Vitamin K2 Supplementation Research Articles

The effect of vitamin K2 supplementation on coronary artery disease in a randomized multicenter trial

Abstract Background Coronary artery calcification (CAC) and especially progression in CAC is a strong predictor of acute myocardial infarction (AMI) and cardiovascular mortality [1]. Observational studies suggest a protective role of vitamin K2 in the development of CAC [2]. Measurement of CAC score in Agatston Units (AU) is common practice, while novel software as AutoPlaque introduces new opportunities to measure coronary plaques [3]. Purpose The aim of this double-blinded randomized multicenter trial is to investigate if vitamin K2 supplementation can reduce the progression of CAC in a population without known coronary disease. Methods AVADEC is a multicenter trial investigating 389 participants randomized to vitamin K2 (720 μg/day) and vitamin D (25 μg/day) versus placebo with a 2-year follow-up from 2018–2019 [4]. The primary endpoint of AVADEC is change in aortic valve calcification. In this substudy, we examined the progression of CAC in participants with no prior coronary disease (no myocardial infarction and/or revascularization) at baseline. Secondary, the change in CAC was evaluated in two prespecified subgroups (low-risk: CAC score <400 AU and high-risk: CAC ≥400 AU at baseline). Non-contrast CT-scans were performed at baseline, 12 and 24 months of follow-up. Contrast CT-scans were performed at baseline and 24 months. CAC score was measured with established software and expressed in Agatston Units (AU). On contrast CT-scans, quantitative coronary plaque composition evaluations were performed by using Autoplaque. Moreover, events (AMI, revascularization and all cause death) were assessed. Results 304 participants (male, mean age 71 years) with no prior coronary disease were identified. The intervention and placebo groups were similar in all traditional cardiovascular risk factors except familial predisposition for cardiovascular disease (14.4% vs. 6.7%, p=0.046). We found progression of CAC in both the intervention and placebo group from baseline to 24 month follow-up (203 AU vs. 254 AU, p=0.089) (Figure 1). The patients with CAC score <400 AU at baseline were equal in progression (77 AU vs. 81 AU, p=0.846). In patients with CAC score ≥400, the progression of CAC was significantly lower in the intervention group (288 AU vs. 380 AU, p=0.047). Yet, preliminary analyses of contrast CT-scans in 180 participants showed no difference in the progression of non-calcified plaque volume (10 mm3 vs. 37 mm3, p=0.276). In addition, the number of events was significantly lower in participants receiving vitamin K2 and D (1.9% vs. 6.7%, p=0.048). Conclusion Patients with no prior coronary disease randomized to vitamin K2 supplementation had a non-significant reduction in CAC development over a 2-year follow-up period. High-risk patients with CAC ≥400 AU had a significantly lower progression of CAC. Additionally, vitamin K2 supplementation significantly reduced the risk of AMI, revascularization and all-cause death. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Danish Cardiovascular Academy (2/3) and the Region of Southern Denmark (1/3).

412.5: Effect of Vitamin K2-Supplementation on Calcification Propensity and Vascular Stiffness in Vitamin K-Deficient Kidney Transplant Recipients: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

412.5: Effect of Vitamin K2-Supplementation on Calcification Propensity and Vascular Stiffness in Vitamin K-Deficient Kidney Transplant Recipients: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Vitamin K1 and progression of cardiovascular calcifications in hemodialysis patients: the VitaVasK randomized controlled trial.

Cardiovascular calcifications are prevented by matrix Gla protein (MGP), a vitamin K-dependent protein. Haemodialysis patients exhibit marked vitamin K deficiency. The randomized, prospective, open-label, multicentre VitaVasK trial analysed whether vitamin K1 supplementation reduces progression of coronary artery calcifications (CACs) and thoracic aortic calcifications (TACs). Patients with pre-existing CACs were randomized to continue on standard care or to additionally receive 5mg of vitamin K1 orally thrice weekly. Hierarchically ordered primary endpoints were progression of TAC and CAC in computed tomography scans at 18months. Linear mixed effects models with repeated measures at baseline and 12 and 18months assessed treatment effects after adjusting for study site. Of 60 randomized patients, 20 dropped out for reasons unrelated to vitamin K1, resulting in 23 control and 17 vitamin K1 patients. The trial was stopped early due to slow recruitment. At 18months, the average TAC progression was 56% lower in the vitamin K1 compared with the control group (p=.039). CAC significantly progressed within the control group, but not within the vitamin K1 group. Average progression at 18 months was 68% lower in the vitamin K1 compared to the control group (P=.072). Vitamin K1 reduced plasma levels of pro-calcific uncarboxylated MGP by 69% at 18months. No treatment-related adverse events were noted. Vitamin K1 intervention is a potent, safe and cost-effective approach to correct vitamin K deficiency and to potentially reduce cardiovascular calcification in this high-risk population.

