Tag Archives: cardiovascular

How to kill a hypothesis

“Why do people insist on defending their ideas and opinions with such ferocity, as if defending honour itself? What could be easier to change than an idea?” J.G. Farrell.

When the orbit of Neptune was found to be irregular, and not to follow classical Newtonian physics, it was suggested that, perhaps, the laws of physics may break down in deep space. Others, rather more pragmatically, suggested that there was another planet out there, interfering with the orbit of Neptune. It was just too far out, and dim, to be seen.

That planet, no longer called a planet, was Pluto. Once observed, it accounted for the distortions in the orbit of Neptune.

When the orbit of Mercury was found to be irregular, and not to follow classical Newtonian physics, it was suggested that there was another invisible planet orbiting closer to the sun. This planet was named Vulcan.

Of course there was no planet Vulcan. The reason why classical Newtonian physics did not accurately predict the orbit of Mercury is because the mass of the sun bent time and space. Classical Newtonian physics had to be replaced by Einstein’s theory of relativity.

What does this tell us?

It tells us that it is very difficult to know if an apparently contradictory observation actually refutes a scientific theory. It also tells us that you can use ad-hoc hypotheses (there is another planet out there) to support a cherished central hypothesis, and that this is a valid scientific technique.

But at what point do you have to admit defeat? How many contradictory observations can you dismiss before you must accept that the game is up, and that your hypothesis is wrong?

I think about this a lot. Mainly with regard to the cholesterol hypothesis, or the diet-heart hypothesis, or whatever term is now current. I have seen evidence that directly refutes this hypothesis again and again and again and….indeed…again.

If anyone wishes to debate this issue with me, I can produce far more evidence contradicting it, than supporting it. Yet still it stands, untouched. In fact I would suggest more people believe in this hypothesis than at any time in human history. Billions of people also take statins to lower their cholesterol levels. As you can imagine, this is more than a little frustrating.

How can you convince people that this hypothesis is wrong? I have tried in many, many, different ways. As have other members of THINCS (The International Network of Cholesterol Skeptics).

Yes, I have helped to convince many thousands of people that cholesterol has nothing to do with heart disease, or cardiovascular disease, or atherosclerosis, or unstable atherosclerotic plaques…

Indeed, stepping sideways for a moment, one of the major difficulties in this area is that the terminology shifts and swirls in front of you, making it impossible even to pin down what you are talking about.

At one time the experts were quite happy to tell us that a raised cholesterol level caused heart disease. Now we have ‘good’ cholesterol and ‘bad’ cholesterol, and ‘light and fluffy’ bad cholesterol and ‘small and dense’ bad cholesterol (which really should be called ‘evil’ cholesterol, I suppose). We have the ratio of good to bad cholesterol, apob-100 levels, particle numbers, sub-fractions of good cholesterol, dyslipidaemia, LDL particle size, or number,  or…..the list goes on and on.

How can you argue against a scientific hypothesis when the damned thing will not stay still from day to day?

That, however, is a bit of a side-issue, although I have come to realise that this constant creation of new types of cholesterol, and sub-fractions, and ratios, is all part of the game that is played to protect the cholesterol hypothesis from refutation. How can you refute a hypothesis that can change into any shape it likes? Answer, you can’t.

Anyway, in my efforts to work out how to change ideas in the wider population I have spent a great deal of time looking at the history of scientific thought. I wanted to gain any insights I could into how people managed to kill off hypotheses in the past.

As part of my education I have tried not to get too depressed by fellow thinkers on the subject. Such as Max Plank, who said:

‘A scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it.’

In short, his view is that you should forget trying to convince people. They will never, ever, change their minds. Max Plank, by the way, was the man who published Einstein’s special theory of relativity (against great opposition).

Another of my scientific heroes is Wilfred Trotter. A man you are unlikely to have come across. Unfortunately, however, he was not much help either:

‘The mind likes a strange idea as little as the body likes a strange protein and resists it with similar energy. It would not perhaps be too fanciful to say that a new idea is the most quickly acting antigen known to science. If we watch ourselves honestly we shall often find that we have begun to argue against a new idea even before it has been completely stated.’

