Believing in impossible things – there is a trick to it

At times, all you can do it shake your head in amazement, and wonder at the ability of people who think of themselves as scientists to make statements that are impossible to reconcile with reality, or logic….or pretty much anything to do with science.

Yesterday, I was sent a copy of a paper called ‘High coronary plaque load: a heavy burden.’ Published in the European Heart Journal in August 2013. It looked at the use of statins to reduce the volume of plaque in arteries. I include three verbatim quotes from the paper:

  • Of particular interest, neither LDL cholesterol levels at baseline nor those after high dose statin treatment could independently predict major adverse cardiovascular events (MACEs)
  • One of the most striking results of this study is the fact that LDL levels at baseline or after statin treatment showed no predictive value for MACEs. This could lead to doubt about the beneficial effect of LDL-lowering therapy. However, as also discussed by the authors, there is overwhelming evidence for the beneficial effects of statin therapy on plaque progression and MACEs.
  • Currently statin therapy is so fundamentally established in clinical practice that its beneficial effect is beyond doubt. Even though it has been demonstrated that in patients receiving statin therapy LDL levels have no additional prognostic value, further lowering of LDL cholesterol levels with novel PCSK9 monoclonal antibodies could further reduce the residual risk in these patients1.

So, the researchers discovered that LDL (‘bad’ cholesterol) levels did not predict major coronary events:  angina, heart failure, heart attacks and suchlike. Neither did the degree of LDL lowering with statins have any correlation with coronary events. At this point, having very clearly established that their research flatly contradicts the cholesterol hypothesis, they finished off by remarking that when the new cholesterol agents arrive, which will lower LDL levels even more than statins, they will ‘further reduce the residual risk in these patients.’

I shall try to reduce this paper to its ineluctable essence.

  • We have found that LDL levels have nothing to do with cardiovascular disease
  • We have found that the degree of LDL lowering with statins does not correlate with cardiovascular events
  • We think we need to the lower the LDL more to prevent cardiovascular disease

‘Alice laughed. ‘There’s no use trying,’ she said. ‘One can’t believe impossible things.’

‘I daresay you haven’t had much practice,’ said the Queen. ‘When I was your age, I always did it for half-an-hour a day. Why, sometimes I’ve believed as many as six impossible things before breakfast. ‘Lewis Carroll – Alice in Wonderland.

I suppose it becomes easier to believe in impossible things if you have a few conflicts of interest to help you along the way…..smooth the pathway of belief, so to speak. Here follows the conflict of interest statement from the paper:

Conflict of interest:

J.W.J. receives research grants from and was a speaker at meetings sponsored by Astellas, AstraZeneca, Biotronic, Boston Scientific, Bristol-Myers Squibb, Cordis, Daiichi Sankyo, Eli Lilly and Company, Medtronic, Merck-Schering Plough, Pfizer, Orbus Neich, Novartis, Roche, Servier, the Netherlands Heart Foundation,the Interuniversity Cardiology Institute of the Netherlands, and the European Community Framework KP7 programme. M.A.dG. has no conflicts to declare. The Department of Cardiology received research grants from Biotronik, Medtronic, Boston Scientific

Corporation, St Jude Medical, Lantheus Medical Imaging, and GE Healthcare.

For those paying attention, you may have noticed the mention of PCSKP monoclonal antibodies earlier.  What are these, I hear you cry. These are the next monstrous regiment of cholesterol lowering agents that are waiting in the wings, engines running smoothly. If you thought statins were heavily promoted – you ain’t seen nothing yet.

You may not be astonished to learn that one or two of the companies listed in the conflict of interest statement of that paper are developing PCSK9 monoclonal antibodies. I wonder if that could have anything to do with the statement……’further lowering of LDL cholesterol levels with novel PCSK9 monoclonal antibodies could further reduce the residual risk in these patients.’

And if that thought depresses you, as it does me, here is a little poem by W.H. Auden to cheer you up:

‘Give me a doctor partridge-plump,
Short in the leg and broad in the rump,
An endomorph with gentle hands
Who’ll never make absurd demands
That I abandon all my vices
Nor pull a long face in a crisis,
But with a twinkle in his eye
Will tell me that I have to die.’

1: Michiel A. de Graaf and J.Wouter Jukema. ‘High coronary plaque load: a heavy burden.’ European Heart Journal (2013) 34, 3168–3170

74 thoughts on “Believing in impossible things – there is a trick to it

  1. celia

    Maybe their message is “You may think lowering LDL with statins doesn’t work, but we have a new product that will lower it so much that you will find that statins just didn’t do a good enough job, so buy our new wonder drug!”

    Reply
  2. pjt13

    OMG, it does just get worse! I have recently been to my GP and a cardiorespiratory consultant following a period of breathlessness and tachycardia while swimming. This has all since disappeared in about the space of a month, However, in the intervening time, concerned for my health I went to my GP who sent many bloods for analysis – all good except Cholesterol 7.9/9.9. Echocardiogram Fine, ECG good, Stress ECG fine, but I have a blood pressure of @ 165/80, not so good. Their solution – statins and attendance at a lipids clinic both of which I have declined. I’m going to go back to my GP though so that he can have another think about what to do about my blood pressure – I don’t think it’s caused by having to debate the uselessness of statins every time I see him, but you never know!

    Cheers and thanks for the enlightening blog posts and videos!

    Paul

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    Head of Department (Nursing)
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    Elizabeth Gaskell Campus
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    Reply
    1. Professor Göran Sjöberg

      Funny world!

      Me, a severely CHD victim, and my wife, severely diabetic, have both at age 67 both continuously blood pressures at 110/60 at rest.

      We are since 2009 eating the most forbidden, Low Carb High Fat diet, with as much saturated fat butter and lard from grass fed animals as we possibly can come across. And no medication.

      Reply
  3. Lorna

    Similar experience to Paul only in my case it was raised TSH and raised LDL cholesterol. Immediate reaction: call from GP at home advising immediate attendance at lipid clinic. No mention of link between hypothroidism and increased cholesterol. No mention of endocrinology. Where is the common sense in such knee jerk, misplaced medical reactions? Don’t what is more unsettling: lack of awareness of a pretty common link or the scare-tactics that accompany ANY raised cholesterol measures regardless of background factors.

    Reply
  4. 'Honest', to the point of being brutal and beyond.

    Dr Kendrick,
    are General Practioners in the UK subject to financial rewards if their branch statitistics meet certian targets on lipd prifile testing and reports. Is there an official NHS stsyem of target setting and payments in other words?
    If so, do you think this aspect influence behaviour and policy seen in practice.
    If it was, or remains the case, how does a cholesterol sceptic GP involved in group practice, as partner perhaps, as locum, or short-term addition to the team, find himself/herself placed amongst his/her cholesterol faithful colleagues?
    Does target setting drive up or drive down standards, and do you think the working environemt in medical rewards innovation and well reasoned departure from standard practice?
    Is the average GP beginning to notice the growing tide of patient resistance where statins are concerned?

    Reply
  5. Richard Gibbs

    Informative link about PCSK9 inhibitors: http://ghr.nlm.nih.gov/gene/PCSK9. Sounds like they could have a real role in some instances of hyper/hypo cholesterolemia. But their use will be extended to those whose levels now exceed current (or new even lower) guidelines. Messing with the rate at which cells absorb LDL in people where this mechanism is functioning properly sounds scary to me; you might end up with cells absorbing more LDL than they can handle, possibly giving people symptoms of FH.

    Somehow they are going to come up with recommendations that make statins “inadequate”, PCSK9 inhibitors “necessary” to reach goal, and don’t damage too many people too severely. Sigh.

    Reply
    1. Stephen Rhodes

      When I first noticed this story in the Grauniad I chanced upon this explanation http://articles.mercola.com/sites/articles/archive/2013/07/29/pcsk9-cholesterol-drug.aspx
      It is difficult to maintain control over one’s blood pressure when you realise that the drug has been developed from research identifying defective genes in people with a rare condition in which they produce insufficient LDL.
      Why are they trying to reproduce a condition present in genetically ‘damaged’ i.e. abnormal people in the normal majority, rather than trying to correct the condition which is abnormal?

