What causes heart disease part IV

I have entitled this little series ‘What causes heart disease?’ But I have been at pains to point out that you cannot possibly establish potential causes heart disease, until you are clear about the underlying process.

By this I mean you can say that smoking causes heart disease – and you would be right. You can also say that Systemic Lupus Erythematosus (SLE) causes heart disease – and you would also be right. You can say that type II diabetes causes heart disease – and you would be, guess what, right. You could say that obstructive sleep apnoea causes heart disease and you would be… right again. Steroids…right again. High levels of fibrinogen…right once more. Cushing’s disease…right. Depression… bang on the button.

But you have to be able to answer the question, how can these very different things lead to the same disease? Or, perhaps you are going to argue they all cause different diseases, that look exactly the same? If so we are doomed, as this would mean that there are a hundred different types of heart disease each with their own individual cause. (I believe this to be unlikely, and am not further discussing it as a possibility).

In short, you cannot simply go around stating that you have identified cause after cause, after cause after cause. Or you can, but it does not help in the slightest with understanding what is going on. It just becomes increasingly confusing. You must establish the process, or processes, that can link all of these potential causes together. Until you can answer this, you are basically just floundering about.

I spent thirty years floundering about in this unending kaleidoscope of risk factors before I decided that it was mission critical to work out what was the actual disease process underpinning CVD. In the end, it came down to this.

The four stage process

Heart disease – or the development of atherosclerotic plaques, followed by the final, fatal, blood clot – consists of four stages. These stages obviously overlap, and interact, and separating them out is a somewhat artificial process. However, I think a degree of separation is necessary for understanding. You can jumble them all around again afterwards.

I should also say that; in this particular blog, I am only going to look at the first stage of the four stage process. And the first stage is endothelial damage.

The endothelium

The endothelium is a single layer of cells that lines all arteries, and veins. At one time endothelial cells were believed to be essentially inert. They just sat there, lining the blood vessels, and not doing much. But, of course, these cells are gigantically, mind-bogglingly, complex.

However, for the sake of this discussion, I am only going to look at three aspects of endothelial cells.

  • Nitric oxide synthesis
  • What happens when endothelial cells are damaged
  • Tissue factor

Nitric oxide synthesis

A critical role of endothelial cells is to manufacture nitric oxide (NO). When it comes to CVD, this little molecule is absolutely key. First, it relaxes the smooth muscle in artery walls, causing them to relax, which opens up the surrounding artery. This then lowers blood pressure.

Within conventional medicine various ‘nitrates’ are given to people with angina, which opens up the coronary arteries, improves blood flow and the oxygen supply improves. The first of these to be discovered was nitro-glycerine. Renamed glyceryl tri-nitrate, and put into tablets to dissolve under the tongue.

NO is also a very powerful anticoagulant – it stops the blood clotting. This is clearly essential as you do not want clots forming on normal blood vessel walls, and when NO levels fall, accidental blood clotting becomes a real possibility.

Healthy endothelial cells produce lots of NO. Stressed and damaged endothelial cells do not. Which means if you have stressed or ‘dysfunctional’ endothelial cells, your arteries are narrower ‘constricted’ and the blood within them more likely to clot.

In recent years it has been recognised that damage to endothelial cells is an early marker of atherosclerosis, as made clear in this paper, entitled: ‘Endothelial dysfunction: the early predictor of atherosclerosis.’

‘Endothelial dysfunction, characterised by reduced NO bioavailability, is now recognised by many as an early, reversible precursor of atherosclerosis.’ 1

Which means that damaged, or dysfunctional, endothelial cells can be recognised by their failure to produce NO. On the slip side, if there is abundant NO in the body this seems, in reverse, to keep endothelial cells healthy.

There are some drugs, supplements, and activities, that can actually increase NO synthesis in endothelial cells, and also the rest of the body. Possibly the most powerful single factor that can do this is sunlight. As highlighted in this paper, where the rather snappy title actually says all that needs to be said: ‘Whole body UVA irradiation lowers systemic blood pressure by release of nitric oxide from intracutaneous photolabile nitric oxide derivates.2

Essentially, if you sunbathe, NO is released throughout the body, and your blood pressure drops (as your arteries open wider). Other studies have found many other major benefits of sun exposure on lung, breast, prostate and colo-rectal cancer, but that is a story for another day.

For now, the focus here is simple. Endothelial cells produce NO, this chemical is vital for CVD health. Any factor that reduces NO synthesis is unhealthy, any factor that increases NO synthesis will protect against CVD.

What happens when endothelial cells are damaged

I am not looking in any great detail here at how endothelial cells are damaged, although there are many, many, things that have a negative impact on the health and wellbeing of endothelial cells. High blood sugar, low blood sugar, steroids, smoking, cocaine, SLE, Obstructive Sleep Apnoea (OSA), and suchlike.

Perhaps the single most important factor that can damage endothelial cells is this – biomechanical stress. By biochemical stress I mean turbulent blood flow, stretching and bending of the blood vessel, high shear stress, high blood pressure, rapid blood flow, points where the blood has to change direction violently.

Violent direction occurs where smaller arteries branch off from larger one e.g. where carotid arteries (that supply blood to be brain) branch from the aorta at the base of the neck. Such points are called bifurcations, and bifurcations are where the biggest and most ‘vulnerable’ atherosclerotic plaques are almost always to be found.

In reality, extreme biomechanical stress only takes place in the larger arteries in the body, where the pressure is high and there are great forces for the endothelium to deal with. A raging white water river. Place a pebble on the side of this maelstrom and it will soon be ripped off and dragged downstream. Veins and the arteries in your lungs, on the other hand, are more like the lazy rivers of East Anglia, slowly meandering along through flat fields.

It is almost certain that the massive difference in the biomechanical stress that endothelial cells have to deal with, in arteries, in comparison to veins and pulmonary blood vessels (the blood vessels in the lungs) fully explains why atherosclerotic plaques never develop in veins and never develop in the pulmonary blood vessels (blood vessels in the lungs). Despite that fact that these blood vessels are exposed to exactly the same ‘risk factors’ as the arteries.

Moving on. It is possible to do more than simply stress endothelial. They can simply be stripped off. If and when this does happen, not only is there no NO at that location, something else far more important comes into play….

Tissue factor

Sitting within all artery walls (and all vein walls too) is a substance called Tissue Factor (TF). It is by far the most powerful clotting agent known to nature. If you expose blood to it, a clot will immediately form, right on top.

This makes sense. If a large blood vessel is damaged, you will bleed to death very rapidly, unless a very strongly constructed blood clot forms right on top of the damaged are, to block the hole. Another point to mention is that TF triggers the ‘extrinsic’ clotting system which simply bypasses a large part of the blood clotting system. Clot right here, right now!

In truth, the system of blood clotting is incredibly complex, and I have not the slightest intention of covering it all here. Probably because I don’t fully understand it myself. However, at its simplest, blood clots consist of two key components. Platelets and fibrin.

Platelets are small ‘sticky’ cells. They are activated by exposure to Tissue Factor (TF), at which point they start clumping together to get the clot started. Whilst doing this they release about five hundred other substances that further activate the entire ‘clotting cascade.’ Then all hell breaks loose.

The end result of all of these clotting factors activating is that small strands of protein called fibrinogen are stuck together for form a long, very strong, string of protein called fibrin. This wraps round platelets, and anything else floating past, and binds everything together in a tight and very strong blood clot.

This clot then sticks very firmly to the site of damage, and grows, until all the damage is covered up. At which point the other five hundred factors that are designed to stop blood clots forming and/or getting too big, stop the clotting process in its tracks.

After the clotting process has been whipped into action, then brought to a halt, we have a blood clot stuck to the inside of the artery wall. Obviously if it grew too big it will have completely blocked the artery – resulting in a heart attack, or suchlike. Assuming, however, that it stopped growing, before completely blocking the artery. What then happens to it?

To be continued.

References:
1: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721957/
2: http://www.ncbi.nlm.nih.gov/pubmed/19797169

What causes heart disease – part III

In most diseases it is best to start at the beginning and work forwards. This should be the case with cardiovascular disease (CVD) too. However, for complex reasons I found myself starting at the end, and working backwards. The main reason for this is that I had to start with certainty. Yet, almost everywhere I looked there was mush. For example, the epidemiology of CVD.

Now you would think that there would be agreement about how many people actually die from CVD in different countries and at different times. Not a bit of it.

A researcher:                                    ‘The French have a low rate of CVD.’

A N Other researcher:            ‘Oh well the French, they don’t agree with the normal definitions, they don’t classify CVD properly. Who knows what the true rate may be?’

True? False? A bit true? Taking another example. I have looked at the figures from the US and, you know what. Not a single person died of Ischaemic Heart Disease before 1948. Amazing. What was protecting them? [Dying from IHD is what you would also call a heart attack, or MI]. What was protecting them was the fact that IHD did not exist in the US as a disease classification, before 1948.

This then changed. In 1948 the World Health Organisation was created, and one of the first things they did was to create an International Disease Classification system (ICD). Heart disease is 1. Cancer is 2. (example for illustrative purposes only). Of course it is a bit more complex than that. Just to look in more detail at Ischaemic Heart Disease: [See box]:

IschemicHD

Not every country took up the ICD system. Until 1968 the French did not use the ICD codes (so I am told, which no doubt means this is not true). Therefore, in France, statistics on deaths from IHD in France, before this date, are completely unreliable.

It goes without saying that, before 1948, no-one else used the ICD system either, because it did not exist. So, what can we tell about the epidemiology of CVD before 1948? Nothing. Or at least nothing you could hang your hat on. IHD would have been mixed within a much broader ‘Heart Disease’ in the death certificate statistics. And heart disease could mean almost anything, from cardiomyopathy to pericarditis, to atrial fibrillation.

Even after the ICD system was introduced, and even after France came on board, many countries clearly did not use it in the same way. Which is why the WHO set up the MONICA study.

‘The MONICA (Multinational MONItoring of trends and determinants in CArdiovascular disease) Project was established in the early 1980s in many Centres around the world to monitor trends in cardiovascular diseases, and to relate these to risk factor changes in the population over a ten year period. It was set up to explain the diverse trends in cardiovascular disease mortality which were observed from the 1970s onwards. There were total of 32 MONICA Collaborating Centres in 21 countries. The total population age 25-64 years monitored was ten million men and women. The ten year data collection was completed in the late 1990s, and the main results were published in the following years. The data are still being used for analysis.’

It was also an attempt to see if different countries were actually looking at the same diseases, and classifying them in the same way. Even after that, the data was still not absolutely clear cut, as further studies were then set up to see if the US system ARIC, and MONICA, actually matched each other. This was 1984.

‘To foster collaboration between the World Health Organization MONICA Project and the NHLBI Study of Atherosclerosis Risk in Communities (ARIC). To ensure that valid comparisons could made between findings in MONICA and ARIC by supporting activities to standardize coding, classification, and analysis of coronary and stroke events, risk factors, and medical care according to MONICA protocol.’

In simple terms, the US has its system, ARIC, and Europe had its system MONICA. Do they actually match? In short we can see that, even as late as 1984, there was clear uncertainty about how diagnoses were being made and how data were being gathered around the world. Did it all match, or not.

Given such uncertainly on both definition and diagnosis, can we say that the US epidemic of CVD in the 1960s actually happened. Or were doctors just putting IHD on death certificates when they didn’t really know what killed the patient. Personally, I think the epidemic did occur. Actually I think it happened a bit earlier. It is my belief that it took a while for US doctors to start using the new-fangled WHO ICD system.

Anyway, the point I am trying to make is that it is incredibly difficult to find the ‘bedrock.’ By which I mean facts that are inarguable. Things you can base your thinking on that are absolutely true, or that are as close to absolutely true, as possible.

Which is why I ended up at the end, the formation of the final, often fatal, blood clot. A blood clot which, generally, forms over an existing atherosclerotic plaque. There is widespread agreement that this is the case. So we can, I think safely, start here.

[There are, undoubtedly other things going on, such as sympathetic stress, mitochondrial damage and acidosis with heart muscle. that play a hugely important role. But the clot is, usually the final event

It is also widely agreed that factors which increase blood clot formation (thrombophilc factors) increase the risk of dying from CVD, and that things that reduce blood clotting reduce the rate of death from CVD. Here are a few things that increase the risk of blood clots forming, in no particular order:

  • Dehydration
  • Waking up in the morning/getting up in the morning
  • Acute physical stress
  • Acute psychological stress
  • Having a high fibrinogen level
  • Diabetes
  • Cocaine use
  • Smoking
  • Cushing’s disease

Here are some of the things that reduce the risk of blood clots

  • Haemophilia
  • Von Willibrand Disease
  • Aspirin
  • Moderate alcohol consumption
  • Clopidogrel
  • Yoga
  • Regular exercise

I suppose I should add that all of the things that increase the risk of blood clotting also increase the risk of death from CVD, and vice versa.

This is hardly a complete surprise. If blood clots kill you, things that reduce blood clots will prevent you from dying, and vice-versa. Let us not fall to the ground in stunned amazement over this statement of the bleeding obvious.

At this point, and slightly out of sequence, I would like to introduce statins to the list of factors that reduce the risk of blood clots

Readers of this blog know that I am not keen on statins, to say the least. However, if the studies are to be believed, they do reduce the risk of CVD. Not to any great extent, but the effect certainly does exist. Many people use this fact to attack my view that raised cholesterol does not cause CVD. ‘Well, what about statins,’ they bellow in delight. ‘They lower cholesterol and reduce the risk of CVD. Case proven…next’

Well, as with all drugs, statins do many other things than lower cholesterol levels. For example:

‘Recent studies have shown that statins reduce thrombosis via multiple pathways, including inhibiting platelet activation and reducing the pathologic expression of the procoagulant protein tissue factor.’1

So, as they say, there. In fact, one could quite sensibly propose that statins work pretty much the same as aspirin. They are anti-coagulants, and lowering blood cholesterol is simply a nasty and unfortunate side-effect of statins.

In reality, statins have a far more important effect on CVD (through other actions also related to clot formation) that I will get to later. I just thought I would pop that statin fact in. I even provided a reference. I have not really done much referencing in this series up to now. I believe that it is very simple to type, for example, ‘regular exercise and reduced thrombus formation’ into Google and see what you get. Or ‘Yoga and reduced blood coagulation.’

Where was I? Oh yes. Things that increase blood clot formation are more likely to kill you from CVD, and vice versa. Nothing controversial here. But the potentially controversial bit starts right here.

Are there two processes or one?

Currently, whilst conventional thinking on CVD accepts that blood clot formation is almost always the final event in CVD. This represents a completely separate process to the development of the atherosclerotic plaque itself. In short, we have two unrelated physiological processes:

  • Plaque formation
  • Clot formation on top of plaque

I apologize for saying, essentially, the same thing in different ways. But I think it is important.

Strange then, is it not, that plaque formation and clot formation share so many risk factors? Smoking, for example. Diabetes, for example. In fact, you could say (with certain provisos) that the risk factors for plaque formation and blood clot formation, are exactly the same.

Which gives one to think. Well it certainly gave me to think. Could it be that plaque formation, and blood clot formation, are simply two different manifestations of exactly the same underlying disease process. From a pure scientific perspective, I liked the idea. I liked it because it seems clumsy to have a disease, CVD, that is made up of two, essentially unelated processes

In medicine, as in all of science, one single disease process always looks much better, much cleaner, and much more likely to be right. This is the principle of Occam’s razor:

‘The principle in philosophy and science that assumptions introduced to explain a thing must not be multiplied beyond necessity, and hence the simplest of several hypotheses is always the best in accounting for unexplained facts.

Next: The four step process of CVD

References:
1: http://www.ncbi.nlm.nih.gov/pubmed/24422578

What causes heart disease – part II

[By heart disease I mean, the development of atherosclerotic plaques in large arteries. Mainly the coronary arteries (supplying blood to the heart) and carotid arteries (supplying blood to the brain). This, I will refer to as Cardiovascular Disease CVD. Not entirely accurate, but language never is.]

At this point, I am going to start at the end. What kills people? (Or what causes myocardial and cerebral infarctions). You might think that this was clear cut, but of course it is not, far from it. For example, there is a major cause of death from ischaemic strokes that has nothing whatsoever to do with CVD. This is Atrial Fibrillation.

