Vitacal study completed

The end of 2018 saw the completion of a double-blind, randomized, placebo-controlled trial that was conducted by Dutch researchers at the University Medical Center Utrecht and aimed at investigating whether vitamin K2 supplementation can influence arterial calcification in patients with type 2 diabetes and known CVD (Vitacal).1,2 Arterial calcification is an independent predictor of coronary events associated with a 3-4 fold increased risk of cardiovascular events. Currently, no effective intervention exists to reduce arterial calcification. However, recent studies showed that vitamin K2 may reduce ongoing calcium deposition in the arteries, and thereby inhibit arterial calcification. The primary objective of the Vitacal study was to determine if MK-7 supplementation leads to stabilization or attenuation of ongoing calcium deposition in the femoral artery as quantified by 18F-NaF PET/CT imaging in patients with type 2 diabetes and arterial disease.

For the purpose of the Vitacal trial men and women above 40 years with diagnosed type 2 diabetes and pre-existing CVD were randomly assigned to 360 µg/day menaquinone-7 or placebo: 35 patients to the menaquinone-7 group (33 completed follow up) and 33 to the placebo group (27 completed follow up). Femoral arterial calcification at baseline and after 6 months was measured with 18F-NaF PET scans as target-to-background ratios (TBR), 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 dependent variable, and treatment and baseline TBR or CT-calcification as independent variables. After 6 months intervention, TBR tended to increase in the menaquinone-7 group compared to placebo (0.25 (95%-CI: -0.02;0.51), p=0.06), though not significant. Log-transformed CT-calcification mass, did not increase in the intervention group compared to placebo (0.50 (95%-CI: -0.23; 1.36), p=0.18). Menaquinone-7 supplementation significantly reduced dp-ucMGP compared to placebo with -205.6 pmol/l (95%-CI: -255.8; -155.3). No adverse events were reported.

The authors of the study concluded that, “Menaquinone-7 supplementation tended to increase active calcification measured with 18F-NaF PET activity compared to placebo, but no effect was found on conventional CT. Additional research investigating the interpretation of 18F-NaF PET activity is necessary.”

Dr. Katarzyna Maresz, president of the International Science and Health Foundation has offered some insight on the shortcomings of the Vitacal trial. “There are several questionable issues concerning this study. The first one is the big difference between the two groups of participants. In the MK-7 group there were people with ‘worse medical condition’, so it is hard to compare ‘more healthy’ group with ‘less healthy’ in my opinion,” she says.

According to the authors of the study, “Participants in the MK-7 group had higher baseline calcification levels, higher phylloquinone intake and more often a low ABI compared to the placebo group.” The Dutch researchers presented the following explanation regarding the first determinant, namely higher baseline calcification levels, “Previous studies on determinants of coronary artery calcification (CAC) progression showed that a high baseline CAC burden was the strongest predictor of CAC progression. In line with this, in our study a high baseline calcification mass was correlated with an increase in calcification mass during follow up. Since calcification mass was higher in the MK-7 group at baseline, this may explain the higher progression of vascular calcification in this group compared to the placebo group.”

As far as the second determinant is concerned, namely higher phylloquinone intake (126.2 mg in MK-7 group vs. 81.7 in placebo group), Dr. Katarzyna Maresz cites some important observations that have already been made by Larsson et al (2018), “Contrary to vitamin K1, vitamin K2 has a more widespread distribution pattern and is hypothesized to play a role in preventing cardiovascular disease by inhibiting vascular calcification. Whereas a high vitamin K1 intake has been shown to increase arterial thrombosis tendency, vitamin K2 has been found to have the opposite effect.”3 “The findings of the Larsson et al study (2018) may shed new light on the Dutch trial, since it has been demonstrated there that genetically higher circulating vitamin K1 levels are associated with an increased risk of large artery atherosclerotic stroke (LAS). Moreover, some previous Mendelian randomization and cohort studies have shown positive associations of circulating vitamin K1 levels with coronary artery disease and calcification. These facts suggest that higher phylloquinone intake may increase the risk of atherosclerotic-related vascular disease,” Dr. Maresz points out. “Also the third determinant, namely a low ABI measurement that is less than 1.00 may be associated with future risk of heart attack and/or stroke,” she adds.

“The second questionable issue is the method that was used in the Dutch trial. 18F-NaF PET is a pretty new technique, not a golden standard,” says Dr. Katarzyna Maresz. “A previous study quoted by the Dutch researchers showed no correlation between 18F-NaF PET activity in the femoral artery and CT images,“ she notices. The authors explained, “In addition, in some studies some areas of macro-calcification showed no 18F-NaF uptake, while other areas with micro-calcification showed high 18F-NaF uptake. […] Since 18F-NaF only is incorporated into the outer surface, our results might reveal a shift from macro- to micro calcification with MK-7 supplementation, by which 18F-NaF uptake increases as seen in our results.”

“Bearing in mind all the previously mentioned flaws of the Vitacal study, the conclusion in the abstract is too strong in my opinion,” summarizes Dr. Maresz. “The conclusion should first focus on the lack of changes in calcification based on a recognized CT method, and later mention that 18F-NaF PET found more active calcification, but the reason of this situation is unknown, maybe reorganization from macro- to micro calcification,” she recaps.


  1. Zwakenberg SR, de Jong PA, Bartstra JW, van Asperen R, Westerink J, de Valk H, Slart RHJA, Luurtsema G, Wolterink JM, de Borst GJ, van Herwaarden JA, van de Ree MA, Schurgers LJ, van der Schouw YT, Beulens JWJ (2019) The effect of menaquinone-7 supplementation on vascular calcification in patients with diabetes: a randomized, double-blind, placebo-controlled trial, European Heart Journal
  3. Larsson SC, Traylor M, Markus HS (2018) Circulating Vitamin K₁ Levels in Relation to Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study, Nutrients 10(11): 1575, doi:10.3390/nu10111575
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