      Reply
  6. Melchior Meijer

    Malcolm, the logic in their reasoning is mind blowing. I’m almost ashamed to be Dutch. Years ago I had to interview this Jukema, whose head is made of the best steel reinforced concrete tainted money can buy. I politely asked him if CETP inhibition really was a good idea, considering its vital role of CETP in the not even fully understood functions of HDL. This was some years before torcetrapib killed several poor sods who happened to be unlucky enough to be randomized into the intervention arm of the first and only torcetrapib trial.

    Me: What makes you think this drug will work?

    J.: Think? Ik know it will work. Because it elevates HDL, of course (you idiot).

    Me: But doesn’t CETP inhibition render the HDL a bit disabled?

    J.: Who told you such rubbish. This intervention elevates HDL. Higher HDL-levels correlate with lower CHD-mortality. Somebody must have taught you this basic information, mustn’t it? HDL prevents cardiovascular events. Any drug that raises HDL thus logically lowers CHD mortality. Now, I have to shortcut this conversation. I’m a busy man.

    As you write in your book, this dragon is invincible. It just grows new heads again and again and again. Poor Tim Noakes, who currently endures harsh attacks by these reckless criminals.

    Reply
    1. Dr. Malcolm Kendrick Post author

      I’m not quite sure that I would call it logic Melchior. As you know I do not think HDL has a causal role in preventing CVD – it tends to be a marker of insulsin resistance. However, as you say, even if it did, CETP inhibition would simply stop it working. No longer can it transfer cholesterol to VLDL, IDL and suchlike, so cholesterol gets stuck in the HDL which get bigger and bigger and then…..I don’t know. Bursts. As you know, I stil have my hat. The one I was going to eat if CETP inhibition worked.

      Reply
  7. David Bailey

    That contradiction is so blatant that I can’t help wondering if the authors are preparing themselves to jump ship – they can then trumpet the fact that they too were coming out with evidence against the cholesterol theory. On the other hand, if the ship continues to float, they can point out that have also endorsed current treatments!

    Reply
  8. Beth

    “Currently statin therapy is so fundamentally established in clinical practice that its beneficial effect is beyond doubt.”

    That is, doctors prescribe it, so it must improve patients health. I’m sure there is a name for this in the canon of logical fallacies.

    The first two points are interesting though … LDL doesn’t cause CAD after all.

    Beth

    Reply
  9. Debra

    Amazing contradictions.
    As for the PCSK9, the more I learn of molecular biology the more I realize what we don’t know about all the functionality of human body proteins. Many proteins made by us have more than one function depending upon context. You start messing with one function of a protein you are bound to interfere with other important effects that protein has (which are probably not even known about). If we could stop being so obsessed with drugs fixing all maladies and concentrated on good diet and exercise I think the world would be better off. Someone famous once said a drug is a substance with many side effects- of which one effect may be desirable!

    Reply
    1. Professor Göran Sjöberg

      I fully agree!
      When I, as a long time researcher in natural science (metallurgy), got interested in the ‘Molecular Biology of the CELL’ – Alberts et al. – I was chocked finding exactly what you mention. The almost incredible complexity of the interactions of our proteins. Basically 25 000 different are around about which we still have identified rather few – as I remember we still know only about one tenth of them (2 500) by function.

      It goes without saying that when you consider the possible intricate interactions between all these proteins the laws of mathematical combination leaves you with an almost incredible number of possible interactions about which we by definition then knows incredible less than about the individual action of each protein.

      It is on this ignorance that the big pharmaceutical business also make their incredible profits.

      Reply
    2. Steve Morrissey

      The use of PCSK9 inhibitors In people with Familial Hypercholesterolemia could be beneficial, though I think that this benefit would not be because they remove LDL from the blood but because they could help LDL and the supply of nutrients (eg vitamin K2) in LDL get to the arterial cells. If this is the case then increasing the nutrient supply might be a better approach.

      However a big danger with PCSK9 inhibitors is that they will leave the body wide open to infection by certain viruses that use LDL receptors as a means of entry into the cells. In the case of certain virus infections the body produces PCSK9 which shuts down LDL receptors in places like the lungs. PCSK9 inhibitors will destroy this defence. I believe that all of the published PCSK9 trials have reported that a side effect in people receiving the inhibitor has been ‘cold/flu like’ symptoms.
      Researchers have found that PCSK9 might be able to inhibit hepatitis C, so the consequences of removing PCSK9 might not be desirable. [1]

      In addition a good body of work has shown that LDL is part of our immune system (it binds onto bacterial toxins) and so depleting the blood of LDL could make people less resistant to bacterial infection.
      It has been noted that people receiving statins seem to be more resistant to a number of infections. One view is that the anti inflammatory property of statins help, a different view is that the people not on statins have lower cholesterol and are therefore less resistant to infection. There was a recent trial in France, they gave statins to patients in intensive care who had ventilator associated pneumonia. The trial had to be stopped at the first review – patients put on statins were dying at a much greater rate than the controls. [2]

      I personally believe that the war on cholesterol has been misguided, cholesterol level is way down on the list of risk factors for heart disease. Arterial calcification has been the number one risk factor and that is what should be tackled.

      (1) PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression†
      Patrick Labonté1 et al.
      Hepatology – Volume 50, Issue 1, pages 17–24, July 2009
      http://onlinelibrary.wiley.com/doi/10.1002/hep.22911/full

      (2) Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial.
      Papazian et al.
      JAMA. 2013 Oct 23;310(16):1692-700. doi: 10.1001/jama.2013.280031.
      http://www.ncbi.nlm.nih.gov/pubmed/24108510

      Reply
      1. Dr. Malcolm Kendrick Post author

        Thank you for your very thoughtful contribution. I believe that PCSK9 inhibitors have already been seen to increase the risk of developing influenza – which would fit well with your observation that these drugs could leave the body open to infection.

      2. Richard Gibbs

        In the link I posted above, http://ghr.nlm.nih.gov/gene/PCSK9, it was stated that a PCSK9 inhibitor could be helpful in treating the type of FH where the PCSK9 is too active and destroys too many LDL receptors. However it won’t be of any use in FH where the LDL receptor or the APO-B100 has mutated so that the LDL cannot bind to the recpetor.

