Vitamin K Question
September 10, 2012 Written by JP [Font too small?]In a recent conversation, I was asked about the safety of Vitamin K supplements in relation to cardiovascular health. The gentleman I was speaking with brought up the possibility of excessive blood clotting or coagulation. The basis for his concern is that some “blood thinning” medications, such as coumadin (Warfarin), work by antagonizing Vitamin K. What’s more, physicians often recommend limiting Vitamin K consumption via food and supplementation in patients using Vitamin K antagonists. But, what about the majority of the population that isn’t using coumadin or related drugs?
Far and away, the most common use of Vitamin K drugs and supplements is to support the skeletal system. Specifically, the use of high dose Vitamin K2 (45 mg/daily) is being investigated as a means of preventing fractures and osteoporosis in middle-aged to senior men and women. The results of many of these trials have been extremely compelling. For instance, a paper published in the March 2012 issue of Osteoporosis International concluded that supplementing the diets of postmenopausal women with 1,200 mg calcium, 800 IU of Vitamin D and 45 mg of Vitamin K2 per day would likely reduce “the lifetime probability of at least one fracture by 25%”. The mega dosage used in these studies can only be achieved by taking pharmaceutical preparations, which supply 15 mg of Vitamin K2 (menatetrenone) thrice-daily. The fact that this form of Vitamin K is now being investigated as an adjunct medication for use with other anti-osteoporotic drugs is also noteworthy.
Lower dosage forms of Vitamin K are widely available in health food stores and natural pharmacies. At least three studies from 2012 reveal that supplementing with trace amounts of Vitamin K confers significant bone building benefits. The dosages used in the trials varied from between 100 mcg to 360 mcg daily. Two of the three studies included additional ingredients which were likewise intended to support healthy bone metabolism – calcium, fish oil, magnesium and Vitamin D3. A few other distinctions bear mentioning: 1) in one of the trials, a different form of Vitamin K (phylloquinone or K1) also demonstrated improvements in bone mass indices; 2) the form of Vitamin K2 used in the lower-dose studies is known as menaquinone-7, a derivative of natto, a fermented soy food.
Apart from the coagulation issue, Vitamin K is of interest to the cardiovascular system because it assists the body in retaining calcium in bones and out of arteries. Studies involving hemodialysis patients, a population that frequently presents low Vitamin K status, reveal that Vitamin K2 supplementation (135 to 360 mcg/daily) effectively lowers the levels of inactive matrix Gla protein or MGP – a substance which is linked to calcification of the arterial wall. In addition, Vitamin K2 has been inversely associated with the risk of metabolic syndrome and type 2 diabetes, possibly by improving insulin sensitivity. Both of these prevalent health threats markedly increase the risk of developing cardiovascular disease.
In closing, the issue of Vitamin K and blood clotting must be addressed. Anyone who is currently using anticoagulant therapy should not significantly alter Vitamin K intake without proper medical supervision. That said, it may be beneficial and possible to supplement with small quantities of Vitamin K2 while using these medications. However, proper testing and medication adjustments will likely be required. For those not taking anticoagulants, the use of Vitamin K2 supplements (menaquinone-7) in dosages of up to 360 mcg/day does not appear to affect thrombin generation – a measure of blood clotting activity.
Note: Please check out the “Comments & Updates” section of this blog – at the bottom of the page. You can find the latest research about this topic there!
Click on the following links to learn more about the studies referenced in today’s column:
Study 1 – Vitamin K Supplementation for the Primary Prevention of Osteoporotic … (link)
Study 2 – Vitamin K Supplement Along with Vitamin D and Calcium Reduced … (link)
Study 3 – Clinical Results of Alendronate Monotherapy and Combined Therapy … (link)
Study 4 – Changes in Parameters of Bone Metabolism in Postmenopausal Women … (link)
Study 5 – Effect of Vitamin K2 Supplementation on Functional Vitamin K … (link)
Study 6 – Combination of Micronutrients for Bone (COMB) Study: Bone Density … (link)
Study 7 – Vitamin K, Vertebral Fractures, Vascular Calcifications and Mortality … (link)
Study 8 – Is Vitamin K Consumption Associated with Cardio-Metabolic Disorders? … (link)
Study 9 – Vitamin K2 Supplementation Improves Insulin Sensitivity via Osteocalcin … (link)
Study 10 – Low-Dose Menaquinone-7 Supplementation Improved Extra-Hepatic … (link)
Nutrient Cocktail May Support Stronger Bones
Source: J Environ Public Health. 2012;2012:354151 (link)
Tags: Osteoporosis, Vitamin K, Women's Health
Posted in Bone and Joint Health, Heart Health, Nutritional Supplements
September 15th, 2012 at 11:56 am
Based on this column, several clients have inquired about products that meet the specifications mentioned in the paragraphs above. So, here’s a partial list of candidates I think are worth considering:
1) MK-7 (low-dosage, natto-based, Vitamin K2)
Brand: Jarrow MK-7 90 mcg softgels
2) Vitamin K2 (high-dosage, menatetrenone)
Brand: Advanced Orthomolecular Research Peak K2
3) MK-7 + Vitamin D3
Brand: Michael’s Naturopathic, Vitamin D3 (1,000 IU) w/ Vitamin K2 (90 mcg)
Be well!