I could fill hundreds of pages with quotes saying the same type of thing. Essentially, people love the ideas they have grown up with, and become deeply emotionally attached to them. Changing them is painful; they dislike and fear new ideas and, will bring forth all the powers of their intellect to do so.

Things are made all the more difficult when you try to convince people who have spent large amounts of their professional life studying a specific area. When someone has become an ‘expert’ in something, and their reputation, and position of authority, is inextricably linked to a certain hypothesis, you are not just attacking an idea, you are attacking them. As noted by Leo Tolstoy:

‘I know that most men, including those at ease with problems of the greatest complexity, can seldom accept even the simplest and most obvious truth, if it be such as would oblige them to admit the falsity of conclusions which they have delighted in explaining to colleagues, which they have proudly taught to others, and which they have woven, thread by thread, into the fabric of their lives.’ Leo Tolstoy

Despite all of this being rather depressing, it has all helped me to establish one clear rule. Do not bother trying to convince people who are ‘experts’ in heart disease that the cholesterol hypothesis is wrong. It is a complete waste of time and energy. The only people who can be convinced are inquisitive people who do not have too much invested in this particular hypothesis.

I have also worked out another rule. Facts are almost completely ineffective at convincing people of anything. Recently, I was reading an article on Daniel Kahneman, Nobel prize winner in economics. He was discussing the irrationality of the financial system. He made many interesting points. For example:

The way scientists try to convince people is hopeless because they present evidence, figures, tables, arguments, and so on. But that’s not how to convince people. People aren’t convinced by arguments, they don’t believe conclusions because they believe in the arguments that they read in favour of them. They’re convinced because they read or hear the conclusions from people they trust. You trust someone and you believe what they say. That’s how ideas are communicated. The arguments come later.’

Once again, if this is true, what can be done? How to change ideas…..

I leave you at this point with a small section of dialogue from the film Inception:

Dom Cobb: ‘What is the most resilient parasite? A bacteria? A virus? An intestinal worm?’

Arthur: ‘Uh, what Mr. Cobb is trying to…’

Dom Cobb: ‘An idea. Resilient, highly contagious. Once an idea has taken hold of the brain it’s almost impossible to eradicate. An idea that is fully formed, fully understood. That sticks, right in there somewhere.’

[he points to his head]

The cholesterol hypothesis is one of the most resilient parasites of all. How to kill it off? All suggestions welcome.

A farewell to statins – part one

In the end I knew that statins would be overthrown. Their time, like the dinosaurs would come to an end.  I also knew it would be nothing to do with me, or any of the other critics. Nor would it have anything to do with the fact that their terrible burden of adverse effects finally came to light.

No, it would be because their patents ran out, which meant that the big pharmaceutical companies could not make eye-watering profits from them anymore. Inevitably, therefore, they would be replaced. Indeed, for years I have watched, with varying degrees of amusement, the unending efforts to unearth the ‘new’ statins. The wonder drugs to be taken by everyone, for the rest of their lives. The ones that will make billions for the pharmaceutical companies, and several millions for the key opinion leaders promoting them.

Steven Nissen had a go with apoA-1 Milano. This is a little story you may want to look up on Wikipedia.  Basically, a small village was found in Italy (near Milan) where people had very low rates of heart disease, and they also had very low levels of HDL ‘good’ cholesterol.

Turning science on its head, it was therefore decreed that their HDL must be especially ‘good’ at preventing heart disease. [Rather than accept that HDL had bugger all to do with heart disease]. So attempts were made to synthesize their form of HDL, then inject it into patients. This was done in small scale clinical studies.

So brilliantly did Nissen sell the results of these studies that a start-up company called Esperion, which funded the trials, was sold to Pfizer for over a billion dollars on the back of the results. If you want to find out more, the HDL synthesized was called ETC-216, not apoA-1 Milano.