      3. Steve Morrissey

        This is to discuss the point Richard Gibbs made and also to try to explain my thoughts a bit better.
        In Familial Hypercholesterolemia (FH) Richard was quite right in noting the potential use where PCSK9 is ‘too active’. I should have been more specific in my initial reply, I was thinking mainly of heterozygous FH where the genes from only one of the parents give rise to faulty LDL receptors.
        Heterozygous hypercholesterolemia affects about 1 in 500 people, homozygous FH where the genes from both parents give rise to faulty LDL receptors is much rarer and affects about 1 in a million [1].
        In cases of heterozygous FH the use of a PCSK9 inhibitor should increase the number of working LDL receptors.
        The primary function of LDL receptors isn’t to clear LDL from the blood; it is to supply the cells with essential nutrients. So a key factor is what happens to the cells when they are deprived of nutrients. Are the cardiovascular problems related to this lack of LDL receptors in FH are due to the high blood levels of LDL or due to the lack of nutrients?
        There was a very recent study looking at this topic, in it they found that mice with faulty LDL receptors had high LDL levels and developed calcified arteries, whereas mice with working LDL receptors and fed on a high cholesterol diet had much higher LDL levels but no calcified arteries [2]. The authors also concluded that the accelerated vascular calcification that occurs in patients with FH was independent of the blood cholesterol levels. The authors of the study briefly touch upon possibly medical therapies to halt or reverse the calcification process which included the use of vitamin K [2]. So the scientific evidence is beginning to suggest that it is the lack of nutrients more than the excess LDL in the blood that causes cardiovascular problems in cases of FH.
        When I saw this study I realised that it provided a missing piece in the puzzle of cardiovascular disease. FH tends to be the “poster child” of the cholesterol theory of heart disease. If it isn’t the cholesterol levels that is the problem, then the main theory behind the present strategy of tackling cardiovascular disease is faulty. I would totally agree with Malcolm Kendrick that the present cholesterol theory of cardiovascular disease has many flaws, and this is to be expected if it is wrong.
        I will briefly going through my understanding of the cardiovascular problem, its link to calcification and the possible role of vitamin K. I will try to be as brief as possible.
        As people get older the CVD death rate rises exponentially however cholesterol levels are dropping, whereas the arterial calcification levels are rising exponentially.
        Arterial calcification is the biggest risk factor for cardiovascular death. It is a bigger risk factor than age [3].
        Arterial calcification makes arteries including the aorta stiff and it can also narrow them. Interestingly studies have shown that the calcification can rupture vulnerable plaque [4].
        A protein called Matrix Gla protein (MGP) has been found to be vital in preventing calcification. Mice born without functional MGP will die within two months since their arteries will calcify and break [5].
        MGP is vitamin K dependent, and it has to be activated by vitamin K locally ie in the arteries in order for it to prevent the arteries from calcifying [6].
        An animal trial has shown that vitamin K supplementation can reverse arterial calcification [7].
        LDLs are a significant means of transporting vitamin K2 to cells [8]. Therefore any problem with LDL receptors will lead to reduced levels of K in the arterial cells and therefore increase the chances of vascular calcification.
        I think there is reasonable evidence that the vitamin K2 (menaquinone) deficiency theory could possibly explain many things in cardiovascular disease including familial hypercholesterolemia.
        Studies of dietary vitamin K2 has shown that there is an association between vitamin K2 intake and arterial calcification [9]
        There has been one small trial using K2 supplementation that has recently been published, it was looking at arterial health in people with kidney disease and the results from it look promising [10]. There are some other ongoing trials, one which should be published shortly. If these and future studies show that increased dietary vitamin K2 intake works, that it slows down, halts or even reverse arterial calcification in people then it should totally change how the whole issue of cardiovascular disease is handled.
        Unfortunately when the first theories were for heart disease were being proposed there were no easy ways of measuring calcification apart from post mortems. Also no one had any idea that proteins like MGP even existed.
        There are more supportive studies than the ones I have listed and I think that they are beginning to form a persuasive argument. I find the idea that the lack of vitamin K2 might explain FH better than the classical theory of too much LDL quite neat! Clearly dietary lack of vitamin K2 is linked to cardiovascular disease in non FH people as well.
        BTW the discussion stimulated me to have a fresh look at apheresis (the process of removing LDL) from the blood of people with FH. The proponents of apheresis say that it is beneficial, though there have not been any double blind control studies confirming this as far as I know. However it did leave a question that needed to be answered since it suggests that the lowering the LDL levels improves the outcomes. I discovered that a possible answer was in a recent study looking at PCSK9 and apheresis [11]; the authors noted that levels of PCSK9 were reduced and they thought that this added to the benefit. The reduced level of PCSK9 would increase the number of LDL receptors and hence it could increase the arterial cell intake of K2 and therefore improve the arterial health.
        Lastly I would like to make my apologies to Malcolm for the length of this piece. In my defence I would just plead enthusiasm!

        (1) NICE Article on Familial Hypercholesterolemia
        http://publications.nice.org.uk/identification-and-management-of-familial-hypercholesterolaemia-cg71

        (2) Fantus D, Awan Z, Seidah NG, Genest J. Aortic calcification: Novel insights from familial hypercholesterolemia and potential role for the low-density lipoprotein receptor. Atherosclerosis 2013 1;226(1):9-15.
        (3) Budoff MJ, Nasir K, McClelland RL. Coronary calcium predicts events better with absolute calcium scores than age-sex-race/ethnicity percentiles: MESA (Multi-Ethnic Study of Atherosclerosis). (vol 53, pg 345, 2009). J Am Coll Cardiol 2009 APR 21;53(16):1474-1474.
        (4) Rambhia S, Liang X, Xenos M, Alemu Y, Maldonado N, Kelly A, et al. Microcalcifications Increase Coronary Vulnerable Plaque Rupture Potential: A Patient-Based Micro-CT Fluid–Structure Interaction Study. Ann Biomed Eng 2012:1-12.
        (5) Luo GF, Ducy P FAU – McKee,,M.D., FAU MM, FAU PG, Loyer E FAU – Behringer,,R.R., FAU BR, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature JID – 0410462 0320.
        (6) Schurgers LJ, Uitto J, Reutelingsperger CP. Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization. Trends Mol Med 2013.
        (7) Schurgers LJ, Spronk HM, Soute BA, Schiffers PM, DeMey JG, Vermeer C. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood 2007 Apr 1;109(7):2823-2831
        (8) Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochimica et Biophysica Acta (BBA)-General Subjects 2002;1570(1):27-32.
        (9) Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MHJ, Van Der Meer IM, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr 2004;134(11):3100-3105.
        (10) The Effect of Vitamin K2 Substitution on Atherosclerosis and Vascular Calcification Markers in Non Dialyzed Patients in Chronic Kidney Disease Stage 3-5. Nephrology Dialysis Transplantation: Oxford University Press Great Clarendon St, Oxford OX2 6DP, England; 2013.
        (11) Tavori H, Giunzioni I, Linton MF, Fazio S. Loss of Plasma Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) After Lipoprotein Apheresis. Circ Res 2013:CIRCRESAHA. 113.302655.

      4. Lorna

        # Steve: I’m not a scientist but I found your explanation enlightening and fascinating. Is there any way levels of Vitamin K can be measured? And when you say that in the past there was no way of measuring calcification, can this calcification now measured by ultrasound, as in the aortic aneurism scanning programme in the NHS? What would your opinion be on a way forward?

      5. Steve Morrissey

        #Lorna
        I am afraid I took some time answering your questions since I want to make sure my answers are correct. I haven’t got all the references in my answer, but please feel free to question any area and I will put the references together.

        Measuring vitamin K levels?
        The vitamin K level can be measured in the blood. However some scientists say that it isn’t a reliable measure of a person’s vitamin K status, since the value is very dependent on what the subject last ate and when.
        Another method is to measure the level of uncarboxylated osteocalcin. (Osteocalcin is a vitamin K dependent protein that looks like it is involved in bone strength and also insulin resistance).
        A more recent method looks at measuring a form of circulating uncarboxylated matrix gla protein (this is an important development since carboxylated matrix gla protein (MGP) appears to be vital in order to prevent arterial calcification). The results from a number of studies indicate that most people are deficient in vitamin K. A study was published a few days ago that looked at adult and children, children had a lot of uncarboxylated osteocalcin which indicates that they need more K for their bone growth, the older adults had increasing levels of uncarboxylated MGP which indicates that they need K as well [1].
        I believe that the present RDA ensures that the proteins involved in healthy blood clotting get activated. However the evidence is that the body preferentially activates these with whatever K is at hand; one theory is that the body does this since arteries hardening will not kill a person for decades whereas a bleed could kill a person in a very short time [2].

        Can calcification be measured by ultrasound?
        Yes, it can be detected by ultrasound however the main methods of measuring coronary arterial calcification are the electron beam CT scan (EBCT) and the multidetector CT scan (MDCT) [3].
        If you read the article [3] on patient.co.uk it provides an introduction to CAC scoring, though I think the article is slightly out of date. It refers to a 2007 paper and says that the CAC score might not add much to the traditional risk factors; papers published since 2007 are saying that it provides better information.
        Most of the research of arterial calcification has been done in the US. Facilities for measuring calcification are much more readily available there.