JP
February 6th, 2015 at 4:25 pm
Update: Vitamin K benefits prediabetics …
http://www.jdmdonline.com/content/14/1/1
J Diabetes Metab Disord. 2015 Jan 14;14(1):1.
Phylloquinone supplementation improves glycemic status independent of the effects of adiponectin levels in premonopause women with prediabetes: a double-blind randomized controlled clinical trial.
BACKGROUND:
Vitamin K, as a cofactor in the gamma carboxylation of certain glutamic acid (Gla) residues, has been related to glucose metabolism and insulin sensitivity. Osteocalcin, also known as bone γ-carboxyglutamic acid, increases β-cell proliferation as well as insulin and adiponectin secretion, which improve glucose tolerance and insulin sensitivity. Thus, the purpose of the present study was to examine the possible role of adiponectin as a mediator of glucose homeostasis following phylloquinone supplementation in premonopause women with prediabetes.
METHODS:
Eighty two women were randomized to consume vitamin k1 supplement (n = 39) or placebo (n = 43) for four weeks. Participants in vitamin K1 treatment group received one pearl softgel capsule containing 1000 micrograms phylloquinone while the placebo group received one placebo capsules daily for four weeks. The Blood samples were collected at baseline and after a four-week intervention to quantify osteocalcin, adiponectin, leptin and relevant variables.
RESULTS:
Phylloquinone supplementation significantly increased serum adiponectin concentration (1.24 ± 1.90 compared with -0.27 ± 1.08 μg/ml), and did not alter total osteocalcin (0.50 ± 4.11 compared with 0.13 ± 1.85 ng/ml) and leptin (-0.29 ± 8.23 compared with -1.15 ± 5.25 ng/ml) compared with placebo. Adjustments for total osteocalcin and adiponectin using analysis of covariance (ANCOVA) did not affect the association of glycemic status with related variables.
CONCLUSIONS:
In conclusion our study demonstrated that phylloquinone supplementation improved glycemic status in premonopausal prediabetic women independent of adiponectin.
Be well!
JP
February 20th, 2015 at 2:20 pm
Update: Vitamin K2 (MK-7) improves arterial stiffness in older women …
http://www.ncbi.nlm.nih.gov/pubmed/25694037
Thromb Haemost. 2015 Feb 19;113(5).
Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: double-blind randomised clinical trial.
Observational data suggest a link between menaquinone (MK, vitamin K2) intake and cardiovascular (CV) health. However, MK intervention trials with vascular endpoints are lacking. We investigated long-term effects of MK-7 (180 µg MenaQ7/day) supplementation on arterial stiffness in a double-blind, placebo-controlled trial. Healthy postmenopausal women (n=244) received either placebo (n=124) or MK-7 (n=120) for three years. Indices of local carotid stiffness (intima-media thickness IMT, Diameter end-diastole and Distension) were measured by echotracking. Regional aortic stiffness (carotid-femoral and carotid-radial Pulse Wave Velocity, cfPWV and crPWV, respectively) was measured using mechanotransducers. Circulating desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP) as well as acute phase markers Interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α) and markers for endothelial dysfunction Vascular Cell Adhesion Molecule (VCAM), E-selectin, and Advanced Glycation Endproducts (AGEs) were measured. At baseline dp-ucMGP was associated with IMT, Diameter, cfPWV and with the mean z-scores of acute phase markers (APMscore) and of markers for endothelial dysfunction (EDFscore). After three year MK-7 supplementation cfPWV and the Stiffness Index β significantly decreased in the total group, whereas distension, compliance, distensibility, Young’s Modulus, and the local carotid PWV (cPWV) improved in women having a baseline Stiffness Index β above the median of 10.8. MK-7 decreased dp-ucMGP by 50 % compared to placebo, but did not influence the markers for acute phase and endothelial dysfunction. In conclusion, long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness.
