I have finally finished researching vitamin K2 and heart disease. I've already published all of the research summaries in this blog, so I will not repeat them again here. However, if you would like to see all of them in one place, check out Vitamin K2 and Cardiovascular Disease at VeganHealth.org.
Here is a summary:
Preliminary evidence suggests that vitamin K2 could reduce the risk of heart disease, but the research is mixed and the positive findings come from only one country. More research is needed. If vitamin K2 reduces the risk of heart disease, it does not mean that eating animal products high in vitamin K2 will also reduce the risk, since animal products often contain other components that may increase the risk of heart disease more than vitamin K2 decreases it. Clinical trials are needed and, luckily, at least one is underway (1).
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In doing my final search for studies on vitamin K2 and cardiovascular disease (CVD), I came across one on type 2 diabetes (1). Since diabetes can be fairly related to CVD, I decided to review it.
As with most of the studies on vitamin K2, the population was from The Netherlands. And just like the research on stroke, it was using the combined data from the Prospect and MORGEN arms of EPIC. After excluding people with prevalent diabetes at baseline, they had a study population of 38,094 men and women. The average daily intake of vitamin K2 was 49 µg in the highest one-fourth versus 15 µg in the lowest one-fourth.
After a median follow-up of 10.3 years, and adjusting for many variables (2), in comparing the highest intakes to the lowest, there was a trend towards a lower risk of diabetes, although the finding was not statistically significant (.80, .62–1.02). When looking at what effect an increase of 10 µg had on the risk of diabetes over the entire range of intakes, there was a borderline statistically significant beneficial association (.93, .87–1.00; p < .038).
The researchers had a number of guesses as to why vitamin K2 might be protective against diabetes, all of which amounted to an indirect effect on insulin sensitivity. They also pointed out that the fact that vitamin K2 comes from animal products might have hidden the true strength of a beneficial effect on type 2 diabetes.
1. Beulens JW, van der A DL, Grobbee DE, Sluijs I, Spijkerman AM, van der Schouw YT. Dietary phylloquinone and menaquinones intakes and risk of type 2 diabetes. Diabetes Care. 2010 Aug;33(8):1699-705. doi: 10.2337/dc09-2302. Epub 2010 Apr 27. | link
2. Variables adjusted for: age, sex, waist circumference, smoking status, physical activity, hypertension, education, alcohol consumption, total energy intake, saturated fat, polyunsaturated fat, monounsaturated fat, protein, fiber, calcium, vitamin C, and vitamin E.
I was getting ready to publish my conclusions regarding vitamin K2 and cardiovascular disease and decided to check PubMed one last time to make sure nothing had come out recently. Sure enough, there was a paper on vitamin K2 and stroke from December!
This study combined the data from the two Dutch cohorts of EPIC, Prospect and MORGEN (1). After excluding people with prevalent stroke or cardiovascular disease at baseline, they had a study population of 35,476 men and women. The average daily intake of vitamin K2 was 49 µg in the highest one-fourth versus 16 µg in the lowest one-fourth.
There was no association found between vitamin K2 and incidence of stroke either with all stroke combined, or with ischemic stroke and hemorrhagic stroke analyzed separately. None of the vitamin K2 sub-types were significantly associated with a reduced risk for stroke.
The researchers considered this finding to be in contrast to some previous population studies that found fermented dairy products to be associated with a lower risk of stroke.
They also pointed out that recent research has suggested that artery calcification (which may be associated with lower intakes of vitamin K2) may not be a cause of stroke as it is for heart disease, and that might explain some of the inverse associations found between vitamin K2 and heart disease whereas none was found for stroke in this study.
This was the only study they, or I, are aware of examining the association between vitamin K2 and stroke.
1. Vissers LE, Dalmeijer GW, Boer JM, Monique Verschuren WM, van der Schouw YT, Beulens JW. Intake of dietary phylloquinone and menaquinones and risk of stroke. J Am Heart Assoc. 2013 Dec 10;2(6):e000455. | link
It appears that I have exhausted the research on vitamin K2 and heart disease that measures direct outcomes in humans. I will summarize that research soon.
In the meantime, I have just finished reading a 2013 double-blinded, randomized, placebo-controlled trial on the MK-7 version of vitamin K2 conducted in The Netherlands (1).
The study included 244 healthy postmenopausal women who received either 180 µg of MK-7 or a placebo in one daily dose for 3 years. Bone measurements were taken after 1, 2, and 3 years.
There were so many measurements of bone health taken in the study at various parts of the skeleton that it would be tedious to read a list of each of them and what was found. Suffice it to say that there were some statistically significant reductions in bone deterioration in the treatment group that tended not to appear until the 3rd year. There was also a trend towards fewer moderate vertebral fractures in the treatment group, but the numbers were too small to determine statistical significance. To me, the trends seem too strong to be due simply to taking so many measurements that by chance some benefits were found from the treatment.
One caveat is that the trial was funded by Nattopharma, a company that makes an MK-7 supplement.