This is what Steven Nissen had to say about the trials.

The fact that you can actually pull major amounts of plaque out of the artery in five or six weeks is an epiphany,” Nissen says. H. Bryan Brewer, chief of the molecular disease branch at the National Heart, Blood & Lung Institute, adds: “Quite to everyone’s surprise, this indicates that we might be able to be much more successful in a shorter period of time than we thought possible.”

By golly it all sounds very exciting, does it not.  Pulling significant amounts of plaque out of artery walls, in six weeks! This is quite amazing, what a brilliant drug. In truth, though, that quote was from 2003. Has anything since happened since to this magical plaque munching HDL? Is it now on the market, saving lives? Well, as you ask, the answer is no.

However, several other HDL raising agents have also been developed in the last few years. Unfortunately, they also raised the risk of heart attacks and strokes – then disappeared. Torcetrapib, dalcetrapib, anacetrapib…. A yes, anacetrapib, not quite gone yet.

Anacetrapib has a knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL,” said Chris Cannon in an AHA press release.  He also said “The lipid effects are jaw dropping in both directions,” Yes, indeed, they were.  Although I am not sure that ‘jaw dropping’ and ‘knock your socks-off’ are truly scientific terms.

But then Forbes ran this headline on the 22nd October

Merck Heart Drug Runs Into New Worry.’ 1

As an aside, you can find out far more about drugs in development by reading Forbes magazine than you will ever get from the scientific journals.

Anyway, I wouldn’t bet the house on anacetrapib as I suspect it will soon follow the other ‘trapibs’ into an early grave. But never mind, Lilly has yet another HDL raising agent waiting in the pipeline, evacetrapib. What is it with these unpronounceable names, and why don’t these companies just give up? However, perhaps this one has a better shot than most, because as Steven Nissen said of dalcetrapib…

Dalcetrapib was always a long shot,” said Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. “The worry all along was that it wouldn’t have enough effect to produce a benefit,”

Then, as he went on to say of evacetrapib

We got everything we could hope for from this drug, and maybe more,” remarked study co-author Steven Nissen, adding that “we are going to move evacetrapib forward as rapidly as possible” into a late-stage trial.” Gosh, he is running a study on evacetrapib too.  He was also lead investigator for Torcetrapib2.

That Steven Nissen, what a busy chap he is?  Wasn’t he the one who said about the new cardiovascular prevention guidelines.  “The evidence was never there” for the LDL targets, he said. Past committees “made them up out of thin air,” he added.  Why yes, I think he was.

Anyway. They have tried raising HDL…fail. They have tried a different way of lowering LDL using ezetimibe. It lowered LDL, and has had absolutely no effect on cardiovascular disease…fail. They have tried combing different HDL raising agents with statins….fail.

You know, you might even begin to think that raising HDL wasn’t that good an idea. Billions have been thrown this target, everything has miserably failed. It is also interesting that LDL lowering agents, other than statins, have failed to have any impact on cardiovascular disease. Has this had any effect on the lipid hypothesis? You must be joking.

Given this litany of disastrous drugs trials, why do I now believe that statins are about to be overthrown? What agents could be out there that are going to sweep them into the dustbin of history.

Clearly it cannot be an agent that lowers LDL even more than statins. Can it? Well, Steven Nissen has recently said the following about LDL lowering. This quote is in connection to new drugs being developed3.

 “….it matters how you lower cholesterol, not just by how much.”

It matters how you lower cholesterol, not just by how much….. Interesting.  Well, if cholesterol does cause heart disease, then it doesn’t really matter how you lower it, does it? The only question is, by how much? Or is Steven Nissen trying to say something else?

As a further aside, if you want to know where the really big bucks are being spent in cardiovascular research, and what is in the pipeline, all you need to do is follow Steven Nissen’s pronouncements. He is the weather vane. You don’t need to be a weather man to know which way the wind is blowing.