Efficacy of vitamin K2 in the prevention and treatment of postmenopausal osteoporosis: A systematic review and meta-analysis of randomized controlled trials.

IntroductionVitamin K (VK) as a nutrient, is a cofactor in the carboxylation of osteocalcin (OC), which can bind with hydroxyapatite to promote bone mineralization and increase bone strength. However, some studies have been inconsistent on whether vitamin K2 (VK2) can maintain or improve bone mineral density (BMD) and reduce the incidence of fractures in postmenopausal women. Therefore, the main objective of this meta-analysis was to determine the effect of VK2 as a nutritional supplement on BMD and fracture incidence in postmenopausal women.MethodsWe searched PubMed, EMBASE, and Cochrane Library databases (published before March 17, 2022) and then extracted and pooled data from all randomized controlled trials (RCTs) that met the inclusion criteria.ResultsSixteen RCTs with a total of 6,425 subjects were included in this meta-analysis. The overall effect test of 10 studies showed a significant improvement in lumbar spine BMD (BMD LS) (P = 0.006) with VK2. The subgroup analysis of VK2 combination therapy showed that BMD LS was significantly maintained and improved with the administration of VK2 (P = 0.03). The overall effect test of the six RCTs showed no significant difference in fracture incidence between the two groups (RR=0.96, P=0.65). However, after excluding one heterogeneous study, the overall effect test showed a significant reduction in fracture incidence with VK2 (RR = 0.43, P = 0.01). In addition, this meta-analysis showed that VK2 reduced serum undercarboxylated osteocalcin (uc-OC) levels and the ratio of uc-OC to cOC in both subgroups of VK2 combined intervention and alone. However, for carboxylated osteocalcin (cOC), both subgroup analysis and overall effect test showed no significant effect of VK2 on it. And the pooled analysis of adverse reactions showed no significant difference between the VK2 and control groups (RR = 1.03, 95%CI 0.87 to 1.21, P = 0.76).ConclusionsThe results of this meta-analysis seem to indicate that VK2 supplementation has a positive effect on the maintenance and improvement of BMD LS in postmenopausal women, and it can also reduce the fracture incidence, serum uc-OC levels and the ratio of uc-OC to cOC. In conclusion, VK2 can indirectly promote bone mineralization and increase bone strength.

Efficacy and safety of vitamin K2 for postmenopausal women with osteoporosis at a long-term follow-up: meta-analysis and systematic review.

Vitamin K2 supplementation has been revealed to be effective in the prevention and treatment of osteoporosis in Japan, but further proof for the effectiveness of this practice is still needed. To investigate whether vitamin K2 supplementation plays a role in maintaining bone mineral density (BMD) and reducing the incidence of fractures for postmenopausal women with osteoporosis at a long-term follow-up. We searched systematically throughout the databases of PubMed, Cochrane library, and EMBASE from the dates of their inception to November 16 2021 in this meta-analysis and systematic review, using keywords vitamin K2 and osteoporosis. Nine RCTs with 6853 participants met the inclusion criteria. Vitamin K2 was associated with a significantly increased percentage change of lumbar BMD and forearm BMD (WMD 2.17, 95% CI [1.59-2.76] and WMD 1.57, 95% CI [1.15-1.99]). There were significant differences in undercarboxylated osteocalcin (uc-OC) reduction (WMD -0.96, 95% CI [-0.70 to 0.21]) and osteocalcin (OC) increment (WMD 26.52, 95% CI [17.06-35.98]). Adverse reaction analysis showed that there seemed to be higher adverse reaction rates in the vitamin K2 group (RR = 1.33, 95% CI [1.11-1.59]), but no serious adverse events related to vitamin K2 supplementation. This meta-analysis and systematic review seemed to support the hypothesis that vitamin K2 plays an important role in the maintenance and improvement of BMD, and it decreases uc-OC and increases OC significantly at a long-term follow-up. Vitamin K2 supplementation is beneficial and safe in the treatment of osteoporosis for postmenopausal women.

