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

What happens to the carbs?

I have found a strange thing happens when I talk to nutritionists about the fate of carbohydrates in the human body. Professors, who shall be nameless, appear unable to admit how basic human physiology works. For example, they may concede a few steps here and there, but they will never, ever, admit to the following chain that I have described below.

1: Carbohydrates, such as fruit and vegetables, bread, pasta… and, of course, less complex sugars – such as the stuff we sprinkle on cornflakes, that we call ‘sugar’, are all turned into simple sugars in the human digestive tract before entering the bloodstream.

2: If you keep eating carbohydrate the resultant simple sugars will, at first, be stored. The human body can pack away around 1,500 calories of sugar. However, once this limit is reached, the liver will turn the rest into fat.

3: The fat that is made in the liver is palmitic acid

4: The next step is that three palmitic acid molecules are attached to a glycerol molecule, to form a triglyceride.

5: These triglycerides will then be packed into Very Low Density Lipoproteins (VLDL) and released into the bloodstream. [Beware of confusion here. For VLDLs are also called triglycerides although, of course, they are not. VLDLs contain triglycerides but they are not the same thing – even if they are called the same thing].

6: When VLDLs reach fat cells (adipose tissue), the triglyceride is stripped out and absorbed into fat cells. Which means that VLDLs gradually shrink.

7: Once a VLDL has lost a large amount of triglyceride it becomes a new, smaller, lipoprotein, which is often referred to as ‘bad cholesterol’ a.k.a. LDL (Low Density Lipoprotein).

8: LDL is taken out of the circulation, primarily, by the liver. Some LDLs are removed from the circulation by other cells around the body that need the cholesterol contained in them.

9: As can be seen, the only source of LDL is VLDL.

Here a couple of quotes from Wikipedia to confirm at least a couple of these steps:

Lipogenesis is the process by which acetyl-CoA is converted to fatty acids. The former is an intermediate stage in metabolism of simple sugars, such as glucose, a source of energy of living organisms. Through lipogenesis and subsequent triglyceride synthesis, the energy can be efficiently stored in the form of fats.

Lipogenesis encompasses both the process of fatty acid synthesis and triglyceride synthesis (where fatty acids are esterified with glycerol to form fats). The products are secreted from the liver in the form of very-low-density lipoproteins (VLDL). VLDL are secreted directly into blood, where they mature and function to deliver the endogenously derived lipids to peripheral tissues. https://en.wikipedia.org/wiki/Lipogenesis

Excess carbohydrates in the body are converted to palmitic acid. Palmitic acid is the first fatty acid produced during fatty acid synthesis and the precursor to longer fatty acids. As a consequence, palmitic acid is a major body component of animals. In humans, one analysis found it to comprise 21–30% (molar) of human depot fat and it is a major, but highly variable, lipid component of human breast milk. https://en.wikipedia.org/wiki/Palmitic_acid

I am half tempted to leave the blog here and let you think about what all of that means for a while. However, I feel the need to make a couple of other points, in no particular order. First, I would like you to think about this fact. The form of fatty acid that the liver chooses to synthesize from sugar(s) is palmitic acid, a saturated fat. Palmitic acid is also the major component of breast milk.

Yet, despite this, we are told that saturated fats are uniquely unhealthy, and eating them leads to heart disease. Indeed, within to the very same Wikipedia article on palmitic acid we learn that: ‘According to the World Health Organization, evidence is “convincing” that consumption of palmitic acid increases risk of developing cardiovascular diseases.’

It seems that we are being asked to believe that the body naturally synthesizes a substance, palmitic acid, that actively damages our health. Not only that, but mothers choose to synthesize exactly the same form of fatty acid in their breast milk, which then increase the chances of their offspring developing cardiovascular disease.

Now just how likely does this seem…exactly? We have evolved to kill ourselves from heart disease? As Spock may have said, ‘its evolution Jim, but not as we know it.’ You would think that if polyunsaturated fats were healthy, this is what the human body might choose to make. But no, we eat super healthy fruit and vegetables and then our body, in a unique and ironic twist of fate, converts them into death dealing saturated fatty acids.

Not only that, but just to rub salt into the wounds, once the liver has synthesized these death dealing fatty acid molecules it then chooses to pack them into VLDLs which have the cheek to shrink down into LDL a.k.a. ‘cholesterol’ and these also kill us with heart disease (allegedly).

Of course, if you actually eat saturated fat, this gets nowhere near the liver. It is digested, packed into chylomicrons, and these very large lipoproteins enter the bloodstream directly through the thoracic duct. Which is a secret passage from the gut that opens out in one of the veins in your neck. When chylomicrons encounter fat cells, the fats/triglycerides are sucked out, and the chylomicron shrinks down to virtually nothing. Chylomicrons, however, do not convert to LDL and have nothing whatsoever to do with heart disease – even according to those who think saturated fat in the diet is deadly.

Yet, despite this knowledge we are continuously told, in all seriousness, that eating saturated fat raises our LDL levels and causes us to die prematurely of heart disease. [You may have noticed that cholesterol has hardly entered this discussion at any point.] When people ask me why I don’t believe in the diet/heart hypothesis, I tend to shrug and move the conversation on.

However, if I am feeling a bit stroppy I tend to reply that ‘Even if you were to believe that a raised LDL levels causes heart disease, the current diet/heart hypothesis does not, and cannot make any sense from a biological or physiological perspective.’ If you were actually looking for a substance that really could raise LDL/cholesterol levels it would have to be carbohydrates a.k.a. sugars. After all the only source of LDL is VLDL, and it is eating too much sugar that raises VLDL levels.

In short, how can it not be that carbohydrates raise LDL levels? This is what a basic understanding of lipid physiology tells us must be true. Yet, people write papers on this phenomenon in a tone of almost stunned surprise. Here for example is a paper called ‘The Effect of Dietary Carbohydrate on Triglyceride Metabolism in Humans’:

When the content of dietary carbohydrate is elevated above the level typically consumed (>55% of energy), blood concentrations of triglycerides rise. This phenomenon, known as carbohydrate-induced hypertriglyceridemia, is paradoxical because the increase in dietary carbohydrate usually comes at the expense of dietary fat. Thus, when the content of the carbohydrate in the diet is increased, fat in the diet is reduced, but the content of fat (triglycerides) in the blood rises. http://jn.nutrition.org/content/131/10/2772S.full#fn-1

This author, writing for the Journal of Nutrition, finds it paradoxical that… increased dietary carbohydrate usually comes at the expense of dietary fat….but the content of fat (triglycerides) in the blood rises. Well, what did they think would happen? That carbohydrates would turn into fairies at the bottom of the garden?

Once the liver and muscles are full of sugar (stored as glycogen – a polymer of glucose) the body can do absolutely nothing else with it, but turn it into fat – through the processes I have described earlier. This is basic, incontrovertible science.

Most people who are interested in the potential benefits of the low carb high fat diet (LCHF), have tended to look at it from the perspective of helping with controlling diabetes, and promoting weight loss. I came at the LCHF diet from my own perspective, which is heart disease.

When you understand the science you find yourself looking at the diet heart hypothesis (fat in the diet raises LDL levels, which causes heart disease) and thinking. This does not make any sense at all. Yet, such is the determination of the nutritional experts to defend their position that they never, ever, talk about ‘what happens to the carbs?’

What happens to the carbs is that they are all turned into saturated fat. This then raises VLDL levels and these, in turn becomes LDL. Yet eating carbs is supposed to be healthy, and eating saturated fat is unhealthy. Go figure.

The world of nutrition is, I am afraid, nuts.

Conflict of interest – not just about money

There is a major spat going on at present around Conflict of Interest. The New England Journal of Medicine (NEJM) appears to be backtracking on the issue, and they are talking about relaxing their rules. The British Medical Journal (BMJ) is very ‘heavy’ on Conflict of Interest (COI) and has been somewhat critical of the NEJM approach – to say the least. See 13th June edition of BMJ.

To give you a flavour, one article in the BMJ has the title ‘Backtracking on conflicts of interest: a very bad idea… A series of articles in the New England Journal of Medicine has questioned whether the conflict of interest movement has gone too far in its campaign to stop the drug industry influencing the medical profession. Here three former NEJM editors respond with dismay.’

My sympathies are almost entirely with the three former editors: Robert Steinbrook, Jerome Kassirer and Marcia Angell. I think bias, and resultant distortion of medical research is a massive problem. So massive that it has become difficult to believe most of the research that is published. I am not alone in my concerns. Here is what Richard Horton (Editor of the Lancet), has to say on the matter:

‘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.’

A half of medical scientific research may be untrue… think on the implications of that for a moment. However, before you focus all your efforts on trying to expose financial conflicts of interest as the solution to all problems, you need to take several steps back. Here are just two of the elephants in the room:

  • Just because someone is getting paid, does not mean they are saying or doing anything that is biased, or distorted. So, by introducing punitive rules on payment from the industry, you could be punishing everyone who has ever received any money, when many of them have done nothing wrong.
  • It is incredibly simple to set up structures that allow money to be paid to a ‘charity’, or a University Department, that can then be filtered down to an opinion leader who can then state, quite truthfully, that they receive no money from the industry. So, if you are going to look for conflicts, you are going to have a dig considerably deeper than looking for a direct transfer of money from pharmaceutical company to doctor. And that is tricky to enforce.

There is also another major issue here, which no-one seems to have discussed at all. Which is that money is most definitely not the only currency available when it comes to ‘bribes.’

At present, COI is seen in very simple terms. A conflict of interest is that someone (usually an international expert in, say, psychiatry) is paid lots of money by a pharmaceutical company. They then say exactly what the pharmaceutical company has written down on a piece of paper for them to say e.g. ‘This new product depressagon is completely safe, highly effective, has no side-effects, and I believe that depressagon should be use, first line, in anyone with depression. Thank you, where’s my cheque.’ The last three words are usually silent.

The International expert then sits on a guidelines committee for depression, and encourages all the other members of the panel to put depressagon on the list of first line drugs to be used in depression – and any other mental illnesses they can think of. At which point the Acme Pharmaceutical Company Inc. makes twenty billion dollars a year from depressagon. Which means that the one hundred million paid to the offshore account of said expert can be considered money well spent.

Of course, it is never as crude as this. Paying people money to say what you want them to say is considerably more subtle and nuanced. A raised eyebrow here, a small cough in the correct place there, an embarrassed silence round the table… the rules of playing the game are complex and never written down anywhere. In fact, if you have to ask how to take part, you don’t get invited.

However, urbane, crude, or not, there is still an assumption that the currency of COI is money, specifically money that ends up the experts bank account (directly, or indirectly). This is nonsense. There are many other things on offer. The most important of which is…power.

If you can work with the industry to attract several hundred million to your University for research; if you can be the lead investigator in several major international studies, then you will gain prestige, influence and power. The University may create an entire department as your plaything. You can have fifty new staff members, you will be asked to sit on prestigious committees. You can advise Governments on health policy.

Money….money. Who needs that? To quote Kevin Spacey playing Francis Underwood in House of Cards:

‘Such a waste of talent. He choses money over power. In this town, a mistake nearly everyone makes. Money is the Mc-mansion in Sarasota that starts falling apart after 10 years. Power is the old stone building that stands for centuries. I cannot respect someone who doesn’t see the difference.’

Up to now, all discussions about Conflict of Interest have focussed purely on payment in money. As if this is the only reason why someone may, ever, be influenced. When a medical expert states proudly they are not paid by pharmaceutical companies this may or may not be true. Tracking the flow of money into and out of Universities and medical charities is a complex old game.

However, no-one seems to have grasped a very important concept. You don’t have to pay someone money to manipulate them. They can be rewarded, instead, with power and influence. Conflict of Interest is about far more than money, and we should stop pretending otherwise.

You’re killing my patients (again)

Some of you may remember that the Australian Broadcasting Corporation (ABC) ran two programs in 2013 about saturated fat and statins. The messages were that saturated fat does not cause heart disease, and statins have more side effects than were reported in the trials, and could do more harm than good in patients at low risk of heart disease.

Massive outrage ensued, at least in Australia, a faraway country of which we know little. However, the battle is important for us all. For it is about crushing free speech and stomping on any criticism of medical ‘experts.’ Which is a very dangerous thing indeed.

After internal investigation, ABC pulled both programs and apologized profusely. Even though they could find nothing wrong with the programme on saturated fat, and only one of seventeen objections was upheld. And this objection was, in my opinion, a relatively minor issue (see a previous blog on the matter).

Just to refresh your memory. Here is the only point in which the programs were felt to have misrepresented the facts, followed by my comment at the time.