Atrial fibrillation (AF), is a condition where the upper chambers in the heart (atria) do not contract in a regular and co-ordinated fashion. Instead, they fibrillate – AF definition : ‘(of a muscle, especially in the heart) make a quivering movement due to uncoordinated contraction of the individual fibrils.’ AF is pretty common.

People who have AF tend to develop blood clots in the atria. These can break loose, and are then ejected from the heart into other parts of the body. Quite commonly these clots travel into the brain. As the artery the clot is traveling down narrows, the clot gets stuck, and blood supply is cut off, leading to an area of ‘ischaemia’ (no oxygen) and a stroke. A cerebral infarction.

Which means that it is perfectly possible to have strokes (cerebral infarctions) that are unrelated to CVD. If, that is, you define CVD as the development of atherosclerotic plaques. You can also have strokes where an artery in the brain bursts, causing bleeding into brain tissue, which is called a haemorrhagic stroke. This is clinically indistinguishable from an ischaemic stroke. You need a brain scan to see what type of stroke has happened.

Ergo, whist death from a stroke is clearly a form of cardiovascular disease, many strokes have nothing whatsoever to do with atherosclerotic plaques – which is what I am calling CVD.

Equally you can die from something commonly defined as a ‘heart attack’ which has nothing to do with atherosclerotic plaque development either. You can, for example, develop a fatal arrhythmia. This is where the conduction system in the heart goes wonky, the heart stops contracting regularly, and you die. [Of course, quite often this happens as part of a myocardial infarction].

If we put aside these forms of dying of strokes and heart attacks, we can then focus more clearly on the event that kills you with CVD? Which is, in general, a clot forming on a vulnerable plaque, and blocking an artery, leading to a myocardial infarction (heart attack).

Looking at strokes. If a clot forms in a carotid artery, it does not tend to block the artery completely. Instead, a part of the clot breaks off, and travels up into the brain where is gets stuck – causing a stroke (as per AF).

But… there are those who disagree with this simple model. Mainly with regard to heart attacks. I am fully aware of a growing movement which states that the myocardial infarction (heart attack) happens first, then the clot forms afterwards. (Incidentally, this concept is not new; it was first proposed over eighty years ago. You may think that is seems completely mad. However, there is strong evidence that would appear to support this ‘reverse’ hypothesis’ (infarction first, then the blood clot forming in the artery).

For example, in many cases after a confirmed and accurately diagnosed myocardial infarction, you cannot find any blood clot in the artery leading to the infarcted area. In other cases, you can find a blood clot that is several days, or weeks old. This age of the clot can be established because of the ‘evolved’ state of the thrombus. In short, there is no ‘temporal’ connection between the blood clot forming and the heart attack occurring.

On the other hand, you can find an acute blockage of a coronary artery that has not caused any symptoms, let alone a myocardial infarction.

Anyway, if you try to bring these facts together you find that:

  • Myocardial infarctions can occur without any clot being found in an artery
  • A clot can form in coronary artery days, or weeks, before any symptoms of an MI
  • A clot can fully obstruct the coronary artery, without causing a myocardial infarction

Given these facts (facts which, incidentally, are not in dispute), you can make a pretty strong case that there is no causal association between a blood clot blocking a coronary artery, and an MI taking place. Instead people can, and indeed do, argue that the process is the other way around. Infarction first, then clot.

Perhaps, now, you can begin to understand why it has taken me thirty years to try and work out the underlying process of CVD. At times I have thought that there isn’t any… but that is another story, for another place

The reverse hypothesis – why it is not correct

I have studied the ‘reverse hypothesis’ – if that is a reasonable term for it – for many years, and I believe that it is wrong. The primary cause of a heart attack is simply a blood clot blocking a coronary artery. However, there are two major complications that lead to the apparent contradictions listed above. In no particular order they are the following:

  • An infarction does not mean that heart muscle dies
  • Collateral circulation develops

What is an infarction?

Cardiology is, unfortunately, dominated by highly simplistic thinking. Namely, plaque develops, clot forms, infarction occurs. The infarction occurring within minutes of the clot formation.

But this is nothing like the reality of what actually happens. Heart muscle, like all tissues in the body, is enormously complicated. If you suddenly reduce the blood supply, it can do several different things. It can infarct, it can hibernate, or it can do nothing much.

Just to look at infarction. The dictionary definition is… ‘obstruction of the blood supply to an organ or region of tissue, typically by a thrombus or embolus, causing local death of the tissue.’ Well, I’ve got news for you, heart muscle does not die (not unless the organism surrounding it dies).

Infarction, in the case of myocardial infarction, does not mean death of the tissue. Instead, the heart muscle undergoes a complex transformation into a different cell type. One that needs far less oxygen to survive and one that cannot do the contracting thing. But it is not dead. Because dead cells become necrotic and necrotic cells disintegrate. After a heart attack do you see disintegrated areas of the heart? No, you most certainly do not. You see a form of scar tissue developing.

There is also a halfway house that lies between infarction, and nothing happening. This is ‘hibernation’, a state whereby heart muscle simply decides to stop contracting/beating (to save oxygen use). If you do MRI scans on the heart, in those with known heart disease, such ‘silent’ regions are a relatively common finding. Sometimes these regions wake up and start beating again, sometimes they do not. Sometimes they go on to infarct.

Adding further to the complication, if a coronary artery starts to narrow, the heart will create small ‘collateral’ blood vessels to get round the narrowing, and keep the blood supply up. When, and if, the artery fully blocks, the collateral circulation will maintain the blood flow, and so nothing very much will happen, even if the coronary artery is fully blocked. Many people survive on collateral circulation alone.

All of which means that, after an artery blocks, one of three things can happen:

  • There is a sudden infarction (could be large enough to be fatal)
  • The heart muscle decides to hibernate, if there is sufficient collateral circulation to keep things ticking along
  • Nothing much happens. If there is high level of collateral circulation, the heart just carries on much as before.

Only in the first case will the obstructive blood clot closely precede the heart attack. In case two the hibernating heart muscle may later decide to infarct, if the circulation does not improve. This can happen under periods of high physical or psychological stress. Thus the formation of the blood clot can precede the infarction by days, weeks or months. Indeed, the clot may have been fully cleared away by the time infarction occurs.

In short, the apparent contradictions to the: clot → blockage → infarct hypothesis can be explained, reasonably easily. So long as you realise that what happens inside the heart is not a case of simple pipe-work, where there a fixed number of tubes (arteries) supply oxygen to a pump (the heart). If you block one tube, the pump is immediately damaged.

Heart attacks and strokes

However, my main reason for disbelieving the ‘reverse hypothesis’ is that the standard model works for both heart attacks and (most) ischaemic strokes.

In ischaemic strokes, as mentioned before, a blood clot forms over a plaque in a carotid artery. This rarely blocks the artery; as carotid arteries are much wider bore than coronary arteries. However, what happens next – after a variable time period – is that the clot breaks off and travels into the brain.

This is, essentially, exactly the same process as a heart attack – except the clot lodges further down the vascular tree. Not only are the processes of stroke and heart attack virtually identical, the risk factors for both are virtually identical. Perhaps most telling is the fact that people with plaques in their coronary arteries almost always have plaque in their carotid arteries, and vice-versa. For example, here is the title of a paper on this topc: ‘Tight relations between coronary calcification and atherosclerotic lesions in the carotid artery in chronic dialysis patients.’1

This is further supported by a study that has just come out, and published in BMJ open. Key points were:

  • We studied the risk of heart disease following a stroke in those patients with no cardiac history. This study is the largest of its kind and, by bringing together multiple data sets, robustly quantifies the risk of heart disease following stroke. As with all meta-analyses, the main limitation of this work relates to publication bias.
  • Most patients with stroke die of heart disease.
  • One in three patients with ischaemic stroke with no cardiac history have more than 50% coronary stenosis.
  • 3% are at risk of developing myocardial infarction within a year of their stroke.
  • Patients with stroke need to be screened for silent heart disease and appropriate and aggressive management of total cardiovascular risk factors is required2.

In short, the two conditions are the same. It is beyond any reasonable doubt that with ischaemic stroke, and myocardial infarctions, we are looking at the same underlying disease. To be frank I don’t think may people would disagree with this. But it does lead to a critical point. Namely has anyone, ever, argued that cerebral infarctions (strokes) happen before the blood clot blocks an artery in the brain?

No they have not. Because to do so would, quite frankly, be bonkers. We can be absolutely certain that blood clots cause infarctions in the brain. Yet many people quite strongly argue that with myocardial infarction it is the other way around. For the reasons outlined above I do not, and cannot, believe this. There is only one process, and no need to start searching for another.

You may wonder why I have gone off in such a wide detour here? There are two reasons. First to make it clear that this area is gigantically complex. Secondly, to reinforce the point that wherever and however you look at CVD, alternative hypotheses have been proposed. Until you have tracked them down, and examined them fully, you cannot really move on.

Next: Some answers.

References:
1: http://www.ncbi.nlm.nih.gov/pubmed/20470277

2: http://bmjopen.bmj.com/content/6/1/e009535.full

What causes heart disease?

I have been somewhat silent on this blog for a while. Mainly because I have been putting together ten thousand words on the true cause of heart disease. Of course, by heart disease I mean the thickenings and narrowings in the larger arteries in the body (atherosclerotic plaques). I am also focussing almost entirely on the arteries supplying blood to the heart (coronary arteries), and the main arteries that supply blood to the brain (carotid arteries).

Whilst atherosclerotic plaques can develop in other arteries that supply, for example, the kidneys, or the bowels, problems here are generally less common, and less severe – although not always. In general, however, the main killers in ‘heart disease’ are heart attacks and strokes (not all strokes, only the most common form of stroke, an ischaemic stroke). So, at the risk of becoming over-pedantic, and simultaneously sloppily inaccurate, I am calling heart disease Cardiovascular Disease (CVD), and looking at heart attacks and strokes.

With that out of the way, what causes cardiovascular disease (CVD)? Whilst it took me only a few days of research, many years ago, to realise that the diet-heart/cholesterol hypothesis was clearly nonsense. It has taken over thirty years to work out what is actually going on. In truth I could not truly progress until it suddenly dawned on me that I should not be looking for causes. For that is a mugs game.

Once you start looking for causes, you find that there is almost nothing that a human can ingest, or do, that has not been claimed to be a cause of CVD, or a cure for CVD. In many cases both… simultaneously. In 1981 a paper was published in the journal Atherosclerosis which outlined several hundred possible ‘factors’ involved in causing or preventing CVD. Today, if you hit Google, or Pubmed, I can guarantee that you could find several thousand different factors. If, that is, you could be bothered.

If you could be bothered, what could you possibly make of ten thousand different things involved in CVD in one way or another? Can they all be true risk factors? Some of them are certainly only associations, not causes. A few are simply statistical aberrations, found in one study and contradicted in another. Even removing them, there are so many, so very very many. Pick your favourite and trumpet it to the world. Vitamin K, Vitamin D, coffee, leafy green vegetables, omega 3 fatty acids, intermediate chain monounsaturated fats, HDL raising agents, selenium, lowering homocysteine…. on and on it goes.

Is there any other hypothesis where you have to fit in ten thousand different factors? No, there is not. Yet no one has been put off identifying more and more things. This is why, I believe, we have such a terrible mess. I amuse myself sometimes looking at the knots the cholesterol hypothesis ties itself into to.

Just to give one example. We have had ‘good’ cholesterol and ‘bad’ cholesterol for some time now. More recently we have ‘bad good’ cholesterol (raised HDL increasing CVD risk during the menopause), and ‘good bad’ cholesterol (light and fluffy LDL that protects against CVD). Now, that’s what I call a non-disprovable hypothesis. A risk factor that can be good, or bad. Or ‘Good bad’ and ‘bad good’.

Whilst contemplating such nonsense it came to me, in a moment of the blindingly obvious, that in order to understand CVD I had to move away from trying to fit ten thousand factors into the biggest intellectual jigsaw known to man, and move on. I had to know what the actual process is. What is actually happening in the arteries.

Once you start to look at CVD through this window, you suddenly realise that very little is ever written on this topic. The world famous cardiology bible ‘Braunwald’s Heart Disease’ is virtually silent on the matter. Or at least it was when I looked through it a few years ago.

In a massive book on heart disease, the process of CVD development is covered in less than half a page. The cholesterol hypothesis itself is usually left completely unexplained. Or there are gaping holes, and bits that you just have to take on faith. Raised LDL leaks/travels/gets into the artery wall where it creates inflammation and plaques develop. The end.

Then you start to ask, so why do plaques never develop in veins? Same structure as arteries, same level of LDL. Why do plaques never develop in the blood vessels in the lungs (pulmonary arteries and veins?). What has oxidised LDL got to do with it? Where does oxidation occur? How does LDL leak into coronary arteries, and carotid arteries, but cannot leak into arteries within the brain itself?

Questions, questions, questions and almost no decent answers. There is a kind of collective brouhaha noise with a lot of ‘well it just does’ thrown in when you start to ask. ‘Explain again, how does LDL get into the arterial wall. Each step please?’. You are usually met with perfect anti-Popparin logic. We know that raised cholesterol causes heart disease, so it must get into the arterial wall using some mechanism or other. And look, there is cholesterol in atherosclerotic plaques. So it must get through.

Of course, it is true you can find cholesterol in atherosclerotic plaques. No-one is going to deny that. But you can also find, for example, red blood cells (RBCs). Now, you might be able to explain how LDL can pass through endothelial cells (the cells that line the arteries) in some fashion. Although I would argue that, if so, why does LDL not pass through endothelial cells in veins. And why cannot it pass through, or between, endothelial cells in the arteries with the brain?

LDL molecules, after all, are minute in comparison to an endothelial cell. However, RBCs and endothelial cells are pretty much the same size. So, please try to explain to me how a RBC finds itself within the artery wall, underneath the endothelium? Try getting one cell, virtually the same size as another, to pass through it. A very clever trick indeed.

Then, if you start exploring further, you find that the cholesterol you find in atherosclerotic plaques almost certainly comes from the cholesterol rich membranes of RBCs.

The view that apoptotic macrophages (dead macrophages) are the predominant source of cholesterol in progressive (atherosclerotic) lesions is being challenged as new lines of evidence suggest erythrocyte membranes contribute to a significant amount of free cholesterol in plaques.’1

Oh look, it seems that the cholesterol does not come from LDL. Anyway, I am jumping ahead of myself here, and getting dragged back into explaining why the cholesterol hypothesis is nonsense. Which is playing the game on the opponents’ pitch, under their rules.

The simple fact is that, to replace the Cholesterol hypothesis, there is a need to come up with something better, which actually fits all the facts. That, of course, is rather trickier as – boy – there are a lot of facts. Also, some of them may seem utterly disconnected.

My simple credo is that, if your hypothesis cannot explain everything about CVD you cannot explain anything. Attempting to do otherwise means that you are left suggesting that there are many different causes, and many different processes, all of which end up causing CVD through non-connected mechanisms. Well if that is true, then we just have to give up. Smoking causes CVD like this, LDL causes it like that, diabetes in a completely different way.

This is why I get so frustrated when people simply shrug their shoulders in a debate on CVD, and retreat to the position of inarguable logic when they tell me that CVD is ‘mutifactorial.’ To which I agree that of course it is bleeding mutlfactorial (as are all diseases). But that the statement itself is meaningless, unless you can then tell me how all the ‘multi’ factors fit together within a single, unified process.

In short, with CVD, if you are going to explain it, you need to be able to explain how, for example, the following factors increase risk, and through what single mechanism, or process. [This is not an exhaustive list by any means, but these are all definite, and potent, causes]:

  • Rheumatoid arthritis
  • Steroid use
  • Systemic Lupus Erythematosus
  • Smoking
  • Kawasaki’s disease
  • Use of Non-steroidal anti-inflammatory drugs e.g. ibuprofen, naproxen and suchlike.
  • Being a deep coal miner – especially in Russia
  • Using cocaine
  • Getting older
  • Getting up in the morning – especially on Mondays
  • Type II diabetes
  • Raised fibrinogen level
  • Cushing’s disease
  • Air pollution
  • Acute physical or psychological stress
  • Chronic kidney disease
  • Avastin – a cancer drug

Looking at one of these risk factors, System Lupus Erythematosus. Young women with this condition have, in some studies, an increased risk of CVD of 5,500%. Compare that with, for example, raised LDL. Even if you believe that it raises the risk of CVD, which is debatable, the increase in risk (as defined by mainstream research) is 66% for a 3mmol/l increase in the LDL level2. Changing the LDL level by this much takes you from low risk, to Familial Hypercholesterolaemia (FH).

