Tag Archives: wellness

Lancet paper critique – Part 3

Finally, you may think, some figures.

In this blog I want to look at some of the figures on adverse effects seen in a number of statin trials – such figures as it is possibly to unearth anyway. Unlike the CTT in Oxford I – along with almost every other researcher in the world – cannot gain access to most of the data. It is all highly confidential.

Official secrets are released in the UK after thirty years. But not, it seems the pharmaceutical company research papers held in Oxford. Clearly, they are far more important to national security. We can only work with what we’ve got – so, here goes:

Now, accountancy heads on, eyelids taped open, strong coffee at the ready. Here come some figures on adverse effects from statins and placebos. These come from very large statin trials – all of which were funded by pharmaceutical giants such as Merck, Pfizer and AstraZeneca.

The main point I want to make here is that the figures themselves appear, frankly, unbelievable. So unbelievable that …I shall leave that next bit unsaid, under advice from lawyers:

In the LIPID trial, the percentage of adverse effects recorded, in those taking a statin (pravastatin) was: 3.2%¹

In the IDEAL trial, the percentage of adverse effects recorded, in those taking a statin (atorvastatin) was: 94.7%²

94.7 ÷ 3.2= 29.6 [Thirty times as many adverse effects seen with a different statin]

Looking at the LIPID trial again, the percentage of adverse effects recorded, in those taking the placebo was: 2.7%¹

In the METEOR trial, the percentage of adverse effects recorded, in those taking the placebo was: 80.4%³

80.4 ÷ 2.7 = 29.9 [Thirty times as many adverse effects seen with placebo]

In the 4S trial, where they used simvastatin 20mg, the percentage of adverse effects recorded, in those taking simvastatin was: 6.0% ⁴

In the IDEAL trial, where they used simvastatin 20mg, the percentage of adverse effects recorded, in those taking simvastatin was: 94.4% ²

94.4 ÷ 6 = 15.7 [Sixteen times as many adverse effects recorded using the same statin, same dose].

If these figures are correct, we have a major problem on our hands. Either the collection of adverse effects data in randomised controlled trials is done in such wildly different and unregulated ways, that the data are completely unusable. And thus, worthless for research purposes.

Or…

The data themselves are heavily manipulated in some way. And are thus equally worthless for research purposes.

The possibility of data manipulation is strengthened by another strange phenomenon that emerges from the data – such as we are allowed to see. Namely, whatever the rate of adverse effects seen within each trial it is the same (or very nearly the same) for both the statin and placebo.

Here is a selection of some big statin studies.

AFCAPS/TEXCAPS: Total adverse effects: lovastatin 13.6%: placebo 13.8%⁵

4S: Total adverse effects: simvastatin 6%: placebo 6% ⁴

CARDS: Total adverse effects: atorvastatin 25%: placebo 24% (ref now missing/gone))

HPS: Muscle pain: simvastatin 5% placebo 6% ⁶

METEOR: Total adverse effects rosuvastatin 83.3%: placebo 80.4% ³

LIPID: Total adverse effects 3.2% Pravastatin: Placebo 2.7% ¹

JUPITER: Discontinuation rate of drug 25% Rosuvastatin 25% placebo. Serious Adverse events 15.2 % Rosuvastatin 15.5% placebo ⁷

WOSCOPS: Total adverse effects. Pravastatin 4.9%%: Placebo 4.5%. Discontinuation rate Pravastatin 29.6% Placebo 30.8% ⁸

IDEAL: Total adverse effects simvastatin 94.4%, atorvastatin 94.7%²

The adverse effects, the serious adverse events, the drop out and trial discontinuation rates – they are always the same for the statin and the placebo (or for one statin vs another) – no matter what the absolute rate may be. Yet the figures range thirty-fold. For both drug and placebo.

When I first dredged together – such figures as I was able to dredge – I thought. Well, I had best not say what I thought, or I would be immediately sued for libel.