‘The program’s treatment of use of statins in secondary prevention focused solely on mortality benefits in a way that reinforced the view that statins were overprescribed and their benefits exaggerated. The principal relevant perspective that statins have wider benefits for this group was not properly presented. This perspective was necessary to a fair understanding of the pros and cons of statin use in this group.’

My Comment: [Turning this into English. What the committee believe they found was that the second Catalyst program ‘Cholesterol drug war’ did not mention that statins have benefits on non-fatal outcomes e.g. non-fatal heart attack, and non-fatal stroke. By failing to emphasize this point it was judged that the program gave a misleading perspective on the overall benefits of statins (in secondary prevention).]

However, all of this was represented as follows:

ABC takes down Catalyst heart disease episodes after review criticism Controversial TV program on cholesterol-lowering statins found to have breached editorial standards.

‘Two episodes of the TV science program Catalyst will be removed from the ABC’s website after an internal review found the program had breached editorial standards on impartiality.

The controversial Catalyst program on statins and heart disease, The Heart of the Matter, was attacked by health experts even before it aired last year.

The presenter of ABC radio’s Health Report, Norman Swan, warned “people will die” as a result of the TV program’s messages about heart medications.

Swan, whose criticism of the program has been vindicated by the independent Audience and Consumer Affairs Unit report, had said the program made him “really angry” because it might affect Indigenous Australians, who are especially likely to suffer from high cholesterol.’ {P.S. Norman, indigenous Australians have lower cholesterol levels than the surrounding population}.

If this was all you had heard about the matter you would assume that ABC had done a very shoddy job, with sloppy and potentially dangerous reporting. Yet all of this ‘howling villagers with pitchforks’ attack was based on a single issue. It should be emphasised that, at no point did the programs suggest that anyone should stop taking a statin, or that statins should not be used in high risk patients.

But the vicious attacks did not stop here, oh no. Now we have a paper in the Medical Journal of Australia, reported yesterday, as follows:

Today, researchers from the University of Sydney and the Australian National University report on the impact of another Catalyst program. In October 2013, Catalyst broadcast a segment highly critical of statins, a class of drug used for lowering cholesterol.

The program questioned the link between cholesterol and heart disease, and suggested the benefit of statins in preventing cardiovascular disease was exaggerated.

There was extensive criticism of the program, including from the ABC’s own Norman Swan and the ABC later removed the episodes from the Catalyst website after an internal review found that the episodes had breached its impartiality standards.

The new report in the Medical Journal of Australia used Pharmaceutical Benefits Scheme data of 191,000 people and found an immediate fall of some half a million fewer statins dispensed to patients in the eight months following the Catalyst broadcasts.

The authors wrote:

This translated to an estimated 60,897 fewer people taking statins over the eight months examined. If patients continue to avoid statins over the next five years, this could result in between 1,522 and 2,900 preventable, and potentially fatal, heart attacks and strokes.

One of the study authors, Associate Professor Sallie Pearson, Scientific Director of the Centre of Research Excellence in Medicines and Ageing at the University of Sydney, said:

What is particularly concerning is that this drop in use was seen in people who were at high risk of cardiovascular disease – for example, those who were also taking medications for diabetes. Heart attacks and strokes are the main killers of people with diabetes.

Statins are recommended for people at high risk of cardiovascular disease because they have been shown to be effective. Like all medications, they have risks and benefits and should only be used as recommended.

The study authors wrote:

Even though the observed effect was relatively small, the prevalence of statin use in Australia and their established efficacy means that a large number of people are affected, and may suffer unnecessary consequences.

Why would anyone have done such a study? The only possible reason is that it was a deliberate effort to destroy any possibility of anyone ever criticising statins again? The whole thing is appalling and disgraceful.

At no point (to restate this yet again,) did the programs suggest people at high risk (secondary prevention) of heart disease stop taking statins. Yet, as you can see, the main attacked focussed on the fact that there was a reduction in people taking statin, in those at high risk of heart disease. What nonsense. Yesterday I wrote the following in a comment on an Australian website ‘The Conversation.’1

Here is the kind of delicious irony we should all enjoy. To quote Sallie Pearson, one of the study authors. ‘What is particularly concerning is that this drop in use was seen in people who were at high risk of cardiovascular disease – for example, those who were also taking medications for diabetes.’

Oh my God, people with diabetes are giving up statins. Well, as statins increase the risk of diabetes by 46%* then it would not be surprising to find a significant number of people with diabetes giving up statins. After all, it would have been, in many cases, the statins that gave them the diabetes in the first place. So, giving up the statins would probably have ‘cured’ their diabetes. And as we all know, to quote Sallie Pearson again…’Heart attacks and strokes are the main killers of people with diabetes.’ Yes, indeed.

Pursue this line of argument for too long and madness shall surely follow.

*The use of statin treatment could increase risk of type 2 diabetes by 46%, as a result of decreases in insulin sensitivity and insulin secretion, according to researchers from the Institute of Clinical Medicine in University of Eastern Finland. http://www.pharmaceutical-journal.com/news-and-analysis/statins-increase-risk-of-type-2-diabetes-study-suggests/20068064.article

P.S. When it comes to statins, 75% stop taking them in the first year anyway. So the Catalyst programme would have been but a drop in a very large ocean. http://www.statinusage.com/Pages/key-findings-and-implications.aspx

P.P.S. As you will see, most people stop taking statins due to adverse drug effects which, according to the programmes critics, do not really exist.

1: https://theconversation.com/abcs-2013-catalyst-program-may-contribute-to-up-to-2-900-heart-attacks-and-strokes-43177

Statins and cancer

(Ho hum, not again)

A number of people have written to me pointing out an outbreak of mass hysteria in the UK press about statins protecting against cancer. I suspect this hysteria has been repeated around the world. Here are the headlines from the eponymous Daily Mail

Statins slash risk of death by cancer: They slow tumour growth

by up to 50% reveal major studies

Experts say there is ‘overwhelming’ evidence that statins can treat cancer

Study showed they cut death rates for bone cancer patients by 55 per cent

GPs should make patients aware of pills’ new benefits, researchers say

I have been aware of claims that statins protect against cancer for many years. They pop up on a pretty regular basis. I have tended to ignore them on the basis that, anyone who is stupid enough to believe such research, deserves all the statins they can get.

However, such is the overblown hype this time, that I feel the need to rouse myself from my slumber, and explain why this is just complete rubbish. I don’t need to read the original studies to do this. I have read enough of these over the years. I hope this does not sound too arrogant, but I will happily apologise if any single thing I write here proves to be wrong.

Not randomised controlled studies

The studies quoted will not have been randomised and controlled. By which I mean they did not take, say, forty thousand people and split them into two, randomised, groups. One group to take statins the other to take a placebo. Then wait, say, five years to see what difference there was.

These studies will have been observational. By which I mean you look at people taking statins and see what happens to them vs. people who do not take statins. Such studies can show associations between two variables. But they cannot prove causality. (They cannot provide ‘overwhelming’ evidence of anything either). This is basic science, page one, paragraph one.

Just to provide one example of this. In 1987 a major observational study showed that women taking HRT had a more than forty per cent reduction in heart disease. At which point it was recommended that women took HRT to protect themselves against heart disease. This was, in fact, written into the guidelines of the American College of Physicians. To fail to prescribe HRT was considered medical malpractice in the USA.1

Some years later came the Women’s Health Initiative (WHI) study. The first randomised primary prevention trial to use HRT, and 17,000 women were involved.

‘Analysis of hazard ratios showed that after 5.2 years, there was a 29% increase in coronary heart disease risk, including an 18% risk of coronary heart disease mortality and a 32% increase risk of nonfatal myocardial infarction. There was a 20% increase in risk of fatal stroke and 50% increase in the risk of non fatal stroke in women assigned to HRT.2

So, a 42% reduction in heart disease turned into a 18% risk of dying of heart disease. In short, observational studies are hopelessly unreliable and often turn out to be complete nonsense. And there is a specific reason why I know these statins studies will be complete rubbish, which I will get to.

Relative not absolute risk

Once again, in these studies, we run into the distorting use of relative, not absolute risk. A fifty per cent reduction in risk can mean something, or nothing very much. It depends what the underlying risk was in the first place. In my book Doctoring Data I covered the use/misuse of relative risk in some depth.

Let us just say that if your underling risk of dying in the next five years is 50%, reducing that risk by 50% is a big deal. If the risk of dying in the next five years is 0.1%, then reducing that risk by 50% is five hundred times less of a big deal.

As for slowing tumour growth by 50%. Well, that could mean almost anything. Did you reduce tumour growth by 1%, 50% or some other number. And does reducing tumour growth actually reduce the risk of dying? Of course, you will always find some super rare cancer e.g. bone cancer, where death rates are cut by 55%.

I would imagine this meant about three deaths verses seven in bone cancer. Basically, however small the absolute figures can be to get to a relative risk reduction of 55%. I would guess there will be no statistical significance figure attached to this reduction. Many questions, almost none of them well be answered, you will find.

The elephant in the room (raised cholesterol protects against cancer)

Here, however, is the big issue. People with higher cholesterol levels are far less likely to die of cancer. Add this to the fact that people with higher cholesterol levels are far more likely be prescribed statins, and you start off with the most gigantic built in bias that it is possible to find.

In 1992 (before statins were being prescribed to more than a select few) a conference was held to look at low blood cholesterol and associations with mortality3. Going back this far in time is important. After this, statin prescribing makes it very difficult to disentangle those with naturally low, or high, cholesterol levels vs. those who were taking statins.

All the major studies of the time were reviewed, with nearly one million participants. As you can see from my little graph, reproduced from the figures in the paper, as cholesterol levels rise, the risk of cancer falls. For women, if your cholesterol level is below four, the risk of dying of cancer is 38% higher than if your cholesterol level is above 6.2mmol/l. In men we are looking at a 27% greater risk with low cholesterol levels. {See chart)

CL-vs-CR

Thus any observational study on lowering cholesterol with statins starts off with a massive inbuilt bias in the two populations. You are looking at one group of people who have a much lower risk of cancer to start with, then giving them statins, then declaring that statins protect against cancer….. just the most absolute unscientific codswallop.

As final warning. Be careful about lowering cholesterol too far. A very large Japanese study (that you will never have heard of, because it was not very supportive of statins) looked at prescribing statins to over forty seven thousand people over six years. As they found:

‘The patients with an exceptionally low TC (total cholesterol) concentration, the so-called ‘hyper-responders’ to simvastatin, had a higher relative risk of death from malignancy than in the other patient groups.’4

In fact, the rate of death from cancer in those whose cholesterol fell the most dramatically was increased by three hundred and thirty per cent (relative risk, apologies for doing this, but I do not know the absolute risk). The authors added this warning:

‘Further analysis is necessary to elucidate why the hyper-responders had an increased risk of death; their baseline characteristics will be described and discussed in detail in the future. Nevertheless, the health of patients who show a remarkable decrease in TC or LDL-C concentration with low-dose statin therapy should be monitored closely.’

Can I return to my slumbers on this issue now?

 

References

1: American College of Phyisicians. Guidelines for Counselling Post-Menopausal Women about Preventative Hormone Therapy. Ann Intern Med. 117:1038-41. (1992)

2: Writing group for the Women’s Health Initiative Investigators. ‘Risks and benefits of oestrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative Randomized controlled Trials’ JAMA (2002)

3: Jabobs et al: Conference on Low Blood Cholesterol and Mortality: Circulation Vol 86, No 3 September 1992

4: Matsuzaki M et al: Large Scale Cohort Study of the Relationship Between Serum Cholesterol Concentration and Coronary Events With Low-Dose Simvastatin Therapy in Japanese Patients With Hypercholesterolemia Primary Prevention Cohort Study of the Japan Lipid Intervention Trial (J-LIT). Circ J 2002; 66: 1087 –1095

Hoorah

The article below was just sent to me be a fellow GP, who shares my concerns about the prescribing of statins to everyone with a pulse. In fact it was he (I am being coy about naming him here) who led the protest against the over-prescribing of statins within the Royal College of General Practice (RCGP). He also led the protest within the General Practice Committee (GPC), which is the part of the British Medical Association (BMA) that negotiates on behalf of General Practitioners. Yes, the structures of medical politics are byzantine indeed.

Anyway, for those who believe that doctors are unthinking drones who stare at computer screens and merely follow the guidelines they see there, tonight you may raise a glass of beer, or wine, or even whisky, to them.

Short warning. Before you read this article, which appeared in PULSE magazine (the most widely read medical magazine for UK GPs) I feel I need to quickly flick through the acronyms.