If we accept that the 66% figure is, indeed, correct, we can see that SLE increases the risk 83 times more than having a very high LDL level. Or, to frame this differently. SLE increases the risk of CVD 8,300% more. Clearly, therefore, SLE has far more to tell us about what really causes CVD than raised LDL ever could. Deep coal miners in Russia have their final, fatal, heart attack aged 42, on average. Children with Kawasaki’s disease can die of a heart attack aged 3.

Here, therefore, are the real causes of CVD. Super accelerated CVD with death at a young age. No need for statistical games. This is the where the answers truly lie. Now comes the difficult bit. How can you fit them all together within a single disease process, without finding anything contradictory?

Ladies and gentlemen, it took me thirty years.

References
1: https://www.researchgate.net/publication/5958670_Free_cholesterol_in_atherosclerotic_plaques_Where_does_it_come_from

2: http://www.jbs3risk.com/pages/impact_intervention.htm

Cholesterol goes up heart disease goes down

As readers of this blog will know well, I do not believe that cholesterol levels have anything to do with heart disease, which would more accurately called coronary artery disease (CAD) or coronary heart disease (CHD). This is not a view that is widely accepted in the medical community, nor in society as a whole. In fact, this view places me very firmly in the ‘nut job’ category. I have been told that my views mean that I feature on several quack watch sites. Hoorah, fame – of a kind – at last.

So when I come across information that supports my position, I am always keen to make as much noise about it as possible. Today, or at least today as I write this, someone sent me an article entitled ‘Continuous decline in mortality from coronary heart disease in Japan despite a continuous and marked rise in total cholesterol: Japanese experience after the Seven Countries Study.

Now, that’s the kind of thing that I like to see. Cholesterol levels go up; heart disease rates go down. Here is the abstract of the paper, published in the International Journal of Epidemiology:

The Seven Countries Study in the 1960s showed very low mortality from coronary heart disease (CHD) in Japan, which was attributed to very low levels of total cholesterol. Studies of migrant Japanese to the USA in the 1970s documented increase in CHD rates, thus CHD mortality in Japan was expected to increase as their lifestyle became Westernized, yet CHD mortality has continued to decline since 1970. This study describes trends in CHD mortality and its risk factors since 1980 in Japan, contrasting those in other selected developed countries.

We selected Australia, Canada, France, Japan, Spain, Sweden, the UK and the USA. CHD mortality between 1980 and 2007 was obtained from WHO Statistical Information System. National data on traditional risk factors during the same period were obtained from literature and national surveys.

Age-adjusted CHD mortality continuously declined between 1980 and 2007 in all these countries. The decline was accompanied by a constant fall in total cholesterol except Japan where total cholesterol continuously rose. In the birth cohort of individuals currently aged 50–69 years, levels of total cholesterol have been higher in Japan than in the USA, yet CHD mortality in Japan remained the lowest: >67% lower in men and >75% lower in women compared with the USA. The direction and magnitude of changes in other risk factors were generally similar between Japan and the other countries.

Conclusions: Decline in CHD mortality despite a continuous rise in total cholesterol is unique. The observation may suggest some protective factors unique to Japanese.’1

This paper was actually published in July, but I missed it until now. I have to say that I like everything about the abstract (and the entire paper) apart from the last ten words. ‘The observation may suggest some protective factors unique to Japanese.’ You may be thinking, what’s wrong with that suggestion. It seems completely reasonable.

I put it to you, members of the jury, that we have a situation whereby we see continuously rising cholesterol levels in a population, whilst the rate of heart disease in that population (already very low), falls even lower. This, despite the fact that their other risk factors are just as high, if not higher than in all the other countries studied. Just to compare and contrast Japan with the USA and the UK. These figures are from the latest year 2008 where all figures are available (figures for men).

COUNTRY JAPAN UK US
% WHO SMOKE 35.4% 23% 17.2%
AVERAGE BP (SYSTOLIC) 130.5mmHg 131.2mmHg 123.3mmHg
CHOLESTEROL LEVEL 5.2mmol/l 5.4mmol/l 5.1mmol/l
% OF POPULATION WITH DIABETES 7.2% 7.8% 12.6%
RATE OF CHD/100,000/year 45.8 143.7 150.7

Perhaps most important thing in this study is that the rate of CHD in men in Japan was 62.4 (per 100,000/year) in the years 1980 – 83, when their average total cholesterol level was 4.8. Since then cholesterol has risen 9% to 5.2mmol/l; meanwhile the CHD rate has fallen by 27%. In fact, this trend of rising cholesterol and falling CHD has been going on since the 1960 – which is also mentioned in this paper2.

More dramatically, the rate of stroke in Japan, which was once the highest in the industrialized world, has dropped by more than 80% over the last fifty years, or so. Most people bring together deaths from coronary heart disease, and stroke, under the overall banner of cardiovascular disease (CVD). Raised cholesterol is considered a major risk factor for both, and statins are prescribed for both. Yet, as cholesterol levels have steadily risen in Japan, deaths from both major forms of CVD have fallen massively.

Where was I. Oh yes, I was putting it to the jury that the evidence from Japan utterly and completely contradicts the cholesterol hypothesis. Utterly and completely. Facts like these should leave the hypothesis as a smoking ruin. But of course, this has not happened, as it never does.

Karl Popper, the famous scientific philosopher, would say that such a finding represents a black swan. If your hypothesis is that all swans are white, finding more and more white swans slightly strengthens the likelihood that your hypothesis is correct. However, if you find one single black swan, your hypothesis is wrong and must be discarded.

Unfortunately, a recurring theme in medical research is that, when someone does discover a black swan, the medical experts immediately come out and tell you that this black swan is not, in fact a black swan at all. It is a swan that may look black but it will, in time, turn out to be have been white all along. A more bullish tactic is to state that, as all swans are white, a black swan cannot be a swan at all. It is a member of a different class. ‘The black bird that looks exactly like a white swan.’

Both approaches come under the banner of ‘Our hypothesis is right, we absolutely know that it is right, so any evidence that contradicts our hypothesis must be wrong.’ Or can be explained away. Otherwise known as painting the black swan white.

Explaining away also comprises a few other, well established, techniques. Firstly, to denigrate the researchers, or their research. They didn’t measure this correctly, the ignored that, they can’t be trusted, this is rubbish work – please ignore. I call this technique ‘kill the unbeliever.’

The next form of explaining is to call your finding a paradox. i.e. we know that this looks just like a black swan, but an explanation will be found at some time for its apparent blackness. Let us simply ignore this finding until the correct explanation comes along to explain it. I call this technique ‘Hide the black swan away in a cupboard and hope everyone forgets it was ever there.’

Fortunately, or unfortunately, depending on your position on the cholesterol hypothesis, these techniques won’t really work here. This study was funded by the National Institutes for Health, which makes it difficult to rubbish the results, or the researchers. Also, the data have been gathered by the WHO under the MONICA study. A massive and high quality data set which I have never seen anyone argue with. It was also published in the International Journal of Epidemiology. Generally considered a high quality medical journal.

Equally, it is rather difficult to call the Japanese data a paradox. We are not looking at a sudden, one-off finding. What we have in Japan is over sixty years of data, all pointing exactly the same way, year after year. The Japanese cholesterol levels have gone up, year on year, and there has been a steady (yet massive overall) reduction in the rate of heart disease and stroke. This data comes from a population of over one hundred million. Sorry guys, this Paradox hasn’t gone away.

It is also exceedingly difficult for mainstream researchers to attack this current data, as the Japanese were once held up as poster boys for the cholesterol hypothesis. ‘Look at the Japanese’ the researchers shouted loudly in the 1960s. ‘Very low cholesterol levels and very low rates of heart disease… case proven.’ In fact, the Japanese data were one of the strongest drivers of the cholesterol hypothesis. It is entirely possible that, without the Japanese data, the cholesterol hypothesis would never have been accepted in the first place.

Well, look at the Japanese today. Not shouting about them from the rooftops now, are we chaps? Sorry, what was that…couldn’t quite hear you. You may be thinking, at this point. Ah, so the Japanese must be genetically protected against heart disease. Well, this is not correct. To quote from the paper again:

‘Studies of migrant Japanese to the USA in the 1970s reported a dramatic increase in CHD rates within one generation of migration. It was thus expected that exposures to more a Westernized lifestyle among native Japanese after World War II (WWII), for example increase in dietary intake of saturated fat, would cause sizeable rise in blood total cholesterol, leading to a considerable increase in CHD rates in Japan. Between 1960 and 1990, dietary intake of fat and cholesterol in Japan more than doubled. The current levels of blood total cholesterol in Japan, especially among individuals born after WWII, are comparable to those in other developed countries, very different from the 2-mmol/l difference in total cholesterol at the time of the Seven Countries Study.

Moreover, age adjusted mortality from other diseases related to Westernized lifestyle, such as colon, breast and prostate cancers, more than doubled during this period. Very surprisingly, age-adjusted CHD mortality in Japan started to decline in 1970 as in Western countries, and has remained one of the lowest in developed countries: >67% lower in men and >75% lower in women compared with the USA, accounting partly for the greatest longevity in the world among Japanese.’

I liked the words ‘very surprisingly’ in that section. There is only one reason why you should be very surprised in science. That is, when everything you thought you knew about something proves to be wrong.

Just to summarize here. The data from Japan are robust, the researchers free from commercial bias. We are not looking at poor quality research, nor are we looking at a paradox, it is a pure black swan. Yes, of course, the researchers tried to find something, anything, that could explain away this finding. They looked at salt intake. Ooops, the Japanese have way higher salt intake than every other country they looked at. Sorry, ignore.

They did find that the Japanese ate more fish than in most other countries and that, my friends, was that. In fact, even they didn’t believe that this provided any explanation. For we are left with this statement at the end of the discussion section:

The lower CHD mortality in Japan compared with the USA is very unlikely to be due to the difference in trends in other CHD risk factors, cohort effects, misclassification of causes of death, competing risk with other diseases or genetics. The observation may suggest some protective factors unique to Japanese which merit further research.’

I shall give you a different conclusion from this study. One that actually fits the facts that these researchers round.

‘A raised cholesterol level is not a cause of CHD/CVD. ‘

There you are, nice and simple. There is no need for the creation of unknown and undiscovered ‘unique’ protective factors. It just fits. And when a hypothesis fits all the facts, without the need for any fancy adaptations, you know that it is right. That, my friends, is called science.

 

References
1:  Continuous decline in mortality from coronary heart disease in Japan despite a continuous and marked rise in total cholesterol: Japanese experience after the Seven Countries Study’ International Journal of Epidemiology, 2015, 1614–1624 due: 10.1093/ije/dyv143

2:   Ueshima H, Sekikawa A, Miura K et al. Cardiovascular disease and risk factors in Asia: a selected review. Circulation 2008;118:2702–09.

Lowering cholesterol – an urgent Christmas appeal

A reader of this blog sent me this e-mail message that she had just received:

This is a special Cholesterol e-News Bulletin asking for your help to draw your urgent attention to a recent decision by NICE that is of great concern to us.

There has been significant progress in the management and treatment of cardiovascular disease (CVD) over the past two decades, which has resulted in an overall decline in CVD deaths in the UK. Heart disease still remains one of the UK’s biggest killers. Over half of all UK adults have raised cholesterol increasing their risk of cardiovascular disease; leading to heart attacks and strokes. Not only does it have a devastating impact on patients and their families, but it also places significant burden on our health service and wider economy.

Innovative new medicines, such as PCSK9 inhibitors, are an exciting development in the treatment of cholesterol, with little known side effects and very good scientific evidence that they work to significantly reduce the levels of bad cholesterol in those at high risk of CVD.

NICE reviewed the first of these PCSK9 medicines and recommended that it should not be available for NHS patients.

HEART UK is concerned by NICE’s recent decision to turn down the use of the first of the PCSK9 medicines. This means patients will not have access to the best possible treatment options to help lower the levels of bad cholesterol, particularly those at high risk such as people with an inherited high cholesterol condition called Familial Hypercholesterolaemia.

NICE are conducting a second round of consultation, closing on Tuesday 8th December, before issuing final guidance. On behalf of the patients in England adversely affected by this decision, please join HEART UK’s efforts to reverse this decision and allow PCSK9 inhibitors to be more freely available for NHS patients.”

NICE = The National institute for Care and Health Excellence. Let us not dwell for too long upon that self-aggrandizing title. NICE was set up in the UK, initially to look at whether or not various healthcare interventions represented good value for money, or poor value for money.

For reasons beyond the understanding of man, they plucked a figure from the sky one day (well not a figure, a range) from £20 – £30K ($33 – $48K) per year. If the intervention cost more than £20 – £30K/year to provide one added year of full quality life, then they turned it down. [One year of full quality life = 1 QALY (quality adjusted life year)]. And breathe.

Of course, NICE make all sorts of exceptions (all cancer drugs get funded no matter how much they cost, or how useless they are – go figure) and the way NICE words out how much interventions actually cost/ per QALY is complete nonsense in many cases. Be that as it may, they do make an effort to say ‘How much!’ ‘You must be joking,’ Reject…bong!

If NICE do say, reject, bong! This basically means that the drug will not be prescribed to anyone in the UK. In addition, such is the influence of NICE that many other countries use their decisions as an important guide for what they will do with regard to funding. So if NICE turn a drug down, this is very bad news from the manufactures or said drugs.

Now, when it comes to the new cholesterol lowering agents (PSCK-9 inhibitors) the manufacturers have a problem. Which is that they cost around £4 – £8K ($6.4 – $12.8) per year, per patient. Now, at those sort of costs, you are going to have to have some seriously impressive benefits. At present, however, the manufacturers have no data on mortality, or morbidity. Which makes the current cost per QALY = infinity. Just slightly above the NICE thresholds.

For those who read my blog you will know that I wrote the following in ‘Changing the definition of Familial Hypercholesterolaemia.’

At present I would think that the response of NICE (to PCSK-9 inhibitors) would be ‘Are you out of your tiny little minds. Why the [[…] insert swear work of choice here], would we fund this?’ At least I would certainly hope this would be their response. Imagine if everyone on statins in the UK, around seven million, changed to PCSK9 inhibitors This would cost £56 billion pounds [$80Bn] a year. A tidy little sum. Half of the entire NHS budget.

As it turns out NICE did turn down the first PCSK9-inhbitor, no surprise there. And this is where HEART UK comes in….

Before going any further I should state that there are, currently, two PCSK9-Inhibtors launched/launching. They are Repatha ‘evolocumab’ made by Amgen. And Praluent ‘alirocumab’ to be co-marketed by Sanofi and Regeneron. They are, to all intents and purposes, identical drugs doing identical things. Remember the names Amgen and Sanofi. Amgen and Sanofi….

Now HEART UK states that it is a charity. HEART UK – The Cholesterol Charity – campaigns to increase general public and policy makers’ awareness of raised cholesterol as a major public health concern. We campaign to keep action on cholesterol at the forefront of the health debate.’ 1

Where do HEART UK get their funding from. Difficult to tell precisely. They claim to get money from public donation… how much? It’s a secret. What I do know is that they receive a very large amount of funding from companies that have cholesterol lowering products. So, for example Nestle, who make Shredded Wheat, pay HEART UK money, and HEART UK says stuff like

‘HEART UK dietician Linda Main said: “Shredded Wheat and Shredded Wheat Bitesize are low in saturated fat and can play an important role in a heart healthy diet and HEART UK is delighted that these products are supporting National Cholesterol Month and the Great Cholesterol Challenge.’2

Kerching!

Of course, when it comes to cholesterol lowering PCSK9-Inhibitors are the big daddies, with the big, big, budgets. So, you would expect that Amgen and Sanofi would be very, very, close to HEART UK. Well, if you expected that, you would be right. If you want to visit the HEART UK website, and look at the sponsors of their conference we have3:

Sanofi:                     Exclusive conference sponsor

Amgen:                   Sponsored symposia 1

Sanofi:                    Sponsored symposia 2

Amgen:                   Privileged sponsor…etc.