Be well!
JP
March 19th, 2015 at 4:04 pm
Update: Supplemental Vitamin K1 improves insulin sensitivity …
http://www.nature.com/ejcn/journal/vaop/ncurrent/full/ejcn201517a.html
Eur J Clin Nutr. 2015 Mar 18.
The effect of vitamin K1 supplementation on sensitivity and insulin resistance via osteocalcin in prediabetic women: a double-blind randomized controlled clinical trial.
BACKGROUND/OBJECTIVES: A relationship between osteocalcin (OC) levels and factors associated with energy metabolism and insulin resistance has been reported recently. The aim of this study was to investigate whether modulation of ostecalcin isoforms via vitamin K1 supplementation would affect glucose metabolism or insulin sensitivity in prediabetic and premenopause women.
SUBJECTS/METHODS: Eighty-two prediabetic women were randomized to consume vitamin K1 supplement (n=39) or placebo (n=43) for 4 weeks. Participants in the vitamin K1 supplement group received one pearl softgel capsule containing 1000 μm of phylloquinone, and the placebo group received one placebo capsule daily for 4 weeks. Blood samples were collected at baseline and after the 4-week intervention period to quantify carboxylated OC (cOC), undercarboxylated OC (ucOC) and relevant variables.
RESULTS: Phylloquinone supplementation increased the serum levels of cOC and decreased ucOC, compared with placebo (12.53±5.95 compared with 7.43±4.85 ng/ml and 2.47±1.91 compared with 4.79±2.43 ng/ml, respectively; P<0.001). Furthermore, intake of phylloquinone supplement led to significant decreases in %ucOC (17.97±12.24 compared with 43.80±19.86) and 2-h post-oral glucose tolerance test (OGTT) glucose (7.32±1.50 compared with 8.62±1.45 mmol/l), and 2- h post-OGTT insulin level (80.34±42.24 compared with 112.43±53.19 μIU/ml) and increased insulin sensitivity index (2.46±0.71 compared with 1.75±0.61) compared with placebo. Overall, a significant association was found between changes in %ucOC and changes in 2-h post-OGTT glucose (r=0.308, P=0.028).
CONCLUSIONS: The results of this study demonstrated that vitamin K1 supplementation for 4 weeks did not affect insulin resistance in premenopausal and prediabetic women but had beneficial effects on glycemic status and insulin sensitivity.
Be well!
JP
August 23rd, 2015 at 3:23 pm
Updated 08/23/15:
http://www.mdpi.com/2072-6643/7/8/5306/htm
Nutrients. 2015 Aug 12;7(8):6739-50.
Dietary Vitamin K Intake Is Associated with Cognition and Behaviour among Geriatric Patients: The CLIP Study.
Our objective was to determine whether dietary vitamin K intake was associated with cognition and behavior among older adults. 192 consecutive participants ≥65 years, recruited in the cross-sectional CLIP (Cognition and LIPophilic vitamins) study, were separated into two groups according to the tertiles of dietary phylloquinone intake (i.e., lowest third below 207 µg/day versus the other two thirds combined). Daily dietary phylloquinone intake was estimated from 50-item interviewer-administered food frequency questionnaire. Cognition was assessed with Mini-Mental State Examination (MMSE); behaviour with Frontotemporal Behavioral Rating Scale (FBRS). Age, gender, social problems, education, body mass index (BMI), comorbidities, history of stroke, use vitamin K antagonists, inadequate fatty fish intake, serum thyroid-stimulating hormone (TSH), vitamin B12, albumin, and estimated glomerular filtration rate were used as confounders. Compared to participants in the lowest third of dietary phylloquinone intake (n = 64), those with higher intake had higher (i.e., better) mean MMSE score (22.0 ± 5.7 versus 19.9 ± 6.2, p = 0.024) and lower (i.e., better) FBRS score (1.5 ± 1.2 versus 1.9 ± 1.3, p = 0.042). In multivariate linear regressions, log dietary phylloquinone intake was positively associated with MMSE score (adjusted β = 1.66, p = 0.013) and inversely associated with FBRS score (adjusted β = -0.33, p = 0.037). Specifically, log dietary phylloquinone intake correlated negatively with FBRS subscore of physical neglect (r = -0.24, p = 0.001). Higher dietary phylloquinone intake was associated with better cognition and behavior among older adults.