  • RCGP = Royal College of General Practitioners
  • NICE = the National Institute of Health and Care Excellence (they look at all the evidence in a medical area, then create the guidelines for treatment that doctors are commanded to follow)
  • QOF = Quality Outcome Framework. A system of payments designed to incentivise General Practitioners to meet various targets e.g. lower blood pressure, measure weight, put people on statins.
  • QRISK = A risk calculator, designed to determine your risk of having a heart attack or stroke in the next five or ten years.

‘The RCGP and the GPC have rejected NICE’s plan to introduce QOF indicators that would see practices rewarded for prescribing statins to patients with a QRISK score above 10%, warning the move threatened the ‘credibility of QOF’.

The move comes as NICE advisors on QOF are due to meet early next week to discuss potential new indicators – including two that would reward practices for prescribing statins to patients newly diagnosed with diabetes or hypertension at a 10% estimated 10-year cardiovascular risk level – which will be up for negotiation for next year’s contract if approved.

The GPC said that it was ‘vital for the credibility of QOF’ that indicators have a robust evidence base, make significant difference to patients and are backed for the profession, adding that these proposals ‘fail on all these counts’.

The RCGP warned that the proposals risked ‘the loss of professional confidence in the healthcare targets they are being asked to meet’.

NICE launched the consultation on proposed new QOF indicators earlier in the year, which included another potential new indicator would pay practices to set up a register of patients with a 10-year risk of 10% or higher, alongside the hypertension and diabetes indicators.

The proposals were made in order to reflect updated NICE lipid modification guidelines, which lowered the 10-year cardiovascular risk threshold at which GPs prescribe interventions, including statin therapy, from 20% to 10%.

This was despite opposition from GP leaders and other leading clinicians concerned about the potential for over-medicalisation of healthy people and diversion of resources away from the sick onto the ‘worried well’.1

‘Get in!’ as they say. I am, to put it mildly, delighted.

1:         http://www.pulsetoday.co.uk/your-practice/qof/gp-leaders-unite-to-reject-nice-proposal-to-put-10-statin-threshold-in-the-qof/20010096.article#.VWh-r8-6eUk

The dog that did not bark in the night

Some of you may have noticed this study, others may not. The amazing ‘wonderdrug’ trial proving that cholesterol lowering drugs have unparalleled benefits on preventing stroke. Here is just one headline from the Daily Express. A major newspaper in the UK.

Statins slash stroke risk by 30 per cent: Millions more should be given drug, say experts

New research has found that the wonderdrugs – which include statins and fibrates – can slash the risk of suffering a stroke by a third in the elderly. And experts now say there is clear evidence that even among the over-75s – a group not routinely prescribed statins – people can benefit from the life-saving drugs.

It is yet more evidence that the cholesterol-lowering drugs are lifesavers and that their benefits outweigh the potential side effects. Lead researcher Christophe Tzourio, Professor of Epidemiology at the University of Bordeaux and Inserm, said: “A one third reduction in stroke risk, if confirmed, could have an important effect on public health.”1

And so on and so forth.

Colleagues of mine love to wave articles like this at me with a triumphant smirk. ‘Seems you’re wrong about cholesterol lowering after all.’ What do you say to that? Eh..’ I usually ask them if they actually read the study. ‘Primary prevention with lipid lowering drugs and long term risk of vascular events in older people: population based cohort study.’2 I ask them this question, but I know that they’ve not. I find it rare to come across a doctor who would ever deign do such a thing as read a scientific paper.

However, when studies like this come out, I do feel the need to raise my enthusiasm to a sufficient level to have a peek at the paper. In this case it was rather easy. This paper was published in the British Medical Journal (BMJ), and I get it delivered to me every week by post. What a quaint thing, actual physical reading material.

My first problem, before I even started reading this study, is that I knew beforehand that a raised cholesterol level is not a risk factor for stroke. Never has been, not anywhere, not in any study I have read. Whilst you can find studies claiming that a raised cholesterol level (LDL) is a risk factor for heart disease [ and you can find others that show the opposite], I have yet to find any study demonstrating any association between raised cholesterol and stroke.

Here, for example, is a short extract from one massive study, the biggest, which looked at four hundred and fifty thousand people over seven million years of observation. It was published in the Lancet:

‘The associations of blood cholesterol and diastolic blood pressure with subsequent stroke rates were investigated by review of 45 prospective observational cohorts involving 450 000 individuals with 5-30 years of follow-up (mean 16 years, total 7·3 million person-years of observation), during which 13 397 participants were recorded as having had a stroke.

Most of these were fatal strokes in studies that recorded only mortality and not incidence, but about one-quarter were from studies that recorded both fatal and non-fatal strokes. After standardisation for age, there was no association between blood cholesterol and stroke except, perhaps, in those under 45 years of age when screened. This lack of association was not influenced by adjustment for sex, diastolic blood pressure, history of coronary heart disease, or ethnicity (Asian or non-Asian).3 [My bold].

Now, if you are unable to find an association between cholesterol levels and stroke in seven point three million years of observation then, you know what, it just ain’t there. In fact, I challenge anyone reading this blog to provide any evidence that cholesterol levels are associated with overall stroke risk. Gulp, that makes me hostage to fortune.

This is why stroke associations struggle when they talk about cholesterol and stroke. They seem desperate to say that raised cholesterol levels cause stroke, but just can’t. Here is how the National Stroke Association fudges the issue.

‘High cholesterol may raise your risk for stroke by increasing your risk for heart disease, a stroke risk factor.4

Whilst it is, of course, true that having heart disease does increase your risk of stroke, and vice-versa, the rest of this statement reveals a yawning gap in logic [For the sake of this argument, let us assume it is true that a raised cholesterol causes heart disease].

A (raised cholesterol) → B (heart disease) →C (Stroke)

A does not → C

Question. If A does not lead to C, how does A lead to B, then leading to C? I shall ask for this to become a question in the Oxford and Harvard entrance exams.

[BTW, if you can work this one out, then please feel free to let me know how it works. Exactly.]

Anyway. We find a study demonstrating that two cholesterol lowering drugs, in this case statins and fibrates, significantly reduce the risk of stroke. But a raised cholesterol level is not a risk factor for stroke. Which means that there can be no possibility that the benefit seen can have been due to cholesterol lowering? That, my friends, is simple logic. No need for Oxford and Harvard to get involved at all. This could be discussed on entrance to kindergarten.

Now, just to add to my short analysis this study I would like to draw your attention to something not remarked upon by the popular press at all. However, I thought that you may find it interesting. It was the following statement from the paper:

‘We found no association between lipid lowering drug use and coronary heart disease (hazard ratio 1.12, 0.90 to 1.40).’ [For those who hate figures/confidence intervals, sorry, I left them in for those who like them].

This was the dog that did not bark in the night.

In summary, here we have a study showing that cholesterol lowering reduced the risk of stroke, when a raised cholesterol level is not a risk factor for stroke. On the other hand, it failed to show any benefit on reducing the risk of heart disease. Some would consider that a study such as this raises more questions than answers. However, with wearisome inevitability, it has been twisted around to provide further proof that everyone should be taking statins. Sigh.

1:              http://www.express.co.uk/news/uk/578174/Statins-stroke-experts

2:              Alperovitch et al: BMJ 25 May 2015 pp12.

3:              Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts The Lancet Volume 346, Issues 8991–8992, 30 December 1995, Pages 1647–1653

4:              http://www.stroke.org/stroke-resources/resource-library/cholesterol-and-stroke

Sorry seems to be the hardest word

I think that the four words ‘I told you so’ should only be thought, and never written down. No-one likes a smart arse. But sometimes it is impossible to resist….just impossible. In this case I have failed. ‘Father forgive me, for I am weak.’ So, here goes…’I told you so.’

Some of you may be aware that the US dietary guidelines are going to be changed. For some reason it is required that the full report is suppressed for about a year. Presumably so that everyone can pile high their defences when the attacks begin. ‘I think you will find that I have always, ahem, supported these ideas.’ Cough, shuffle of papers….cough. ‘Sorry, no time to take questions.’ Exit left.

The entire report, I believe, stretches to about a bazillion pages. However, here are four of the highlights.

  • Cholesterol is to be dropped from the ‘nutrients of concern’ list. [I love that phrase ‘nutrient of concern’].
  • Saturated fat will be… ‘de-emphasized’ from nutrients of concern, given the lack of evidence connecting it with cardiovascular disease.’ [Whatever de-emphasizing may be. Pretending you never said it in the first place, I suppose].
  • There is concern over blanket sodium restriction given the… ‘growing body of research suggesting that the low sodium intake levels recommended by the DGAC (Dietary Guidelines Advisory Committee) are actually associated with increased mortality for healthy individuals.’
  • And…’ The identification and recognition of the specific health risks posed by added sugars represents an important step forward for public health.’

In short. Cholesterol is healthy, saturated fat is healthy, salt is healthy and sugar is unhealthy. I have pulled those four points out of a press release by the Academy of Nutrition and Dietetics, which I reproduce in full, below.

Academy of Nutrition and Dietetics Commends Strong, Evidence-Based Dietary Guidelines Report

The Academy of Nutrition and Dietetics, the world’s largest organization of food and nutrition professionals, commends the 2015 Dietary Guidelines Advisory Committee for drafting a strong, evidence-based Scientific Report outlining recommendations and rational for the forthcoming 2015 Dietary Guidelines for Americans. The Academy supports these recommendations that will improve how and what Americans eat.

“The Academy applauds the evidence-based systematic review of the literature, which is vital to the DGAC’s assessment of the science,” said registered dietitian nutritionist and Academy President Sonja L. Connor. “We commend the Department of Health and Human Services and the Department of Agriculture for their commitment to the Nutrition Evidence Library and their ongoing efforts to strengthen the evidence-based approach for assessing the scientific literature for future dietary recommendations.”

In comments recently submitted to USDA and HHS, the Academy supports the DGAC in its decision to drop dietary cholesterol from the nutrients of concern list and recommends it deemphasize saturated fat from nutrients of concern, given the lack of evidence connecting it with cardiovascular disease.

“Despite some criticism suggesting that changed recommendations illustrate concerns about the validity of the nutrition science upon which the Dietary Guidelines are based, the DGAC should change its recommendations to be consistent with the best available science and to abide by its statutory mandate,” Connor said.

The Academy also expresses concern over blanket sodium restriction recommendations in light of recent evidence of potential harm to the overall population. “There is a distinct and growing lack of scientific consensus on making a single sodium consumption recommendation for all Americans, owing to a growing body of research suggesting that the low sodium intake levels recommended by the DGAC are actually associated with increased mortality for healthy individuals,” Connor said.

The Academy supports an increased focus on reduction of added sugars as a key public health concern. “Among the identified cross-cutting issues, the evidence is strongest that a reduction in the intake of added sugars will improve the health of the American public. The identification and recognition of the specific health risks posed by added sugars represents an important step forward for public health,” Connor said.

In its comments, Academy also emphasizes that enhanced nutrition education is imperative to any effective implementation. “It is critical to ensure that individuals making diet and behavior changes in accordance with the Dietary Guidelines have access to the resources and support necessary to succeed. HHS and USDA must have sufficient resources to commit to improving a number of initiatives,” Connor said.

“The Academy appreciates the opportunity to comment on the Scientific Report and to serve as a resource to HHS and USDA as they finalize the 2015 Dietary Guidelines and develop resources to implement and promote their use,” Connor said.1

In one way, I commend this press release. At least it has made no real attempt to fudge what is now going to be said. These are the facts.

But you know what. Organisations like this have been haranguing the entire population of the world about the dangers of cholesterol, saturated fat, and salt for the last thirty years. Foodstuffs which they now seem happy to admit, cause no harm, indeed they are almost certainly good for you.

At the same time, they have bombarded us with messages to consume sugar(s). They usually call them carbohydrates, which is disingenuous in the extreme. Carbohydrates are all just sugars in disguise. A disguise that the digestive system can strip off in a few minutes.

Yes, all those healthy fruit and vegetables are simply extended chains of simple sugar(s). And once they enter your digestive system, your body cares not whether or not you ate a carrot or a sugar cube. It delivers them into your bloodstream as sugar [primarily glucose and fructose].

Now there have been a number of people, including me, who have been saying for years that cholesterol and saturated fat are perfectly healthy, salt is good for you and sugar (in large amounts) is bad. We have all been dismissed as cranks and idiots who would have caused the deaths of thousands of people, if they had ever dared to listen to what we had to say.

It turns out the cranks and the mavericks were right. The experts were wrong. Completely and utterly wrong. Damagingly wrong. Whilst the words ‘I told you so’ are temptingly easy to say; and saying them should be resisted. There is another, single word, that appears impossible to say.

Sorry.