Vitamin K2 as a potential therapeutic candidate for the prevention of muscle cramps in hemodialysis patients: A prospective multicenter, randomized, controlled, crossover pilot trial

ObjectivesMuscle cramps occur in 33% to 78% of patients with dialysis. The etiology of muscle cramps is poorly understood, and no clear evidence-based prevention or treatment strategies exist. Improved interventions are urgently needed. The aim of this study was to investigate the effect of vitamin K2 in reducing the frequency and severity of muscle cramps in hemodialysis (HD) patients. MethodsThis multicenter, randomized, placebo-controlled, crossover clinical trial was conducted from June 2019 to May 2020. Each participant received vitamin K2 (360 µg/d) or placebo for two 4-wk phases, and then crossed to the alternative arm for two 4-wk phases after a 2-wk washout. The primary endpoint was the frequency of muscle cramps during HD. The secondary endpoints were severity and duration of muscle cramps during HD. ResultsA total of 523 patients with maintenance HD were screened for muscle cramps, including 41 patients with muscle cramps refractory to conventional interventions, were enrolled. Nineteen patients in the vitamin K2-initial group and 20 in the placebo-initial group completed the protocol, and were included in the final analysis. Vitamin K2 reduced the frequency, duration, and severity of muscle cramps in HD patients (all P < 0.05). The frequency, duration, and severity of muscle cramps in HD patients increased again after crossing over to the placebo. There were no serious adverse events. One patient experienced gastrointestinal discomfort when taking vitamin K2. ConclusionsThis pilot trial demonstrated that vitamin K2 supplementation could decrease the frequency, duration, and severity of muscle cramps in HD patients.

The Impact of Vitamin K2 (Menaquionones) in Children’s Health and Diseases: A Review of the Literature

Vitamin K2 activates vitamin K-dependent proteins that support many biological functions, such as bone mineralization, the inhibition of vascular stiffness, the improvement of endothelial function, the maintenance of strong teeth, brain development, joint health, and optimal body weight. Due to the transformation of food habits in developed countries over the last five decades, vitamin K and, specifically, vitamin K2 intakes among parents and their offspring have decreased significantly, resulting in serious health implications. The therapeutics used in pediatric practice (antibiotics and glucocorticoids) are also to blame for this situation. Low vitamin K status is much more frequent in newborns, due to both endogenous and exogenous insufficiencies. Just after birth vitamin K stores are low, and since human milk is relatively poor in this nutrient, breast-fed infants are at particular risk of a bleeding disorder called vitamin K deficiency bleeding. A pilot study showed that better vitamin K status is associated with lower rate of low-energy fracture incidence. An ongoing clinical trial is intended to address whether vitamin K2 and D3 supplementation might positively impact the biological process of bone healing. Vitamin K2 as menaquinone-7 (MK-7) has a documented history of safe and effective use. The lack of adverse effects of MK-7 makes it the ideal choice for supplementation by pregnant and nursing women and children, both healthy and suffering from various malabsorptions and health disorders, such as dyslipidemia, diabetes, thalassemia major (TM), cystic fibrosis (CF), inflammatory bowel diseases (IBD), and chronic liver diseases. Additionally, worthy of consideration is the use of vitamin K2 in obesity-related health outcomes.