Be well!
JP
August 23rd, 2015 at 3:27 pm
Updated 08/23/15:
http://www.aulamedica.es/nh/pdf/9471.pdf
Nutr Hosp. 2015 Jul 18;32 Suppl 1:10-3.
[Intake of vitamins D and K, and their impact on health in female population].
INTRODUCTION: Vitamins D and K are essential for maintaining bone and its deficiency has been associated with several chronic diseases.
OBJECTIVES: To know the intake of vitamins D and K in female population and analyze their involvement on health.
METHODS: Literature research regarding the topic.
RESULTS: Intake of vitamin D in the Spanish female population from 17 to 60 years is lower than the estimated average requirement in the 95.5% of the studied participants and 30.2% of the Spanish population does not meet the established adequate intake for vitamin K. Several studies have emphasized the importance of maintaining optimal nutrition status of vitamin D for its role in the maintenance of bone, but also for its involvement in body weight control and prevention of diseases (cardiovascular disease, type 2 diabetes, cancer). Vitamin K deficiency is also associated with decreased bone density and increased cardiovascular risk besides exerting a protective effect against type 2 diabetes.
CONCLUSIONS: In female population, the intake of vitamin K, but especially vitamin D, is often lower than recommended. Since a worse nutritional status in these vitamins is associated with damage in bone health, weight control, as well as an increased risk of several diseases, it seems appropriate to monitor and improve their intake.
Be well!
JP
August 23rd, 2015 at 3:33 pm
Updated 08/23/15:
http://www.tandfonline.com/doi/abs/10.1080/07315724.2015.1026004?
Not all studies yield positive results. But, they’re still important to know about!
J Am Coll Nutr. 2015 Jul 9:1-7.
Effects of Vitamin K on Matrix Metalloproteinase-3 and Rheumatoid Factor in Women with Rheumatoid Arthritis: A Randomized, Double-Blind, Placebo-Controlled Trial.
OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease characterized by an increase in some autoantibodies and proteolytic enzymes, leading to joint destruction. Although recent investigations have considered vitamin K as an anti-inflammatory nutrient with an important role in bone metabolism, there is currently limited information on its efficacy in RA. We aimed to examine the effects of vitamin K1 (phylloquinone) on the biomarker of joint destruction and autoantibody in patients with RA.
MATERIALS AND METHODS: This was a randomized clinical trial in which 64 women with RA who fulfilled the eligibility criteria were randomly allocated to an intervention or a control group. Vitamin K1 or placebo was administered to the participants for 8 weeks. Baseline characteristics and anthropometric measures were obtained. Clinical status using disease activity score in 28 joints (DAS-28), serum levels of matrix metalloproteinase-3 (MMP-3), and rheumatoid factor (RF) were assessed before and after the intervention.
RESULTS: The serum level of MMP-3 compared with the baseline values did not change significantly in the groups. However, the serum concentration of RF decreased significantly in the vitamin K1 group (p = 0.041). Intergroup comparison showed no significant change in RF serum level after adjusting for relevant confounders (p > 0.05).
CONCLUSIONS: Vitamin K1 supplementation at 10 mg/day for 8 weeks did not alter joint destruction and immune status in the patients with RA compared with the controls.
Be well!
JP
May 27th, 2016 at 2:46 pm
Updated 05/27/16:
http://pubs.acs.org/doi/abs/10.1021/acs.jafc.6b00938
J Agric Food Chem. 2016 May 24.
Measurement of Multiple Vitamin K Forms in Processed and Fresh-Cut Pork Products in the U.S. Food Supply.
Vitamin K food composition data have historically been limited to plant-based phylloquinone (vitamin K1). The purpose of this study was to expand analysis of vitamin K to animal products and to measure phylloquinone and 10 forms of menaquinones (vitamin K2) in processed and fresh-cut pork products. Nationally representative samples of processed pork products (n = 28) were obtained through USDA’s National Food and Nutrition Analysis Program, and fresh pork (six cuts; n = 5 per cut) and bacon (n = 4) were purchased from local retail outlets. All samples were analyzed by high-performance liquid chromatography (phylloquinone and menaquinone-4) and atmospheric-pressure chemical ionization-liquid chromatography-mass spectrometry (menaquinone-5 to menaquinone-13). Although low in phylloquinone (<2.1 ± 0.5 μg of phylloquinone per 100 g), all processed pork products and fresh pork cuts contained menaquinone-4, menaquinone-10, and menaquinone-11 (range: [35.1 ± 11.0]-[534 ± 89.0] μg of menaquinones per 100 g). The total menaquinone contents of processed pork products were correlated with fat contents (r = 0.935). In summary, processed and fresh-cut pork products are a rich dietary source of menaquinones that are currently unaccounted for in assessment of vitamin K in the food supply.