        What is the way forward?
        Well it depends on what you mean by the question.
        On a general medical scientific level:-
        Scientifically there are about 20 known vitamin K dependent proteins. 7 vital ones are connected with healthy blood clotting.. A couple of these proteins also seem to have anti inflammatory effects. Others are involved in bone strength, insulin resistance [4], anti calcification, wound repair, muscle repair, possibly cartilage repair, anti cancer, central nervous system health, and also the transport of thyroxin and vitamin A. A number of them have unknown functions.
        Vitamin K by itself is linked to brain health, less inflammation and possibly the functioning of the immune system.
        Epidemiological studies have linked increased intake of vitamin K (especially the K2 variant) to lower cancer rates, heart disease, diabetes, osteoporosis and also less knee osteoarthritis.
        Vitamin K2 has been around for over 3.5 billion years, before animal life developed. All of our cells evolved in a world with vitamin K2 in it.
        A number of British studies have indicated that vitamin K intake has been decreasing, whether this is linked to the rise in diabetes is an interesting question.
        I would say a valuable way forward would be for the government to invest money into research into the effect of vitamin K in all of these areas concerned with aging and also in the areas of child health. The potential benefit is enormous. However the reality is that most of the medical establishment do not seem to know much about vitamin K (apart from the connection with blood clotting). Worldwide there has been a growth in scientific interest in vitamin K and the vitamin K dependent proteins, and I have now seen papers being published from many different universities not just from the few departments specialising in vitamin K.
        Regarding cardiovascular health there are a number of ongoing studies, one of these has finished and has been reported to be successful in showing that arteries become less stiff after 3 years of supplementation with K2, however it has not yet been published in a journal.

        On a personal level:-
        I personally would recommend eating green vegetables since they contain good amounts of vitamin K (note: clearly this isn’t a radical view!), unfortunately there is no evidence that the form of K in green vegetables (K1) will help greatly with cardiovascular disease, but it should be beneficial in other areas (diabetes?). It looks like cheese is beneficial since it contains lots of K2, indeed cheese was one of the main sources of vitamin K2 in many of the epidemiological studies (if you think about France and Switzerland, the intake of cheese could explain their lower CVD rates and higher life expectancy).
        I consider properly fermented cheese to be probably the most heart healthy item in shops and I tend to be amused that they have a virtually solid red on the traffic light coding system, it doesn’t contain sugar and so it has 1 green segment otherwise it will be a total red!
        So either I have gone terribly wrong or the food health agency has gone terribly wrong! 
        Time will tell.
        Some people take vitamin K2 supplements, this includes me. When I learnt about vitamin K2 over 4 years ago I was totally surprised, I had been investigating arterial calcification and was amazed to find that it was theoretically possible to reverse arterial calcification. I decided to supplement as well in order to make sure my intake was adequate. Since that time I have carried on finding out as much about vitamin K as possible. And as a result I have started on a part time M.Sc course in Medicinal Chemistry.
        Does K2 work on a personal level?
        In terms of the effect of vitamin K2 on myself and others, I would say one major effect has been an improvement in knee health. This came as a surprise, after about 5 months of taking K2 I realised that I could bend my right knee properly again and that it no longer hurt. Other people have reported similar benefits and I know of a couple of people who actually started taking K2 not for cardiovascular benefits but for their knees problems and it has worked. So I keep a good eye on papers on vitamin K and knee health like the one I referred to earlier [5].
        The only measure I have regarding arterial health has been blood pressure; I have been measuring once a week for the last 4 years. It used to be 143 over 86, it has gone down to 124 over 70 and this change has been a consistent trend. I have the theory that it indicates that my aorta has become less stiff since high systolic BP is linked to the hardening of the arteries. I don’t take any blood pressure meds so I would say that there has been an anti aging effect.
        However scientific studies are needed for things to be proved beyond doubt.

        (1) – Theuwissen E, – Magdeleyns EJ, – Braam LAJLM, – Teunissen KJ, – Knapen MH, – Binnekamp IAG, et al. – Vitamin K status in healthy volunteers. – Food Funct (-):-.
        http://pubs.rsc.org/en/content/articlelanding/2013/fo/c3fo60464k#!divAbstract

        (2) McCann JC, Ames BN. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr 2009 OCT 1;90(4):889-907.
        http://www.ncbi.nlm.nih.gov/pubmed/19692494

        (3) http://www.patient.co.uk/doctor/Coronary-Artery-Calcium-Score.htm
        (4) Choi H, An JH, Kim SW, Park KS, Jang HC, Kim SY, et al. Vitamin K2 supplementation improves insulin sensitivity via osteocalcin metabolism: A placebo-controlled trial. Diabetes Care 2011;34(9).
        http://www.ncbi.nlm.nih.gov/pubmed/21868771

        (5) Misra D, Booth SL, Tolstykh I, Felson DT, Nevitt MC, Lewis CE, et al. Vitamin K deficiency is associated with incident knee osteoarthritis. Am J Med 2013;126(3):243-248.
        http://www.ncbi.nlm.nih.gov/pubmed/23410565

      6. Dr. Malcolm Kendrick Post author

        Thank you for you amazingly informative post. It is a pleasure to find that my blog is stimulating such an informative discussion. I am wondering about how to turn this into a true meeting place of minds. No idea how to go about this.

      7. Lorna

        #Steve, that is an immensely informative and wide-ranging explanation of the role of Vitamin K. As a non-scientist, I found it fascinating and clear. It has enhanced what I am learning about the complexity of issues involved in CHD and other conditions. Two points were prompted by your reply: the role of Vitamin K in carrying thyroxine around the body – as a number of hypothyroid patients have difficulties converting the prescribed levothyroxine (T4) into T3, could vitamin K be significant in this problem and would supplementation with Vitamin K help them? If Vitamin K is helping to reduce your blood pressure, then a role in tackling this wide-spread problem of high blood pressure seems worth investigating. I can’t recall seeing Vitamin K on the shelves of Holland & Barratt – where do you get your supply?
        As for the helping the knees, my husband will be glad to hear there may be another supplement that could help besides glucosamine (years of twisting around on football and rugby pitches have taken a toll here!)
        Many thanks for the time taken to educate me on this issue.