The effect of vitamin K1 on arterial calcification activity in subjects with diabetes mellitus: a post hoc analysis of a double-blind, randomized, placebo-controlled trial

Coronary and aortic artery calcifications are generally slow to develop, and their burden predicts cardiovascular disease events. In patients with diabetes mellitus, arterial calcification is accelerated and calcification activity can be detected using 18F-sodium fluoride positron emission tomography (18F-NaF PET). We aimed to determine whether vitamin K1 supplementation inhibits arterial calcification activity in individuals with diabetes mellitus. This was a post hoc analysis of the ViKCoVaC (effect of Vitamin-K1 and Colchicine on Vascular Calcification activity in subjects with Diabetes Mellitus) double-blind randomized controlled trial conducted in Perth, Western Australia. Individuals with diabetes mellitus and established coronary calcification (coronary calcium score>10), but without clinical coronary artery disease, underwent baseline 18F-NaF PET imaging, followed by oral vitamin K1 supplementation (10mg/d) or placebo for 3 mo, after which 18F-NaF PET imaging was repeated. We tested whether individuals randomly assigned to vitamin K1 supplementation had reduced development of new 18F-NaF PET positive lesions within the coronary arteries and aorta. In total, 149 individuals completed baseline and follow-up imaging studies. Vitamin K1 supplementation independently decreased the odds of developing new 18F-NaF PET positive lesions in the coronary arteries (OR: 0.35; 95% CI: 0.16, 0.78; P=0.010), aorta (OR: 0.27; 95% CI: 0.08, 0.94; P=0.040), and in both aortic and coronary arteries (OR: 0.28; 95% CI: 0.13, 0.63; P=0.002). In individuals with diabetes mellitus, supplementation with 10mg vitamin K1/d may prevent the development of newly calcifying lesions within the aorta and the coronary arteries as detected using 18F-NaF PET. Further long-term studies are needed to test this hypothesis.This trial was registered at anzctr.org.au as ACTRN12616000024448.

Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure.

Hyperphosphataemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate, have been shown to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K binding by PBs may offset the beneficial effects of phosphate reduction in reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC. We performed 3/4 nephrectomy in rats, after which warfarin was given for 3 weeks to induce vitamin K deficiency. Next, animals were fed a high phosphate diet in the presence of low or high vitamin K2 and were randomized to either control or one of four different PBs for 8 weeks. The primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-computed tomography (µCT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analysed in vasculature using uncarboxylated matrix Gla protein (ucMGP) specific antibodies. The combination of a high vitamin K2 diet and PB treatment significantly reduced VC as measured by µCT for both the thoracic (P = 0.026) and abdominal aorta (P = 0.023), compared with MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2-treated groups in both the thoracic (P < 0.01) and abdominal aorta (P < 0.01) as compared with high vitamin K2-treated groups. Moreover, a high vitamin K diet and PBs led to reduced vascular oxidative stress. In an animal model of kidney failure with vitamin K deficiency, neither PB therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC.

Influence of vitamin K2 on lipid precursors of inflammation and fatty acids pathway activities in HepG2 cells.

Vitamin K2 (VK2) is one of the two types of vitamin K present most in the human diet. VK2 seems to have a beneficial effect on inflammation related to type 2 diabetes mellitus. The aim of this study was to evaluate the influence of VK2 on lipid precursors of inflammation in lipid-overloaded human liver hepatocellular carcinoma cells. Cells were incubated with VK2 and/or palmitic acid (PA). The concentrations of lipid fractions and their fatty acid compositions were measured by gas-liquid chromatography. The expression of proteins involved in the inflammatory process was detected using western blotting. The concentration of triacylglycerols (TAGs), activities of the n-3 pathway in TAGs, and lipooxygenase 15 expression were significantly elevated in cells incubated with PA and VK2. In the same group, a marked elevation in diacylglycerol (DAG) 20:4 was observed. VK2 supplementation lowered the expression of tumour necrosis factor-alpha and interleukin-6 compared to that in the PA group. The data indicate that VK2 redirects fatty acid metabolism into the deposition of a safe TAG fraction by increasing the concentration of anti-inflammatory n-3 polyunsaturated fatty acids in this fraction. Moreover, VK2 stimulates the synthesis of anti-inflammatory factors and has anti-inflammatory effects by reducing DAG 20:4.

Development of the BioHybrid Assay: Combining Primary Human Vascular Smooth Muscle Cells and Blood to Measure Vascular Calcification Propensity.