Be well!
JP
June 15th, 2016 at 2:20 pm
Updated 06/15/16:
http://www.ahjonline.com/article/S0002-8703%2816%2930023-0/abstract
Am Heart J. 2016 Jul;177:17-24.
Sugar-sweetened carbonated beverage consumption and coronary artery calcification in asymptomatic men and women.
BACKGROUND: Sugar-sweetened carbonated beverage consumption has been linked to obesity, metabolic syndrome, type 2 diabetes, and clinically manifest coronary heart disease, but its association with subclinical coronary heart disease remains unclear. We investigated the relationship between sugar-sweetened carbonated beverage consumption and coronary artery calcium (CAC) in a large study of asymptomatic men and women.
METHODS: This was a cross-sectional study of 22,210 adult men and women who underwent a comprehensive health screening examination between 2011 and 2013 (median age 40 years). Sugar-sweetened carbonated beverage consumption was assessed using a validated food frequency questionnaire, and CAC was measured by cardiac computed tomography. Multivariable-adjusted CAC score ratios and 95% CIs were estimated from robust Tobit regression models for the natural logarithm (CAC score +1).
RESULTS: The prevalence of detectable CAC (CAC score >0) was 11.7% (n = 2,604). After adjustment for age; sex; center; year of screening examination; education level; physical activity; smoking; alcohol intake; family history of cardiovascular disease; history of hypertension; history of hypercholesterolemia; and intake of total energy, fruits, vegetables, and red and processed meats, only the highest category of sugar-sweetened carbonated beverage consumption was associated with an increased CAC score compared with the lowest consumption category. The multivariable-adjusted CAC ratio comparing participants who consumed ≥5 sugar-sweetened carbonated beverages per week with nondrinkers was 1.70 (95% CI, 1.03-2.81). This association did not differ by clinical subgroup, including participants at low cardiovascular risk.
CONCLUSION: Our findings suggest that high levels of sugar-sweetened carbonated beverage consumption are associated with a higher prevalence and degree of CAC in asymptomatic adults without a history of cardiovascular disease, cancer, or diabetes.
Be well!
JP
December 18th, 2016 at 11:33 pm
Updated 12/18/16:
http://ajcn.nutrition.org/content/early/2016/12/07/ajcn.116.137281.abstract
Am J Clin Nutr. 2016 Dec 7.
Dietary soy and natto intake and cardiovascular disease mortality in Japanese adults: the Takayama study.
BACKGROUND: Whether soy intake is associated with a decreased risk of cardiovascular disease (CVD) remains unclear. A traditional Japanese soy food, natto, contains a potent fibrinolytic enzyme. However, its relation to CVD has not been studied.
OBJECTIVE: We aimed to examine the association of CVD mortality with the intake of natto, soy protein, and soy isoflavones in a population-based cohort study in Japan.
DESIGN: The study included 13,355 male and 15,724 female Takayama Study participants aged ≥35 y. At recruitment in 1992, each subject was administered a validated semiquantitative food-frequency questionnaire. Deaths from CVD were ascertained over 16 y.
RESULTS: A total of 1678 deaths from CVD including 677 stroke and 308 ischemic heart disease occurred during follow-up. The highest quartile of natto intake compared with the lowest intake was significantly associated with a decreased risk of mortality from total CVD after control for covariates: the HR was 0.75 (95% CI: 0.64, 0.88, P-trend = 0.0004). There were no significant associations between the risk of mortality from total CVD and intakes of total soy protein, total soy isoflavone, and soy protein or soy isoflavone from soy foods other than natto. The highest quartiles of total soy protein and natto intakes were significantly associated with a decreased risk of mortality from total stroke (HR = 0.75, 95% CI: 0.57, 0.99, P-trend = 0.03 and HR = 0.68, 95% CI: 0.52, 0.88, P-trend = 0.0004, respectively). The highest quartile of natto intake was also significantly associated with a decreased risk of mortality from ischemic stroke (HR = 0.67, 95% CI:0.47, 0.95, P-trend = 0.03).