It should be noted that 180 µg of MK-7 is a much higher dose than you can get from animal products. In the Prospect-EPIC study, MK-7 intake from animal products ranged only from 0 – 2.2 µg (2). In contrast, the fermented soybean product, natto, has much higher amounts of MK-7 (about 775 µg per 100 g (3)).
1. Knapen MH, Drummen NE, Smit E, Vermeer C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013 Sep;24(9):2499-507. | link
2. Gast GC, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM, Witteman JC, Grobbee DE, Peeters PH, van der Schouw YT. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009 Sep;19(7):504-10. | link
3. Abstract of: Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M. Intake of fermented soybean (natto) increases circulating vitamin K2 (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals. J Bone Miner Metab. 2000;18(4):216-22. | link
A reader pointed out an abstract of a cohort study looking at heart disease and vitamin K2 intake (1), the only one I’ve seen that was not from The Netherlands.
In this case it was the EPIC-Heidelberg cohort from Germany and their findings disagreed with The Netherlands studies depicted in the previous K2 posts.
Vitamin K1 was found to be inversely associated with a fatal heart attack (.49, .25-.94), while vitamin K2 was not associated with incidence (1.21, .81–1.80) or fatal (1.09, .46–2.62) heart disease.
Results were adjusted for smoking, body mass index, waist circumference, hypercholesterolemia, high blood pressure, aspirin use, physical activity, education, and intakes of energy, fat, alcohol, calcium, and folate.
In another short report, a letter to Lancet described a trial in which people on dialysis with osteoporosis were given 45 mg/day of vitamin K2 (2). After six months, their LDL cholesterol had gone from 225 to 195 mg/dl. After treatment was discontinued, cholesterol levels returned to normal.
A couple caveats about this: 45 mg/day of vitamin K2 is about 1,000 times more than a normal intake, and these are very high LDL levels in a rather ill population which might not apply to healthy people.
1. Nimptsch K, Rohrmann S, Linseisen J, Kaaks R. Dietary intake of vitamin K and risk of incident and fatal myocardial infarction in the EPIC-Heidelberg cohort study Gesundheitswesen 2010; 72: V143-DOI: 10.1055/s-0030-1266323 | link
2. Nagasawa Y, Fujii M, Kajimoto Y, Imai E, Hori M. Vitamin K2 and serum cholesterol in patients on continuous ambulatory peritoneal dialysis. Lancet. 1998 Mar 7;351(9104):724. | link
In Vitamin K2: Part One and Vitamin K2: Part Two, I reported some weak associations suggesting that vitamin K2 (found in animals foods), but not vitamin K1 (found in plant foods), might play a role in protecting against heart disease.
Part Three is on yet another study from The Netherlands, this time a component of the The Rotterdam Study published in 2004 (1). Unlike the other other two studies, this one had much stronger results.
The study had a prospective component in which 4,807 men and women aged 55 years and older were followed for an average of 7.2 years. At baseline, all participants were given an ECG to determine if they had heart disease and were excluded if they did.
Vitamin K2 intake was positively associated with the intake of total fat, saturated fat, and calcium, as well as body mass index, and diabetes; it was inversely associated with intake of polyunsaturated fatty acids.
For vitamin K1, the results once again showed it not to be associated with a reduced risk of heart disease (nor mortality).
In model 1, that adjusted for age, gender, and total energy intake, when comparing the group with the highest daily intake (> 33 µg) of vitamin K2 to the lowest (< 22 µg), K2 was associated with a reduced risk of heart disease (.71, .51-1.00), death from heart disease (.59, .35-.99), and overall mortality (.81, .67-.98). These findings are borderline statistically significant.
However, in model 2 that adjusted for factors in model 1 and also body mass index, smoking status and history, diabetes, education, and intake of alcohol, saturated fat, polyunsaturated fat, flavonols (a group of antioxidants), and calcium, the associations became much stronger for heart disease (.59, .40-.86), death from heart disease (.43, .24-.77), and overall mortality (.74, .59-.92).
There was also a cross-sectional component of the study in which 4,473 people were given x-rays at baseline to determine if they had aortic artery calcification. Vitamin K2 intake was inversely associated with severe calcification in model 1 (.56, .39-.80) and model 2 (.48, .32-.71).
As for the possibility of reverse causation (in which people with poor health decided to eat fewer foods high in K2), the authors said, “In contrast to phylloquinone [K1], intake of menaquinone [K2] (mainly MK-4 from eggs and meat, and MK-8 and MK-9 from cheese), is not related to a healthy lifestyle or diet, which makes it unlikely that the observed reduction in coronary risk is due to confounding. Subjects with a history of MI were excluded from the analysis to avoid bias that may arise from intentional changes in diet.”
They also said, “We hypothesize that menaquinones in cheese (MK-8 and MK-9) could exert a beneficial effect in the cardiovascular system and that the high cheese consumption in France and the Mediterranean countries may possibly account for lower prevalences of [heart disease].”
Although the results from this one study are fairly strong, it takes a lot more than one cohort study to justify recommendations for preventing chronic disease. You could combine these results with those for the studies reviewed in Vitamin K2: Part One and Part Two, but those studies are not nearly as strong. Finally, all of these studies included only older people from The Netherlands; we need data from other regions.