Background: Vascular calcification is an active process that increases cardiovascular disease (CVD) risk. There is still no consensus on an appropriate biomarker for vascular calcification. We reasoned that the biomarker for vascular calcification is the collection of all blood components that can be sensed and integrated into a calcification response by human vascular smooth muscle cells (hVSMCs). Methods: We developed a new cell-based high-content assay, the BioHybrid assay, to measure in vitro calcification. The BioHybrid assay was compared with the o-Cresolphthalein assay and the T50 assay. Serum and plasma were derived from different cohort studies including chronic kidney disease (CKD) stages III, IV, V and VD (on dialysis), pseudoxanthoma elasticum (PXE) and other cardiovascular diseases including serum from participants with mild and extensive coronary artery calcification (CAC). hVSMCs were exposed to serum and plasma samples, and in vitro calcification was measured using AlexaFluor®-546 tagged fetuin-A as calcification sensor. Results: The BioHybrid assay measured the kinetics of calcification in contrast to the endpoint o-Cresolphthalein assay. The BioHybrid assay was more sensitive to pick up differences in calcification propensity than the T50 assay as determined by measuring control as well as pre- and post-dialysis serum samples of CKD patients. The BioHybrid response increased with CKD severity. Further, the BioHybrid assay discriminated between calcification propensity of individuals with a high CAC index and individuals with a low CAC index. Patients with PXE had an increased calcification response in the BioHybrid assay as compared to both spouse and control plasma samples. Finally, vitamin K1 supplementation showed lower in vitro calcification, reflecting changes in delta Agatston scores. Lower progression within the BioHybrid and on Agatston scores was accompanied by lower dephosphorylated-uncarboxylated matrix Gla protein levels. Conclusion: The BioHybrid assay is a novel approach to determine the vascular calcification propensity of an individual and thus may add to personalised risk assessment for CVD.

Vitamin K2 (Menaquinone-7) supplementation does not affect vitamin K-dependent coagulation factors activity in healthy individuals.

Background:Vitamin K has long been regarded as a procoagulant drug by physicians, and concerns have been raised with regard to its effects on hemostasis. Although many studies have shown that vitamin K supplementation is safe for thrombotic events, the effect of vitamin K supplementation on the activities of vitamin K dependent procoagulation factors in healthy individuals is not available.Objectives:This study aimed to investigate whether vitamin K2 supplementation at recommended doses affects the activity of vitamin K dependent procoagulation factors in healthy individuals without any anticoagulation treatment.Design:Forty healthy volunteers between 25 and 40 years of age were recruited. Menaquinone-7 (MK-7) was administrated at 90 μg for 30 days. Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and blood coagulation factors II, VII, IX, and X activities and Protein induced by vitamin K absence or antagonist-II (PIVKA-II) were measured on days 0 and 30 after MK-7 administration.Results:PT, APTT, and TT showed no significant differences on day 30 when compared with baseline. The activities of coagulation factors II, VII, IX, and X on day 30 showed no significant differences with those at baseline. PIVKA-II levels were unchanged after 30 days of MK-7 supplementation.Conclusions:MK-7 supplementation at recommended dosage does not affect vitamin K-dependent coagulation factors’ coagulation activity, and does not enhance the carboxylation of prothrombin in healthy individuals. This indicated that MK-7 administration does not alter hemostatic balance in healthy populations without anticoagulation treatment.

Vitamin K2 as a New Modulator of the Ceramide De Novo Synthesis Pathway.

The aim of the study was to evaluate the influence of vitamin K2 (VK2) supplementation on the sphingolipid metabolism pathway in palmitate-induced insulin resistant hepatocytes. The study was carried out on human hepatocellular carcinoma cells (HepG2) incubated with VK2 and/or palmitic acid (PA). The concentrations of sphingolipids were measured by high-performance liquid chromatography. The expression of enzymes from the sphingolipid pathway was assessed by Western blotting. The same technique was used in order to determine changes in the expression of the proteins from the insulin signaling pathway in the cells. Simultaneous incubation of HepG2 cells with palmitate and VK2 elevated accumulation of sphinganine and ceramide with increased expression of enzymes from the ceramide de novo synthesis pathway. HepG2 treatment with palmitate and VK2 significantly decreased the insulin-stimulated expression ratio of insulin signaling proteins. Moreover, we observed that the presence of PA w VK2 increased fatty acid transport protein 2 expression. Our study showed that VK2 activated the ceramide de novo synthesis pathway, which was confirmed by the increase in enzymes expression. VK2 also intensified fatty acid uptake, ensuring substrates for sphingolipid synthesis through the de novo pathway. Furthermore, increased concentration of sphingolipids, mainly sphinganine, inhibited insulin pathway proteins phosphorylation, increasing insulin resistance development.