And now, to bring the two strands of this little tale together. NICE have just turned down the first PCSK9-inhbitor and so we have HEART UK reaching out to everyone that they know, or have contact with, to plead with them to sign a petition ‘On behalf of the patients in England adversely affected by this decision, please join HEART UK’s efforts to reverse this decision and allow PCSK9 inhibitors to be more freely available for NHS patients.’ Sob. But what about Tiny Tim?

Some people, were they to be truly cynical, would allege that HEART UK may not be trying to get NICE to reverse their decision on PCSK9 – inhibitors, for the great good of humankind. But because they are being paid large sums of money by the manufacturers of PCSK9-inhbitors. Shame on anyone for thinking such a thing. With Christmas coming this should be a time of peace and happiness. Such cynicism has no place in my thoughts. No sirree.

[And for my Christmas quiz the reader with the best answer to the following question will have it published on my blog. ‘What is a health charity, and should they be allowed to accept sponsorship from pharmaceutical companies?’]

1: http://heartuk.org.uk/policy-and-public-affairs

2: http://heartuk.org.uk/latest-news/article/press-release-shredded-wheat-to-support-heart-uks-national-cholesterol-mont

3: http://heartuk.org.uk/news-and-events/meetings-conferences/heart_uk_annual_conference/sponsors

Attacking those who criticise statins – again

[First, I have not blogged for a while due to a significant illness in a close family member, so my time has been rather squeezed to zero. It is also hard to write unless my mind is 100% clear. Thing are now looking a lot better, on the illness front. Thanks to those who enquired if I was all right]

Here is the title of a paper which has just come out in the European Heart Journal. ‘Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: a nationwide prospective cohort study.’ Sune Fallgaard Nielsen and Børge Grønne Nordestgaard.

I was sent it before publication date to see what I made of it. Well, my first thought was that it bore amazing relationship to a paper published the Medical Journal of Australia (MJA) which came out earlier this year1.

The Australian paper was written following two programmes aired on The Australian Broadcasting Corporation (ABC) in 2013, under the ‘Catalyst’ banner. The first programme criticised the diet-heart hypothesis of heart disease. The second was critical of statin over-prescribing. [I have written about this saga before a few times].

The Catalyst programmes were written and produced by Dr. Maryanne Demasi who was then attacked and hounded and virtually forced out of her job. I have an interest on this issue as I advised Maryanne on the programmes before they went out. I warned her that she would be amazed by the vitriol that would pour down upon her.

The most brutal attack came in the paper in the MJA called ‘The crux of the matter: did the ABC’s Catalyst program change statin use in Australia?’ Cutting through all the impenetrable statistical bollocks, and weird assumptions that were made by the authors, the key sentence is, as follows:

‘…this [the impact of the Catalyst programmes] could result in between 1522 and 2900 preventable, and potentially fatal, major vascular events.’

Taking this story down to its ineluctable essence, this is what happened

  • Maryanne Demasi wrote and produced a documentary critical of the over-prescribing of statins
  • The cardiovascular establishment in Australia was outraged and attacks rained down
  • Researchers (if they can be called that) tried to establish how many people may have stopped taking statins as a result of the programme
  • They concluded that tens of thousands of patients stopped, causing at least 1522 preventable deaths.

So, Maryanne Demasi killed at least fifteen hundred people? You think that too harsh a statement. Well that is the exact message these authors were trying promote, put into its starkest terms. This tale was commented on in ‘MJA insight’ a sister publication to the Medical Journal of Australia:

‘A SUSTAINED and significant decrease in overall statin dispensing, affecting more than 60 000 people, has been blamed on a 2013 episode of the ABC program Catalyst, which criticised statin medications.

Dr Jennifer Johns, a Melbourne cardiologist and president of the National Heart Foundation, told MJA InSight that while Catalyst was produced by a highly regarded and trusted network, the report on statins was “extremely misleading”.

“The program did get it wrong — and people believed it”, Dr Johns said.’ 2

Of course, the programme did not ‘get it wrong.’ The programme was balanced and… well, I am not going into all that again.

However, it seems that one statistically warped attack in an established medical journal is not enough. Now, a group of researchers in Denmark have gone one step further. They have looked at all the negative stories about statins over fifteen years and concluded that the 111 negative stories about statins resulted in a cumulative 9% increase in statin discontinuation. Resulting in, who knows, a million deaths? A billion. The entire population of the Earth?

‘The odds ratios for early statin discontinuation vs. continued use were 1.09 (95% confidence interval, 1.06–1.12) for negative statin-related news stories.’3

Of course, in the same time period, there were 731 positive statin studies (about one a week). So, how the hell they managed to disentangle the effect of a 111 negative studies against over seven hundred positive studies is anyone’s guess. I found the entire paper full of weird and completely unprovable assumptions. And, yet, still it got published.

However, despite its inherent nonsense, this study can now be used as ‘evidence’. Which means that anyone who dares to write anything critical of statins can be accused of killing people in their thousands, their hundreds of thousands. How long before any article critical of statins is banned? Not long, I suspect.

Scientific debate, dontcha just love it? ‘Love it, we are banning it. People will do as they are told!’

[The corresponding author of the Danish study was Børge Grønne Nordestgaard. Tel: +45 3868 3297, Email: boerge.nordestgaard@regionh.dk Perhaps you might like to write to him and ask him why he did this study, and what he wanted to happen as a result of it? What was its scientific purpose? Or you may have your own, far better, questions.]

 

1: https://www.mja.com.au/journal/2015/202/11/crux-matter-did-abcs-catalyst-program-change-statin-use-australia

2: https://www.mja.com.au/insight/2015/22/catalyst-effect

3: European Heart Journal doi:10.1093/eurheartj/ehv641

Changing the definition of Familial Hypercholesterolaemia

I am grateful to Mike Sheldrick, a reader of this blog for spotting some news, that was not entirely expected by me. For reasons that I will explain later. As you may know two new cholesterol lowering drugs have now launched. Two PCSK9 inhibitors. I call them the ‘dreaded’ PSCK9 inhibitors. I have written about them a few times. There has been surprisingly little noise about them so far, at least in the UK. Not sure about the US or the rest of the world. They are called Repatha and Praluent. Catchy eh!

These drugs have two major problems at present, at least from a money making perspective. They have no outcome data, by which I mean that they have not been shown to reduce the risk of heart attacks, strokes… or anything else for that matter. (They have been launched purely on their ability to lower LDL to violently low levels). They are also extraordinarily expensive. In the UK Praluent will cost between four thousand to eight thousand pounds ($6 – $12K) per year, depending on the dose1.

Which means that the NHS can, if it so wishes, pay eight thousand pounds a year for a drug that does not actually do anything – other than lower a surrogate marker for heart disease. Now, this may not be seen as bargain of the year. I can imagine great battles are going on right now between the pharmaceutical companies and NICE. The organisation that decides if a drug is cost effective, or not.

At present I would think that the response of NICE would be ‘Are you out of your tiny little minds. Why the [[…] insert swear work of choice here], would we fund this?’ At least I would certainly hope this would be their response. Imagine if everyone on statins in the UK, around seven million, changed to PCSK9 inhibitors This would cost £56 billion pounds [$80Bn] a year. A tidy little sum. Half of the entire NHS budget.

So, what to do? You have this amazing cholesterol lowering super-drug that does nothing, and it is enormously, eye-wateringly expensive. Come on, come on. Think!

To be frank, I thought that the primary marketing tactic would be to claim that statins actually have many, many horrible side-effects – that no-one noticed until…. there were new drugs to be launched of course. Which would mean that all those people who were ‘statin intolerant’ would need to take PCSK9 inhibitors instead. To get that horrible, damaging LDL level down. There is no doubt that the attack on statins is currently happening, but there has been more resistance to this than expected.

So, what else can you do? Well, there is one population where cholesterol lowering is seen as absolutely essential. The population is those who have familial hypercholesterolemia (FH). This group has always been considered at such a high risk of dying from heart attacks and strokes, that no clinical trials have even been done. You just do anything, and everything, to get the cholesterol (LDL) levels down, no questions asked. [No evidence of benefit needed either]

At present about one in five hundred people have FH and, when I started thinking about, I realised that this is really a big enough market for PCSK9 inhibitors. Just to do some simple sums. There are sixty-five million people in the UK at present. If one in five hundred has FH, that represents an FH population of 130,000. If every single one of these people goes on the higher dose of one of these drugs, the total sales would be £1Bn/year. In the UK alone. That is a blockbuster in anyone’s eyes.

If we transpose these figures to the US. The total population in the US is three hundred and twenty million. Which means that 640,000 people will have FH. With Praluent selling at $14,000/year, that would be $9Bn/year in sales in the US alone. Worldwide we are talking tens of billions a year. Of course, there are two virtually identical drugs out there, Praluent and Repatha, so divide the market by at least two – and there are more PCSK9 inhibitors in the pipeline.

Reducing this market still further, not everyone will take an injectable medication every two weeks, no way. And so the total market, though still massive, shrinks down ever further. Realistically, you might get a maximum of a quarter of those with FH on your drug. Amgen, for example would have to cope with piddling sales of $10Bn/year worldwide. Which will not do, not at all. More money must be made.

Of course, the simplest thing to do, to get round the problems with market size is simple. Make the market bigger. And the easiest way to do this is to widen the criteria for Familial Hypercholesterolaemia (FH). And lo, it has come about. The American Heart Association has stated that the level of LDL at with FH can be diagnosed is to be lowered:

“More people may be diagnosed with familial hypercholesterolemia (FH) using criteria contained in a new scientific statement published by the American Heart Association. The expanded definition could also mean more patients will be eligible to receive expensive cholesterol-lowering drugs, including the new PCSK9 inhibitor drugs, (Repatha from Amgen and Praluent from Sanofi/Regeneron)….

The new criteria for heterozygous FH sets an LDL level of at least 190 mg/d L (4.9mmol/l) for adults who have a similarly affected first-degree relative, premature coronary artery disease, or a positive genetic test. According to Mann, 3% of the population has LDL levels over 190 mg/dL level, but, she points out, “less than 1% of the population has FH. You could have docs diagnosing people with HeFH or HoFH* solely so that their insurance will cover a medication, such as PCSK9 inhibitors. That could be very confusing for patients.”2

*HeFH = Heterozygous Familial Hypercholesterolaemia (affects 1:500 – high LDL levels)

*HoFH = Homozygous Familial Hypercholesterolaemia (affects 1:1,000,000 – super-high LDL levels)

In one simple stroke, the market for PCSK9 inhibitors in the US has been increased from 640,000 to 1,920,000. Or, in monetary terms, $9Bn to $27Bn. There, that’s more like it. In the UK the market goes up to 400,000, with max PCSK9 sales going from one billion to three billion pounds sterling. A clever little trick.

I must say that I, possibly the most cynical human on the entire planet, never thought they would do this. I discounted as just too brazen. It would just be likely to be laughed out of court. Silly me. No-one is laughing. Experts are rubbing their chins and nodding sagely at the wisdom of this move. New swimming pools all round, is what they are probably thinking.

Do you think that the American Heart Association’s (AHA) decision here may have been affected by commercial sponsorship? This, of course, would be impossible to say – without getting sued senseless for libel.

However, I had a little look around the AHA, and Amgen, also the ‘non-profit’ FH Foundation and Amgen, and suchlike. Here is one statement from the AHA site. ‘Amgen is a proud sponsor of the American Heart Association’s Heart360 Toolkit3. Ho hum Needless to say. Amgen are also ‘proud’ sponsors of various AHA meetings.

In addition, Amgen are also a foundation ‘corporate sponsor’ of the FH foundation4. They are probably very proud of that too. Finding these financial relationships can be a little tricky, as they are usually hidden in the depths of various websites. Perhaps other mike care to improve on this list…. Probably not that hard to do.

Money makes the world go around, the world go around, the world go around.’

1: http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=5687

2: http://cardiobrief.org/2015/11/05/new-definition-of-familial-hypercholesterolemia-could-expand-patient-population-for-expensive-cholesterol-drugs/

3: golowcholesterol.com/tag/amgen/

4: https://thefhfoundation.org/about-us/sponsors/

How much longer will you live if you take a statin?

How much longer will you live if you take a statin?

About a year ago I submitted a paper to the BMJ entitled ‘Statins in secondary prevention, lives saved or lives extended.’ To be more accurate, I was the lead author of the paper. So I should say ‘we’ submitted a paper. I have to report that the paper was rejected, re-written and rejected again. In the end I couldn’t get it published.

The main aim of the paper was to point out that the most important reason why someone would take a ‘preventative medicine’ of any sort, was to increase their life expectancy. The question ‘how much longer will I live if I take this tablet for, say, five years?’ Seems a reasonable question to ask and, in turn, have answered. Interestingly no patient has ever asked me this question, so I have never had to answer it.

What we have instead is the repeated use of relative risk. Which is often framed in the following type of way: ‘Atorvastatin/Lipitor will reduce the risk of dying of a heart attack by 36%’… and suchlike. Whilst that figure is true, or at least it was true in one study funded and run by Pfizer… who sell atorvastatin, I knew that a figure like that was horribly misleading. It gave the impression of a gigantic reduction in risk. ‘Your risk of dying of heart disease will be reduced by more than a third!’ Surely you would be mad not to take it, wouldn’t you?

However, how does a figure like that pan out in the most important outcome of all. Namely, increase in life expectancy? I had done a few ‘back of a cigarette packet calculations’ on this, and I was getting some pretty unimpressive figures. But to get it absolutely right I contacted a professor of statistics at the Medical Research Council and asked him if he could work out an exact figure, using real mathematics.

We chose the two most positive studies on statins ever done. The Scandinavian Simvastatin Survival Study (4S) and the Heart Protection Study (HPS). These were secondary prevention studies. By which I mean studies done on people who had already had a heart attack or stroke, or suchlike and were at great risk of having a ‘second’ event. So these were very high risk people, where the benefits of statins would be at their greatest.

Looking at the Heart Protection Study (HPS) done in the UK, we used a technique for analysing survival time called RMST (restricted mean survival time). I won’t go into the details. The HPS study lasted for five years, and we calculated that the average increase in survival time was 15.6 days. This was at the end of five years of treatment (with a confidence interval of 5 days either side). For 4S, the figure was 17 days.

Framing this slightly differently, what this meant was that taking a statin for one year, in the highest risk group possible, would increase your life expectancy by around three days. We thought that people should know this. Unfortunately, the BMJ thought otherwise. Such is life.

However, more recently the BMJ did decided to publish another paper entitled: ‘The effect of statins on average survival in randomised trials, an analysis of end point postponement1.’ They used slightly different mathematical techniques, including the ‘quick method.’ To quote:

‘We also calculated all areas in a less technical manner, that is, by drawing one or more triangles by hand on magnified paper prints of the survival curve for each study and then calculating the areas of these triangles by standard arithmetic. This is referred to as the quick method.

I have to admit that’s my kind of maths. Get out the pencils and draw it all out by hand. They also looked at more studies than we did, and aggregated them. Which has benefits and disadvantages. Sometimes you are not comparing like with like. However, the main results of their study, and their conclusions, were as follows:

Results: 6 studies for primary prevention and 5 for secondary prevention with a follow-up between 2.0 and 6.1 years were identified. Death was postponed between −5 and 19 days in primary prevention trials and between −10 and 27 days in secondary prevention trials. The median postponement of death for primary and secondary prevention trials were 3.2 and 4.1 days, respectively.

Conclusions: Statin treatment results in a surprisingly small average gain in overall survival within the trials’ running time. For patients whose life expectancy is limited or who have adverse effects of treatment, withholding statin therapy should be considered

Overall their findings were far less impressive, even, than ours. They calculated, approximately, a single day of increase in life expectancy for each year of taking a statin. Slightly more in secondary prevention, slightly less in primary (people who have not previously had a heart attack or a stroke).

The main take away message I believe, is the following. Statins do not prevent fatal heart attacks and strokes. They can only delay them. They delay them by about one or two days per year of treatment. For those who have read my books you will know that I have regularly suggested we get rid of the concept of ‘preventative medicine’. We need to replace it with the concept of ‘delayative medicine’.

You cannot stop people dying. You can only make them live longer. How much longer is the key question. With statins this question has been answered. You can, to be generous, add a maximum of two days per year to life expectancy.