      8. Steve Morrissey

        # Dr Malcolm Kendrick
        Thank you for your comment, I am glad that you found my post informative. I find it helpful seeing other people’s ideas and questions, they make one think about one’s own ideas and stimulate you into looking at areas you hadn’t considered before. This explains my delay in responding! Lorna’s question on transthyretin made me look into that particular protein in more detail.
        #Lorna
        Transthyretin, vitamin K, thyroxine, beta amyloid plaque, glucagon and insulin,
        I was using a text book on vitamin K for my description of the function of transthyretin. I would confess that after I read that section in the book I thought that transthyretin was just involved in thyroxine transport and then left it at that since the other vitamin K dependent proteins were looking more exciting! I have since found that transthyretin is involved in much more than the transport of thyroxine.
        Please be aware that what I am writing below is based on things I have learnt about transthyretin in the past weeks. I have tried to include all the references so that things can be checked more easily. The discovery that transthyretin contained a section that was dependent on carboxylation by vitamin K was only made in 2008 [1]. I don’t think that a method has been developed in order to determine whether a transthyretin protein has been carboxylated by vitamin K. And as far as I know there haven’t been any studies that have look at the effect of reduced vitamin K on transthyretin. I have not seen any other papers regarding connections between vitamin K and transthyretin.
        Transthyretin seems to have been around some time and it doesn’t seem to have changed much [2], which tends to imply that it’s make up is very important and that variations are likely to be detrimental , this suggests that it is dependent on vitamin K for its full range of functions. One question is whether transthyretin needs to be carboxylated by vitamin K for it to work in all its functions.
        Transthyretin isn’t the only transporter of thyroxine in the human body; there are two other transporters, thyroxine- binding globulin and albumin. A study in rats has shown that polychlorinated biphenyls bind onto transthyretin resulting in compensatory transthyretin production and hypothyroidism [3]; however the transport of thyroxine in rats isn’t the same as humans. So I don’t know whether vitamin K would have a significant effect on thyroxine levels.
        Transthyretin is made in a number of places in the body, they include the liver, the pancreas and also a region of the brain called the choroid plexus. The choroid plexus handles the transfer of thyroxine to the cerebrospinal fluid (CSF) and it also handles waste products from the CSF. It is estimated that 12 % of the protein produced by the choroid plexus is transthyretin, and the transthyretin produced goes into the CSF [4]. It looks like transthyretin is the main transporter of thyroxine in the brain; thyroxine is absorbed from the blood by the choroid plexus and is then transferred to the transthyretin in the CSF.
        Transthyretin has been used as an indicator of malnourishment; however it has been found that in fasting plasma transthyretin levels decrease but the transthyretin level in the CSF stays the same [5]. This could imply that transthyretin has important functions for brain health.
        It has been found that there is a connection between CSF transthyretin and Alzheimer’s disease. Lower levels of transthyretin in CSF are linked to Alzheimer’s disease [5, 6]. Transthyretin appears to be able to bind to beta amyloid in whatever form it takes , neutralise any toxicity and transport beta-amyloid away [5, 6, 7, 8, 9 & 10]. So it looks like CSF transthyretin could be vital for the health of the brain. If transthyretin is dependent on vitamin K for this then it would be an exciting development.
        I would note that other studies have indicated that low vitamin K intake has detrimental effects on the brain during aging, including associations with Alzheimer’s disease. Vitamin K has a number of functions that can all be beneficial for brain health [11, 12] regardless of the effect on transthyretin.
        There has also been some interesting research on the link between transthyretin and glucose control. Pancreatic alpha cells produce transthyretin and helps the cells produce glucagon (the glucagon is needed to prevent the blood glucose level dropping too much) [13].
        Also it has been found that the beta cells in the pancreas absorb transthyretin, and that this transthyretin help the beta cells produce insulin and also stay healthy [14, 15]. Again there has been some research which has indicated that vitamin K intake is linked to lower rates of diabetes, also that vitamin K supplementation has decreased insulin resistance. How much these effects can be down to the link between transthyretin and vitamin K is unknown.
        So transthyretin seems to be a very useful protein. An important question for all of the above is whether the transthyretin needs to be carboxylated by vitamin K in order to do its job. Going by the other vitamin K dependent proteins I would say that the answer could be yes, that it needs to be carboxylated. However I don’t think anyone has yet analysed how much of the transthyretin in the blood has been carboxylated, or indeed how much of the transthyretin in the CSF has been carboxylated by vitamin K.

        Vitamin K, arterial stiffness and blood pressure
        Arterial stiffness is a cause of high blood pressure (especially isolated systolic hypertension) is arterial stiffness. The aorta stiffening will make the systolic blood pressure rise since the aorta is no longer expanding so well when the heart pumps blood into it. The blood pressure medications used at present reduce the blood pressure by a variety of methods eg reducing the amount of fluid or relaxing the blood vessels. In the case of arterial stiffness these medications are just treating the symptoms, however high blood pressure can cause damage and so the blood pressure by these medications is a useful function. I think I mentioned earlier that there has been a 3 year study on the use of vitamin K2 supplementation in post menopausal women, the results on the effect on bone health has been published however the effect on arterial health has yet to be published (though it is said to be positive).

        Vitamin K2 supplements
        Holland and Barrett do sell vitamin K2; it is in their bone health section. There are other suppliers and you can find them on the Internet, they come in a variety of doses ranging from 45 micrograms to 200 micrograms of the MK7 form. I would just note that in the 3 year trial I mentioned previously they used doses of 180 micrograms/day of the MK7 form of K2.
        If people are taking warfarin or a similar anti vitamin K drugs then there is an issue with taking vitamin K supplements and indeed eating lots of green vegetables or cheese.
        Vitamin K2 has now been accepted as part of a medical food to treat osteoporosis in the US (I would note that the combination of K2 with vitamin D3 is looking extremely promising for osteoporosis). The EFSA has given the go ahead for vitamin K2 to be added to food.

        Vitamin K and knees
        I thought I would provide some references for the effect of vitamin K on knee problems. There have been a number of studies in the US and in Japan that have found an association between lack of vitamin K in the diet and knee osteoarthritis. In a Japanese study of food intake in 719 people over the age of 60 only one dietary item was found to be inversely associated with knee osteoarthritis, which was vitamin K [16]. Their conclusion was that “vitamin K may have a protective role against keen osteoarthritis and might lead to a disease modifying treatment”. In another Japanese study it was found that people with knee osteoarthritis had high levels of uncarboxylated osteocalcin which is indicative of vitamin K deficiency [17]. An American study looked at the development of knee osteoarthritis in 1180 older adults over a period of 30 months, vitamin K levels were measured at the beginning and at the end, it was found that subclinical vitamin k deficiency was linked to the development of osteoarthritis. The authors stated that further study of vitamin K was warranted either to see if vitamin K could treat/prevent osteoarthritis [18].

        References
        (1) Franz T, Ruggeberg S, Horn P, Li X, Vajkoczy P. Detection of a-Carboxy-Glutamate as Novel Post-Translational Modification of Human Transthyretin. Protein Peptide Lett 2008;15(1):43-46.
        (2) Schreiber G. The evolutionary and integrative roles of transthyretin in thyroid hormone homeostasis. J Endocrinol 2002;175(1):61-73.
        (3) Han D, Kang S, Park O, Cho J, Won C, Park H, et al. Hypothyroidism induced by polychlorinated biphenyls and up-regulation of transthyretin. Bull Environ Contam Toxicol 2010;84(1):66-70.
        (4) Schreiber G. The evolution of transthyretin synthesis in the choroid plexus. Clinical chemistry and laboratory medicine 2002;40(12):1200-1210.
        (5) Serot J, Christmann D, Dubost T, Couturier M. Cerebrospinal fluid transthyretin: aging and late onset Alzheimer’s disease. Journal of Neurology, Neurosurgery & Psychiatry 1997;63(4):506-508.
        (6) Han S, Jung ES, Sohn J, Hong HJ, Hong HS, Kim JW, et al. Human serum transthyretin levels correlate inversely with Alzheimer’s disease. J Alzheimer’s Dis 2011;25(1):77-84.
        (7) Li X, Buxbaum JN. Transthyretin and the brain re-visited: is neuronal synthesis of transthyretin protective in Alzheimer’s disease. Mol Neurodegener 2011;6(79):1750-1326.

        (8) Brouillette J, Caillierez R, Zommer N, Alves-Pires C, Benilova I, Blum D, et al. Neurotoxicity and memory deficits induced by soluble low-molecular-weight amyloid-β1–42 oligomers are revealed in vivo by using a novel animal model. The Journal of Neuroscience 2012;32(23):7852-7861.
        (9) Cascella R, Conti S, Mannini B, Li X, Buxbaum JN, Tiribilli B, et al. Transthyretin suppresses the toxicity of oligomers formed by misfolded proteins in vitro. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 2013;1832(12):2302-2314.
        (10) Yang DT, Joshi G, Cho PY, Johnson JA, Murphy RM. Transthyretin as both a Sensor and a Scavenger of β-Amyloid Oligomers. Biochemistry (N Y ) 2013;52(17):2849-2861.
        (11) Ferland G. Vitamin K, an emerging nutrient in brain function. Biofactors 2012;38(2):151-157.
        (12) Presse N, Belleville S, Gaudreau P, Greenwood CE, Kergoat M, Morais JA, et al. Vitamin K status and cognitive function in healthy older adults. Neurobiol Aging 2013;34(12):2777-2783.
        (13) Su Y, Jono H, Misumi Y, Senokuchi T, Guo J, Ueda M, et al. Novel function of transthyretin in pancreatic alpha cells. FEBS Lett 2012.
        (14) Dekki N, Refai E, Holmberg R, Köhler M, Jörnvall H, Berggren P, et al. Transthyretin binds to glucose-regulated proteins and is subjected to endocytosis by the pancreatic β-cell. Cellular and Molecular Life Sciences 2012;69(10):1733-1743.
        (15) Refai E, Dekki N, Yang S, Imreh G, Cabrera O, Yu L, et al. Transthyretin constitutes a functional component in pancreatic β-cell stimulus-secretion coupling. Proc Natl Acad Sci U S A 2005;102(47):17020-17025.
        (16) Oka H, Akune T, Muraki S, En-Yo Y, Yoshida M, Saika A, et al. Association of low dietary vitamin K intake with radiographic knee osteoarthritis in the Japanese elderly population: dietary survey in a population-based cohort of the ROAD study. Journal of Orthopaedic Science 2009;14(6):687-692.
        (17) Naito K, Watari T, Obayashi O, Katsube S, Nagaoka I, Kaneko K. Relationship between serum undercarboxylated osteocalcin and hyaluronan levels in patients with bilateral knee osteoarthritis. Int J Mol Med 2012;29(5):756.
        (18) Misra D, Booth SL, Tolstykh I, Felson DT, Nevitt MC, Lewis CE, et al. Vitamin K deficiency is associated with incident knee osteoarthritis. Am J Med 2013;126(3):243-248.

