Vitamin K2 Supplementation in Hospitalised COVID-19 Patients: A Randomised Controlled Trial

Abstract

Background: In observational studies, high levels of desphospho-uncarboxylated matrix gla protein (dp-ucMGP) that result from vitamin K deficiency were consistently associated with poor clinical outcomes during COVID-19. Vitamin K-activated matrix gla protein (MGP) is required to protect against elastic fibre degradation, and a deficiency may contribute to pathology. However, intervention trials assessing the effects of vitamin K supplementation in COVID-19 are lacking. Methods: This is a single-centre, phase 2, double-blind, randomised, placebo-controlled trial investigating the effects of vitamin K2 supplementation in 40 hospitalised COVID-19 patients requiring supplemental oxygen. Individuals were randomly assigned in a 1:1 ratio to receive 999 mcg of vitamin K2-menaquinone-7 (MK-7)-or a placebo daily until discharge or for a maximum of 14 days. Dp-ucMGP, the rate of elastic fibre degradation quantified by desmosine, and hepatic vitamin K status quantified by PIVKA-II were measured. Grade 3 and 4 adverse events were collected daily. As an exploratory objective, circulating vitamin K2 levels were measured. Results: Vitamin K2 was well tolerated and did not increase the number of adverse events. A linear mixed model analysis showed that dp-ucMGP and PIVKA-II decreased significantly in subjects that received supplementation compared to the controls (p = 0.008 and p = 0.0017, respectively), reflecting improved vitamin K status. The decrease in dp-ucMGP correlated with higher plasma MK-7 levels (p = 0.015). No significant effect on desmosine was found (p = 0.545). Conclusions: These results demonstrate that vitamin K2 supplementation during COVID-19 is safe and decreases dp-ucMGP. However, the current dose of vitamin K2 failed to show a protective effect against elastic fibre degradation.

Keywords: COVID-19; desmosine; dp-ucMGP; matrix gla protein; menaquinone-7; vitamin K.

Figure 1

Flowchart of KOVIT trial. COVID-19: Coronavirus 2019; ICU: Intensive Care Unit. ^a One patient withdrew from participation on study day 2, and one patient withdrew from participation on study day 5. ^b Patient withdrew from participation on day 9 of the study intervention.

Figure 2

Visual representation of decline in desphospho-uncarboxylated matrix gla protein (dp-ucMGP) in the intervention (n = 20) and control groups (n = 20). The regression equation of the mixed model analysis was transferred to Excel, and subsequently, relevant choices for age at the start, BMI, gender, treatment and study day were inserted, resulting in an outcome for dp-ucMGP used for visual representation with a significant steep decline in the intervention group (p = 0.008).

Figure 3

Desphospho-uncarboxylated matrix gla protein (dp-ucMGP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), desmosine, interleukin-6 (IL-6), D-dimer and circulating vitamin K2 menaquinone-7 (MK-7) plasma levels of patients receiving either vitamin K2 or placebo. Figures show a combined before–after plot and boxplot of measured outcome parameters. Dashed lines indicate upper levels of normal ranges. All parameters were measured at different points in time during hospital admission. ‘Pre’ is the first blood sampling after inclusion and before the start of tablet supplementation. ‘Post’ is the last blood sampling point of individual patients; this day can vary between 2 and 14 days. During that time period, patients were admitted and received our supplements. ‘Day 2/3’ and ‘Day 4/5’ are time points in which the next blood sampling was taken. Blood was sampled every other day (on Monday, Wednesday, Friday or Saturday/Sunday).