Vitamin K2 Supplementation for the Prevention and Treatment of Rheumatoid Arthritis

ObjectivesTo investigate the effects of vitamin K2 supplementation on the prevention and treatment of rheumatoid arthritis(RA). MethodsVitamin K2 and rheumatoid arthritis were searched in Pubmed from inception until December 2020. ResultsStudy 1: Vitamin K2 inhibited the proliferation of mitogen-activated PBMCs of RA patients with an IC50 value of 3,288.47 ± 4,910.02 ng/mL. There was a significant correlation between IC50 values of vitamin K2 and patient-related factors of RA patients (p < 0.05), such as C-reactive protein (CRP), rheumatoid factor, anti-cyclic citrullinated peptide antibody (ACPA), matrix metalloproteinase-3, Pre-DAS-28 (CRP), and ∆DAS-28 (CRP). Methotrexate inhibited the proliferation of mitogen-activated PBMCs of RA patients with a IC50 value of 22.83 ± 12.47 ng/mL. IC50 values of methotrexate only showed significant correlation with ACPA (p = 0.0158, r = 0.6905); Study 2: A significant decrease in MK-7 treated group for the levels of undercarboxylated osteocalcin (ucOC), erythrocyte sedimentation rate (ESR), disease activity score assessing 28 joints with ESR (DAS28-ESR), C-reactive protein (CRP) and matrix metalloproteinase (MMP-3) was found. In MK-7 treated group, a marked decrease in RA clinical and biochemical markers for moderate and good response compared to non-responders was observed in ucOC, ESR and DAS28-ESR. A marked increase in the levels of MK-7 for the moderate and good responders compared to non-responders was observed; Study 3: as compared to the MK-4-naïve group, the MK-4-treated group showed lower serum CRP (1.7 ± 0.2 vs. 0.5 ± 0.1 mg/dl; P < 0.001), MMP-3 (220.4 ± 21.9 vs. 118.0 ± 14.4 ng/ml; P < 0.001), and DAS28-CRP (2.9 ± 0.1 vs. 2.4 ± 0.1; P < 0.05). The patients who were additionally treated with MK-4 showed significant decreases in serum CRP (1.1 ± 0.2 to 0.6 ± 0.2 mg/dl; P < 0.001), MMP-3 (160.1 ± 25.6 to 125.0 ± 17.8 ng/ml; P < 0.05), and DAS28-CRP (3.1 ± 0.2 to 2.4 ± 0.1; P < 0.001). ConclusionsVitamin K2 supplementation could provide a benefit for the prevention and treatment of RA patients via its immunosuppressive function and improving disease activity. Funding SourcesNo.

Is vitamin K2 supplementation effective in reducing fractures in adults?

Is vitamin K2 supplementation effective in reducing fractures in adults?

Effects of vitamin K2 supplementation on atherogenic status of individuals with type 2 diabetes: a randomized controlled trial