Which means that if you were to take a statin for thirty years you could expect to live about two months longer. (Possibly three, more likely one). Assuming, and this is a big assumption, that none of the trials done have been in any way biased towards statins. Even though every single one was funded by the pharmaceutical industry. Further assuming that any benefits seen in the trials will continue for the next twenty-five years.

Why, you may ask, has the pharmaceutical industry never chosen to present the results of the statin trials in this way? In truth that is a bit of a silly question. I think anyone with a half functioning brain knows why the pharmaceutical industry has never chosen to present the result of the statin trials in this way. A 36% reduction in fatal heart attacks does sound rather better than, one extra day of life for every year you take a statin – best case scenario in primary prevention… Does it not?

Ref:
1: Kristensen ML, et al. BMJ Open 2015;5:e007118. doi:10.1136/bmjopen-2014-007118

The longest journey

Whilst on a short break I picked up the Times Newspaper on Friday the ninth of October. There were two headlines. The main one was ‘Fizzy drinks giant pays millions to diet experts.’ On the other side of the page was ‘Revolution for FIfa after Blatter gets red card.’

The fizzy drinks company was, of course, Coca Cola. I wondered why the headline did not say ‘Coca Cola pays millions to diet experts.’ Perhaps that was just a step too far to upsetting a major advertiser. Although I note that the picture of Sepp Blatter had a large Coca -Cola sign above his head. So, somebody at the Times clearly has a sense of humour.

Now I looked at these headlines and I thought, as I find myself doing most of the time nowadays. Corruption, corruption, corruption everywhere. Sepp Blatter is almost heroic in his ability to brush aside allegations against him and his organisation. ‘I knew nothing about anything.’ Seems to be his defence. Well, if he didn’t know anything he’s incompetent, if he did, he is corrupt. I suspect both.

As for Coca Cola. They just pay ‘experts’ large sums of money, and the expected messages flow forth. According to the Times article they set up the European Hydration Institute to promote… hydration. Which sounds quite innocuous and nothing to do with Coca-Cola at all.

However, guess which drinks people should hydrate themselves with. Why…. Let me think. They get a Professor Ron Maughan to state the dehydration was an ‘unrecognised danger’ for drivers. Drivers should regularly stop and buy drinks to ensure they are properly hydrated with drinks such as… Why… let me think.

Of course, by pretending the European Hydration Institute is some sort of independent academic body, such messages are not simply seen as adverts for Coca Cola, Oasis, and suchlike. This arm’s length marketing is a very old trick now. Heart UK is a charity which is dedicated to warning of the dangers of cholesterol. Heart UK ruthlessly promotes cholesterol lowering as the most important function of the medical profession. Of course it is almost entirely funded by pharmaceutical companies who make cholesterol lowering drugs. [I would say entirely funded, but I am not absolutely sure about this].

Various experts give talks on behalf of Heart UK, paid for by Heart UK, then claim they receive no money from the pharmaceutical industry. Which is, of course, technically correct. They do not receive money from the pharmaceutical industry. Heart UK receives money from the pharmaceutical industry, they then pay the expert, and the expert need not even declare a conflict of interest. ‘How dare you say that I take money from the pharmaceutical industry, you dirty knave…. I did this work for a charity. A charity I say.’

This is also how Sir Rory Collins works. He runs the Clinical Trial Service Unit (CTSU) in Oxford. It runs trials that are almost entirely funded by the pharmaceutical industry. Nearly three hundred million pounds sterling ($500m) over the last ten years or so. He states he receives no money from the pharmaceutical industry, and therefore is not biased in any way. Once again…Industry pays CTSU, CTSU pays Sir Rory Collins = no payment from industry and no conflicts of interest. And if you believe that.

Wherever you look. Wherever I look it is the same old story. Experts are inevitably bought and paid for by one company or another. The messages that come out are universally supportive of the company’s products. If you are not sufficiently supportive the companies will go find something else to turn into an ‘expert.’

As the Times reports ‘In 2013 Spanish researchers found that scientific papers on sugary drinks that were sponsored by or had potential conflicts of interest with the food and drink industry, including Coca-Cola were five times more likely to find no link with obesity than similar papers that were independently funded. They recommend “special efforts to preclude funding by parties with vested interests at all levels.’

In truth, I don’t care that much about Fifa and the endemic corruption thereof. If people can be bribed sufficiently to hold a World Cup in Qatar, average summer temperature 50c, the world is not going to come to an end. Although a few footballers might. Obviously, it would be better if the countries with the best bid actually won, but no-one is going to die. Probably.

However, if companies such as Coca-Cola can fund research that distorts science and promotes the consumption of sugary drink, and helps to create millions upon millions of people with type II diabetes then this is very serious stuff indeed. The increase in morbidly and mortality could end up bankrupting health services around the world.

I know that all organisations and companies, if they are not properly policed, will end up travelling the road to corruption. It seems an immutable law of commerce. In a way I don’t blame the companies. They are, by their nature wolves. If I have a thousand sheep in a field and find the wolves circling, I do not say the wolves, ‘now, really, I do not want you to eat the sheep. Do you promise?’

Wolves: ‘Yes, we promise.

Shepherd: ‘Good.’

Next day, shepherd arrives, sheep mostly eaten, wolves fat. Well, what do you expect? Wolves eat sheep. It is what they do. If you want to stop this happening, build a bloody great fence, or buy some guns, or both. Don’t rely on wolves to suddenly start acting like sheepdogs.

No, I don’t blame the companies for being companies. I blame our politicians. It is only they who can create a system of policing and punishment that will stop companies corrupting researchers, or corrupt researchers demanding money from companies. Yes, this is not a one way street. You can’t have corruption if researchers don’t take bribes.

Unfortunately politicians seem perfectly uninterested in corruption in the medical field. Is it because they themselves are being bribed. I am certain that this is part of it. In the UK large numbers of MPs are non-exec directors of private health companies, and the corporate world swirls around and within the political arena far, far, too closely. Before the last election David Cameron stated that lobbying would be next great scandal.

He says nothing of the sort now, yet lobbying and manipulating on behalf of large corporations has become worse and worse. The UK has not yet reached the situation in the US where lobbyists outnumber politicians by about a hundred to one…. Or thereabouts. And when politicians stop being politicians they immediately become lobbyists. But we heading in that direction.

So where are we? A long, long way down the longest road. The road that ends with everyone in any position of power becoming, essentially, a spokesman for large corporations, where there is no-one left who can or will do anything to stop it. Because, sadly, they are all in it together. I write that last sentence and think, oops, have I just become a conspiracy theorist. Then I think. No, I am not a conspiracy theorist, I am simply Winston Smith.

Study 329 – where the hell is the outrage?

To quote from the BMJ ‘No correction, no retraction, no apology, no comment…’

Study 329 was started in 1994 by Smith Kline Beecham, which shortly become part of the larger conglomerate Glaxo Smith Kline (GSK). Study 329 looked at the use of paroxetine, an anti-depressant, in adolescents with depression.

Following this study paroxetine was promoted and marketed heavily by GSK as demonstrating, in the words of GKS marketing materials: ‘REMARKABLE Efficacy and safety’. Over two million prescriptions were then written for children and adolescents in the US.

However, in 2002 the FDA considered study 329 to be a ‘failed trial.’ In 2003 the UK recommended that paroxetine should not be used in children and adolescents with depression because it increased the risk of self-harm and potentially suicidal behaviour.

In 2004 the FDA placed a black box warning on all antidepressants in adolescents and children stating that they increased the risk of suicidal thinking and suicidal behaviour in these groups. In 2012 GSK finally agreed to pay £2Bn for fraudulently promoting paroxetine.

But the story does not end here. A group of researchers, who had been heavily critical of this trial, finally managed to get hold of the raw data and carried out a re-analysis under the restoring invisible and abandoned trials (RIAT) initiative. Yes, this saga has been a long one.

The reanalysis was recently published in the BMJ with sadly predictable results. The primary conclusion was that ‘Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was increase in harms in both groups.’

This is in stark contrast to the original trial results. When it was first published it appeared to demonstrate very clearly that paroxetine was both safe and effective in adolescents with depression. According to GSK it demonstrated ‘.remarkable efficacy and safety’ However, using exactly the same trial data, reanalysed by independent researchers, we now find that paroxetine was both useless and damaging.

So, what has been the consequences for those involved in the initial trial and the writing up thereof? For those who read the BMJ, you will know that I am now quoting verbatim here:

  • Despite subsequent FDA and MHRA warning about increased risks of suicidal thinking and behaviour and GSK receiving a record fine, partly for illegal off-label promotion of the drug, the original report has not been retracted or even had a correction
  • Academic and professional institutions have failed to publically address the many allegations of wrongdoing
  • None of the named authors had intervened to correct the record. An internal enquiry by the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) concluded that no further action was necessary
  • Brown University remains silent over its involvement in the study. It refuses even to confirm or deny whether any investigation took place1

I will add to this that a co-author of study 329, Karen Wagner, named eight times in the 2011 US Department of Justice complaint against GSK, is currently the president elect of the American Academy of Child and Adolescent Psychiatry – whose journal, the JAACAP, is where the original study was published.

Taking stock. What do we have? A study was done, and published, demonstrating that paroxetine was safe and effective. The trial data were heavily promoted, resulting in millions of children and adolescents being prescribed paroxetine.

The reality is that this drug was completely ineffective and increased the risk of suicide (amongst other things). This has all been known for many years. The latest re-analysis simply confirms everyone’s worst fears.

So surely someone, somewhere, got punished? No they did not. Not only that, but the original published study has not even been retracted. It still sits in the medical database. A young and innocent researcher could come across it, and reference it, and use data from it to support a grant application for a study to use antidepressants in children.

If this were not all completely and absolutely one hundred per-cent fact, you might think we have a possible plot line for a dystopian novel here. A story of terrible corruption where large corporations can distort data through one hundred and eighty degrees, and get away with a fine. A world where bent researchers promote research that results in more children committing suicide, and then move on positions of greater power and authority – with no censure from anyone. To become presidents of major medical societies, for example.

Frankly I don’t think I would dare to write a novel with a plot so completely outrageous. Surely someone, somewhere, would be punished for this behaviour. Surely the paper would be retracted. Surely a co-author of such a study would not be in line for a prestigious position. Surely the public would rise up in outrage.

In truth, it seems, nothing is going to happen at all. I must dig out 1984 and read it again, just to depress myself even further.

1: BMJ 2015;351:h4629

A Swiss Investment Bank gets it completely one hundred per cent right

[Yes, that’s right, a Swiss Investment Bank!]

A kind reader of my blog pointed me at a report by Credit Suisse entitled ‘Fat, the New Health Paradigm.’ I suppose I half expected the usual. Saturated fat causes heart disease, cholesterol causes heart disease. ‘We are a respected bank, what the hell did you expect – that we would rock the boat in some way. Don’t be daft.

What seems to have happened is that they actually looked at the evidence in this area and came to the conclusion that the current dietary advice is utter bollocks and is not based on anything at all. I shall start with a few key points from the Introduction:

‘Saturated fat has not been a driver of obesity: fat does not make you fat. At current levels of consumption the most likely culprit behind growing obesity level of the world population is carbohydrates. A second potential factor is solvent-extracted vegetable oils (canola, corn oil, soybean oil, sunflower oil, cottonseed oil). Globally consumption per capita of these oils increased by 214% between 1961 and 2011 and 169% in the U.S. Increased calories intake—if we use the U.S. as an example—played a role, but please note that carbohydrates and vegetable oils accounted for over 90% of the increase in calorie intake in this period.

A proper review of the so called “fat paradoxes” (France, Israel and Japan) suggests that saturated fats are actually healthy and omega-6 fats, at current levels of consumption in the developed world, are not.

The big concern regarding eating cholesterol-rich foods (e.g. eggs) is completely without foundation. There is basically no link between the cholesterol we eat and the level of cholesterol in our blood. This was already known thirty years ago and has been confirmed time and time again. Eating cholesterol rich foods has no negative effect on health in general or on risk of cardiovascular diseases (CVDs), in particular.

Doctors and patients’ focus on “bad” and “good” cholesterol is superficial at best and most likely misleading. The most mentioned factors that doctors use to assess the risk of CVDs—total blood cholesterol (TC) and LDL cholesterol (the “bad” cholesterol)—are poor indicators of CVD risk. In women in particular, TC has zero predictive value if we look at all causes of death. Low blood cholesterol in men could be as bad as very high cholesterol1.’

At one point they go on to say…

Here is our final hypothesis on why health authorities have remained so certain of their position and unwilling to change their view on saturated fats, omega-6 or carbohydrates:

  1. Health authorities advance very slowly and are afraid to change the market’s status quo (not a wise medical posture).

We have known since the 1960-70s that dietary cholesterol has no influence on blood cholesterol. Yet it took more than fifty years for the USDA/USDHHS to lift recommended upper limits of fat consumption. It took close to 20 years in the U.S.—that was quick—to ban transfats. So we should not look at public health authorities as leading indicators of potential health hazards, but rather as lagging behind.

Bureaucracy tends to move slowly, but when the health risks tied to “incorrect” information are so high, one would hope for swift action and the courage to reverse past mistakes. There was no fundamental reason to move from butter to solvent extracted vegetable oils. If we assume that research was the main reason—as it was claimed at that time—the health authorities now have enough information to change their recommendations, or if still in doubt issue no recommendations.

All quite extraordinary. This report is about as scathing as an organisation like Credit Suisse could possibly be. They have stripped apart the evidence on eating fats and saturated fats. They have come to exactly the same conclusions as I, and many others, have done. When they say:

There was no fundamental reason to move from butter to solvent extracted vegetable oils

That means, there was not one single scrap of evidence. Nothing, zip, nada, zero. So when you see various flower-like margarine manufactures promoting their products as super-healthy…. You know it is just the most complete nonsense. Even a Swiss Investment Bank says so.

And what do they have to say on raised cholesterol levels? Well they have many things to say, mainly that it does not cause heart disease. The shortest summary of their conclusions would be the following:

We can draw the following conclusions:

  1. High cholesterol (above 240mg/dl) (this is 6.2mmol/l) is only a marker of higher cardiovascular death for men. Please note that high cholesterol does not cause heart attacks, it is just a marker.
  2. For all other illnesses, higher cholesterol levels pointed to lower death levels. Why? Because cholesterol helps support, or is a marker of, a better immune system.

I know that this report will be ruthlessly attacked and vilified. Mainly on the basis that it was written by a Bank! And what can bankers possibly know of medical research? How very dare they? My own view on this is that, you know, anyone can read medical research, and if you are in possession of a functioning brain you can also work out what that research is saying.

Indeed, in my opinion, the best placed people to review any form of research are those who do not have a dog in the fight. The authors of this report have no reputations to maintain in medical research. They have no reason to support one side or the other. These people represent an investment bank, and all they are interest in doing is advising their ‘customers’ on what is really true, and what is likely to happen. They are a bit like bookmakers. No emotions involved just ‘what are the odds.’

As they say that odds are, as follows

‘The bottom line of these assumptions is that fat consumption per capita is likely to soar by 23% from now until 2030, protein by 12%, and carbohydrates will likely decline by 2%. This implies annual compound growth of 1.3% for fat consumption, compared to 0.9% over the last fifty years. Total demand for fat will be much higher—43% up for fat or 1.9% a year— given the 16% growth in the global population expected over the next fifteen years.’

Pork bellies are a ‘buy.’ How strange to find myself on the same side of an argument as a Swiss Investment Bank. I would have given you bloody good odds on that yesterday.

1: https://doc.research-and-analytics.csfb.com/docView?language=ENG&source=ulg&format=PDF&document_id=1053247551&serialid=MFT6JQWS%2b4FvvuMDBUQ7v9g4cGa84%2fgpv8mURvaRWdQ%3d

Tranny fats ha ha ha

[An apology. Some people have objected to the work Tranny, as this is considered offensive to trans-gendered individuals. I was attempting a play on words from Roddy Doyle’s well known book Paddy Clarke ha ha ha. I had not the slightest intention of causing offense in this way, and I apologise if I have done so. I hope the title can be taken in the ‘innocent’ way that it was meant]

Many years ago a man, who they say, had an ego the size of a planet decided that he just knew what caused heart disease. It was cholesterol consumption in the diet that raised blood cholesterol and killed us all. Unfortunately, for him, he did some research that however much cholesterol you ate, it had no effect on the cholesterol level in the blood.