1: http://www.newswise.com/articles/academy-of-nutrition-and-dietetics-commends-strong-evidence-based-dietary-guidelines-report

Hats off to the Japanese

(Raised cholesterol is good for you)

For many years I have told anyone who will listen that, if you have a high cholesterol level, you will live longer. Equally, if you have a low cholesterol level, you will die younger. This, ladies and gentlemen, is a fact. The older you become the more beneficial it is to have a high cholesterol level.

This fact has become more difficult to demonstrate recently as so many people have been put on statins that the association between cholesterol levels and mortality has been twisted, bent and pumelled into the weirdest shapes imaginable. However, Japan, provides some very interesting data. Japan has always had a very low rate of heart disease, an enviable life expectancy, and… generally low cholesterol levels. Aha!, surely this means that low cholesterol levels are good for you? Well….

Well, here is the introduction to a one hundred and sixteen page review of the cholesterol hypothesis published in the Annals of Nutrition and Metabolism. It was published on April 30th 2015. I have just finished reading it for the first time. I thought I would share the Introduction, in full:

High cholesterol levels are recognized as a major cause of atherosclerosis. However, for more than half a century some have challenged this notion. But which side is correct, and why can’t we come to a definitive conclusion after all this time and with more and more scientific data available? We believe the answer is very simple: for the side defending this so-called cholesterol theory, the amount of money at stake is too much to lose the fight.

The issue of cholesterol is one of the biggest issues in medicine where the law of economy governs. Moreover, advocates of the theory take the notion to be a simple, irrefutable ‘fact’ and self-explanatory. They may well think that those who argue against the cholesterol theory—actually, the cholesterol ‘hypothesis’— are mere eccentrics.

We, as those on the side opposing the hypothesis, understand their argument very well. Indeed, the first author of this supplementary issue (TH) had been a very strong believer and advocate of the cholesterol hypothesis up until a couple of years after the Scandinavian Simvastatin Survival Study (4S) reported the benefits of statin therapy in The Lancet in 1994. To be honest with the readers, he used to persuade people with high cholesterol levels to take statins. He even gave a talk or two to general physicians promoting the benefits of statins. Terrible, unforgivable mistakes given what we came to know and clearly know now.

In this supplementary issue, we explore the background to the cholesterol hypothesis utilizing data obtained mainly from Japan—the country where anti-cholesterol theory campaigns can be conducted more easily than in any other countries. But why is this? Is it because the Japanese researchers defending the hypothesis receive less support from pharmaceutical companies than researchers overseas do? Not at all. Because Japanese researchers are indolent and weak? No, of course not. Because the Japanese public is skeptical about the benefits of medical therapy? No, they generally accept everything physicians say; unfortunately, this is also complicated by the fact that physicians don’t have enough time to study the cholesterol issue by themselves, leaving them simply to accept the information provided by the pharmaceutical industry.

Reading through this supplementary issue, it will become clear why Japan can be the starting point for the anti-cholesterol theory campaign. The relationship between all-cause mortality and serum cholesterol levels in Japan is a very interesting one: mortality actually goes down with higher total or low density lipoprotein (LDL) cholesterol levels, as reported by most Japanese epidemiological studies of the general population. This relationship cannot be observed as easily in other countries, except in elderly populations where the same relationship exists worldwide.

The mortality from coronary heart disease in Japan has accounted for around just 7% of all cause mortality for decades; a much lower rate than seen in Western countries. The theory that the lower the cholesterol levels are, the better is completely wrong in the case of Japan—in fact, the exact opposite is true. Because Japan is unique in terms of cholesterol-related phenomena, it is easy to find flaws in the cholesterol hypothesis.

Based on data from Japan, we propose a new direction in the use of cholesterol medications for global health promotion; namely, recognizing that cholesterol is a negative risk factor for all-cause mortality and re-examining our use of cholesterol medications accordingly. This, we believe, marks the starting point of a paradigm shift in not only how we understand the role cholesterol plays in health, but also how we provide cholesterol treatment.

The guidelines for cholesterol are thus another area of great importance. Indeed, the major portion of this supplementary issue (from Chapter 4 onward) is given over to our detailed examination and critique of guidelines published by the Japan Atherosclerosis Society. We dedicate a large portion of this work to these guidelines because they are generally held in high regard in Japan, and the country’s public health administration mechanism complies with them without question. Physicians, too, tend to simply obey the guidelines; their workloads often don’t allow them to explore the issue rigorously enough to learn the background truth and they are afraid of litigation if they don’t follow the guidelines in daily practice.

These chapters clearly describe some of the flaws in the guidelines—flaws which are so serious that it becomes clear that times must change and the guidelines must be updated. Our purpose in writing this supplementary issue is to help everyone understand the issue of cholesterol better than before, and we hope that we lay out the case for why a paradigm shift in cholesterol treatment is needed, and sooner rather than later. We would like to stress in closing that we have received no funding in support of writing or publishing this supplementary issue and our conflicts of interest statements are given in full at the end.

Here is the introduction to the chapter on cholesterol and mortality:

All-cause mortality is the most appropriate outcome to use when investigating risk factors for life threatening disease. Section 1 discusses all-cause mortality according to cholesterol levels, as determined by large epidemiological studies in Japan. Overall, an inverse trend is found between all-cause mortality and total (or low density lipoprotein [LDL]) cholesterol levels: mortality is highest in the lowest cholesterol group without exception. If limited to elderly people, this trend is universal. As discussed in Section 2, elderly people with the highest cholesterol levels have the highest survival rates irrespective of where they live in the world.

I don’t think that I really need to say anything else, other than to repeat this fact. If you have a high cholesterol (LDL) level, you will live longer. This is especially true of the elderly.

Ann Nutr Metab 2015;66(suppl 4):1–116 DOI: 10.1159/000381654

Medicine – science or religion?

[Never admit that you are wrong]

Medicine has always occupied an often uncomfortable space between science and belief. I remember when I started medical school the Dean of the medical school welcomed us to the main lecture hall. He told us how wonderful it was that we had chosen to become doctors, and waffled on for a bit about how we were the chosen few. He finished his speech with these words, which etched themselves into my brain… ‘Welcome to the brotherhood.’

Of course the parallels between medicine and religion have always been obvious to anyone who has eyes to see. The patient consultation as confessional. The use of long latin words that the patient cannot understand. The rituals and incantations of medicine have clear parallels with religion. Or would that be the other way round. You could go on and on.

It is easy to understand why many aspects of medicine and religion mirror each other. Particularly if we look at one very important aspect of religion. Namely, protection against terrible things happening to you. Humans, once they became aware of their mortality, very rapidly felt the need for protection against an unpredictable and dangerous world. Earthquakes, storms, crop failures, plagues, early death… that type of thing.

Very early on, religious leaders realised the power and status you could command if you claimed to be able to understand why such terrible things happened. And, more importantly, how to stop them. Build a big temple, pray to a god, don’t shave your hair, sacrifice a pig, don’t eat pigs…. give the priests lots of money, and suchlike. The people, in turn, were extremely eager to do these ‘right’ things in order to feel a sense of protection, a removal of fear.

Of course, none of this actually stopped anything. But when terrible things still occurred it was because you (you sinner) didn’t pray in the right way, or someone else (a heretic) was deliberately praying the wrong way and causing bad things to happen. ‘Find the heretic in our midst and burn them.’ Or whatever. A good idea not to have ginger hair or a club foot at such times.

Over time, a million and one reasons were developed by clever priests to explain why, despite all the incantations, gifts, temples built, and sacrifices, bad things were not prevented. However, there was one reason that could never be countenanced. Namely that the priests were completely wrong, and had no idea what they were talking about. For, if the priests were wrong then…well then, terrible things just happened and there was nothing you could do to stop them.

How frightening is that. Thus, it was not just were the priests desperate to keep their power that kept their religion going, the people were equally desperate to believe that the priests knew what they were doing. It could be described as a conspiracy of the willing. ‘I will protect you. Yes, you will protect me.

It was usually only when plagues and earthquakes and lack of rain and suchlike went on for a prolonged period of time that the people rose up against the priesthood and bashed their skulls in. Usually to be replaced by the ‘new model priesthood’, with another bunch of newly discovered incantations. ‘The absolutely new true truth is revealed,’ rpt.

Then, luckily, along came science and we started to learn what caused bad things to happen in the first place. Earthquakes weren’t due to the displeasure of Gods. Infections were caused by viruses and bacteria and suchlike. More and more that used to be unknown, and terrifying, became explained and, at least in some cases, controlled.

As science advanced, and became the best way to explain the physical world medicine, which used to be a branch of the priesthood, moved towards becoming more scientific. However, one of the primary social drivers behind medicine remained ‘this is how the world works, and we can protect you from it’.

Thus, although in many ways, medicine became more scientific, it maintained of the key social functions previously carried out by religion. ‘We can stop bad things happening to you. You do not need to be frightened. If you do as we say’

This form of mutual dependency works extremely well when the medical profession really does know how to stop things happening, and the medical leaders know exactly what they are doing. However, there is a heavy price to be paid for establishing yourself in the position of ‘certainty’. A position of belief requirement.

Primarily, it becomes extremely difficult for you, or the rest of the brotherhood, to admit that you don’t know something? Or that things you have been telling people, or doing, are in fact useless or wrong. Because if you start doing that, you fear you may lose your hard won authority, control and respect. Equally, if patients no longer believe, or trust in you, or your advice, what then? Fear stalks the land. Metaphorical skull crushing looms.

This is why, if you are a patient who feels that your treatment has not worked as you were told it would, or should, you will not find an eager audience for your complaints within the medical profession. Equally if you question or refuse the sacrament, sorry treatment, your doctor is likely to become very angry with you.

Additionally, if a doctor cannot discover what is causing your symptoms, or they have no tests to diagnose you, you are likely to be told that there is nothing actually wrong with you. The medical profession cannot easily admit to ignorance. In such situations, the only explanation that can be countenanced is that ‘you are making it up.’ Unexplained symptoms become ‘somatisation’. Side effects from drugs, such as statins, are due to ‘nocebo’ effects.

A million reasons will be found as to why the treatment has not worked in your case. Or why you got worse. The only explanation that cannot be allowed is that the doctors are completely wrong, and do not know what they are talking about.

If you find a whole group of patients who feel that their condition is not being treated well, and you band together to get the medical profession to think again, you will run up against a brick wall. You will simply be written off as cranks, and dismissed. The priesthood does not take kindly to being exposed as wrong.

See under, treating thyroid patients like children.

Treating Thyroid patients like children

Here is an imagined, but not far off the truth, conversation between a doctor and a patient.

‘Why can’t I have T3 doctor? I feel so much better when I do?’

‘Because I say so, now go away.’

Nowadays doctors, at least when they are in training, are repeatedly told that they must NEVER be paternalistic. To do so will result in immediate censure. In the UK it is also a very rapid way of failing the GP entrance exams. We are told that we must explore the patients’ expectations, listen to their worries and fears, and work with them in partnership to lead to a therapeutic partnership…. or some such left wing bollocks. [Joke]

How exactly that fits within the National Institute of Health and Care Excellence (NICE) guidelines is up for grabs. For those who don’t know, NICE decide on which drugs and interventions can be prescribed, or paid for, within the NHS. So you can explore expectations with your patient till the cows come home, only to find that you cannot prescribe what the patient wants, even requires. Even if it makes them feel much better and costs very little. Would you call this paternalism? Oxford entrance exam, discuss.

Don’t get me wrong, I think rationing is increasingly vital for healthcare provision, and at one point I supported NICE. I now realise how naïve and misguided I was…but that is a discussion for another day.

Where was I? Oh yes, T3. Most people have never heard of it. But I am willing to bet that if you have heard of it, and you are a patient, you will certainly know all about this particular hormone. You will definitely know about a thousand times as much as your GP, who may nod sagely when you mention T3. But frankly they are unlikely to have any idea what it is, or does.

To be honest, until about a year ago I had no real idea what T3 was either, but I have learned quite a lot since. Wikipedia states that: ‘The thyroid hormones, triiodothyronine (T3) and its prohormone, thyroxine (T4), are tyrosine-based hormones produced by the thyroid gland that are primarily responsible for regulation of metabolism.’ I would like to draw your attention to the fact that, in Wikipedia, at least, T3 is mentioned before T4 – which makes it more important?

In reality, in a physiological sense at least, T4 comes before T3, in that T4 is produced almost exclusively by the thyroid gland in a ratio of about 17:1 T4 to T3. Once inside various tissues and organs T4 is then converted to T3, where it becomes the biologically active hormone.