As for the 94.4% and 94.7% figures. These came from the IDEAL study where simvastatin was compared with higher dose of atorvastatin in 8,888 participants. A big trial. However, the CTT dismissed IDEAL from its analysis, as it did not meet their self-appointed criteria.

I wonder if their summary dismissal of IDEAL might have had anything to do with the fact that this was a trial where almost every single participant suffered an adverse effect from taking a statin. They dismissed the METEOR trial because they decided that only trials with a thousand participants would be included in their meta-analysis, and METEOR only had 984. Wow, how … convenient.

The IDEAL trial is also very telling in a couple of other ways. As mentioned earlier, in the earlier 4S study, 20mg simvastatin was used as the active drug. The adverse event rate from this dose was 6%. In the IDEAL study, exactly the same dose of simvastatin was used. However, in this case, it led to an adverse event rate of 94.4%.

A fact which is made even more strange by the knowledge that, about half the participants had been taking simvastatin before this trial began, and the participants were specially selected as being ‘simvastatin tolerant.’ Their words, not mine.

Therefore, one would also expect them to be generally ‘statin’ tolerant – as all statins have pretty much the same spectrum of adverse effects – if somewhat dose dependent.

You really could not make this stuff up. We have a group of people included in a trial of statins, fifty per cent of whom were already known to be ‘simvastatin tolerant’, yet 94.4% of them suffered an adverse drug reaction … to simvastatin. God knows what would have happened if they were not tolerant. All turn blue and explode perhaps.

Yes, IDEAL was not a double-blinded study, this is true. But is anyone seriously trying to suggest that the nocebo effect can lead to sixteen times as many people reporting adverse effects. If so, please provide some …a little … any evidence for any such massive difference. And good luck with that.

I have studied both placebo, and nocebo, research papers in some detail. Which are often the same papers. They are, I should probably say here, far from perfect. As you can probably imagine this is an area fraught with confounding variables and observer effect. But the differences found are consistently small, around five per cent or so.

Importantly, the placebo effect – where fewer adverse effects are reported when people think they are taking a medication – has almost exactly the same impact as the nocebo effect – in reverse. Therefore one, effectively, cancels the other one out. Something you might intuitively expect to be the case ⁹.

There is certainly nothing anywhere in the literature to suggest that the nocebo effect can explain anything more than, perhaps, a doubling in adverse effects that are reported. Absolute maximum. Ergo, the figures from the RCTs make no sense. Unless, that is, your interpretation is that they may not be … entirely aligned with that little thing we call, the truth.

Serious adverse effects

Perhaps most importantly, and far more difficult to explain away with a rapid waving of the hands and a repeated muttering of ‘not-blinded, not-blinded, not-blinded….’ The rate of a serious adverse events in IDEAL was:

Simvastatin: 47.4%

Atorvastatin: 46.5%

Here, we are not talking about diarrhoea, or mild leg pain, or blurry vision, or headache. The definition of a serious adverse event in a clinical trial is, as follows:

‘…any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity.’

These are not the sort of things you can imagine happening to you, having first read about them on a patient leaflet. It is particularly difficult to simply imagine that, for example, you are dead. Yet nearly half of the participants in this trial suffered a serious adverse event.

This was one of the very few trials where they published any data on any serious adverse events. [How, just how, are they allowed to get away with this? Sorry to keep banging on about this, but I mean …what?]

Anyway, very nearly half the people in this clinical trial, where all participants took a statin, suffered a serious adverse event …. How did the authors deal with this elephant, nay mastodon, in the room? They dealt with it by using the following sentence:

‘The results indicate that patients with myocardial infarction may benefit from intensive lowering of LDL-C without increase in noncardiovascular mortality or other serious adverse reactions.’

[Note the word reaction here. Thisthis implies a ‘reaction’ to the drug, which is not what an SEA is. Right here, right under our noses, yet another critical semantic trick is being played out. Seemingly small, possibly unimportant? In truth massively distorting. SAEs cannot be defined as ‘reactions’, as that is not what they are. Peer reviewers where art thou? Polishing their pro-statin reputations, no doubt.