No matter.’ He laughed gaily. ‘What is the point of a good hypothesis if you cannot change it upon a whim?

So he then decided that it was dietary fat that raised cholesterol levels in the blood and caused us all to die of heart disease. Only it wasn’t that one either. So then he thought it was animal fat (wrong again!) and finally settled upon saturated fat.

Then, through a combination of his forceful personality, and a good bit of merciless bullying anyone who disagreed, Ancel Keys promoted his message far and wide, and those in power decided he was right.

This set in chain a whole series of seemingly disconnected phenomena. The first of these was to start telling everyone that they should not be eating saturated fats, assumed to be animal fats, or else they would die. Thus, recommendations about what was healthy to eat became moved away from those horrible, unhealthy fats, and focussed entirely on eating carbohydrates.

At which point the obesity epidemic began- as you would expect. This was closely followed by the epidemic of diabetes – as you would expect. If you know anything about human physiology.

Then it was realised that diabetics, who were more likely to develop heart disease than anyone else really, really, should not eat any sort of fat. Saturated or otherwise. They were all advised to switch to eating carbohydrates. This of course, makes perfect sense. We have a group of people who cannot control their blood sugar levels, so we tell them to eat almost nothing but sugar.

We now spend more on medication for diabetes than any other form of medicine in the world. Why, because no-one can get their blood sugar levels under control any more. Quelle surprise?

In parallel with this nonsense it was decided that we should replace saturated fats with ‘healthy’ polyunsaturated fats and suchlike. Which inevitably included trans-fatty acids. These were first discovered many years ago, when oils were turned into margarine. The margarine was, at first, coloured pink – as it was considered unfit for human consumption, and was only fed to animals.

Gradually trans-fats, which are also polyunsaturated fats, found their way into almost everything anyone ate – including of course margarine (no longer coloured pink, instead with pretty coloured flowers on the tub). MacDonald’s were virtually forced into cooking their fries in vegetable fat, so that no-one would be exposed to the deadly, evil saturated fats. Hey ho, what happens to vegetable fats at high temperatures? Well, they turn into trans-fatty acids, of course. Who knew? Apart from all chemists in the world.

More recently we find that trans-fatty acids are uniquely unhealthy substances that should be banned, and excluded from human consumption. What a surprise, a range of chemical compounds almost unknown to nature may not be healthy….well, who’d a thunk? This morning I was listening to a debate on the radio about whether the UK should ban all trans-fatty acids. [Well, you can’t ban them all, because some are found in natural foodstuffs.]

I just sat and listened, and thought that the entire world of nutrition was bonkers, and remains bonkers. An egocentric megalomaniac called Ancel Keys decided that ‘HE KNEW’ what caused heart disease, and would brook no dissent. His legacy is that we now force carbohydrates into diabetics, and almost everyone else. We also forced manufacturers to stop selling saturated fat and, instead, switch to super-healthy trans-fats. We made MacDonald’s French fries uniquely unhealthy. A perfect and delicious irony. Accuse MacDonald’s of selling unhealthy food, then make them do it.

God knows how many have died prematurely because of this complete and utter nonsense. Tranny fats, ha ha ha.

The Augean Stables – part II

It has become clear that much of medical research is flawed, and so inherently biased that much of it/most of it simply cannot be relied upon. One of the strongest critics of this current situation is a brilliant statistician, Professor John P Ionnadis. His seminal paper on the subject of medical research, which is nearly ten years old now, was entitled ‘Why Most Published Research Findings Are False ‘. I include the abstract here:

‘There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias1.’

Has his work been contradicted by anyone? The answer would be a resounding… no. In fact, all that has happened over the last ten years is more and more confirmation that medical research has become worse.

This is an incredibly worrying situation, yet very few people seem in the slightest bothered. The status quo remains in status. When new medical studies come out the press continue to regurgitate the findings as though they are unquestioned gospel. Experts have maintained their status as demi-gods, to be fawned upon as though their work is beyond any possible reproach.

Guidelines, the ones that instruct doctors on how to treat various conditions, are still published without any provisos. Guidelines which are based on evidence that… ‘may often be simply accurate measures of the prevailing bias.’ But woe betide any doctor that fails to follow said guidelines, for they may well be struck off the medical register. In the US, you could end up in jail.

All of these things are bad enough, and there are many other problems. However, in this blog, I want to focus on another issue. Namely, what about placebo controlled studies? Just to make it clear, for those who know a great deal about this area, I am not looking at the issue of ‘what the hell is in placebos anyway, cos it sure as hell ain’t inert substances.’ Whilst the fact that you cannot find out what manufacturers actually put in placebos, which should be inert ‘sugar pills’, but most certainly are not, is extremely important, that is an issue for another day.

Today’s issue is as follows. We have reached a situation in medical research where it may never be possible to find out if certain treatments actually work. Sub-header… ‘And in which case we are all doomed.

Here is the context. Once a treatment has been found to be superior to a placebo, it will be deemed unethical ever to carry out a placebo controlled study ever again. That may not mean much to many people, so I shall expand – using a concrete example (yes, statins again).

If placebo controlled studies have shown that statins reduce the risk of heart disease, and for the sake of argument let us accept that this is true, where does this leave us? It leaves us in the position whereby, if anyone wanted to set up a study to try and disprove that statins are no better than placebo, they will never be given permission to do so.

Why not? Well, before you are allowed to carry out a clinical study, you have to present it to an ethics committee. This committee will look at the proposal and decide if it is indeed ‘ethical.’ Exactly what this means is up for debate. However, if you decided to study the speed at which cars need to run into children, to result in a fifty per cent mortality rate, I imagine you would be turned down by the ethics committee.

More prosaically, if you have found that statins reduce the risk of dying of heart disease vs placebo, then you will no longer be allowed to do a placebo controlled statin trial ever again. The reason for this is that you have already ‘proved’ that statins are superior to placebo. So it will argued that any volunteer placed in the placebo arm of your study would be suffering avoidable harm. Bong! Ethics committee says no. We know statins work, so it is unethical not to give them.

The only studies the ethics committees will allow would be statins vs. statins and a new drug. Equally you would not be allowed to study a new drug vs. placebo, at least not for an indication where statins had shown a benefit. Because everyone ‘at risk’ should be on a statin already.

Now, I have some sympathy for pharmaceutical companies in this situation. If statins reduced the risk of heart disease by 50% (made up figure), then any new drug can only provide an incremental benefit over statins – there is only 50% possible benefit left. So you need to study more people, over a longer period, to demonstrate superiority over statins. A higher hurdle than statins had to get over to be approved.

In another way, obviously, I have less sympathy. Let us suggest that all of the statin trials were biased. Let us further suggest that statins do not have any benefit over placebo. Is there any evidence for this? Well, the only major non pharmaceutical funded study on statins vs placebo was ALLHAT-LLP. Which was run by the National Institutes for Health (NIH). It was reported thus:

‘Washington, DC – Surprising results of an unblinded but randomized comparison of pravastatin (Pravachol® – Bristol-Myers Squibb) vs “usual care” in patients with hypertension and moderate hypercholesterolemia enrolled in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) show that pravastatin did not significantly reduce either all-cause mortality or fatal or nonfatal coronary heart disease (CHD) in these patients.’

So, no benefit at all. This study was immediately attacked by all the ‘experts’ and dismissed as being useless, not enough LDL lowering, not enough difference from standard care blah, blah. Nothing to see here, move along.

However, I find it interesting that the only statin study which was not funded by the pharmaceutical industry was completely negative. You may even believe that this would give people pause for thought. If so, silly you.

Where does this leave us though? Well, as already stated, you can never, ever, do another statin vs placebo study. For it would be unethical to do so. You can never do a cholesterol lowering study on any other drug vs placebo either, for it would be unethical to do so. If the statin trials were all correct and unbiased and without the slightest doubt attached to them….fine. If, however, these trials were simply accurate measures of the prevailing bias then we are completely screwed.

This leaves us in a situation whereby if we test other drugs against statins, we are testing a drug against a drug that we cannot be certain has any benefits at all. So, what can we prove? Nothing. Which means that the very foundations of all future research in this area have been built on a bog.

So, what can we do? Carry on believing that all the research done is correct and above any suspicion of bias and manipulation. If so, fine, but you may have trouble sleeping at night. If not, you are going to have to tear apart all of the research that has been done, and do it again. I think that makes the task of Hercules look pretty easy.

1: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0020124

2: http://www.medscape.com/viewarticle/785851

The Augean stables

For many years it was possible to start a clinical trial, on a drug, without telling anyone that you were doing so. Then, if it turned out to be negative you could just slip it under the carpet and never let anyone know you were doing it. This is what happened with many antidepressant trials. Positive, publish. Negative, bury. Unsurprisingly, the results for antidepressant treatment looked pretty damned good.

Another little trick was to keep the primary end-point of the trial secret. To explain. Say you started a study on statins where you most wanted to look at the effect on overall mortality – whether taking statins meant more people were alive at the end of the study, than those taking a placebo. In this case overall mortality would be the ‘primary end-point’.

You could also measure other outcomes, or end-points. For example, you see how many people were admitted to hospital with angina, or how many people needed an angiogram and/or stent. Or how many people suffered a non-fatal heart attack or stroke. You can, in fact, measure many different things. These would usually be called secondary end-points.

Up until fairly recently, if you failed to reach your primary end-point – the term normally used for this sorry state of affairs would be ‘failed to reach statistical significance’ – you didn’t need to let anyone know. You could just say. ‘Oh look, the number of episodes of angina was significantly reduced, as was hospitalisation for chest pain and the rate of non-fatal strokes.’ Success!

Man on Clapham omnibus:          ‘But, but, I thought you said the trial was going to look at overall mortality.’

Pharmaceutical company:           ‘How do you know that, we never told anyone what the primary end-point would be.’

Yes, I know, pharmaceutical companies cannot speak. But you get the general idea.

Now, if you start trawling around your data, you can almost always find something somewhere got better. And if something else got worse, you can just fail to mention it. Essentially, therefore, unregistered clinical trials are not worth the paper that they are written on. Especially, of course, if they never got written on any paper at all.

In the year 2000 the major US group the National Heart, Lung, and Blood Institute (NHLBI) decided that any studies they were going to fund (these are non pharma company studies) must register all end-point/primary outcomes, before the study started. This means that the trial investigators could not manipulate the results post-hoc.

A group of researchers recently looked at 55 large clinical studies funded by the NHLBI between 1970 and 2012 to see if the transparency rules had made any difference. What they found should shake the foundations of medical research…but it almost certainly won’t:

  • 57% of studies (17/30) published before 2000 showed a significant benefit in the primary outcome
  • 8% (2/25 trials published after 2000 showed a significant benefit in the primary outcome

As the researchers said ‘The requirement of prospective registration in ClinicalTrials.gov is most strongly associated with the trend towards null clinical trials. The prospective declaration of the primary outcome variable required when registering trials may eliminate the possibility of researchers choosing to report on other measures included in a study. Almost half of the trials [published after 2000] might have been able to report a positive result if they had not declared a primary outcome in advance.1

Pharmaceutical companies have been asked to register trials since 2005.

At this point I am going to try and join two thoughts together. Almost every study done on blood pressure lowering, blood sugar lowering and cholesterol lowering was done before the year 2005. I only choose these three areas as they are the three area of maximum drug prescribing in the world. Billions upon billions are spent in these areas, hundreds of millions are ‘treated’.

The evidence used for this mass medication of the Western World is demonstrably, horribly, biased. Had companies been forced to register their trials prior to publication, positive results would have been reduced by at least 49%. Almost certainly far more. You could put this another way around and say that it very likely that only 8% of studies would have been positive.

We do not know which trials would have been positive, or which negative. Yet we have based the entire edifice of drug treatment, of hundreds of millions of people, on unreliable nonsense. The study in PLOS is only the latest demonstration of this fact. The database of medical research – everything until at least 2005 is a gigantic festering mess. It needs to be stripped out and cleansed.

Do you think this is too strong?

Well I shall now quote Dr Marcia Angell, Dr Richard Horton and Dr Richard Smith. Editors of, respectively, the New England Journal of Medicine, the Lancet and the British Medical Journal. The three highest impact factor journals in medical research.

It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgement of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as editor of the New England Journal of Medicine.’ Marcia Angell.

‘The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.’ Richard Horton

‘The poor quality of medical research is widely acknowledged, yet disturbingly the leaders of the medical profession seen only minimally concerned about the problems and make no apparent efforts to find a solution.’ Richard Smith

Who, in a position of power, will finally wake up and realise that the vast database of medical research stinks of bias and manipulation. Who can we call upon to take up the gigantic and painful task of clearing out the Augean stables?

1: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132382

Four legs better

I spend far too much of my life reading about heart disease and heart disease research and suchlike. As a consequence of this I also consider myself something a ‘Kremlin watcher’. I am always on the lookout for the subtle, carefully crafted and coded messages that are allowed to escape into the outside world from the inner enclaves of power in the medical establishment.

Once something interesting appears, I then try to work out what game is afoot. What you have to recognise is that even the most apparently innocent announcement is crammed with hidden meaning:

Statement:                   ‘Comrade Yushkin has been promoted to the Department of Internal Affairs.’

Interpretation:              ‘Comrade Yushkin has made too many enemies and he has been stabbed in the back by those he thought were friends and kicked out of the Politburo. He is now going to languish in a backwater for the rest of his miserable, pointless, political career. So, for those who thought Yushkin was a rising star…tough.’

Try this one for size:

‘Some prominent cardiologists have questioned the 2013 guidelines, but the ACC and AHA have shown little appetite to return to LDL targets. “LDL may or may not correlate to cardiovascular outcomes,” Dr. Kim Allan Williams, president of the ACC, told Reuters last week1.’

This little nugget was part of a news story about the dreaded PCSK-9 inhibitors, carried by the Reuters news agency. These are blockbuster cholesterol lowering drugs that are descending upon humanity.

However, that is a side issue for the moment. I think we need to return to the comment. ‘LDL may or may not correlate to cardiovascular outcomes.’ Nine little words that you could pass over without really noticing they were there. I would, however, suggest you paid them a little more heed.

The American College of Cardiology (ACC) is at the very epicentre of conventional thinking about heart disease. Now the president…. Kim Williams, el Presidenté himself, has made this statement. “LDL may or may not correlate to cardiovascular outcomes,”

You may think, oh well, little slip of the tongue, nothing to see here, move along. Oh no, absolutely not. Whilst I would be amongst the first to criticise and castigate the ‘experts’ in charge of cardiovascular disease research. There is one thing I would never accuse them of, and that is of being careless.

There is no way on earth that this comment would have been made by mistake. It would have been thought about very carefully indeed. Equally, if Kim Allan Williams had thought he was being quoted in error, he would have asked the journalist to obliterate that statement. Before any interview he would almost certainly demand editorial control over copy. I know I always do.

So, what are we looking at here? I believe that what we are looking at here, ladies and gentlemen, is a major repositioning manoeuvre. For year after year we have been told that a raised LDL is the most important causal risk factor for heart disease.

However, when the latest ACC/AHA (American Heart Association) guidelines came out in 2013 there were no longer any targets for LDL lowering. If someone was at high risk for cardiovascular disease suddenly, lo and behold, you just gave a high dose statin. You did not need to measure what happened to the LDL level, you just prescribed the statin and that was that.

In one way this changed nothing at all, in another way it changed everything. What we had here was an admission, though no-one will admit it, that statins reduce the risk of cardiovascular disease through mechanisms other than LDL lowering. This was shortly followed by the AHA admitting that cholesterol in the diet has nothing to do with raising cholesterol and/or causing heart disease.

More recently several papers have come out clearly demonstrating that saturated fat in the diet has nothing to do with cardiovascular disease. In case you missed it, this paper was in the BMJ last week….

‘Russell J. De Souza, ScD, RD, from McMaster University, Hamilton, Ontario, Canada, and colleagues published their synthesis of observational evidence online August 11 in the BMJ.

Consumption of saturated fats is not associated with all-cause mortality, cardiovascular disease, coronary heart disease (CHD), ischemic stroke, or diabetes2.’