      9. Lorna

        #Steve, an amazingly detailed explanation of some of the roles of Vitamin K – thank you for the time and trouble taken share your research into so many sources. A couple of responses from me: you say there is an issue of taking Vitamin K and eating lots of green vegetables and cheese – is this because there is a potential ‘overdose’ of Vitamin K in these circumstances? And your research indicates that a dosage of approx 180 (like the trial) would be an optimum amount to take per day – or am I reading this too implicitly?
        Once again, many thanks and my good wishes for the success and application of your research for the M.Sc
        Lor

      10. Steve Morrissey

        #Lorna
        I just rechecked my posting and realised I had left some words out in a couple of sentences.
        I have highlighted the words with asterisks.

        Pancreatic alpha cells produce transthyretin and *the transthyretin* helps the cells produce glucagon (the glucagon is needed to prevent the blood glucose level dropping too much) [13].

        In the case of arterial stiffness these medications are just treating the symptoms, however high blood pressure can cause damage and so the blood pressure *reduction* by these medications is a useful function.

        Many thanks for your questions.

      11. Steve Morrissey

        #Lorna
        Since safety is a vital factor it has taking me some time to prepare an answer for your questions. Apart from trying to find out if vitamin K is beneficial I also try to find out if vitamin K is linked to adverse effects. There is an artificial form of vitamin K, namely K3. It has been linked to adverse effects; fortunately it cannot be sold to the public. At one time it was the only form that could be manufactured. I believe it has been used in animal feed and I think it might have been used many years ago for babies.

        Green vegetables, cheese and warfarin.
        The statement about cheese and green vegetables was made in the context of people who are taking warfarin. People are prescribed warfarin in order to reduce the effectiveness of their blood clotting, this is done for a number of reasons eg they have atrial fibrillation or they have an artificial heart valve fitted. This treatment means they have to have their blood clotting ability continually checked to make sure they are in the required range. A major problem is when the clotting ability is reduced too much and they suffer bleeding. Warfarin works by inhibiting vitamin K, therefore the extent of its ability to work is dependent on how much vitamin K is consumed by the patient. If the patient eats a lot of K then they might be prescribed a higher dose of warfarin, the following week they don’t eat much K and then they are in danger of suffering a bleed.
        The use of warfarin means that the medical profession is having to micromanage something that is controlled naturally in the vast majority of people. People not on warfarin do not have this problem. Eating foods with high levels of vitamin K is not a problem for people who are not taking warfarin..

        Note about Warfarin and Calcification
        There are questions on the benefit of warfarin since studies have shown that warfarin treatment causes arterial calcification [1]. This is because it stops the anti calcification protein matrix gla protein being activated. Also vitamin K is vital for the development of foetuses and warfarin has been found to be harmful to foetuses. There are newer anticoagulants being developed which are not anti K and so hopefully these problems will be overcome when they become available.

        Vitamin K and Blood Clotting
        I have come across concern in some people and indeed some doctors that vitamin K causes the blood to thicken and could cause unwanted clotting. This fear does not seem to be based on any scientific evidence.
        Vitamin K does not affect blood clotting directly, it activates the blood clotting factors (II, VII, IX and X) and it activates the anti clotting proteins (C, S and Z). Once all of these proteins are activated nothing more happens, if you take more vitamin K it does not doubly activate any of these proteins. However the additional vitamin K should help ensure that the other vitamin K dependent proteins such as the ones linked to bone and arterial health are activated.
        Some of the vitamin K supplements suppliers say that it promotes stable blood clotting, and I think that they are right. One study of babies indicated that the body tries to keep the activation of the anti clotting and the clotting proteins in balance when the level of vitamin K is low [2].
        If the levels of activated proteins are low then an imbalance is more likely to occur since some of the anti clotting proteins have other functions. For instance protein S has an independent anti inflammatory function. Protein S exists in three forms in the body:-
        1. Uncarboxylated protein S – no known function, useless? – caused by lack of vitamin K
        2. Carboxylated protein S – anti clotting, low levels are a risk factor for deep vein thrombosis.
        3. Carboxylated protein S combined with C4 binding protein – this is an anti inflammatory compound.
        Lack of vitamin S is linked to deep vein thrombosis. Medical articles on protein S deficiency mention that one cause is a deficiency in vitamin K. The study on babies [2] also found that over the period that the measurements were taken that the level of protein S was dropping in neonates who were deficient in vitamin K.
        If the body has enough vitamin K it is programmed to use it in a sensible fashion. It is low levels of K that are linked to clotting problems.

        Safety of vitamin K
        People in Japan are prescribed daily doses of 45,000 micrograms of vitamin K2 (MK4) for osteoporosis. This is a large amount of K2, it has been reported that a very small number of people on this treatment have reported side effects like skin rash and gastrointestinal problems. Whether this is due to the K2, the other material in the capsules or to their other medication is a question. Whether one needs as much as 45,000 micrograms of K2 a day is also another question.
        The manufacturer of this particular K2 (Glakay) has a information leaflet describing the effectiveness, also the reported side effects and the toxicity of vitamin K2 [3]. The Glakay document mentions the toxicity test in animals; it describes doses of 2000 mg/kg/day of K2 for 12 months to dogs, there was no toxicity effect on the dogs. This is 2,000,000 micrograms/kg/day, so the equivalent for 70 Kg person would be daily doses of 140,000,000 micrograms K2 per day.
        There was another series of tests on vitamin K2 (MK7) [4]. These were on toxicity, rats were given a single dose of 2,000mg/kg of K2 (MK7) – there was no adverse effect. Rats were then given 10 mg/kg body weight of K2 (MK7) for 90 days again there were no observable adverse effects. The 10 mg/kg would be equivalent to a 70 kg person taking 700,000 micrograms of the MK7 form of K2 per day for 90 days.
        So it looks like vitamin K2 is not toxic, even in extremely high doses.
        Babies all over the world are given vitamin K injections (about 1 to 2 mgs) to avoid the very small risk of vitamin K dependent bleeding (VKDB) which can cause disablement or death. In some countries babies are given oral vitamin K, in Denmark babies are given 2 mgs at birth and then 1 mg a week for 3 months. In the period from 1992 to 2000 in Denmark, 384,000 babies were treated by this method and no cases of VKDB were reported [5]. This is done to prevent a 1 in 100,000 chance of a bleed. No adverse effects have been reported. Roughly speaking this is equivalent to an adult receiving a one of dose of 40,000 micrograms and then about 15,000 micrograms once a week. If excess vitamin K caused any problem I think it should be apparent.
        The EFSA have agreed that vitamin K2 can be added to food. I believe that the addition of K2 to food will occur once a few more studies have been published.
        (Note: Where I have used mg it is 1 milligram).