BackgroundThis study was aimed to examine the effects of vitamin K2 supplementation on atherogenic status, assessed by insulin resistance (IR)-related indexes, in patients with type 2 diabetes mellitus (T2DM).MethodsIn this double-blind, controlled trial, 68 patients with T2DM on the oral glucose-lowering medications were randomly allocated into two groups receiving daily intakes of 360 μg MK-7 or placebo for 12 weeks. Eight different IR-related indexes were calculated at the baseline and end of the trial.ResultsAt the end of the study, atherogenic coefficient (mean ± SD: − 0.21 ± 0.45 vs. 0.02 ± 0.43; p = 0.043), triglyceride-glucose index (8.88 ± 0.55 vs. 9.23 ± 0.69; p = 0.029), and atherogenic index of plasma (0.37 ± 0.27 vs. 0.51 ± 0.24; p = 0.031) were significantly lower in the vitamin K2 group, compared to the placebo. However, after accounting for their baseline values, the differences were no more significant. No significant differences were observed in Castelli’s Ӏ and ӀӀ risk indexes, the ratio of triglycerides to high-density lipoprotein cholesterol, lipoprotein combine index, and the metabolic score for insulin resistance index between the two groups at the end of the study.ConclusionsDaily intakes of 360 μg vitamin K2 in the form of MK-7 for 12 weeks could not improve the IR-related indexes of Cardiovascular Diseases risk.Trial registrationThe trial was registered on Iranian Registry of Clinical Trials registry (Trial ID. IRCT20190824044592N1) on 22 December 2019. The record can be found at https://en.irct.ir/trial/41728.

CHANGE IN HEMODYNAMIC PARAMETERS AND CAROTID STIFFNESS INDICES AFTER VITAMIN K2 SUPPLEMENTATION IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Objective: Vitamin K2 is a cofactor of gamma-carboxylase activating group of vitamin K-dependent proteins involved in vascular calcification and arterial stiffness. Data on the protective effects of vitamin K2 supplementation in the progression of vascular damage in patients with type 2 diabetes mellitus (T2DM) are scarce. Aim: to investigate the change in systolic (SAP), diastolic (DAP), pulse (PP), mean (MAP) blood pressure, central systolic aortic pressure (CASP), pulse wave velocity (PWV) and beta-stiffness index (BSI) in patients with T2DM after vitamin K2 supplementation. Design and method: We included 18 patients with T2DM (mean age 59.09 ± 8.5 men 38.8%) who received Vitamin K2 (Menaquinone-7) 75 μg once daily for a period of 4 weeks. Patients with overt cardio-vascular diseases, uncontrolled blood pressure and vitamin K-antagonists intake were excluded from the study. Hemodynamic parameters were measured using an A-pulse CASP-AL device. Carotid stiffness indices were measured by one-point echo-tracking method with Aloka Hitachi Prosound on the both common carotid arteries (CA). Results: All hemodynamic parameters showed increased values compared to the baseline: SAP (+5 mmHg) (p = 0.1), DAP (+2.9mmHg) (p = 0.19), PP (+1.4mmHg) (p = 1.4), MAP (+3.4 mmHg) (p = 0.08). CASP increased from 119.8 ± 12.1mmHg to 126.8 ± 11.4 mmHg (+5 mmHg), and this change was significant (p = 0.02). PWV on the right CA did not change significantly before (7.0 ± 1.48 m/s) and after (7.19 ± 1.28 m/s) supplementation (p = 0.47), similar to BSI 10.08 ± 3.41 and respectively 10.51 ± 3.99 (p = 0.61). PWV on the left CA before supplementation is 7.01 ± 1.22 m/c, respectively after 7.19 ± 1.56 m/c (p = 0.49). BSI on the left CA is 9.97 ± 2.79, resp. 10.69 ± 5.07 (p = 0.43). Conclusions: Vitamin K2 supplementation for four weeks showed significant increase in CASP in our cohort of patients with T2DM. The other hemodynamic parameters as well as the indicators of carotid stiffness do not change significantly. A limitation of our study is the small number of patients included and the short period of intake of vitamin K2, which may not lead to morphological changes in the vessel wall. More extensive research is needed in the field.

Effects of Combined Vitamin K2 and Vitamin D3 Supplementation on Na[18F]F PET/MRI in Patients with Carotid Artery Disease: The INTRICATE Rationale and Trial Design.