In essence, the investigators simply brushed aside the fact that 94% of participants suffered an adverse effect with statins, and that very nearly half of the participants suffered a serious adverse event. Move along now, nothing to see here.

Adverse events/effects – serious adverse events (SAEs)?

At this point I feel the need to explain the difference between a drug related adverse effects/event and a serious adverse event (SAEs). They do sound like pretty much the same thing, and most people think they are the same thing. Are serious adverse events simply the serious subset of the overall adverse events figure?

No. And I have to say this particular topic is highly confusing … deliberately so? It took me a while to get my head round it.

A drug related adverse effect, or event, is an unpleasant thing deemed to have been caused by the drug e.g. rash, muscle pain, a headache. Unpleasant, damaging to quality of life, but not life threatening.

Are serious adverse effects (SAEs) also caused by the drug?

The answer is both yes, and no. And no and yes – and maybe. SAEs are complicated, but important to understand. For, within a single figure, lies the potential for much statistical mischief. And much statistical mischief there, indeed, is.

There are three sub-sets of SAEs:

An SAE can be caused by the drug – e.g. liver failure, muscle breakdown
An SAE can be something that is supposed to have been prevented by the drug e.g. a heart attack.
An SAE may have nothing whatsoever to do with the drug – someone develops bowel cancer (which, obviously, might have something to do with the drug, that you didn’t expect to see. Another issue for another time)

Given that there are three types of SAE, all wrapped up within the same overall number, does it mean anything at all? Can any sense be made of it?

Well, first you have to split the single figure into its component parts.

Drug related SAEs – serious events caused by the drug
Drug preventable SAEs – serious events that the drug is designed to protect against
Coincidental SAEs – serious things that just happen by chance (maybe)

Disentangling can be tricky when you cannot see the vast majority of the data that makes up the headline SAE figure. Although some trials did release more than others e.g. METEOR, ALHAT-LLP, and IDEAL. Strangely, none of these trials made it into the CTT meta-analysis. Yet another inexplicable coincidence, no doubt.

Anyway, let us start the great disentanglement by first looking at coincidental SAEs. That is, serious events that happen by chance. If the trial is big enough then you should see the same number of ‘coincidental’ SAEs in both the statin and placebo arms. Maybe one or two more on either side. For the sake of this argument, we can ignore these, assuming the drug didn’t actually cause unexpected SAEs.

Once you have got rid of ‘chance’ SAEs, you have two left. Drug related SAEs and drug preventable SAEs.

In a trial of statins, the investigators are hoping to see fewer cardiovascular SAEs. By which I mean there should be fewer cardiovascualar (CV) deaths e.g. heart attacks and strokes. There should also be fewer non-fatal heart attacks and strokes, and fewer angina attacks, or stents inserted etc. In short, fewer serious CV events.

If there is a reduction in cardiovascular SAEs, there should also be a reduction in overall SAEs in the statin arm. If not, this means that the statin must be causing as many SAEs as it is preventing. Whatever those SAEs may be.

If we look at the IDEAL study in a little more detail, we find the following – with regard to serious adverse cardiovascular events.

Simvastatin = 30.8%

Atorvastatin = 26.5%

The first thing to say here is that is a hell of a lot of CV events. More than a quarter of those taking high dose atorvastatin suffered a serious cardiovascular event, and nearly a third of those taking simvastatin. Over a time period of just under five years. So much for the super preventive power of statins.

Back on point. What we have here is a difference of 4.3% in cardiovascular SAEs between simvastatin and atorvastatin.

Ergo, there should also be a difference of 4.3% in overall SAEs. But there is not. There is a difference of 0.9%. [47.4% vs. 46.5%]. Herein lies the great unexplained gap of 3.4% inSAEs. Not really a gap, more of a giant chasm. Both clinically, and statistically, hugely significant.

What fills that gap? What indeed?