        Optimum Amount of K2 – 180 micrograms K2 MK7?
        Well this is an interesting question. My answer is I don’t know. People vary in their ability to absorb and use vitamin K. People vary in the ways that vitamin K is transported around the body and the different forms of K are transported differently. However 180 micrograms K2 (MK7) is a reasonable amount that should have a beneficial effect. There will be better understanding as more studies get done.
        There are a range of forms available in the diet; K1 from green plants, K2 (MK4) from meat, K2 (MK6, 7, 8, 9, …) from fermented products (cheese, natto, yogurt, etc) and probably also from liver.
        It had been found that K1 can be converted by animals into K2. However an important factor is getting the K1 into the appropriate organ, once the K1 ends up in the liver it doesn’t seem to go anywhere else. The MK7 form does go to the liver but it is able to leave the liver in VLDL, so it looks more able to get to other parts of the body.
        As I mentioned previously Dutch scientists found that they needed to use a minimum of 180 micrograms of K2 (MK7) per day. Another study in people with kidney disease found that higher doses were needed.
        To get an idea of how much K2 (MK7) could be consumed naturally from diet I would refer to a Japanese study on osteoporosis, it described stronger hip bones in women consuming over 4 packs of natto per week [6]. They stated that one pack of natto contains about 350 micrograms of K2 (MK7) and so the total weekly consumption of vitamin K2 (MK7) in the group of women with the higher intake would be over 1,400 micrograms, ie over 200 micrograms per day.
        A Greek study (7) looking at a combination of vitamin D3 and vitamin K for bone health, found benefits with both K1 and K2 (Mk7), they used a dose of 100 micrograms with both forms of vitamin K.
        When I first started taking K2 myself I started off with 50 micrograms for 1 week, and then increased the amount by 50 micrograms a week until I got up to 350 micrograms/day of the MK7 form of K2. My GP regards me as a vitamin K2 guinea pig; he didn’t seem to regard my intake as excessive. Bear in mind that people who take vitamin supplements are usually talking about milligram figures, also if you look at medications they all tend to be in the milligram range.
        I would note that I have tried 15 mg a day of vitamin K2 (MK4) out of curiosity. I didn’t notice any difference. I decided to stick to a quantity and type that I could get from the diet – if I ate natto.
        Out of interest the NHS has a write up on vitamin K. I don’t agree with the viewpoint since the author doesn’t seem too aware of the latest research [8]. However with important subjects it is very important to look at different viewpoints.

        The Future
        I would like to quote from the conclusion in a recent paper by Italian medical researchers [9].
        “Vitamin K2 deficiency has recently been recognized as a protagonist in the development of vascular calcification and osteoporosis. Data reported so far are promising and, dietary supplementation seems a useful tool to contrast these diseases. However, large studies or solid clinical correlations regarding vitamin K2 deficiency and its pathologic consequences are needed to confirm these preliminary experiences.”
        The one hope I have is that these studies and trials will be done. I also hope that studies on the effect of vitamin K2 on many other illnesses will be carried out. The potential benefit is enormous.

        References
        (1) Zhang Y, Tang Z. Research Progress of Warfarin-associated Vascular Calcification and its Possible Therapy. J Cardiovasc Pharmacol 2013.
        http://europepmc.org/abstract/MED/24072176

        (2) Matsuzaka T, Tanaka H, Fukuda M, Aoki M, Tsuji Y, Kondoh H. Relationship between vitamin K dependent coagulation factors and anticoagulants (protein C and protein S) in neonatal vitamin K deficiency. Arch Dis Child 1993;68(3 Spec No):297-302.
        http://adc.bmj.com/content/68/3_Spec_No/297.abstract

        (3) Glakay Information sheet.
        http://www.mims.com/thailand/drug/info/Glakay/?type=full
        Note:- if the link doesnt’ work you can try searching using the terms – Glakay side effect.

        (4) Toxicol Mech Methods. 2011 Sep;21(7):520-32. doi: 10.3109/15376516.2011.568983. Epub 2011 Jul 25.
        Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7.
        Pucaj K, Rasmussen H, Møller M, Preston T.
        http://www.ncbi.nlm.nih.gov/pubmed/21781006

        (5) Acta Paediatr. 2003 Jul;92(7):802-5.
        Weekly oral vitamin K prophylaxis in Denmark.
        Hansen KN, Minousis M, Ebbesen F.
        http://www.ncbi.nlm.nih.gov/pubmed/12892158

        (6) Ikeda Y, Iki M, Morita A, Kajita E, Kagamimori S, Kagawa Y, et al. Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study. J Nutr 2006;136(5):1323-1328.
        http://jn.nutrition.org/content/136/5/1323.full

        (7) Kanellakis S, Moschonis G, Tenta R, Schaafsma A, van den Heuvel EGHM, Papaioannou N, et al. Changes in Parameters of Bone Metabolism in Postmenopausal Women Following a 12-Month Intervention Period Using Dairy Products Enriched with Calcium, Vitamin D, and Phylloquinone (Vitamin K-1) or Menaquinone-7 (Vitamin K-2): The Postmenopausal Health Study II. Calcif Tissue Int 2012 APR;90(4):251-262.
        http://www.ncbi.nlm.nih.gov/pubmed/22392526

        (8) Vitamins and minerals – Vitamin K NHS
        http://www.nhs.uk/Conditions/vitamins-minerals/Pages/vitamin-k.aspx

        (9) Flore R, Ponziani F, Di Rienzo T, Zocco M, Flex A, Gerardino L, et al. Something more to say about calcium homeostasis: the role of vitamin K2 in vascular calcification and osteoporosis. Eur Rev Med Pharmacol Sci 2013;17(18):2433-2440.
        http://www.ncbi.nlm.nih.gov/pubmed/24089220

  10. Michelle Hough

    I laughed out loud when I read the quotes but then stopped myself because this is not funny. People are still taking these things when there is no reason for them to do so. I can just see the headline ‘Super Statin Cures All’ in the media. A very scary thought.

    Reply
  11. dearieme

    I did like the Auden.

    Are the authors of the paper trying to signal “Help: we are trapped in a disgusting incentive system but we want bits of truth to leak out nonetheless”?

    Reply
  12. james

    Interestingly mr. Jukema states after listing his extensive connections to Big Pharma : I will not present recommendations regarding use drugs or devices from companies with which I have a financial relationship. No Michelle this is not funny. I am just wondering when something like this Jukema and De Graaf stuff could be labeled as criminal intent.

    Reply
    1. Richard Gibbs

      There’s a lot of waffling in that response without any citing definitive studies. The most amazing part I found was “There’s debate about how much benefit women receive from this approach because they develop heart disease later and clinical trials of statins have often not gone on long enough to show the magnitude of effect. But absolute risk tools cope with that by adjusting for gender.” There aren’t any long term statin studies and how exactly do you adjust risk tools when there isn’t any evidence to base them on. The bottom line should be “there’s no evidence that taking statins is beneficial”.

      Reply
  13. Arie Brand

    Malcolm, I have asked you this question before but you are now perhaps in a better position to answer it. What do you think of Pauling – Rath’s so-called “unified theory of heart disease” and the related therapy proposed by the cardiologist Dr.Thomas Levy:
    daily 6 gr.Vitamin c, 6 gr. Lysine, 2gr. Arginine and 2 gr.Proline.

    There is very little discussion of it on the internet.

    Reply
    1. Dr. Malcolm Kendrick Post author

      I have always like Pauling and Rath’s hypothesis. I promote arginine, vitamin C, K, B(s), coenzyme Q10 and l-carnitine. Anything that can raise NO levels, increase energy production in mitochondria, protect the artery/endothelium from damage must be a good thing. However, there is no one singel answer. The development of atheroclerosis is a process, a bit like a car rusting. You need several factors working together to cause damage. Vitamin C alone is not the answer. EPCs are not the answer. Lots of things, working together, are the answer.