Whichever does come first, it can be argued that T3 that is the key thyroid hormone, because T4 is basically a ‘prohormone.’ From Wikipedia again: ‘A prohormone refers to a committed precursor of a hormone, usually having minimal hormonal effect by itself. The term has been used in medical science since the middle of the 20th century. Though not hormones themselves, prohormones amplify the effects of existing hormones.’ Although the figures are not absolutely clear cut, it is usually stated that T3 is five times more biologically active than T4.

Therefore, if someone is hypothyroid, which is normally taken to mean that the thyroid gland is not producing a sufficient quantity of thyroid hormone, you would want to prescribe the active hormone T3, would you not?

This is a rather rhetorical question because what doctors do, at least since the 1960s, is to prescribe synthetic T4 (levothyroxine). Once T4 is in the body it is converted to T3 (through the kidneys, liver, spleen and brain – and numerous other thyroid hormone receptors throughout the body) and does its thing. In most cases this is a perfectly good treatment. However, there is a kicker, which I will get to.

At this point I feel I need to add that hypothyroidism is a very, very common condition. By the age of 60, 10% of people have ‘lab’ test abnormalities that would define them as having subclinical hypothyroidism. At least 2% of the population has overt, clinical, symptoms. Which means that we are talking about millions of people in the UK, possibly tens of millions in the EU and US.[It affects women ten times as much as men].

TSH

I now need to bring in another player called Thyroid Stimulating Hormone (TSH). As with all systems in the human body, a negative feedback loop controls the function of the thyroid gland, and it works something like this:

If you have a high T4 level, this is detected by the pituitary gland, which sits deep within your brain. At which point the pituitary gland reduces the production of Thyroid Stimulating Hormone. As TSH is the hormone that instructs the thyroid gland to produce T4/T3, production of T4/T3 falls. [There are actually a couple of other steps, but this is essentially what happens].

If T4 falls too far, the pituitary gland swings into action to produce more TSH. In turn stimulating the thyroid gland to manufacture more T4…and so it goes. Up and down, up and down, up and down. Endlessly until, of course, you get too old and drop dead. And there ain’t no feedback loop for that.

TSH is also important in that it is usually the substance you measure to decide whether or not someone is hypothyroid. If TSH is very high this means it is trying to ‘drive’ the thyroid gland into action – and failing. You also use the TSH level to determine the dose of T4 that is required as replacement therapy. If the level of TSH is low, this suggests you may be giving too much T4. If the level of TSH is high, this suggests you may be giving too little.

As you may have noticed, at this point I have slipped into talking about TSH and T4, with T3 getting very little mention. That is because this is where the medical profession now stands. Hypothyroidism means high TSH and low T4. You are getting adequate thyroid replacement hormone if TSH in the ‘normal’ range. End of.

Here is what the Royal College of Physicians (RCP) and the British Thyroid Association (BTA) have to say on the matter. Key points only

  • The only validated method of testing thyroid function is on blood, which must include serum TSH and a measure of free thyroxine (T4).
  • Overwhelming evidence supports the use of Thyroxine (T4) alone in the treatment of hypothyroidism. Thyroxine is usually prescribed as levothyroxine. We do not recommend the prescribing of additional Tri-iodothyronine (T3) in any presently available formulation, including Armour thyroid, as it is inconsistent with normal physiology, has not been scientifically proven to be of any benefit to patients, and may be harmful. [Then again, it may not be – harmful, that is]

An aside – (Additional information, as provided to me)

I should mention here that I have been told that the RCP has been asked on numerous occasions to cite references to research/studies showing “overwhelming evidence supports the use of thyroxine (T4 alone)”, but to date, they have provided none. A Freedom of Information (FOI) request that the RCP provide such evidence – again met with no response. A request was made via the ‘Ask for Evidence’ website, run in association with ‘Sense About Science’ asking for evidence on the safety and efficacy of L-T4 as a treatment for hypothyroidism. This request was directed to the RCP who eventually responded stating “The RCP’s guidance is based on the opinion of an expert panel which was temporarily formed for this purpose. The evidence they used to form their individual opinions has not been collated and therefore the RCP cannot provide any evidence list”1 (Jolly, as they say, good)

Restricting the diagnosis and treatment of hypothyroidism to measuring T4 and TSH, and nothing else, is the approach that seems to be used by conventional medicine in the rest of the World. I recently received an e-mail from someone in Singapore telling me that their doctor was about to be struck off for prescribing T3 to patients- against Singaporean medical rules. In the UK, T3 testing is virtually banned, and the medical authorities are making it virtually impossible to prescribe T3 in any form.

In the UK, a doctor called Gordon Skinner was repeatedly dragged in front of the General Medical Council (GMC) for prescribing thyroxine to patients whose T4 and TSH levels were in the ‘normal range’. He was also attacked for prescribing natural thyroid extract (NDT) (a combination of T4 and T3) to his patients – who he felt would benefit. He is now dead. It has been suggested that constant and repeated efforts to strike him off the medical register may have had an impact on his health. I couldn’t possibly say.

Now, there is no doubt that this area is highly complex and for those who know this area, you will be aware that I am keeping things as simple as possible. But I think it is important to make a few points:

The lab tests, especially for TSH, are far from 100% reliable, to say the very least. In fact the man who developed the test in the UK, at Amersham International in Wales, has told me that the test is virtually worthless in many cases (especially continuous testing when patients are taking thyroid hormone replacement).

The conversion of T4 into T3 can be significantly reduced in some people. So these individuals can have normal T4 and TSH, but they are still effectively hypothyroid. For those who are interested in a bit more detail, there is a population with a defective DIO2 gene. This blocks T4 to T3 conversion, and results (amongst other things) in reduced T3 levels in the brain, which can lead to mood disorders2. I mention this single example to make it clear that there is solid scientific evidence to back up the conjecture that it is possible to be functionally ‘hypothyroid’ with normal blood tests.

A lot of people have reported significant improvements in their health through taking thyroxine, with normal blood tests, and also natural thyroid extract when their laboratory tests were ‘normal’. Please look at this article in the Daily Telegraph3…then look at the comments section – which is very, very telling. A cry of despair!

I am not going into further detail of how T4 binding and conversion in various organs can be affected by stress hormones, inflammation, trauma, adrenal insufficiency, lack of converting enzymes in tissues, and infection of various sorts. I shall just keep this simple by stating that it is possible to have enough T4, even T3 in your bloodstream, but these hormones have reduced ‘bioavailability’. This is not crank ‘woowoo’ stuff. This is real and measurable and you can find studies on this in peer-reviewed medical journals.

Far more telling, from my point of view, is the fact that hundreds, indeed thousands of patients report that, although their blood tests were normal, they felt terrible, and that they have felt so much better when they have been given ‘excess’ T4 and/T3, or NDT (natural desiccated thyroid). Whilst there is no doubt that some of them are, to quote a medical colleague, ‘not tightly wrapped.’ I have spoken to many, many, people who are calm, rational and reasonable, and their stories are compelling. A hellish existence that was ‘cured’ by Dr Skinner and his like. I refuse to believe that all of these patients are ‘somatising’ fruitcakes.

Comparing the use of SSRIs and ‘Unconventional’ Treatments for Hypothyroidism

At this point I will change tack slightly. For I think it is fascinating to compare and contrast the treatment of depression using SSRIs, with hypothyroid patients who complain that they are unwell, despite ‘normal’ T4 and TSH tests.

Today, almost all doctors you speak to believe that depression is due to a low level of serotonin in the brain. This is why they prescribe SSRIs (Selective Serotonin Reuptake Inhibitors) by the lorry-load. Drugs such as Prozac, Zoloft, Paxil etc.To quote from a recent article in the BMJ ‘Serotonin and depression, the marketing of a myth’4.

‘…the number of antidepressant prescriptions a year is slightly more than the number of people in the Western World.’

This all happens despite the fact that:
‘There was no correlation between serotonin reuptake inhibiting potency and antidepressant efficacy. No one knew if SSRIs raised or lowered; they still don’t know. There was no evidence that treatment corrected anything.’

In short, with depression, there is no lab test, no way of measuring the impact of anti-depressants. They are prescribed purely and simply on the basis of the patient history. Equally, there is no doubt at all that SSRIs have significant side-effects, some of which are very, very serious e.g. increased suicidal tendency. They are also addictive and patients can end up stuck on them for years. So, they do cause harm.

Equally, as you may be aware, clinical trial data in this area have been horribly distorted….

“…That said, the fact that the class of antidepressants known as the selective serotonin reuptake inhibitors (SSRIs), are basically useless in treating depression in children and adults is not news to the FDA. Back on September 23, 2004, during testimony at a hearing before the House Oversight and Investigations Committee on Energy and Commerce, Dr Robert Temple, the FDA’s Director of the Office of Medical Policy, discussed the agency’s review on the efficacy of SSRIs with the children.”

He noted that it was important in a risk-benefit equation to understand the benefit side. “Of the seven products studied in pediatric MDD (Prozac, Zoloft, Paxil, Celexa, Effexor, Serzone and Remeron),” he testified, “FDA’s reviews of the effectiveness data resulted in only one approval (Prozac) for pediatric MDD.”

“Overall,” Dr Temple said, “the efficacy results from 15 studies in pediatric MDD do not support the effectiveness of these drugs in pediatric populations.”

Also in 2004, a study of previously hidden unpublished data as well as published studies on five SSRIs, was conducted by Tim Kendall, deputy director of the Royal College of Psychiatrists’ Research Unit in London, to help analyze research to draw up the clinical guidelines for British regulators, and published in the Lancet.

Following his evaluation, Mr Kendall stated: “This data confirms what we found in adults with mild to moderate depression: SSRIs are no better than placebo, and there is no point in using something that increases the risk of suicide.”

In 2005, the British Medical Journal published another study that concluded that SSRIs are no more effective than a placebo and do not reduce depression.

In December 2006, at the most recent FDA advisory committee meeting held to review studies on SSRI use with adults, SSRI expert, Dr David Healy, author of, “The Antidepressant Era,” told the panel that the efficacy of SSRIs has been greatly exaggerated, while the actual studies reveal that only one in ten patients responds specifically to an SSRI rather than a nonspecific factor or placebo.

In February 2008, Irving Kirsch’s study at the Department of Psychology at the University of Hull is the first to examine both published and unpublished evidence of the effectiveness of selective serotonin reuptake inhibitors (SSRIs), which account for 16 million NHS prescriptions a year. The largest study of its kind concluded that antidepressant drugs do not work. More than £291 million was spent on antidepressants in 2006, including nearly £120 million on SSRIs. 4

Critics complain that industry funded studies are presented in ways to exaggerate benefits and obscure side effects. “These include failure to publish negative results, the use of multiple outcome measures, and selective presentation of ones that are positive, multiple publication of positive study results, and the exclusion of subjects from the analysis,” according to the paper, “Is Psychiatry For Sale,” by Joanna Moncrieff, in People’s Voice.”5

So we have an interesting medical conundrum, do we not? On one hand, doctors are more than eager to prescribe antidepressants at the drop of a hat, based entirely on the patients reported symptoms. No need for any blood tests, and no evidence that they work for the vast majority of people.

On the other hand, if a patient dares to say that they feel better taking T4 when their blood tests are normal, or if they say they feel better taking a combination of T3 and T4/NDT, they are dismissed as ‘somatising.’ Which is a posh medical way of saying, you are making your symptoms up and we don’t believe you. Equally, if a patient complains of continuing symptoms and that they don’t feel better when they are taking T4 (or T3 and T4) and their blood test results show ‘normal’ they are again accused of ‘somatising’6

The world, my friends, has gone nuts and, in a bitter irony, the medical profession – at least in this area – has become institutionally paternalistic. ‘You cannot be feeling better, because your blood tests say you were never unwell. So you cannot have treatment. And you, Dr Skinner and your like. If you dare treat patient’ symptoms you will be attacked and struck off from medical practice.’ Now I have looked long and hard, and I have found no evidence, from anywhere, that giving T3, in the dose that’s needed, causes any significant medical problems, and I have listened to repeated testimony from people who feel they have greatly improved.

As for antidepressants, these mostly useless addictive drugs that can increase suicide risk. ‘Have as many as you like for as long as you like. Because we fully believe everything you say about your symptoms….’ No need for any silly tests, or anything like that.

Compare and contrast, then try to make some sense of the medical world that we now live in.

Sigh.

P.S. Because I am considered to have alternative views about medical matters, many people contact me to help promote their ‘alternative’ ideas. Some I believe to be completely whacko, I smile sweetly and move on. Some I cannot decide. Other issues, once I start looking into the evidence, I find the evidence compelling.