INTRICATE is a prospective double-blind placebo-controlled feasibility study, assessing the influence of combined vitamin K2 and vitamin D3 supplementation on micro-calcification in carotid artery disease as imaged by hybrid Sodium [18F]Fluoride (Na[18F]F) positron emission tomography (PET)/ magnetic resonance imaging (MRI). Arterial calcification is an actively regulated process and results from the imbalance between calcification promoting and inhibiting factors. Considering the recent advancements in medical imaging, ultrasound (US), PET/MRI, and computed tomography (CT) can be used for the selection and stratification of patients with atherosclerosis. Fifty-two subjects with asymptomatic carotid artery disease on at least one side of the neck will be included in the study. At baseline, an Na[18F]F PET/MRI and CT examination will be performed. Afterwards, subjects will be randomized (1:1) to a vitamin K (400 µg MK-7/day) and vitamin D3 (80 µg/day) or to placebo. At the 3-month follow-up, subjects will undergo a second Na[18F]F PET/MRI and CT scan. The primary endpoint is the change in Na[18F]F PET/MRI (baseline vs. after 3 months) in the treatment group as compared to the placebo arm. Secondary endpoints are changes in plaque composition and in blood-biomarkers. The INTRICATE trial bears the potential to open novel avenues for future large scale randomized controlled trials to intervene in the plaque development and micro-calcification progression.

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity.

The pathological role of vitamin K2 in Alzheimer’s disease (AD) involves a definite link between impaired cognitive functions and decreased serum vitamin K levels. Vitamin K2 supplementation may have a protective effect on AD. However, the mechanism underlying vitamin K2 protection has not been elucidated. With the amyloid-β (Aβ) cascade hypothesis, we constructed a clone containing the C-terminal fragment of amyloid precursor protein (β-CTF/APP), transfected in astroglioma C6 cells and used this cell model (β-CTF/C6) to study the protective effect of vitamin K2 against Aβ cytotoxicity. Both cellular and biochemical assays, including cell viability and reactive oxygen species (ROS), assays assay, and Western blot and caspase activity analyses, were used to characterize and unveil the protective role and mechanism of vitamin K2 protecting against Aβ-induced cytotoxicity. Vitamin K2 treatment dose-dependently decreased the death of neural cells. The protective effect of vitamin K2 could be abolished by adding warfarin, a vitamin K2 antagonist. The addition of vitamin K2 reduced the ROS formation and inhibited the caspase-3 mediated apoptosis induced by Aβ peptides, indicating that the mechanism underlying the vitamin K2 protection is likely against Aβ-mediated apoptosis. Inhibitor assay and Western blot analyses revealed that the possible mechanism of vitamin K2 protection against Aβ-mediated apoptosis might be via regulating phosphatidylinositol 3-kinase (PI3K) associated-signaling pathway and inhibiting caspase-3-mediated apoptosis. Our study demonstrates that vitamin K2 can protect neural cells against Aβ toxicity.

Effect of Vitamin K2 Alone or in Combination on Various Bone Turnover Markers Amongst Postmenopausal Females.

BackgroundOsteoporosis is common in postmenopausal women. Some studies have demonstrated the usefulness of vitamin K through the action of bone-specific proteins and osteoblast and osteoclast activities. However, no systematic review had explored this aspect in postmenopausal women. Hence, this systematic review aimed to explore the effect of vitamin K2 alone or in combination with other agents (vitamin D3 or calcium) on various bone turnover markers (BTMs) and bone mineral density (BMD) in postmenopausal women.MethodsMEDLINE, ScienceDirect, PubMed, and Google Scholar were searched to identify relevant studies using specific inclusion criteria. Data extraction and quality assessment were carried out using standardized tests, and the results were narratively synthesized and presented in the form of tables.ResultsVitamin K2 was beneficial in inducing an improvement or preventing deterioration, as evidenced by the BMD and osteocalcin (OC), undercarboxylated OC (ucOC), carboxylated OC (cOC), and γ-carboxylated OC levels. However, its effect was not conclusive when procollagen type 1 N-terminal propeptide, carboxyterminal propeptide of type I procollagen, C-terminal telopeptide of type I collagen, bone alkaline phosphatase, deoxypyridinoline, and N-terminal telopeptide levels (NTX) and ucOC:cOC or cOC:ucOC, and NTX:creatinine ratios were examined.ConclusionsVitamin K2 supplementation combined with vitamin D and calcium was found to be advantageous. However, vitamin K2 supplementation cannot replace the existing treatment options. In addition, vitamin K2 should be used with caution, considering its interactions with food and other drugs.