      Reply
      1. Kevin O'Connell

        Don’t forget chocolate (proper dark stuff):
        Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: a randomized controlled trial. JAMA. 2007 Jul 4;298(1):49-60. PMID: 17609490 ….
        “…small amounts of polyphenol-rich dark chocolate as part of a usual diet efficiently reduced BP and improved formation of vasodilative nitric oxide.”
        yum, yum.

    2. Raymond Haagensen

      Re, Pauling and Rath,
      Have you seen this book?
      A (Patented) Heart Disease Cure That Works!: What Your Doctor May Not Know. What Big Pharma Hopes You Don’t Find… by David H Leake (Jul 4, 2012)

      Reply
  14. David Bailey

    Is there any possibility that the war against trans fats is also not justified? Here is what Wiki has to say about trans fats:

    http://en.wikipedia.org/wiki/Trans_fat

    At the start of the article, it blames trans fats for altering LDL and HDL levels, but if these don’t cause heart disease, then at least this criticism of trans fat is invalid!

    The problem, of course, is that it is easy to become wary of all health scares though I don’t plan to smoke my first cigarette any time soon!).

    David

    Reply
    1. Richard Gibbs

      Short answer: No.
      Longer answer: The basic omega-6 fatty acid (linoleic acid) and the basic omega-3 fatty acid (linolenic acid) are the building blocks for eicosanoids (hormone like substances such as prostaglandins and leukotrienes). If you start partially hydrogenating these fatty acids (which is certainly the case with soybean oil since it contains both) you are transforming those acids in an unpredictable way, but they will end up with unnatural trans bonds. No one really knows how these unnatural fats will interact with the enzymes that make eicosanoids, i.e they might inhibit the production of eicosanoids or make some unnatural eicosanoid like molecules.
      This is really why trans-fats are bad; it has nothing to do with their effects on lipid levels.

      Reply
      1. Richard Gibbs

        In the US the FDA has finally announced its intention to effectively eliminate trans-fats from food. I first learned about trans-fats 20 years ago and effectively eliminated them from the family diet. My children certainly seemed healthier after we did that. I think 20 years is probably a typical time for an idea to make its way into the mainstream. About 45-50 years ago I heard a then famous scientist (but can’t remember who) say “You never disprove a theory, but eventually its supporters die out”, so 20 years is probably about the right time frame for a theory’s supporters to at least retire!

      2. David Bailey

        Has anyone looked for and found eicosanoids with trans bonds, or detected abnormal levels of these compounds in humans or animals who have eaten trans fats, and is there any animal evidence that trans fats actually cause disease? To be clear, I am not pushing this idea, I am just curious as to how great this danger is.

        I mean, obviously it is undesirable to consume unnatural compounds of any sort, particularly those whose structure is close to a biologically active molecule, but I noticed that efforts to remove trans fats are criticised here:

        http://junkscience.com/2011/05/04/why-illinois-proposed-ban-on-trans-fats-should-be-stopped-fact-sheet/

        Paradoxically if they just finished the hydrogenation, they would end up with a natural product again!

      3. Dr. Malcolm Kendrick Post author

        I beleive I have read papers where this has been found – I shall go back and have a look. I think you are, of course, right to be skeptical of non-skeptical skeptics. I start from a simple baseline. Trans-fats are very rarely found in nature, so it is exceedingly unlikley that our cell membranes and/or receptors are designed to incorporate them into their structure. Whilst it is impossible to work out the harms that this may cause, it is likely that a wide range of harms could occur. In short. There is no need to eat trans-fats, the body is not designed to ingest them, they could cause harm (the evidence suggests that they do), so I can see no reason not to avoid them if possible.

      4. Professor Göran Sjöberg

        Agree!

        After my very severe heart attack 1999 I decided to cut out all “partially saturated fats” – read margarine – from my diet due to what I, at that time, had found out about trans-fats. I think that was the best decision I have ever made in my life.

  15. dearieme

    ‘I heard a then famous scientist (but can’t remember who) say “You never disprove a theory, but eventually its supporters die out””

    The originator of this view is usually said to be Max Planck. Decades ago I read about a paper by a psychologist who had looked into the facts. He said it was false: broadly, older physicists had proved as likely as younger ones to adapt their views to revolutionary physics.

    Reply
      1. Mike Wroe

        Dr Kendrick

        Fascinating blog, as always. Thank you.
        Can you reconcile the statement of the authors of this piece in the European Heart Journal with the three separate studies one in Atherosclerosis, Vol. 225, Issue 1, one in Circulation, Vol. 112, 2005 and the other in Diabetes Care. August 8, 2012.
        In the European Heart Journal the authors say “there is overwhelming evidence for the beneficial effects of statin therapy on plaque progression”.
        Professors Sultan and Hynes, (whose paper in Open Journal of Endocrine and Metabolic Diseases you have reviewed in an earlier blog) summarised their interpretation of the evidence in the three latter studies as follows “statins are associated with triple the risk of coronary artery and aortic artery calcification.
        Both can’t be right!

      2. Dr. Malcolm Kendrick Post author

        There is only one interpretation of the statin data that makes sense – I believe. Statins do not work by lowering cholesterol levels, they have other mechanisms of action.

      3. dearieme

        No, it meant that they’d been persuaded to the same substantial degree. Maybe The Real Problem is middle-aged scientists mud-wrestling for money and power.

  16. Rural patient

    PJT13 – Maybe my problem vaguely resembles yours. Everything seems to be OK for a fairly long and healthy life … except BP. FBG is 5.2, TGs are 0.8, TC is 5.3 (bog-standard, not high as yours is).

    BP is very variable according to my mood at the time and was once as high as 180/110 measured in the doctor’s surgery. Usually it’s around 140/90 or under.

    I’d really like lower BP but if I go near the NHS the side-effects of the tablets seem worse than the disease.

    Have others found any dietary “tweaks” to get it down to nearer 120/70? I already eat LC though and I’ve been thin all my life.

    Did highish BP have an obscure evolutionary advantage?? Maybe 140/90 is not disastrous if one’s over 60 and other blood tests seem alright. But it doesn’t seem that desirable.

    Reply
  17. dearieme

    Q for Doc K. Is there a rational way to discover whether high BP is a Bad Thing, and, if so, to identify the threshold for badthinginess?

    Reply
    1. Dr. Malcolm Kendrick Post author

      High BP is a bad thing. It is, primarily, a sign that there is something wrong with the CV system. Is there a threshold. Not easy to say. My own view is thave anything over 160 systolic and 110 diastolic means you are at increaseed risk of a CV event. Does lowering it create benefit….hmmmm. I think the concept of hysteresis is relevent here.

      Reply
  18. Lorna

    So if BP is lowered by medication, what happens to the underlying problem? And if, as some ppeople describe, a change to a low carb diet has helped, how has the high carb diet created the high BP?

    Reply
      1. Lorna

        Thanks for the clear answer. If blood pressure reducation doesn’t change the underlying problem, why isn’t the underlying problem investigated alongside the BP medication? Seems potentially a lot of tablets to give out to alter BP numbers rather than treat the condition?

  19. Kim Brebach

    Great piece, Malcolm, thank you.
    Over the years, I’ve observed a 25-year cycle in the life of drugs:
    first 5 years: magic bullet, no side effects
    next 5 years: magic bullet, a few insignificant side effects
    next 5 years: great drug, but it does have side effects (rarely serious)
    next 5 years; very useful drug but some serious side effects. We have a new, even better drug in the pipeline.
    next 5 years: the old drug wasn’t as good as we thought, but this new drug class is much more effective and has no side effects
    (repeat cycles)

    Reply
    1. Richard Gibbs

      Of course it also relates to the length of patent protection.

      In light of the new ACC/AHA guidelines it seems that the new PCSK9 inhibitors are going to be a harder sell. Currently in the US, to get a new drug on the market it has been satisfactory for a drug company just to show that it reduces LDL (as I think was the case with Crestor). Now it looks like they will have to show benefits based on mortality and/or reduction of adverse events.

      Reply
  20. Pingback: Has there been a paradigm shift in nutrition? | Informed Health

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