To help answer this question I will take you back to an earlier statin meta-analysis done several years ago by the University of British Columbia – a part of the Cochrane Collaboration. This was a paper looking at statins in primary prevention (people with no known CV disease). They highlighted the exact same issue that I am discussing here. In their words:

‘In the two trials where serious adverse events are reported, the 1.8% absolute reduction in myocardial infarction and stroke should be reflected by a similar absolute reduction in total serious adverse events. [MI and stroke are, by definition, serious adverse events].

However, this is not the case; serious adverse events are similar in the statin group, 44.2%, and the control group, 43.9%. This is consistent with the possibility that unrecognized serious events are increased by statin therapy, and that the magnitude of the increase is similar to the magnitude of the reduction in cardiovascular serious adverse events in these populations.

This hypothesis needs to be tested by analysis of total serious adverse event data in both past and future statin trials. Serious adverse event data is available to trial authors, drug companies and drug regulators. The other measure of overall impact, total mortality, is available in all 5 trials and is not reduced by statin therapy.’¹⁰

Their conclusion.

‘Conclusions: If cardiovascular serious adverse events are viewed in isolation, 71 primary prevention patients with cardiovascular risk factors have to be treated with a statin for 3 to 5 years to prevent one myocardial infarction or stroke.

This cardiovascular benefit is not reflected in 2 measures of overall health impact, total mortality and total serious adverse events. Therefore, statins have not been shown to provide an overall health benefit in primary prevention trials.’

Their conclusion: unrecognized serious events are increased by statin therapy

[This group changed their minds on the use of statins in primary prevention some years later. Based mainly on the results of the only primary prevention study to show benefits on overall mortality. The JUPITER study. I think they were wrong to do so, but they did. However, it had nothing to do with their SAE analysis, which still holds true – and ever unanswered. I have added the CV event data from JUPITER in an additional blog, as it became too complicated to explain here].’

To go back to my earlier question. ‘What fills that 3.4% gap?’

What fills that gap is, until proven otherwise, excess SAEs caused by the higher dose atorvastatin. Something that should be of real concern to everyone prescribing, or having high dose atorvastatin prescribed for them.

Instead, in IDEAL, here is what we got by means of an explanation.

‘The results indicate that patients with myocardial infarction may benefit from intensive lowering of LDL-C without increase in noncardiovascular mortality or other serious adverse reactions.’

This is, in reality, the exact opposite of what they actually found. Here we see, in black and white, an increase of 3.4% in ‘other’ un-named SAEs that were most likely caused by the high dose atorvastatin.

And, until independent researchers can see the raw trial data, which only the CTT can currently see, we cannot possibly accept the idea that more intensive statin lowering of LDL-C does not cause other serious adverse reactions.

Nor can we accept the headlines that followed Lancet paper that triggered my response

‘Cholesterol-lowering drugs called statins, used by millions, are far safer than previously thought, a major review has found.

Leaflets in packs should be changed to reflect this and avoid scaring people off using the life-saving pills, say the authors.’ ¹¹

‘Safer?’… The CTT Oxford study had nothing to do with safety, or SAEs. Nothing, at all. It did not look at life-threatening drug related adverse events; it looked at the less damaging drug related effects such as muscle pain. Safety, where art thou. Not here.

To be frank I have never been that bothered by the relatively minor drug related effects of statins. If you stop taking them, they go away … hopefully (though not always). Although they may be the harbinger of greater health problems. Muscle pain > myopathy > rhabdomyolysis > dead.

I have been far more concerned with SAEs and/or irreversible damage caused by statins. Something not even considered by the CTT in Oxford. But I have seen many people who I am absolutely certain were severely damaged by statins. Leading to lifelong disability and damage. Crippled, for life.

I have also witnessed patients who have, literally, risen from their beds, as if by a miracle, when they stopped taking the damned things. Hundreds, thousands, who have written to me telling me their very upsetting stories or pain and damage, and utter dismissal by their doctors. You think I am just making this up?