Now the president of the ACC is telling us that LDL may or may not correlate to cardiovascular outcomes. You would have to say that the diet-heart/cholesterol hypothesis is beginning to look a little threadbare right now. One might even say it is dead. However, like the biggest, stupidest dinosaurs, it will stumble about crushing people underfoot for several years before it finally crashes to the ground.

When it does, finally, expire we will have found something very interesting has happened. The ‘experts’ who ruthlessly promoted the diet/heart cholesterol hypothesis a.k.a ‘absolute bollocks’ for the last ‘few decades will have moved their position completely. They will no longer be coaching us all to chant ‘four legs good, two legs bad’. We shall have a new slogan:

‘Four legs good, two legs better.’

Those in power will remain in power. Thus endeth today’s lesson.

References:

1: http://www.reuters.com/article/2015/08/10/us-health-cholesterol-cvs-idUSKCN0QF1RY20150810

2: http://www.medscape.com/viewarticle/849401?src=wnl_edit_medn_wir&spon=34&impID=792944&faf=1#vp_1

Turning diabetes upside down

I have written about diabetes quite a few times. Thus far, I must admit, I have kept the discussion relatively conventional. Anyone who has read my previous blogs may not think so, but compared to what I really believe, everything has taken place close to the middle ground. Time, I believe, to start turning diabetes upside down, give it a good shake, and see what it looks like from a completely different angle.

Some of you may have watched Professor Unger’s fascinating YouTube lecture on type II diabetes. If not, here it is. I recommend it1. To keep things as simple as possible, his view is that the key hormone that drives diabetes is glucagon, not insulin. Indeed, by focussing almost entirely on insulin and sugar/glucose, we cannot understand what is going on with type 2 diabetes, as we are only looking at a small part of the picture. In addition, we are looking at it the wrong way round.

He is, of course right. Now, stop, stand on your head…

Ready, here we go. The critical requirement of human metabolism is to ensure that there is a high enough level of glucose to power the brain. Without sufficient glucose the brains shuts down and dies. Not all the cell types in the brain need glucose and all brain cells can also metabolise ketone bodies, to an extent. (Ketone bodies are synthesized in the liver from fatty acids). However, the bottom line is this. If your blood sugar level drops below about 2mmol/l, and stays there, you will enter a hypoglycaemic coma and die.

Which means that it is absolutely critical that this does not ever occur. In order to prevent this happening we have a hormone that keeps blood sugar from dropping this low. It is called Glucagon. It is produced in alpha-cells in the pancreas (right next to where insulin is produced). How does it work? Here is a short, standard, explanation from diabetes.co.uk:

Glucagon plays an active role in allowing the body to regulate the utilisation of glucose and fats.

Glucagon is released in response to low blood glucose levels and to events whereby the body needs additional glucose, such as in response to vigorous exercise.

When glucagon is released it can perform the following tasks:

  • Stimulating the liver to break down glycogen to be released into the blood as glucose
  • Activating gluconeogenesis, the conversion of amino acids into glucose
  • Breaking down stored fat (triglycerides) into fatty acids for use as fuel by cell

Of course, this statement from diabetes.co.uk is true. However, I would ask you to review ten of the words again, and think about them for a moment or two. ‘Glucagon is released in response to low blood glucose levels.’

Now, you almost certainly do not recognise it, but here is the crux of the entire blood diabetes/insulin /glucose discussion. Those ten words, innocent thought they may seem, have been driven by upside down thinking, and represent the exact point where things go wrong.

This not deliberate, indeed the concept is so familiar, so unquestioned, that you almost certainly have no idea what I am talking about. At this point you are probably wondering, ‘what the hell is Kendrick on about here?’

Indulge me for a moment whilst I re-frame that statement.

As it stands, we are given to believe that glucagon is the reactive hormone, only produced when blood sugar levels drop. Insulin, on the other hand, is the key hormone, the controller of metabolism and blood sugar levels. Glucagon only activates to increase blood sugar after insulin (or exercise) has caused it to fall too far. Which is why we have these ten words: ‘Glucagon is released in response to low blood glucose levels’

You think this is not important, just playing with words. Then try this alterative statement on, and see how it fits. ‘Glucagon keeps the blood sugar level high enough to ensure that the brain has sufficient glucose to function. If, however, the glucose levels rise too high, the body produces insulin to counteract the effects Glucagon. This brings blood sugar back down.’

In one way, I am saying exactly the same thing as diabetes.co.uk said. Looked at in another way, however, and I have just changed everything. No longer is insulin the key hormone, it is now ‘merely’ the subservient hormone, produced to counter the effects of too much glucagon.

Once you have changed your thinking around this way, it should come as absolutely no surprise to find the following. If you have a mouse, and you destroy its beta-cells (insulin producing dells in the pancreas) it will become diabetic, and die. However if you get rid of the glucagon producing cells as well, the animal will not have a high sugar level and will not be diabetic – despite having no insulin at all. It will also appear to be completely healthy.

In addition, if you give such a mouse, that cannot produce either glucagon, or insulin, a glucose ‘meal’ the blood sugar level will rise, and then fall, in pretty much the same pattern as a ‘normal’ mouse. Ergo, the body does not need insulin to keep blood sugar levels down. There are other mechanisms that the body can use. I am sure that having insulin help to optimize blood sugar control, but it is far from essential.

Of course, this type of experiment has never been done in a human – for obvious reasons. However, I do not think there is any reason to doubt that the results would be pretty much the same. Which means that, crikey, insulin is not required for blood sugar control… If I tell my medical colleagues this they absolutely and completely refused to believe it. However, it is true. They choose not to believe it, because it undermines what they think is true.

In fact they think what almost everyone else things. Which is that the insulin/glucose: glucose/insulin model of diabetes is correct. It certainly appeared to explain what we saw in type I diabetes, whereby you gave insulin to those with high sugar levels [those who could not produce insulin, the underlying cause of type I diabetes] and they were ‘cured. Whilst the discovery of insulin and the treatment of type I diabetes was a medical triumph, it is also where the thinking went wrong.

It blinded everyone to fact that insulin is not the key hormone in glucose metabolism. It is simply there to act as a negative feedback mechanism to control glucagon. Unfortunately, since Banting Best and MacLeod, we have become stuck with the insulin/glucose paradigm.

If the blood sugar rises, whatever the underlying cause, we call it diabetes and drive it down…sigh. The more it rises the harder you drive it down….Sigh. The lower you get the blood sugar down the better…sigh. How do you do this? Mainly by giving drugs that force beta-cells to produce more insulin, or by adding in drugs that work with insulin to lower blood sugar levels, or by injecting additional insulin.

How well does this work? Some of you will have heard of the ACCORD study, others will not. In this study researchers, tried to force blood sugar levels down as far as possible using intensive treatment. They found the following:

‘Until last week, researchers, doctors and every medical professional has believed for decades that if people with diabetes lowered their blood sugars to normal levels, they could not only prevent the complications from diabetes, but also reduce the risk of dying from heart disease. But the Accord Study, (for Action to Control Cardiovascular Risk in Diabetes), a major NIH study of more than 10,000 older and middle-aged people with type 2 diabetes has found that lowering blood sugar actually increased their risk of death.2

There is one other way of lowering blood glucose, by using insulin ‘sensitising’ drugs. In diabetes most doctors look at metformin as the wonder drug. This drug improves ‘insulin sensitivity’ i.e. it helps to reduce insulin resistance. It is the absolute mainstay of type 2 diabetes treatment. Once again, however, it is targeted at purely the insulin/glucose model:

‘Metformin has been the mainstay of treatment for type 2 diabetes since 1998 when the UK Prospective Diabetes Study showed reduced mortality with metformin use compared with diet alone. Recently a French meta-analysis of 13 random controlled trials questioned the central role of metformin in the care of patients with diabetes. In this meta-analysis, in which 9560 patients were given metformin and 3550 were given conventional treatment or placebo, metformin did not significantly affect the primary outcomes of all cause mortality or cardiovascular mortality. The secondary outcomes—myocardial infarction, stroke, heart failure, peripheral vascular disease, leg amputation, and microvascular complications—were also unaffected by treatment with metformin.3

Today we have a virtually unquestioned model of diabetes that is very simple, and easy to understand. It should be simple to understand as it works like this. If the blood sugar goes up, the body produces insulin to lower it. If the blood sugar goes down, the body produces less insulin and the sugar level goes up.

This has meant that, if you find someone had high blood sugar levels, you basically hit them with insulin. I call insulin the ‘glucose hammer’ and, as a wise man once said. ‘If the only tool you have is a hammer, pretty soon everything starts to look like a nail’.

Reducing glucagon…. anybody?

1: https://www.youtube.com/watch?v=VjQkqFSdDOc

2: http://www.diabetes-book.com/normal-blood-sugars-questioned/

3: http://www.bmj.com/content/351/bmj.h4023.full?ijkey=AN2nBwW6h3wuQJK&keytype=ref

A tale of mice and men

(PCSK9 and diabetes)

I look into my crystal ball and I see…. I see another wave of diabetes. Yes, the great Nostrokendrickos has spoken. Why do I predict this? Well, I see those given PCSK 9 inhibitors developing diabetes. I see the pharmaceutical companies telling us that this was completely unexpected, a paradox, and not clinically relevant anyway. Hold on…. no the vision is fading….it is gone.

Being an old fashioned type of person I have this strange belief that the body does not produce complex enzymes for a laugh. It takes a lot of energy and resources to make enzymes, or any another form of highly structured protein. If there is no need for them, and what they do, the body sighs with relief and stops making them. Then, over the years, evolution gets rid of the enzyme altogether. It’s kind of how evolution works.

So when we do have an enzyme Proprotein convertase subtilisin/kexin type 9 (PCSK9) I think: What is its purpose? Can it simply be there by mistake? To be frank, I am not entirely sure what the purpose of this enzyme is, but I now know that if you do not have it, bad things can happen. Here is a study which looked at what happens to mice with no PCSK9:

‘Proprotein convertase subtilisin/kexin type 9 (PCSK9), a liver-secreted plasma enzyme, restricts hepatic uptake of low-density lipoprotein (LDL) cholesterol by promoting the degradation of LDL receptors (LDLR). PCSK9 and LDLR are also expressed in insulin-producing pancreatic islet b-cells, possibly affecting the function of these cells. Here we show that, compared to control mice, PCSK9-null male mice over 4 months of age carried more LDLR and less insulin in their pancreas; they were hypoinsulinemic, hyperglycemic and glucose-intolerant; their islets exhibited signs of malformation, apoptosis and inflammation. Collectively, these observations suggest that PCSK9 may be necessary for the normal function of pancreatic islets1.’

Sorry, I realise that the language is a bit technical, so here is a quick interpretation.

  • PCSK9 is an enzyme that degrades/destroys LDL receptors, so cells cannot absorb so much LDL (a.k.a. ‘bad’ cholesterol)
  • Without PCSK9, beta-cells in the pancreas (where insulin is made) absorb too much LDL
  • These LDL ‘overfilled’ beta cells were found to be malformed, dying (apoptosis) and inflamed
  • Mice without PCSK9 which had these ‘overfilled’ beta-cells were also glucose intolerant, did not produce enough insulin and were hyperglycaemic a.k.a. there were diabetic

That was mice, what of men? (And, of course women). Well, if we look at people with familial hypercholesterolemia (FH), they have a lack of LDL receptors, or the receptors don’t work so well due to malformations, or both. Therefore, you get less LDL inside cells, including beta-cells. Therefore:

‘In the cross-sectional analysis from the Netherlands, patients with familial hypercholesterolemia were found to have a 51% lower odds of having type 2 diabetes compared with relatives without the cholesterol disorder, and diabetes prevalence varied by gene mutation type…. Hovingh and colleagues hypothesized that this reduced risk occurs because pancreatic beta cells in people with the condition have decreased cholesterol uptake and improved function and survival2.’

Hovingh was almost certainly right.

Now some people will, no doubt, grab hold of this research to tell us that ‘As we told you all along LDL is dangerous and damaging, it even causes diabetes by harming beta-cells.’ I am sort of waiting for an ‘expert’ to tell us this. Maybe they already have. At which point I shall approach them from behind, then hit them repeatedly with a large wet kipper. I shall then announce, with great satisfaction…

‘No, you idiot, what this shows us is that excess LDL inside cells is damaging and dangerous, but that has absolutely nothing whatsoever to do with having a high LDL level in the bloodstream…..you idiot.’

Anyway, adding this information together with the study on mice, it seems that the basic function of PCSK9 may simply be to ensure that cells do not absorb too much LDL from the bloodstream, thus protecting them from: malformation, inflammation and death. It certainly seems to be true of beta-cells in the pancreas. Is it true for all other cells – who knows, but it is a bit worrying is it not?

What is certainly true is that PCSK9 inhibitors will almost certainly increase the risk of diabetes, to an even greater extent than statins. This seems entirely predictable; in fact I predict it now. I also predict that the increased risk of diabetes will take years to emerge. This will be for various reasons that I would like to go into, but fear libel suits.

However, when this adverse effect does eventually emerge I know that it will greeted with astonishment and surprise by the ‘experts’ and, at least in public, by the pharmaceutical companies marketing these drugs. Although I am perfectly certain that they know all about this research… they always do. They ain’t stupid.

The great Nostrokendrickos has spoken. Put this article in a time capsule, to be opened when PCSK9 inhibitors are found to cause diabetes.

References:

1: Majambu Mbikay, Francine Sirois, Janice Mayne, Gen-Sheng Wang, Andrew Chen, Thilina Dewpur, Annik Prat, Nabil G. Seidah, Michel Chretien  Fraser W. Scott: ‘PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities.’ FEBS Letters 584 (2010) 701–706

2: http://www.medpagetoday.com/Cardiology/Diabetes/50429

P.S. I wonder what other research they are aware of? I think I might go and find out.

Here they come – take cover

Apart from Rosuvastatin/Crestor, all the statins have lost patent protection, and so the world has changed. I probably need to explain a bit about Patent Protection. If a pharmaceutical company discovers a new, potentially beneficial chemical/drug, it can claim patent protection for twenty two years from the date of first registration of that new chemical compound. Then the clock starts ticking.

So you need to get going to do all sorts of testing on your new chemical to make sure that it actually does something considered useful e.g. kill bacteria, or attack cancer cells, or control progression of rheumatoid arthritis. You also need to ensure it doesn’t kill people, using the sort of doses you would give to achieve a clinical effect. You should ensure that it doesn’t react badly with other commonly used drugs, and on and on.

This all takes time, and costs a lot of money. Companies tell you it costs hundreds of millions to get a drug to market, perhaps even a billion, but their figures are always held tightly to their chest. It certainly costs a lot. How much exactly…no idea. As for the amount of time? Probably about eight to ten years from discovery to launch.

After launch, the companies then have around twelve to fifteen years to sell the drug as hard as they can, whilst they have an effective monopoly. During this window of opportunity they can fix the price wherever they like. This is usually bang on what medical systems think they can afford, or just a sneaky bit more. ‘Oh go on, you know you want it.’

However, once patent protection is gone, generic drug manufacturers that have been waiting in the wings like vultures, can make that exact same drug and sell it, in competition with the company that discovered the drug in the first place – or any other company that wants to make it.

Because generic companies have not had to go through the hugely expensive drug development process, their costs are much less, therefore they can afford to sell the drug far cheaper and still make money. At which point the big companies such as Glaxo, or Pfizer lose interest. Their business model requires enormous profits to support their equally enormous overheads. Selling drugs at a 5% margin is not what they do. They have a workforce of tens of thousands to support.

Getting back to the point in hand. Statins are now, effectively, out of patent. They were the most profitable drugs in the history of the pharmaceutical industry. Lipitor/atorvastatin made tens of billion dollars in profit each and every year it was in patent, and turned Pfizer into the biggest drug company in the world. But statins are now cheap as chips.

Various attempts have been made to combine statins with drugs such as ezetimibe and carry on the patents – you get extra protection for combinations. A few billion has been added here and there. However, the seam of gold has effectively been hollowed out.

So what to do? Shrug your shoulders and move on to a different therapeutic area. Or…? Over the years, billions upon billions have been spent making the statin market into something absolutely massive. This market could also be described as the ‘cholesterol lowering market.’ Everyone, or just about everyone, knows their cholesterol level. They have been trained to be terrified of having a high cholesterol level, and they want it brought down. Bell rings, dog salivates.