I certainly find the evidence that a large number of people are effectively hypothyroid, with ‘normal’ thyroid blood tests, to be virtually overwhelming. Both from a scientific/physiology basis, and also from a patient testimonial basis.

I now firmly believe that the medical profession is currently doing these people a great disservice, and that the guidelines on the treatment of ‘hypothyroidism’ are rigid, autocratic, and just plain wrong (for a significant minority).

As with all medical matters that I write about, I have no axe to grind, no horse in the race, no financial links to anyone or anything with regard to treating thyroid patients. I simply hope this article can have some positive impact. For it seems very clear to me that many thousands, hundreds of thousands, of people are suffering unnecessarily. And I would like it to stop.

References:

  1. http://www.scottish.parliament.uk/S4_PublicPetitionsCommittee/General%20Documents/PE1463_AAA_Petitioner_19.11.14.pdf
  2. “Common Variation in the DIO2 Gene Predicts Baseline Psychological Well-Being and Response to Combination Thyroxine Plus Triiodothyronine Therapy in Hypothyroid Patients”http://press.endocrine.org/doi/pdf/10.1210/jc.2008-1301
  3. http://www.telegraph.co.uk/news/health/alternative-medicine/10985192/Could-a-renegade-doctor-save-your-life.html
  4. Serotonin and Depression, the marketing of a myth.’ BMJ2015;350:h1771
  5. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al. “Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration.” 2008, PLoS Med 5(2): e45 doi:10.1371/journal.pmed.0050045: Access full article at http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050045
  6. http://www.lawyersandsettlements.com/articles/ssri_birth_defects/ssri-secret-00642.html#.VT-ycCG6eUk
  7. Professor A Weetman – http://www.medscape.com/viewarticle/524955

 

Further postscript

Malcolm – we need to clear up the fact regarding the definition of ‘hypothyroidism’ which is “underactivity of the thyroid gland” according to the RCP Policy Statement on the diagnosis and management of hypothyroidism. Hypothyroidism is easily diagnosed and more often than not, easily treated with L-thyroxine only. However, what is being missed by everybody is that over 300,000 UK citizens (15% of the thyroid community – millions worldwide) have a normally functioning thyroid GLAND, but the hormone it is secreting is not getting into the cells where it does its work. These are the folk who need T3, in combo. with T4, T3 alone or in NDT. The RCP teaching curriculum makes no mention of the possibility of a non-thyroidal condition where patients suffer the same symptoms and signs of hypothyroidism that may need to be treated with a different medication or hormone. When these patients complain of continuing symptoms when treated with L-T4 monotherapy, many are given an incorrect diagnosis of ME, CFS, FM, depression, functional somatoform disorder – or even old age blah, blah, blah – and sent on their way without further investigation or treatment. This is a serious business, which the RCP and BTA choose to ignore.

The NHS

[A slight divergence of theme]

As an election looms in the United Kingdom of Great Britain, the National Health Service has become the usual political football. All political parties now claim to love it and want to hug it, and squeeze it, and spend eye watering sum of money on it. Because, for the next three weeks or so, they truly ‘care’. Sincerity, once you can fake that, you’ve got it made.

A UK politician, Nigel Lawson, once called the NHS “the nearest thing the English have to a religion”. This, of course, rather pissed off the Scots, Welsh and Northern Irish. Forgetting that England is not the only country in the United Kingdom is something English politicians just, unconsciously, do. They now wonder wonder why the Scots are all going to vote for the Scottish National Party in a few weeks time. ‘But how could anyone possibly dislike us?’ Oh well.

But what is the NHS? It is, to state the bleeding obvious, a National Health Service. It is paid for out of taxes which are gathered with the usual threats of punishment and fines. The Government then hands it out, well over a hundred billion pounds (~$150Bn), through a mind-bogglingly complicated bureaucratic system, losing vast chunks as it goes.

What pitiful sum finally remains is spent on the healthcare of the people of the United Kingdom (including Scotland, Northern Ireland and Wales). Although Scotland would claim it now has its own NHS, sort of. As would Wales, and Northern Ireland, sort of.

Whatever country you are in, the key underlying principle of the NHS is that it is free at the point of use. If you turn up at a GP, or accident and emergency, or hospital, whatever is wrong with you, you are charged, not a penny. Yes, it is free.

Actually this is not quite true. Dentistry used to be part of the NHS, but most people now pay for dentistry. Many people also pay for prescriptions, and it is eye-watering expensive to get a decent hearing aid. Also you cannot get medical equipment for free, e.g. a nebuliser. So the NHS is mainly free, but this concept is being sneakily eroded.

I know that many Americans believe the NHS to be some terrible ‘communist’ system where you queue forever, cannot get expensive treatments, and people wither and death in dimly lit hospital corridors whilst uncaring staff blow their noses on your sheets and cackle as they stride past in their jackboots. The NHS, at least as reported over here, seems to be held up as the poster child of an ‘evil’ system by those on the right wing of American politics.

I would just like to point out that it costs less than a half (as a percentage of GDP) of American healthcare. Yet, almost all measurable outcomes for health in the UK are better than in the US. Looking at the single most important outcome, which is overall life expectancy; people in the UK live longer than in the US. As do, it should be added, the French, Germans, Italians, Danish, Swedish, Spanish… Indeed, in virtually every way you choose to measure it, US healthcare comes last of all developed countries in the Western World. Just saying. So, the NHS may not be perfect, but please, please, let us not drift into US style healthcare provision.

However, having said all this, I still have a huge problem with the NHS. In that, it is no longer a ‘free at the point of access healthcare delivery system paid for out of taxes’. It has become ‘The NHS.’ Sounds of trumpets and a celestial choir. A kindly bearded figure sits on a throne in the clouds, beaming, surrounded by angels. Hallelujah, hallelujah.

Many years ago, the one thing that Margaret Thatcher said which, more than anything else, marked her out as an evil witch (in the eyes of many) was when she said that ‘there is no such thing as society.’ This is all that most people remember her saying, and they still hate her for it.

It marked her out as an uncaring monster, which is why they song ‘The witch is dead’, from the Wizard of Oz, got to number on in the UK charts shortly after she died. Not, perhaps, the UK’s finest hour.

In fact, the full quote was as follows:

“I think we’ve been through a period where too many people have been given to understand that if they have a problem, it’s the government’s job to cope with it. ‘I have a problem, I’ll get a grant.’ ‘I’m homeless, the government must house me.’ They’re casting their problem on society. And, you know, there is no such thing as society. There are individual men and women, and there are families. And no government can do anything except through people, and people must look to themselves first. It’s our duty to look after ourselves and then, also to look after our neighbour. People have got the entitlements too much in mind, without the obligations. There’s no such thing as entitlement, unless someone has first met an obligation.” http://briandeer.com/social/thatcher-society.htm

As for me, I don’t really believe that there is such a thing as ‘society’ either. But not, perhaps for exactly the same reason as Margaret Thatcher. My problem is when an abstract concept becomes a real thing which is a form of ‘magical thinking.’

For example, on the left we have those who believe in ‘society’ and ‘the NHS’. On the right we have those who believe in ‘the Market.’ As in, the market won’t like this, or the market won’t like that. When the EU tries to bail out Greece, we are told that the Markets will stop this from happening. This idea, I believe, derives mainly from Adam Smith’s ‘The invisible hand of the market.’

I say. ‘Can you please introduce me to the ‘the Market’. Could I have a word with the market to understand what it thinks?’ Oops, silly me. There is no ‘market’. There are just individual bankers and financial workers and economists. These, in turn, are just individual men and women, with a high percentage of psychopaths sprinkled in.

You see, Market does not exist, it purely an abstract concept. Yet we talk about it as if it were almost a person, an entity with powers beyond mere mortal man. God like, in fact. The ‘invisible and all-powerful hand.’ Kind of like the vision of Emmet in the Lego Movie when he saw ‘The hand’.

When Nigel Lawson called the NHS the nearest thing the English have to a religion, he was right. In that many people have also raised ‘the NHS’ to a status of an entity. A super-corporeal being, infused with special powers and goodness beyond our understanding. An ‘invisible’ hand that works in mysterious ways to improve the health of the nation.

However, until we can stop thinking of the NHS as some sort of deity, and start thinking about the most equitable way to fund and provide healthcare in a rational way, all discussions about healthcare will become bogged down in cant and emotion. People will continue to wave banners about emblazoned with ‘Save the NHS.’ Politicians will gaze at television cameras with that special, coached, excruciating limpid expression on their face talking about how much they care about ‘the NHS.’ Bleurrgghh!

Guys, there is no such thing as ‘the NHS.’ There are paramedics and porters and lab technicians and nurses and managers and doctors and some buildings and equipment. What is the best way to use these resources to provide the biggest bang for your bucks? End of.

Sorry, I shall start slagging off statins again next week.

Dead men don’t bleed

I think I have become a connoisseur of scientific double-think. Swilling the most ridiculous statements around my glass with relish, and enjoying the finest vintages. Last week, whilst I was on holiday, someone sent me a piece about statins and coronary artery calcification. I’m not sure what such people think I do on my holidays – but reading medical reports is not one of them.

However, the moment I read this article, it immediately brought to mind a story about a patient who had a fixed delusion that he was dead. The psychiatrist he was seeing had repeatedly tried, and failed, to get this patient to admit that he was deluded. One day a conversation took place

Psychiatrist:    ‘Would you accept that dead people do not bleed?’

Patient:            ‘Of course.’

Psychiatrist:    Pulling needle from pocket. ‘Would you allow me to prick your thumb to see if you do bleed?’

Patient:            ‘Go ahead doc, nothing will happen.’

Psychiatrist:    Pricks the thumb of the patient, which then bleeds. ‘Aha!’

Patient:          Looks down with interest. ‘Well what do you know, I guess dead people do bleed after all.’

For many years now it has become, almost a known fact, that a highly significant sign of Coronary Artery Disease (CAD) is calcification of the coronary arteries. The most widely accepted thinking is that calcification represents the final stage of atherosclerotic plaque development. It is a clear indication that your arteries have been developing atherosclerotic plaques over the years. Or, to quote Medscape on the issue:

‘First and foremost, calcium is a marker for a diseased artery1.’

The same article expands on this simple quote: “Coronary calcium is part of the development of atherosclerosis; …it occurs exclusively in atherosclerotic arteries and is absent in the normal vessel wall.” Simply put, the presence of calcification in the epicardial coronary arteries indicates that the patient has coronary atherosclerosis.’

This could not be more clear, and has been almost unquestioned. Lots of calcium in your arteries means lots of arterial disease. More = bad. Less = good. Sorry to labour the point, but I am doing it for a reason.

Sherlock:         ‘So, my dear Watson. If we find that one of our treatments for heart disease is increasing the amount of calcification in the arteries, it would seem strange. Would it not?’

Watson:           ‘Indeed.’

Sherlock:         ‘And what, pray, does this make you think?’

Watson:           ‘I’m not entirely sure that I know what you are getting at?’

Sherlock:         ‘Think my dear Watson. Think.’

Watson:           ‘Our ideas about heart disease are wrong?’

Sherlock:         ‘Precisely.’

Statins, as we know, reduce the LDL/cholesterol level in the bloodstream. They also reduce (albeit not by very much) the risk of dying of heart attacks – and strokes. The current thinking, as I am sure everyone knows, is that excess LDL/cholesterol in the blood causes atherosclerosis. Ergo, lowering the level will reduce the burden. If this model is correct then, as LDL/cholesterol levels go down, we should lower the risk of atherosclerosis… and therefore we should see less calcium in the arteries. I know, I am labouring the point again.

However – as I have known for some time – this is not what we see. If you take statins you will increase the amount of calcium in the arteries.

CLEVELAND, OH – ‘The results of a new study suggest that there is a paradoxical relationship between calcification of the coronary artery and atheroma volume among individuals treated with statin therapy. In the analysis, statins, specifically high-intensity statin therapy, actually promoted coronary calcification.2

So, there you have it. At this point, if you are a scientist, you have a few possible explanations that you could look at. (Assuming that this research is correct – and no-one seems to doubt that it is true). You could, for example, say that that statins do not work by lowering LDL/cholesterol, and therefore must provide benefits through another mechanism. How else could you reduce the risk of heart disease, whilst increasing the atherosclerotic burden?

However, if you have a fixed delusion, namely that raised LDL/cholesterol is the most important causal factor in heart disease, and that lowering it must be beneficial, you need to look down at your, now, bleeding thumb and switch the game through one hundred and eighty degrees.

So, what would you do? What explanation would you come up with?

Well, and here I paraphrase. Steven Nissen – one of the most powerful and inexhaustible supporters and promoters of LDL/cholesterol lowering – a man of great influence throughout the world of cardiology. This man looked down at his thumb and said.

