An astonishing article appeared in “The Guardian” on 30th October. You can find it at https://www.theguardian.com/lifeandstyle/2018/oct/30/butter-nonsense-the-rise-of-the-cholesterol-deniers. Basically it states that accepted wisdom over the dangers of cholesterol is correct, and those that seek to deny this are dangerous lunatics. The article is shot through with snide digs at the deniers, implying they are not proper researchers because they don’t hold tenured posts, that their opinions are published in obscure or second-rate journals and that their views are as damaging as Andrew Wakefield’s views on MMR vaccine causing autism.
When Galileo (and Copernicus for that matter) first suggested, with good scientific evidence, that the earth went round the sun he was subjected to abuse, vilification and was ostracised. Every attempt was made by the scientists of the day to rubbish his theory. Oh well, it was suggested, he isn’t a proper astronomer, so what does he know to produce a theory that all we experts refute categorically?
Sounds familiar, perhaps.
Let’s get a few things straight. I was a rheumatologist in my working life, so deferred to my cardiology colleagues on matters cardiac. When I found my serum cholesterol was very high I consulted my GP and readily accepted the prescription of a statin. I developed an odd inflammation in my shin shortly after the first statin. The technical term was tenosynovitis of the tibialis anterior muscle; in lay terms this was pain on walking, with a peculiar grating feeling if I put my hand over my shin and worked the muscle. I had never encountered this among the myriad soft tissue lesions I saw in my clinics so consulted the Internet, where I found a case report of the condition related to statin intake. So I stopped my statin . The problem went away. I sought further advice. My GP gave me another one. This time within 24 hours I had developed severe shoulder and hip girdle muscle pains, so bad during the night that I was unable to sleep. I attributed this to the new statin, and stopped that. After an interval I was prescribed yet another. I had no adverse effects for a couple of months, and then found I was struggling to climb hills and could not lift heavy garden items. On a long slope I simply ran out of steam, and had to stop and wait a few minutes. Normally I could lift two 50 litre bags of compost together; now i could not lift even one.
By this time I had discovered the existence of statin myalgia, so took myself to the hospital lab to get my blood checked. My creatine kinase level (that’s an enzyme which goes up with muscle damage, or rhabdomyolysis) was significantly elevated. I consulted a lipid specialist and we agreed I should not take them any more. My cholesterol remains high.
I write this preamble because the anti-Galileans of the cholesterol world talk blithely of a nocebo effect – one where you get a side-effect because you are expecting to get one. – which explains, in their eyes, the reports of side-effects that they claim are grossly exaggerated in numbers. But you can’t suffer from a nocebo effect if you don’t expect it. Neither can such an effect cause significant enzyme changes on blood tests. Never mind; whatever the real incidence that’s not entirely relevant to this piece, but my experience led me to a new world of the cholesterol-heart hypothesis, and to the statin skeptic network called THINCS. And we are, I believe, modern Galileos, whose questioning of received wisdom (if you can call it that) is beginning to lead to denigration and persecution. Will we be proved right? Let’s look at some facts.
It is undeniable that statins do reduce the risk of a major cardiac event. But the first question is – by how much? If you read the statin-favourable reports and research studies you will think that the risk reduction is around 50%, which is pretty impressive. However you must ask first what the risk was in the first place. If the risk is 4%, then a reduction of 50% means it becomes 2%. So it’s not really very impressive at all. Statistics are not easy; I have seen many examples of trials conducted by perfectly respectable researchers who have used the wrong statistical analysis method by accident (or ignorance) and not-so-respectable ones who find a method, or select data, so they produce an apparently significant result. But quoting a risk reduction of 50% – the relative reduction – is deception when the absolute reduction is only 2%. Why do people do this? It makes the results look better, but in the end they start believing their own myths. And if you look at the prolongation of life it amounts to a few days, let alone years. Not a lot, as Paul Daniels would have said.
So the effects of statins are overstated and misrepresented.
The next question is why do statins reduce risk (although perhaps, as the reduction is so piddling, we shouldn’t bother). But I did bother, because I found something that blew the whole cholesterol thing out of the water.
There is unimpeachable evidence that if you suffer from severe rheumatoid arthritis (RA) then your risk a a major cardiovascular event is very high – possibly even higher than if you are diabetic. If you successfully treat the arthritis with so-called disease-modifying drugs, this risk reduces substantially. But the cholesterol level in the blood goes up.
Here we have an oxymoron. Give statins, cholesterol falls and cardiac risk falls (a bit). Give drugs that make RA patients better, cholesterol rises, but cardiac risk falls (quite a lot). Explain.
For about seven years I put this paradox to rheumatologists, physicians and others. No-one could explain it. They huffed and puffed and mumbled and came up with all manner of crazy theories. So we have a Black Swan. Received wisdom in the eighteenth century was that all swans were white. Then Australia was discovered and lo! there were black ones. So the received wisdom was wrong. It only takes a single contrary observation to destroy a theory. In medicine one tests a theory exactly thus; you make a hypothesis, and set out to disprove it (it’s called a null hypothesis). The null hypothesis is that statins reduce cardiac risk because they reduce cholesterol. Yet if we reduce cardiac risk by treating a disease characterised by inflammation, cholesterol goes up. So the null hypothesis is by definition proved to be false. You can have any number of things supporting a null hypothesis, but it takes just one that doesn’t to turn things over.