CONCLUSION: Data suggest that natto intake may contribute to the reduction of CVD mortality.
Be well!
JP
June 26th, 2017 at 5:35 pm
Updated 06/26/17:
https://www.ncbi.nlm.nih.gov/pubmed/28646812
Altern Ther Health Med. 2017 Jul;23(4):26-32.
Oral Consumption of Vitamin K2 for 8 Weeks Associated With Increased Maximal Cardiac Output During Exercise.
Background • Vitamin K1 and K2 are not typically common in a Western diet because they are found in a variety of fermented foods. Vitamin K2 in particular has been demonstrated to restore mitochondrial function and has a key role in production of mitochondrial adenosine triphosphate. Thus, it is reasonable to speculate that dietary supplementation with vitamin K2 could increase the function of muscle with high mitochondrial content (ie, skeletal and cardiac muscle).
Objective • The purpose of this study was to determine if 8 wk of dietary supplementation with Vitamin K2 could alter cardiovascular responses to a graded cycle ergometer test. Design • The study was a randomized controlled trial.
Setting • The study took place in the Applied Physiology Laboratory of the Department of Biological Sciences at the University of North Texas (Denton, TX, USA).
Participants • Participants were aerobically trained males and female athletes (N = 26). Intervention • Participants were randomly assigned either to a control group that received a rice flour placebo or to an intervention group that received vitamin K2. For weeks 1 to 4, participants received 300 mg/d; for weeks 5 to 8, they received 150 mg/d. Subjects assigned to the control group received similar doses to mirror the intervention group. Subjects consumed the supplements during an 8-wk period while they maintained their typical exercise habits.
Outcome Measures • At baseline and postintervention, participants completed a standard, graded exercise test on an electronically braked cycle ergometer. Before the test, participants were fitted with a mouth piece, and their oxygen consumption, carbon dioxide production, respiratory rate, and respiratory exchange ratio were measured. In addition, participants were fitted with skin-mounted electrodes that measured noninvasive cardiac output, stroke volume, and heart rate. To assess the cumulative exercise change, an area-under-the-curve (AUC) value was calculated separately for each outcome variable at each treatment time point.
Results • Vitamin K2 supplementation was associated with a 12% increase in maximal cardiac output, with P = .031, with a trend toward an increase in heart-rate AUC, with P = .070. No significant changes occurred in stroke volume.
Conclusions • Although vitamin K2 supplementation has previously been reported to improve cardiovascular function in diseased patients, to the research team’s knowledge, the current study is the first to report its potential in active individuals. More research is needed to fully evaluate the potential effects of the observed effects.
Be well!
JP
January 3rd, 2018 at 3:28 pm
Updated 1/3/18:
http://www.mdpi.com/2072-6643/9/12/1334/htm
Nutrients. 2017 Dec 8;9(12).
Prevalence and Effects of Functional Vitamin K Insufficiency: The PREVEND Study.
Matrix Gla Protein (MGP) is a strong vitamin K-dependent inhibitor of soft tissue calcification. We assessed the prevalence of functional vitamin K insufficiency, as derived from plasma desphospho-uncarboxylated MGP (dp-ucMGP), and investigated whether plasma dp-ucMGP is associated with all-cause and cardiovascular mortality in a large general population-based cohort. We included 4275 subjects (aged 53 ± 12 years, 46.0% male) participating in the prospective general population-based Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. The prevalence of functional vitamin K insufficiency (i.e., dp-ucMGP > 500 pmol/L) was 31% in the total study population. This prevalence was significantly higher among elderly and subjects with comorbidities like hypertension, type 2 diabetes, chronic kidney disease, and cardiovascular disease (~50%). After 10 years of follow-up, 279 subjects had died, with 74 deaths attributable to cardiovascular causes. We found significant J-shaped associations of plasma dp-ucMGP with all-cause (linear term: hazard ratio (HR) (95% confidence interval (CI)) = 0.20 (0.12-0.33), p < 0.001; squared term: 1.14 (1.10-1.17), p < 0.001) and cardiovascular mortality (linear term: 0.12 (0.05-0.27), p < 0.001; squared term: 1.17 (1.11-1.23), p < 0.001). These associations remained significant after adjustment for potential confounders. Whether the correction of vitamin K insufficiency improves health outcomes needs to be addressed in future prospective intervention studies. Be well! JP