‘I guess coronary artery calcification is a good thing after all.’

In truth his actual words were:

“We have some physicians—some, not a lot—advocating for serial calcium scans to determine whether or not patients are doing well,” he said. “If you give them a high-dose of a statin and their calcium goes up that might actually be a good thing. Instead of saying, ‘Oh my goodness, your coronary calcium is increasing,’ we might be able to tell patients, ‘Your coronary calcium is up, your plaques are stabilizing.’ “

Or, as George Orwell may have put it. ’Four legs good, two legs better.’ ‘The creatures outside looked from pig to man, and from man to pig, and from pig to man again; but already it was impossible to say which was which.”

References

1:         http://emedicine.medscape.com/article/352189-overview

2:          http://emedicine.medscape.com/article/352189-overview#aw2aab6b3

A victory

Here is the title of a scientific paper that will make your eyes glaze over

‘Randomized Phase II Study of 5-Fluorouracil Hepatic Arterial Infusion with or without Antineoplastons as an Adjuvant Therapy after Hepatectomy for Liver Metastases from Colorectal Cancer.’ http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120064

It was published in the Public Library of Science (PLOS) on the 19th of March, and I danced a little jig of happiness. For I helped these researchers get this paper published, a battle that has taken well over a year. Just to blow my trumpet a little, here are the Acknowledgements:

‘We thank all patients who consented to participate in this study and Dr SR Burzynski for free supply of antineoplastons for this study. We appreciate greatly the editorial assistance provided by Dr. Malcolm Kendrick, Central and Eastern Cheshire Primary Care Trust, UK.’

In truth, my wife did most of the heavy lifting in editing the paper, whilst I took all the credit. Oh well, such is life. I shall buy her a bunch of flowers from the local petrol station.

I realise that, at this point, you have not the slightest idea what I am talking about, so I shall step you back in time. Three years ago, or thereabouts, I was speaking to Pete Cohen. He is a life coach and health guru, and all round good guy. He told me about his partner who had developed a brain tumour, gliobastoma. I hasten to add I am not giving away patient confidentiality here, Pete has written about this, and blogged about it many times. http://www.teamhannah.com/

Hannah had received orthodox treatment in the UK, but the prognosis was still very poor. These tumours are very difficult to eradicate, and usually recur quite quickly. To quote a recent paper ‘Median survival times of all patients diagnosed in the 2000-2003 and 2005-2008 periods were 8.1 and 9.7 months.’ 1

An ‘average’ survival time of about nine months is a very depressing thought. (Although it tends to be a bit longer in younger patients). Pete then spent a great deal of time effort, and eventually money, trying to find an alternative treatment. An oncologist, who will never be named, suggested Pete looked at the results from Dr Burzynski’s clinic in Texas.

The results certainly looked impressive, and Pete’s partner started on infusions of antineoplastons, which Burzynski has been using for patients with glioblastomas for many years. Some of you may have heard of Burzynski, for he is regularly condemned as being a complete dangerous maverick. A man who plays on parent’s desperate need for someone to help their children suffering from terminal brain cancer etc.

If you look Burzynski up on the internet there is a complete diatribe of vitriol rains down upon him. Put him in the Andrew Wakefield camp. The BBC assassinated his character in a half hour programme a couple of years ago. To read what is written of him, you would think he is the sort of man who would happily pitchfork babies into the back of a lorry.

However, as someone who is regularly attacked for being a maverick myself, I consider attacks from mainstream medicine, and the media to be a badge of honour, and I pay little attention to such things. I like to look into things myself, and make my own mind up. Clearly some of those attacked for being dangerous mavericks are, indeed, dangerous mavericks. Others are not. Into which camp did Burzinski fall, I wondered?

The first thing about Burzynski’s treatment was that, in Hannah’s case, it seemed to be working. The tumour had gone. As least it was no longer detectable on MRI scans. It has still gone, and Hannah remains well. Will it remain in remission forever? I know not.

Of course a single case is not proof, never is, never will be. But recurrence free survival of several years is extremely uncommon in Gliobastoma, so a single case is rather more powerful evidence than in many other conditions. I then communicated with Burzynski and gained access to his many, many, case histories. Whilst many patients did die, a significant number were surviving longer than would be expected. In some cases patients were alive twenty years later.

I agreed to write up a number of his case histories and got some of them published here and there. It was always a battle do so, batting away objection after objection. Have no doubt that the ‘authorities’ know exactly who Burzinski is, and they do what they they can to stop anything he does being published, anywhere. Often there was just blank refusal to publish anything, once the name was seen.

I was then contacted by someone, who shall currently remain nameless, who told me that a group of Japanese researchers had done work on antineoplastons as adjuvant (add-one) therapy for patients with liver metastases following colorectal cancer. They did not know how, or where, to publish it. So I agreed to look at it, and try and get it published in a peer-reviewed journal.

They were turned down by Lancet Oncology (no surprise), and a couple of other journals. I suggested PLOS (Public Library of Science), which has a high impact and tends to be a bit more open to non-mainstream articles. So we sat down to write, rewrite, edit, alter and adapt.

To be honest, I have never, ever come across so many objections by the peer reviewers. Stuff that was so trivial, so difficult to answer. Re-write, re-write, re-write. Water down the conclusions. I thought by the end of it, nothing would be left, although the most important points did, just about, survive.

Of course this was not a study on gliobastoma, but it was a carefully controlled (not placebo controlled, as that would be impossible) study of high quality. Setting out to answer the question, can antineoplastons benefit patients suffering late stage cancer?

The answer is that they can. They work. They are not a miracle cure; they are not the answer to cancer. But they have clear and clinically significant benefits. So Burzinski is not a maverick… well, he is a maverick, but his (terribly named) antineoplastons significant effects in cancer. So he is the right sort of maverick, in that he is challenging the status quo – and he is right.

Will his work now be accepted, will Burzynski ever be allowed to treat patients again? Probably not. So, a victory, but probably a small one. Meanwhile, in the UK, Charles Saatchi’s efforts to allow ‘mavericks’ to try and treat cancer are being well and truly crushed. ‘We have enough innovation’ is the cry – by the establishment – that most innovative of groups.

I would counter-argue that innovation by large University departments, and pharmaceutical companies, is not really, innovation at all. They just plough the same old furrows, looking to unearth the occasional goody that was missed in the past.

Their most fervent wish is to cry ‘Eureka’ (I have found it – the thing that I knew was there). The true maverick, however, is on a restless quest for ‘that’s funny.’ For only in the ‘that’s funny’ moments does science truly progress.

1: http://www.ncbi.nlm.nih.gov/pubmed/22045118

NICE?

Don’t bother me with facts, son. I’ve already made up my mind,” Foghorn Leghorn

NICE stands for the National Institute for Health and Care Excellence. It is a little known fact that it started life as the National Institute for Cost Effectiveness, before rapidly transforming into the National Institute for Clinical Effectiveness, then the National Institute for Clinical Excellence. As you can see it changed again, and now it should be NIHCE, but we do so like our acronyms also to be words. A life of simple puns is the life for me.

I was involved with NICE early on; I set up their first website for them, before being rather rudely elbowed aside. Naively, at the time, I thought the underlying concept of NICE was sound. An attempt to try to work out which medical interventions both worked, and also provided good value for money. This would bring rational thinking to the complex and difficult world where limited resources have to be rationed in some way.

Clearly, I knew that the Government of the time had basically set NICE up to act as a barrier to attacks by the public and a restless media. As everyone knows, the minute you refuse treatment to a young child for, say, cancer, the front pages of the newspapers light up in outrage. By getting NICE to say no, the Government could cower behind NICE’s decisions in relatively safety.

For, as we all know, even if a treatment costs two million, and the chances of success are one in a hundred, most people simply adopt the ‘pay anything, do anything, to save this child.’ mode. The counter argument, that I could use that two million to save fifty lives elsewhere rarely gets an airing. ‘A child is dying….’ Is an argument that usually shuts everyone else up pretty quickly. You can look a tad heartless, very rapidly.

In reality, the cowering didn’t last too long, for as some of you will know, the UK Government is now happy to pay almost unlimited monies into the cancer drugs fund. NICE says it is too expensive… don’t worry, ‘Our caring kind and compassionate Government is willing to pay anything for cancer drugs.’

Of course this rather destroys the entire point of NICE whose decisions are simply bypassed, and also makes it clear that people with cancer are considered far more valuable than anyone else. ‘Dying of motor neurone disease, or heart failure, or kidney disease…. Sorry mate, no money. We have spent it all on cancer drugs.’ The NHS, for a system so terrified of discrimination, against anyone, on the grounds of anything, it seems strange to positively discriminate in favour of people with one form of disease vs. another. Oxford entrance exam, discuss.

Don’t worry, it has long been clear that vote winning irrationality will crush evidence and judgement at every turn.

Anyway, I am getting far away from the point of why I set out to write this blog. NICE, like most organisations started out with a fairly clear aim. To look at medical interventions, then decide which ones provided enough benefit, at reasonable cost, to be funded. But it has grown and grown, or perhaps I could say that its role has metastasised.

It now has become – primarily – a guideline generating monster. Every couple of weeks NICE will drop six hundred pages of ‘how condition x must now be treated,’ onto the medical profession. Dense and verbose and boring and very, so very very, long, and then what?

Are they rules, must they be followed? This all becomes very opaque. Last year NICE decided (super short summary) that everyone with a risk of a cardiovascular event greater than 10%, over the next ten years, should be put on a statin. There was much debate, and the BMA (British Medical Association) voted – unanimously – that these guidelines should not be followed.

Did this make any difference? No. Did it make any difference that the Local Medical Committees (that represent all GPs) at their annual conference voted unanimously against these guideline? No. What are NICE doing about the fact that, at least, two thirds of GPs are completely ignoring these guidelines. Nothing…yet. No debate, no discussion. Nothing. They know that, over time, their guidelines will solidify into something that becomes, effectively, mandatory.

Our great and magnificent guidelines have been written, they shalt be distributed to the populace who shalt fall upon them with gratitude. This is the word of NICE.’ The huge stone gate to the citadel, that encloses the enclave of the wise men of NICE, then swings shut, until the next holy set of guidelines will be brought out, to magnificent fanfare. ‘All hail the NICE guidelines.’

Can you discuss anything with them? No, you cannot. A number of people, including me, wrote an open letter to NICE criticising the guidelines. NICE deigned to read our letter, they reviewed their own decision making, and they decreed that they could find no errors in what they had done. They were good enough to inform us of this fact citing the eminence of their ‘experts’ whose greatness and wisdom passes all mortal understanding.

Then what could we do? Nothing. NICE, you see, are both the prosecution and the defence council, the Judges and the Supreme Court all wrapped in one. There is no higher authority. There is no executive, no Ombudsman. The only authority that can review a NICE guideline is… NICE.

Which means that, for example, when a study comes out showing that long term statin use increases the risk of Parkinson’s disease by 230% (Relative Risk increase)1, NICE can feel free to totally ignore it. In fact, when confronted with this study they said it was ‘nonsense.’ An interesting response, I felt, before they had even seen it.

Ignoring NICE’s view that this study was nonsense, I did a little calculation based on this paper. It went something like this.

Parkinson’s disease affects about 1 in 250 people. It is not rare, but not that common. The NICE guidelines on statins mean that, at the very, very, least, 50% of people should take statins from the age of fifty, for the rest of their life [how many actually will is a moot point, but stay with me here].

If 50% of people take statins and the risk of Parkinson’s increases by 230% it follows that the 1/250 lifetime risk of developing Parkinson’s becomes an extra 2.3×1/250/2 = 0.0046.

IN short, the NICE guidelines will result in an extra 0.0046% of the population developing Parkinson’s. On the face of it, this may not seem like a massive problem. But the population of the UK is around sixty million, and if we multiply sixty million by 0.0046, we get 276,000. That is more than a quarter of a million people who will develop Parkinson’s disease who would not otherwise have done so.

Just from a purely economic basis, this would be hugely costly. Like all things in medicine, it is difficult to establish exactly how much it costs to look after a Parkinson’s patients, but in the UK it has been estimated as between £3,500 to £10,000 per year2. (Up to $100K in the US, I have read).

Multiply these two figures by 275,000 and we get a range of: £962,500,000 – £2,750,000,000/year ($1.443 – $4.12Bn/year)

Now you can argue these figures, and I am sure that NICE would – were they ever to engage in this debate. They will say that Parkinson’s is less common than this (I have seen both higher and lower estimates), they will argue the exact costs, they will bore you into submission with NPVs and suchlike.