In parallel with successfully raising the spectre of having a high cholesterol, the level of cholesterol considered ‘high’ has also been inexorably driven down. Years ago a high level was something over 7.5mmol/l (~300mg/dl). In Europe anything about 5.0mmol/l is now consider high. In the US it is 5.2mmol/l, otherwise known as 200mg/dl (the US and the rest of the world use different units of measurement). However, even that has been further lowered. In those at ‘high risk’ the cholesterol level needs to be below 4.0mmol/l.

The average cholesterol level of human is about 5.5mmol/l (very broad brush stroke), which means that we find ourselves in the weird, yet unquestioned situation, where around 85% of the entire population of the world is now considered to have a high cholesterol. Boy that is some market. Almost every one alive, and with a pulse, should be taking a statin. And people almost demand them ‘I must get my cholesterol level down, now!’

As a pharmaceutical company you certainly do not want to walk away from that, the land of milk and honey…and money. A perfectly prepared market, desperate for anything that lowers cholesterol. Even gaining one percent of that market would mean about twelve million people worldwide… in counties rich enough to pay. If your drug costs a thousand pounds, dollars, or Euros a year, that is still twelve billion pounds dollars or Euros each and every year. Twelve billion profit a year. Be still my beating heart.

And to access that market, all you need to do is to find another way of getting cholesterol down. [Using new drugs that can be patented, and sold at a price that makes a whopping profit]. As a quick aside, the HDL ‘good’ cholesterol raising agents all crashed and burned before you ever knew they existed. They raised HDL and also raised the rate of death from heart disease at the same time. Ooops. So maybe HDL isn’t ‘good’ cholesterol after all. Shhhh, let that be our little secret.

So the industry looked around, and studied everything they could, and they have come up with Proprotein convertase subtilisin/kexin type 9 inhibitors. However, you must ensure that you don’t ever call them that, or everyone’s eyes will simply glaze over followed rapidly by sleep. So this moniker has been shortened to PCSK9 inhibitors. Very catchy.

How do they work? Put as simply as I can. Low Density Lipoprotein (LDL) a.k.a. ‘bad’ cholesterol I is removed from the circulation by binding to an LDL receptor, which is then pulled into the cell. The LDL is ‘unpacked’ and the receptor broken down by PSCK9. However, if you block PCSK9, the receptor lives to fight another day. It is sent back out to the surface of the cell, binds to LDL again and pulls it in. With more and more receptors waving about, the LDL is more rapidly removed from the circulation and the ‘cholesterol’ level drops.

It is true that if you give people a PSCK9-inhibor the LDL/cholesterol levels certainly drop very dramatically. Even more so than with statins. Hoorah! LDL levels can reach virtually zero. Hoorah! Drool! Kerching! As you might expect, a number of pharmaceutical companies have decided to develop their own, very slightly different versions, of PCSK9 inhibitors, and they will all be launching shortly. The one hitting Europe and the US first is likely to be Praluent. Made by Sanofi and Regeneron. It will be given a more catchy brand name when it launches. Cholestegon, or something of the sort.

Of course the hype is going to be monstrous. Newspaper front pages will hail these drugs are life savers, super-statins, Governments must fund them, blah, blah, blah. Billions upon billions will be spent marketing them. Well, you have to speculate to accumulate don’t you.

Experts a.k.a. rent-a-quote dancing bears will do their thing…. ‘Roll up, put money in the jar and the bear will sing and dance any tune you like…’ Yes, experts will dance the tune, and sing the songs required of them by the industry….kerching, kerching, kerching, ker-bloody-ching. ‘Why can’t I see my reflection in the mirror any more mummy?’

Papers will appear in journals that will be reproduced, and repackaged, to be presented to doctors; giving all the scientific reasons why PCSK9-inhibitors need to be used. There are, however, one or two little problems to be resolved.

  • Statin hype
  • Cost
  • Injectable
  • No outcome data

Statin hype

Having spent billions convincing everyone that statins are uniquely effective, have no side effects, and also cure cancer, bacterial infections, HIV, the Ebola virus, bad breath, poor conversational ability, and other things too numerous to mention, your main competitor is the ‘wonder’ drug you created in the first place. Which is also now very cheap.

So, dear pharmaceutical companies, you are going to have to attack statins to create some space in the cholesterol lowering world. We can already see this happening, with sad looking ‘experts’ confirming how terribly disappointing it is that some people just cannot tolerate statins…when I say some, I mean about 25%. ‘But I thought you said statins had no adverse effects.’

Expert: ‘I know, that is what I once thought, but it seems…sob…that many patients have difficulties…sob. Sorry, I am very emotional about all this.’

Pharmaceutical company executive whispers:It’s OK, you can have your money now. There there, don’t get so worked up. You can have your swimming pool.’

Cost

Statins now cost about thirty pounds a year. PCSK9 inhibitors will be in the region of five to ten thousand – so I have been told. If so, health authorities are going to be very, very, unhappy. They will see budgets spiralling out of control. This could kill these products stone dead in many countries. However, the companies will be very careful to ensure that they will only be looking for them to be used in a very small sub-set of high risk, statin intolerant patients. [And if you believe that, you will surely believe anything].

Injectable

These drugs impact on processes within the cell nucleus itself, so they are monoclonal antibodies. They cannot be taken orally, as they would be broken down in the stomach/gut, so they have to be injected. Every two weeks or so, you will need to have an injection. This can be painful and also inconvenient. This will limit uptake. Then again, some people believe that if you inject something, it must be more powerful.

No outcome data

Whilst PCSK9 inhibitors definitely lower LDL, there is no data on their effect on cardiovascular mortality, or any other form of mortality either. They are launching purely on their cholesterol lowering ability. A surrogate outcome. This, of course, saves the tiresome and costly requirement of demonstrating that they actually work. But it may make it rather tricky for them to gain full approval without any proof of efficacy. Or maybe not.

Despite the problems listed above these drugs are coming. Will they be a success? Well those working in pharmaceutical companies are not stupid. They would not be spending billions unless they were pretty certain of success.

What will success look like? Well, frankly, I am sure that they would be happy with one percent of the population taking PCSK9 inhibitors. That would be about three million in the US, four million in Europe, five million in the rest of the world – in countries that have enough money to pay. This is a total market of one hundred and twenty billion pounds/dollars a year. Not bad. Three drugs sharing one hundred and twenty billion is forty billion each, per year, for fifteen years. That is $600Bn lifetime drug earnings.

If they were to succeed in squeezing the market up to ten per cent, that would be a market of one thousand two hundred billion a year. Greater than the GNP of almost every country in the world, up to about Canada. My guess is that they will get to about two to three percent. This market will consist of those with very high cholesterol levels who are ‘statin intolerant’. Yes, be ready for the phrase ‘statin intolerant’, it is how those poor unfortunates who cannot take statins due to adverse effects will be described in future.

Speculating wildly, if they did manage to get everyone on a statin to convert to a PSCK9 inhibitor then the entire GNP of nations would be gone. In the UK, twelve million, or so, are ‘eligible’ for statins. Twelve million times ten thousand is one hundred and twenty billion pounds. That is slightly more than the entire budget of the NHS. Money well spent?

You have been warned.

What happens to the carbs – part II

My interest in nutrition began many years ago as part of my over-riding interest in cardiovascular disease. This means that, unlike many other people, I backed into this area with no great interest in the effect of food on health. For most doctors nutrition takes up about an hour of the medical degree course. We are pretty much given to understand that it is of little medical significance. Eat a balanced diet…end of. I also paid nutrition about that much heed.

However, because of the power and influence of the diet/heart hypothesis I felt the need to understand more about this whole area, and how the system of digestion and metabolism actually worked. At first my interest was purely to find out if there was any clear and consistent association between diet and cardiovascular disease (which I shall call heart disease from now on, as it is simplest to do so).

Like many others, before and since, I could not find any such association. Nor could I find any biochemical or physiological reason why saturated fat, in particular, could cause heart disease. That issue, of course, represents a long and winding road that I am not going down here.

However it did not take long before I became side tracked by the very powerful and consistent association between heart disease and diabetes. People with diabetes have far higher rates of heart disease than people who do not. In the case of women with diabetes, the increase in risk hovers around five times the rate of non-diabetics. So it became clear that I would need to understand diabetes, if I was going to fully understand heart disease.

This led me into the looking at the underlying causes of diabetes (type II). At first it seemed blatantly obvious that type II diabetes was primarily due to insulin resistance (it is far less clear now). In its simplest form, insulin resistance means that you need a higher level of insulin to drive down blood sugar levels, because something is ‘resisting’ its effects. Of course, like everything else, it is rather more complex than this, but I will leave it at that for now.

It also became clear that you can have mild/moderate insulin resistance for many years before you develop frank diabetes. Confronted with resistance to its effects, the body simply increases insulin production to keep blood sugar within the normal range. In this state, sometimes called ‘pre-diabetes’ you do not actually have a high blood sugar, especially not in the fasting state. This, of course was when most blood sugar level measurements were taken. Yes guys, look for a metabolic condition when it isn’t actually visible …very sensible.

However, mild to moderate insulin resistance, even if blood sugar levels are not consistently raised, is not benign. It is associated with a whole series of other metabolic abnormalities such as: central obesity, raised VLDL/triglycerides, low HDL, high blood pressure, high levels of blood clotting factors – to name but a few. In addition you can also find higher sugar levels, and higher insulin levels in the post-prandial state (after eating). Most importantly, to my mind, mild to moderate insulin resistance is also associated with a far higher rate of heart disease.

In the early days, ‘pre-diabetes’ came under many different monikers. Just to give you four:

  • Reaven’s syndrome
  • Syndrome X
  • Insulin resistance syndrome
  • Metabolic syndrome

This caused a lot of initial confusion, but once I chased them all down, it because clear that these different names were simply describing the same phenomenon, which is probably best described as insulin resistance syndrome. Although this title carries its own problems.

The next question, of course, is what causes the insulin resistance? The wisdom was, and remains, that it is caused primarily by obesity. This was based on the observation that, as people got fatter, the risk of diabetes increased almost exponentially. One paper I read many years ago stated that younger obese women had around forty times the risk of diabetes, compared to women of normal weight. That is what you call a strong association. Perhaps causation may even be whispered?

In short, if you added together what was clear about diabetes and insulin resistance, you got a model of type II diabetes which looked pretty much like this:

  • You eat too much food
  • You put on weight
  • As you put on weight you become more and more insulin resistant
  • At first you will develop insulin resistance syndrome
  • If you keep putting on weight you will become so insulin resistant that you will develop frank type II diabetes

I call this the ‘blowing up a balloon’ theory of diabetes. As a balloon expands you have to blow harder and harder to overcome the resistance. As you get fatter and fatter you need more and more insulin to force fats into fat cells. As with many things in medicine this is a nice simple story. It is also very easy to understand, and it is tantalisingly close to being correct

As always, however, when presented with a model like this, my immediate reaction is to try and smash it to bits with contradictory evidence. I figure that any theory that can withstand repeated assault is likely to be correct. On the other hand.

I started by looking at the extremes, as I always do. Beginning with the most obese group people on the planet earth, namely Sumo wrestlers. I wanted to know how many of them have diabetes, and it did not take long to discover that, whilst in training, none of them have diabetes.

I then searched for the opposite end of the spectrum. Were there people with no adipose tissue, and how many of them had diabetes? Surprisingly, there is one such group, the least obese people on earth. They are those with Beradinelli-Siep lipodystrophy. This is a genetic abnormality which means that these poor unfortunates have almost no fat cells. How many of them have type II diabetes? Well, all of them actually.

I then looked for the population with the highest rate of diabetes in the world. This happens to be the Pima Indians of North Mexico/Southern US. I have seen figures reporting that over 80% of adult males Pima Indians have type II diabetes. It may even be more. And yes, they are very obese.

However, there are two other very interesting facts about the Pima Indians. First, they have a very low rate of heart disease. Or they did last time I looked. Perhaps most importantly, in their youth, when they are not obese, they produce far more insulin in response to food than ‘normal’ populations. Or, to put this another way, they are hyper-insulinaemic before they are obese, and long before they become diabetic. So their excess insulin production is not a result of becoming fatter. The causal chain is the other way around.

I have found that if you speak to most doctors about these facts, a look of complete incomprehension passes over their faces. ‘That cannot be right.’ Of course if you believe in the ‘blowing up a balloon’ model of diabetes, then the Pima Indians, Sumo Wrestlers and those with Beradinalli-Siep lipodystrophy do not make any sense. However, in science, when observations do not fit your hypothesis, it is the hypothesis that needs to change, not the facts.

Just to summarize these ‘paradoxical’ facts:

  • You do not need any fat cells to develop diabetes/if you have no fat cells there is a 100% probability that you will be diabetic
  • You can be very , very, obese and not have diabetes
  • You can have increased insulin production long before you become obese (and/or insulin resistant). You become obese later

Just to remind you of the current model.

  • You eat too much
  • You get fat
  • As you get fat you become more insulin resistant
  • In order to overcome this resistance you produce more insulin
  • Eventually you cannot produce enough insulin, the system ‘burns out’ and you develop type II diabetes

Where and how can the paradoxical facts be fitted? The answer is that they cannot. Ergo, the model is wrong. However, luckily, there is another model that fits all the facts. One that I prepared earlier:

  • You produce too much insulin
  • This forces your body to store fat
  • You become obese
  • At a certain point insulin resistance develops to block further weight gain
  • This resistance becomes more and more severe until…
  • You become diabetic

This model explains the Pima Indians. Can Sumo wrestlers be fitted into this model? Yes, with a couple of addendums. Sumo Wrestlers eat to become fat, because added mass provides a competitive advantage if you are trying to shove someone else out of a small ring, before they do it to you.

To achieve super-obesity, they wake up, train for two hours, then eat as much as they can of a high carbohydrate, low fat, broth. They then lie about for a few hours allowing the high insulin levels created by the high carbohydrate diet to convert excess sugars to fat, storing this in adipose tissue. Later on they train very hard again, then eat, then sleep. Rpt.

The reason why they do not become diabetic is on this regime is simply because they exercise very, very, hard. They burn up all the sugar/glycogen stores in the liver and muscle whilst exercising, which means that when they eat, the sugar(s) can – at least at first – be easily stored in muscle and liver (so there is no insulin resistance to overcome). However, once these guys stop training, things do not look so good. Diabetes lurks..

Those with Beradinelli-Siep lipodystrophy have the reverse problem to Sumo Wrestlers. Because they have no fat cells there is nowhere to store excess energy to go. If they eat carbohydrate/sugar, the first 1,500 calories can be stored as glycogen – after that there is nowhere left. If the liver converts sugar to fat, there is nowhere for that to go either. So, you get ‘back-pressure’ through the system. It doesn’t matter how high the insulin level gets, if you have nowhere to store energy you have nowhere to store energy. End of.

Whilst those with lipodystrophy cannot tell us much about diabetes and obesity in ‘normal’ people. This condition does make it very clear that diabetes – insulin resistance, high insulin and high sugar levels – is primarily an issue with energy storage and how the body goes about this storage, and the role that insulin plays. If there is somewhere for excess energy to go easily, insulin levels will not go up, and nor will blood sugar levels.

But what of ‘normal’ people. Can normal people be fitted into the updated model of type II diabetes? Well, of course, they can. But you need another step in the new model, the first step. Which means we have a new causal chain, and it looks something like this ‘You eat too much carbohydrate.’ Adding in this step gives us the new model:

  • You eat too much carbohydrate/sugar
  • You produce too much insulin
  • This forces your body to store fat
  • You become obese
  • At a certain point insulin resistance develops to block further weight gain
  • This resistance becomes more and more severe until…
  • You become diabetic

The best thing about this model is that it works. It is not contradicted by Sumo Wrestlers, Pima Indians of those with lipodystrophy. It explains the association between obesity and diabetes, and how insulin resistance develops. It may not be perfect, but it is a bloody site better than the simplistic model we have got. The one that says, if you eat fat, you will get fatter, then diabetic…. Bong! If you are diabetic you should eat carbohydrate and sugar, not fat…Bong!

How long before mainstream medicine rejects this mainstream model? Another fitty years or so, I would guess