Enter Malcolm Kendrick, another cholesterol skeptic, a deep thinker, careful research analyst, and GP without some giant research department (therefore suspect in the eyes of the anti-Galileans). What if the mechanism of action of statins has nothing to do with cholesterol? Suppose that cardiovascular risk is increased because of blood vessel inflammation and that statins reduce this? Well. It all fits, doesn’t it? And by golly there’s plenty of evidence for coronary artery inflammation. You get it in RA and other connective tissue diseases. You find it on pathological examination under a microscope. And it explains otherwise inexplicable things. Like – how does a large cholesterol molecule get through the blood vessel wall? It can’t, if the wall is intact, because it’s too big. But suppose the wall is damaged, and tries to repair itself, but the process doesn’t quite work. Why, then you can find cholesterol the wrong side of the wall lining. It’s there as part of an incomplete healing process. It has nothing whatever to do with its concentration in the blood but will happen more often where there is blood vessel damage. Oh, and by the way, that occurs in diabetics and smokers too. There are an awful lot of scientists and cardiologists who find this hypothesis attractive, and despite asking the anti-Galileans to pick it to pieces for some reason they haven’t. Perhaps they can’t but I would like to see them try.
I would prefer to explain this as follows: Statin use (A) causes a small reduction in cardiac risk (B). A also causes a fall in cholesterol (C). A leads to B, and A leads to C. But that does not mean that C leads to B. A fall in cholesterol is more likely to be a side-effect, or epiphenomenon – something clearly observable but irrelevant.
Another question of mine has been why you find cholesterol deposits in arteries, but not in veins, where the pressure is less and the flow can be sluggish. If cholesterol was to be deposited anywhere it ought to be here, like silt in a river. Explain. (Actually don’t bother, because there’s more coming that makes that unnecessary).
So statins work by reducing inflammation; that they reduce cholesterol is by the by. Now I don’t really care whether severe statin side-effects occur in 20 % or 2% but others do, on the basis that if patients cannot take a statin they MUST HAVE SOMETHING!!! You would be amazed at the number of people I saw with clear-cut statin side-effects (effect occurs, stop, effect disappears, restart, effect reappears – that’s called re-challenge, and QED for cause and effect) who were otld, 0redered even, to carry on because otherwise they would DIE!
So a new injectable drug was produced called evolucumab. Its cholesterol-lowering effects are remarkable. It’s far, far better than a statin. It’s also very, very expensive. Does it reduce cardiac events far, far better than a statin? No! Why not? Perhaps it doesn’t have any anti-inflammatory properties, but we won’t know in all probability as the major trial looking at outcomes was terminated early. The death rate in those on the active drug was higher. There is a suspicion that it would have been higher still if the trial had continued. Even Sir Richard Thompson, past president of the Royal College of Physicians, said any benefit was “amazingly small”. So here is another oxymoron. Statins reduce cholesterol a bit and reduce cardiac events a bit. Evolucumab reduces cholesterol a lot but doesn’t reduce cardiac events. Explain.
Well, the obvious explanation is that any cardiac benefits of statins have nothing to do with cholesterol.
Next question. Where does cholesterol come from?
You thought you ate it, didn’t you? It’s in all that butter and other saturated fat that forms such a large part of your diet. Actually it’s not that large a part, but anyway most of the cholesterol you find in the bloodstream (80% or so) is made in the liver. From what, you ask? How about carbohydrate? Whatever, an increase in dietary cholesterol slows the liver’s own production (this is called homeostasis). So fiddling with your cholesterol intake is not much use, as your liver will defy your good intentions and simply make more. If your level is high, probably your genes made you that way.
I wonder whether you are beginning to doubt received wisdom. It is interesting, if sad, that the whole concept of cholesterol irrelevance was effectively proposed several decades ago by Dr John Yudkin, who saw sugar as the villain, but who was himself vilified and ostracised. And the work of Ancel Keys who was key (sorry) to the adoption of the cholesterol-heart hypothesis, was fatally flawed. Out of the countries from which demographic data was analysed he picked those that best fitted his hypothesis. Had he used it all he would not have found any significant correlation. Indeed most of the trials looking at serum cholesterol and heart disease conducted before 2000 have methodological flaws. Confine reviews to trials after that date and even the relative risk improvement begins to look unexciting.
So there it is. The hypothesis is based on shaky data analysis, falls over under intense scrutiny because of inherent contradictions and is also suspect because some of the later trials cannot be independently assessed. Sceptics have persuaded erudite journals that trial data should be made available for independent analysis. Yet one of the most strident anti-Galileans, Sir Rory Collins, refuses to do this for his own work. If it’s so cast iron right, what is there to hide, one might ask. And what need is there for the anti-Galileans to make snide remarks questioning the credibility and integrity of their critics? Likening us to the disgraced Andrew Wakefield, who has fooled people with fraudulent data, is frankly offensive. We have faked no data, falsified no trials, merely picked major holes in those of others. We have raised no scares, unlike those who have accused us of killing people by telling them to stop their statins.
What did Socrates say? “When the debate is lost, slander becomes the tool of the loser.”
Remember: all of us sceptics were reared on the heart-cholesterol hypothesis but it is us who have been open-minded enough to question its validity. If we are wrong, give us the evidence. Prove that our hypothesis has fatal flaws. In other words, put up or shut up.