You can argue all you like on the minutia, but if this paper is right, and I see no reason to suspect it is not, the NICE guidelines will inevitably result in hundreds of thousands of extra people developing Parkinson’s disease, at a cost of billions to the NHS. Leaving aside the added suffering and Disability Added Life Years (DALYs) this will bring.

Now this represents a massive and very major issue. If NICE were to take this research seriously, they would have to reconvene and review the evidence, and work out the ‘new’ costs and harms to patients, and perhaps they would have to reverse their guidance.

However, I know that they will not do this. They will just ignore this paper, and the implications thereof. I knew this would happen even before they started off by calling it nonsense, as you will remember they did that before they even read it. Even if they do actually read it, they will dismiss it as just one study to set against (my most hated of phrases) the ‘weight of evidence in favour of statins.’

The simple truth is that there is too much at stake here for NICE, and the entire spider’s web of interconnected reputations, and status, and opinion leaders, and money, for NICE to ever reconsider their guidance on statins. Facts and evidence are puny weapons in this battle.

NICE?

Next week, dear reader, we shall examine the economic consequences of statins increasing the risk of type II diabetes by 46%. Get ready for some pretty gigantic figures. The zeros, they shall stretch as far as the eye can see.

1: Huang X et al: ‘Statins, Plasma cholesterol, and risk of Parkinson’s Disease. A Prospective study.’ J of Movement Disorders (epub ahead of print).

2: http://www.bgs.org.uk/index.php/topresources/publicationfind/goodpractice/376-parkinsonsdisease

What does cause heart disease?

I have danced around this subject for a long time – as regular readers may have noticed. One of the problems in this area is that you have to start with definitions. Which is somewhat tedious, but also rather necessary? Last week, for example, I read someone argue that we should not use the word cancer, we should talk about cancers. Which is true. Multiple myeloma and pancreatic cancer are both usually called cancers, but they don’t have a great deal in common.

Heart disease is also a pretty meaningless term. Do you mean pericarditis, hypertrophic obstructive cardiomyopathy, aortic stenosis, coronary artery disease etc. et bleeding cetera. In fact, in 1948 the World Health Organisation, recognising the need for accurate definitions, made the first stab at creating an international disease classification (ICD) system. Prior to this, for example, Ischaemic heart disease did not exist. Which meant that you could die of a myocardial infarction in the US, but you could not do so in France – because the French had no term for such an event.

Issues such as this mean that trying to look back in time to ascertain death rates from specific diseases in different countries is a fairly pointless exercise. The French, just to pick on them again, did not accept the ICD system until 1968 – typical, you might say. Even when countries do accept the ICD system, it is difficult to be certain that people are using it in the same way. When I started in medicine a very common diagnosis at death, in the elderly, was bronchopneumonia. ‘The old man’s friend.’

Essentially, when an old person died, and you weren’t really sure what they died of, you put down bronchopneumonia. Try doing that today and the local coroner will be on the phone before you can say Harold Shipman. Now you have to die of something rather more specific – even if the patient is a hundred and two and have been going downhill for the last year.

‘I think they died of old age, Mr Coroner sir. But please sir can I write bronchopneumonia.’

‘Bronchopneumonia! You want more bronchopneumonia!’

In the UK we have now conquered bronchopneumonia. Today, the scourge that used to wipe out millions of elderly people, hardly kills anyone at all. Hooray, great celebrations, all around. My goodness it is a miracle of modern medicine… or not.

Yes, be very careful with medical definitions, and not just because they can often just follow the fashion of the day. Also, because, once you think you have defined something this can constrain your thinking to a painful degree.

Ischaemic heart disease would be what most people think of as heart disease. But just for starters, it is not a disease of the heart; it is a disease of the arteries supplying blood to the heart – through the coronary arteries. The ‘disease’ itself is atherosclerosis (thickening and narrowing of the arteries), and the condition underlying this atherosclerotic plaque development.

This is, sort of covered by ICD 414.0

414.0 Coronary atherosclerosis

Atherosclerotic heart disease

Coronary atheroma

Coronary (artery) sclerosis

But is 414.0 what actually kills you? You can have coronary arteries blocked up to 70:80:90 even 100% without having a heart attack a.k.a. a myocardial infarction:

‘We conclude that total occlusion of the major coronary artery occurs commonly in patients with chronic coronary disease, but is associated with myocardial infarction in only 65%.2

On the other hand you can find people with completely clear coronary arteries who have died of – what has been clearly diagnosed as – a myocardial infarction. Here is a paper from the European Heart Journal published last year, entitled: ‘Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management.’

‘Myocardial infarction with no obstructive coronary atherosclerosis (MINOCA), a syndrome with several causes, is frequent in patients admitted with the diagnosis of M (myocardial infarction ‘heart attack’ my words). An accurate and systematic diagnostic work-up, is crucial for the identification of the cause of MINOCA in each individual patient, and then for risk stratification and for the implementation of the most appropriate forms of treatment. Yet, patients with MINOCA, in particular those with angiographically normal-coronary arteries, are frequently labelled as ‘non-cardiac patients’, thus missing the opportunity to appropriately treat patients with an outcome worse than previously believed.1

In this study they found that about 5 – 25% of those admitted with ‘infarctions’ had no coronary atherosclerosis. So ischaemic heart disease/MI can very frequently occur without the presence of any atherosclerotic plaques at all.

Unfortunately, the plot thickens even further. In many cases it can be found that a large blood clot (thrombus) can form in an artery days or weeks before the myocardial infarction actually occurs.

Here is an interesting little section from an article with a very boring title: ‘The temporal relationship and clinical significance of plaque substrate in healing coronary thrombi from sudden deaths attributed to rupture and erosion.’

‘Although the morphology of the culprit plaque has been extensively studied, especially rupture, relatively little is known about the temporal relationship between the onset of acute coronary events and thrombus maturation. The occurrence of nonlethal ruptures recognized by accumulated fibrous tissue at healed repair sites suggests that healing thrombi represent an episodic cycle of lesion progression. Moreover, thrombi from fatal plaques are in various stages of healing, further suggesting that death might not necessarily coincide with the initial onset of thrombus formation.3

Now, in English.

The thrombus ‘clot’ formation – the thing that is supposed to kill you within minutes of hours after forming – may well not actually occur shortly before you die. It can occur days or ever weeks earlier. Which mean that, in many cases the thrombus forms, the artery blocks, and nothing happens until – in some cases – weeks later.

This does not really fit with the current model of heart disease, which is very simple, and it goes something like this:

  • The coronary arteries gradually narrow and thicken.
  • At some point, a thrombus forms on top of one of the narrowest bits (the plaque),
  • This blocks the artery completely.
  • The heart muscle then rapidly runs out of oxygen and infarcts (dies).
  • In around 50% of cases you die as the heart stops beating, or goes into fibrillation – or suchlike

I call this the plumbing model of heart disease. Pump, pipes, blockage to the pipe in the pump …death. However, you can have final stage 100% occlusive atherosclerotic plaques without an MI. It is also perfectly possible have an MI without atherosclerosis. In addition, the formation of a thrombus does not necessarily correlate in any way, in timescale, with the MI – at all.

Because of all these problems with the current model, it would be perfectly possible to argue that we have the entire process of ‘heart disease’ the wrong way round. Indeed, I regularly communicate with a Brazilian called Carlos Monteiro, a researcher who proposes the myogenic theory of heart disease. He believes that the MI starts within the heart muscle itself, and the clot in the arteries comes afterwards.

His reasoning – following on from the work of his father in Law, the cardiologist Dr Mesquita is, as follows:

  • Clinical observations showing the absolute lack of efficacy of anticoagulants in the treatment of unstable angina pectoris. Unstable angina is considered to be a stage leading to myocardial infarction
  • The strong correlation of myocardial infarction with stress or unusual physical activity
  • Frequent coronary angiographies showing no obstructions in the presence of myocardial infarction
  • Many anatomic-pathological studies have demonstrated no relationship between thrombus and infarction, which led many authors since the 1940s to consider coronary thrombosis—the clot in the arteries—as a consequence of acute myocardial infarction, not its cause
  • The development of coronary thrombus after a heart attack, demonstrated experimentally4

True or false, right or wrong? Can the myogenic theory explain more of what we actually see? Yes, no, maybe. Personally, I don’t think his theory is correct in totality, although it has many correct bits in it. Causality is always a bugger, which way round do things go? This before that, or that before this? Are things actually related at all?

Sorry to say that I provide no further explanations. Or this blog would end up three hundred pages long, and I will not impose such a thing on anyone. What I hope to have made clear is that we have models and definitions of heart disease/IHD/MI that cannot be considered even remotely adequate. Whatever is going on, it is a far more complex and interesting thing than the plumbing model.

Which boils down to one simple thing. Namely that to ask the question, what causes heart disease, is easy. But in order to try and answer it we have to establish, as clearly as is possible, what the bloody hell is this disease? If find that you cannot find the answer to anything whilst sinking into a bog, or staring into the fog. Both of which seem the activities of choice of my cardiology colleagues.

 

References:

1: http://eurheartj.oxfordjournals.org/content/early/2014/12/12/eurheartj.ehu469

2: http://onlinelibrary.wiley.com/doi/10.1002/clc.4960060203/pdf

3: http://dare.uva.nl/document/2/106726

4: http://www.westonaprice.org/author/cmonteiro/

The hydra

I was thinking about the astonishing resilience of the cholesterol hypothesis the other day – something I often do. As you may know the ‘authorities’ in the US have now decreed that cholesterol in the diet is no longer a dietary factor of concern, as it has no effect on cholesterol levels in the blood.

Well my, my, this was discovered sixty years ago by Ancel Keys. However, several decades later various US Departments seem to have noticed this astonishing fact. They have sprung into immediate action and proposed that cholesterol is removed from the guidelines – as a dietary substance to be avoided (well it hasn’t quite happened yet, but it will).

No doubt they will take about two hundred pages of verbose guff to state this, along with all the reasons why no-one was actually wrong, and no-one ever really said that cholesterol in the diet should be avoided in the first place blah blah de blah. I certainly would not expect that the words ‘we were wrong’ will be found anywhere in the document, at least not in that order.

Blimey though, sixty years to get rid of a recommendation with never a scrap of evidence to support it. Not a single scrap. Of course, cholesterol in the blood is still bad. At least bad cholesterol is still bad, whereas good cholesterol is still good. Even though neither thing is actually cholesterol at all. But why let science get in the way of a good scientific hypothesis.

Hydra, or blob.

I was thinking should I call this blog, the ‘hydra’ or the ‘blob’. Because, when it comes do the cholesterol/diet-heart, or the ‘whatever you now want to call it, because you can call it almost anything you like hypothesis’ we see both mechanisms, multiplication and growth/mutation.

From the hydra perspective, if you cut off the head, this hypothesis simply grows a couple more. We now know it is not cholesterol in the diet that is bad. But anyway that doesn’t matter, for another head grew years ago. It is the ‘saturated fat is bad head’. If you attack that, it is the ratio of saturated to polyunsaturated head that suddenly appears. And if you attack that, the monounsaturated head appears, or the odd-chain saturated fat head, or even chain, or short chain. Chop chop, more heads.

In the blood, it is not LDL ‘bad’ cholesterol that is the problem, it is the new head of the ratio of good to bad cholesterol. Or is it dyslipidaemia, or it is oxidised cholesterol, or particle numbers, or small dense ‘bad’ cholesterol, or light fluffy ‘good (and simultaneously) bad’ cholesterol. Chop, chop. OMG not more bloody heads.

However, there are also good reasons for calling the many headed cholesterol hypothesis the blob, as it just grows and grows bigger. Attack it with contradictory evidence and is also capable of engulfing it, using your evidence to grow bigger and stronger. ‘Run for your lives.’

The French have a high cholesterol diet, a high cholesterol level in the blood, and low rates of heart disease. ‘Ah yes, that it because they eat lightly cooked vegetables, eat lots of garlic and drink red wine.’ The blob, gentle readers shrugged, grew a few pseudopods and engulfed these contradictions, digesting them with a contented sigh.

Eventually the hypothesis became ‘multifactorial’ a state in which any attack on any part of it is doomed to fail amongst a forest of heads attached to a monstrous blancmange like organism. The cholesterol hypothesis has become so massive and shapeless that any attempt to attack it is doomed to failure. You will be simply turned to stone, or engulfed. It will be lot longer than another sixty years before this hypothesis will finally keel over and die – I fear.

After all, the fact that cholesterol in the diet has no effect on cholesterol levels in the blood has had not the slightest discernible effect on a hypothesis that began life as… the cholesterol hypothesis. Although I defy anyone to tell me what it has now become.