randomly assigned men and women with type 2 diabetes and CVD to 360 µg/d menaquinone-7 (MK-7) or placebo for 6 mo. Femoral arterial calcification at baseline and 6 mo was measured with 18sodium fluoride positron emission tomography (18F-NaF PET) scans as target-to-background ratios (TBRs), a promising technique to detect active calcification. Calcification mass on conventional computed tomography (CT) scan was measured as secondary outcome. Dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) concentrations were measured to assess compliance. Linear regression analyses were performed with either TBR or CT calcification at follow-up as the dependent variable, and treatment and baseline TBR or CT calcification as independent variables.

Results: We randomly assigned 35 patients to the MK-7 group (33 completed follow-up) and 33 to the placebo group (27 completed follow-up). After the 6-mo intervention, TBR tended to increase in the MK-7 group compared with placebo (0.25; 95% CI: -0.02, 0.51; P = 0.06), although this was not significant. Log-transformed CT calcification mass did not increase in the intervention group compared with placebo (0.50; 95% CI: -0.23, 1.36; P = 0.18). MK-7 supplementation significantly reduced dp-ucMGP compared with placebo (-205.6 pmol/L; 95% CI: -255.8, -155.3 pmol/L). No adverse events were reported.

Conclusion: MK-7 supplementation tended to increase active calcification measured with 18F-NaF PET activity compared with placebo, but no effect was found on conventional CT. Additional research investigating the interpretation of 18F-NaF PET activity is necessary. This trial was registered at clinicaltrials.gov as NCT02839044.

Keywords: cardiovascular disease; diabetes; menaquinone-7; vascular calcification; vitamin K.

Copyright © American Society for Nutrition 2019.

Figures

FIGURE 1
FIGURE 1
Flowchart of study participation. CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate.
FIGURE 2
FIGURE 2
Absolute changes in TBR (left) and calcification mass (CT; right) in the placebo and vitamin K group between baseline and 6-mo intervention, presented as medians ± SDs and medians (IQRs), respectively. CT, computed tomography; TBR, target-to-background ratio.
FIGURE 3
FIGURE 3
dp-ucMGP concentrations in the placebo and vitamin K group at baseline, 3 mo, and 6 mo intervention, including medians and IQRs. The gray boxes represent the vitamin K group (n = 33), and the black boxes represent the placebo group (n = 27). dp-ucMGP, dephosphorylated–uncarboxylated matrix Gla protein.

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