In a relatively quick search of PubMed, I could not find any other studies looking at the association between vitamin K2 and heart disease in humans. In fairness to me, the search was quick because so few results were returned. But I will be looking around some more and also reviewing more studies on vitamin K2 and other diseases in the upcoming days.
At this point in time, I am not going out to get vitamin K2 supplements. However, I’m also not dismissing the idea that in a few weeks from now, I might be.
1. Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004 Nov;134(11):3100-5. | link
In Vitamin K2: Part One, I reported on a study from EPIC that followed 16,000 women for 8 years and found an arguably borderline statistically significant, beneficial association for vitamin K2 and the prevention of heart disease.
The same group of researchers, from The Netherlands, published another study of 564 post-menopausal women, comparing their vitamin K intakes to coronary artery calcification (1).
The theory is that vitamin K activates proteins that sequester calcium. Vitamin K1 is cleared from the bloodstream for use in the liver while vitamin K2 is much more likely to be found in the vessel walls where it can prevent calcium from being deposited in the vessel walls.
As predicted, the results showed that vitamin K1 was not associated with a reduced amount of coronary artery calcification. Vitamin K2, however, was associated with reduced risk in a borderline statistically significant manner.
In comparing the highest one-fourth of intake to the lowest, in the model adjusted only for age, the risk was barely statistically significant at 0.82 (0.68–0.99).
In the model adjusted further for smoking, diabetes, BMI, hypertension, educational attainment, HDL and LDL cholesterol, the risk was 0.85 (0.72–1.02); not statistically significant.
And in the model adjusted even further for alcohol consumption and energy-adjusted intake of protein, calcium and fiber the risk was back to statistically significant at 0.80 (0.65–0.98).
Interestingly, the women in the highest intake of vitamin K2 also had the highest intake of calcium at 1,317 mg per day, and calcium and vitamin K2 intakes were significantly associated with each other. Ditto for protein (but not fiber).
Why would women with the highest calcium intake have the lowest amount of artery calcification? Well, as I have written about before, dietary calcium does not appear to cause calcification of the arteries until calcium intakes reach at least 1,400 mg per day, if at all (see Calcium Supplements – The Final Word?).
MK4 was the only vitamin K2 subtype that showed an individual trend towards less artery calcification.
People should keep in mind that this study was cross-sectional, making it a less reliable form of evidence than a prospective study (other things being equal).
In summary, vitamin K2 intake was weakly associated with a lower risk for artery calcification.
1. Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009 Apr;203(2):489-93. | link
In the past year and a half, vitamin K2 has been the second most common topic, after oxalate, that I’ve received questions about.
Vitamin K2 is relevant to vegan diets because the only plant food that has an appreciable amount is natto, a fermented soy product that most of us don’t eat and which has a taste many people don’t care for.
Until recently, mainstream science has considered K2 to be unnecessary both because people can get the same benefits from K1 (which is found in leafy greens) and because K2 is made by common intestinal bacteria. But then research came out at the end of the 00’s suggesting that K2 might have benefits.
My plan is to review the studies on K2 more closely to try to figure out to what extent, if any, vegans are setting themselves up for heart disease, osteoporosis, or other diseases by not having an intake of vitamin K2.
A quick refresher on the forms of vitamin K:
– Phylloquinone is vitamin K1 and found primarily in plant foods, especially leafy greens.
– Menaquinone (forms MK4 through MK10) is vitamin K2. It is found in animal tissues and made by bacteria.
More background info can be found in the article vitamin K at VeganHealth.org.
The first study I’ll review is from one of the two Dutch cohorts of the European Prospective Investigation Into Cancer (EPIC). It was published in 2009 (1). They followed over 16,000 women for an average of 8 years.
The researchers did a fairly rigorous job in measuring vitamin K intake which ranged from 1 – 128 µg, with an average of 29 µg.
They found that every 10 µg increase in vitamin K2 intake was associated with an decreased risk of heart disease but the finding was of only borderline statistical significance (.92, .85 – 1.00). Interestingly, even though they divided the group into quartiles of vitamin K2 intake, they did not report on the relative risk between the different quartiles.
In contrast, intake of vitamin K1 was not associated with risk of heart disease.
Unlike Aglaée Jacob, the authors caution against getting vitamin K2 through typical animal foods:
“Thus, although our findings may have important practical implications on [cardiovascular disease] prevention, it is important to mention that in order to increase the intake of vitamin K2, increasing the portion vitamin K2 rich foods in daily life might not be a good idea. Vitamin K2 might be, for instance more relevant in the form of a supplement or in low-fat dairy. More research into this is necessary.”
I’m skeptical that their findings have important practical implications for cardiovascular disease prevention, but I’ll be reviewing other papers in the days ahead to find out more.
1. Gast GC, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM, Witteman JC, Grobbee DE, Peeters PH, van der Schouw YT. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009 Sep;19(7):504-10. | link
I just updated VeganHealth.org with a page on vitamin K. Some people have claimed that you must eat animal products in order to obtain one of the two main types of vitamin K. After reviewing the research, that does not appear to be the case. Click here to read more about it.