…… (to be continued)

 

1: http://www.forbes.com/sites/matthewherper/2013/10/22/merck-heart-drug-runs-into-new-worry/

2: http://online.wsj.com/news/articles/SB10001424052702304363104577389353232022644

3: http://www.forbes.com/sites/johnlamattina/2013/09/05/esperions-novel-approach-to-lowering-cholesterol-will-it-be-successful/

They have now, officially, all gone mad?

The Mad Hatter: ‘Have I gone mad?’

Alice: ‘I’m afraid so, you’re completely bonkers, but let me tell you something, the best people usually are.’

Alice in Wonderland

I find myself quoting Alice in Wonderland more and more these days. I now think it was never a children’s book, it was an accurate scientific analysis of human behaviour.

As many of you are aware the American medical authorities have come up with the latest guidelines to reduce cardiovascular risk. A major part of the guidelines is now to inform us all that we should forget about lowering cholesterol (LDL) levels, and just take a statin…. no matter what¹.

This is how the New York Times put it:

First, the guidelines have moved away from achieving target cholesterol levels.
Americans have long been urged to focus on their laboratory numbers. Many people are obsessive about checking their cholesterol levels and pursuing even better numbers. Doctors have been told to focus on these numbers and, in some cases, the quality of their care was assessed by the percentage of their patients with low cholesterol levels.

Those days are over. The new guidelines recognize that for patients who have exhausted lifestyle efforts and are considering drug therapy, the question is not whether a drug makes your lab tests better, but whether it lowers your risk of heart disease and stroke. Studies over the past several years have shown that improving your lab profile with drugs is not equivalent to lowering your heart risks².

One of the most influential cardiologists in the world, Steven Nissen, had this to say:
“The evidence was never there” for the LDL targets, he said. Past committees “made them up out of thin air,” he added.

Past committees made them up out of thin air….. Let me try that statement again…. Past committees made them up out of thin air. Exactly. Ex-bleedingly-zactly.

So, ladies and gentlemen, you have been conned. Utterly, completely and barefacedly conned, for the last thirty years. Your cholesterol level has absolutely no impact on your risk of cardiovascular disease. You think not? Well, that is precisely what they are saying in these guidelines. If not in quite such plain words.

But, of course, I am not being entirely fair to them. The level of LDL may actually matter after all – according to the same guidelines. For, as the New York Times article goes on to say.
There’s one exception to the numbers rule. People with very high levels of the harmful cholesterol known as LDL still need to worry about targets. The new guidelines set that LDL level at 190 milligrams per deciliter – but the principle is that if people have very high cholesterol levels, then their cardiovascular risk is so high that it is likely that treatment to reduce the levels would offset any risks of the drug treatment.

So, your LDL level doesn’t matter in the slightest, unless it is a very high level. Then the level does matter a great deal. Please explain, oh great cardiologists, does LDL, or does it not, cause cardiovascular disease.

Well, it seems that it both does, and does not, simultaneously. Amazingly, we have achieved a quantum state with LDL. It simultaneously exists as a molecule that can both cause – and not cause – CVD. Which means, of course, that the levels must be both lowered, and not lowered. Yes, well, this makes perfect sense. At least it would to a lunatic.

Perhaps if we open the box with the ‘at risk cat’ in it, we will find that this new version of Schrodinger’s cat died of a heart attack caused by LDL. Alternatively, it did not. Before opening the box, it exists in both possible states. It is an interesting variation on a theme.
The most astonishing thing is not that these people are now talking the most complete gibberish. They have been doing this for years. The most astonishing thing is that the vast majority of the population will still listen to what they have to say – and follow their advice.
Well, good luck with that all you billions of mad people, following the advice of these mad scientists Good luck with that indeed. I salute you. Meanwhile I shall attempt to find the answer to a far more important question than what causes heart disease.

“Why is a raven like a writing desk?”

1: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437740.48606.d1
2: http://well.blogs.nytimes.com/2013/11/12/3-things-to-know-about-the-new-cholesterol-guidelines/