I will remind you of the Barney Calman e-mail to Professor Sir Rory Collins and his co-collaborators at the CTT as he put together his article in the Mail on Sunday, attacking me for my dangerous criticism of statins.

‘Dear all, thank you again for all your input into this article so far. I wanted to readdress the issue of finding a case study. One of the key factors in your collective argument is that criticism of statins discourages use amongst high-risk patients, and this is a public health threat. Since putting calls out we have been inundated by stories of people who have stopped taking statins and felt far healthier.

We’ve had two quite dramatic stories of patients who have been taken off statins by their doctors because of developing serious liver problems, and then died. The families themselves both naturally question whether statins caused the problems. What we haven’t had is a single story which backs your thesis, and obviously I’m concerned.’ [but not concerned enough to pay any attention to these tales, clearly]

Ah yes, but these are mere anecdotes, so easily dismissed when we have the utterly concrete and believable figures from the almighty randomised controlled (industry funded) clinical trials to disprove the evidence of our own eyes.

Digging the figures

I know that for a lot of people this analysis will have been really heavy going. Figures, statistics, unfamiliar acronyms. I would apologize, but in truth, I cannot really do so. To quote the great Michel de Montaigne:

‘Difficulty is often a tool used by scholars to hide the lack of substance in their studies.’

The CTT paper is difficult to read and understand. All the statin studies are equally difficult. They are filled with complex graphs and statistics, they use arcane terminology, and terms that have to be painstakingly unwrapped. Such as, what does a Serious Adverse Event actually mean? One simple acronym, a page and a half of explanation required to explain it.

In fact, all words they use are chosen with great care. Even the title of the Lancet paper is misleading and yet, still, just about, technically correct. You wouldn’t be able to pin them down in a court of law. The words would slip and slither away from your grasp.

In short, I have to go into the detail, for this is where the game is played. In the murky world of assumptions and acronyms. Assumptions that can drive complex statistical games in any direction you want. Clever, clever, games. I hope that by shedding light on a few of the games, you can see more clearly what is going on here.

I do wish all researchers were on the same page, the same side, searching for the truth, rather than making it almost impossible to see. I wish this type of forensic analysis was not required. But it is.

Next, and finally in this series, I will outline the assumptions the CTT in Oxford made, which allowed them to claim what they did. And finish here with a quote from the BMJ:

‘Analysis of AE (adverse event) data is frequently inappropriate and RCT reports published over a recent period in high impact general medical journals often provide insufficient and inconsistent information to allow a comprehensive summary of the safety profile to be established.’ ¹²

Addendum. Next, is a blog on the JUPITER trial.

1: Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels | New England Journal of Medicine

2: https://jamanetwork.com/journals/jama/fullarticle/201883

3: Effect of Rosuvastatin on Progression of Carotid Intima-Media Thickness in Low-Risk Individuals With Subclinical Atherosclerosis: The METEOR Trial | Cardiology | JAMA | JAMA Network

4: PII: S0140673694905665

5: Primary Prevention of Acute Coronary Events With Lovastatin in Men and Women With Average Cholesterol Levels: Results of AFCAPS/TexCAPS | Cardiology | JAMA | JAMA Network

6: Gurm

7: Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein | New England Journal of Medicine

8: Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia | New England Journal of Medicine

9: Placebo and nocebo effects and mechanisms associated with pharmacological interventions: an umbrella review – PMC

10: Therapeutics_Initiative_48_Statins_role_2003.pdf.pdf

11: https://www.bbc.co.uk/news/articles/c80142p2g00o

12: Analysis and reporting of adverse events in randomised controlled trials: a review | BMJ Open

The latest Lancet paper on adverse effects – part two

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Under-reporting or over-reporting?

I am going to start part two by looking at the evidence for statins causing ‘non-imagined’ adverse effects. Or, to put it another way, real effects. My own view on this is that the adverse effects of statins are significantly under-reported. Mainly because patients often don’t associate the drug with the problem. Such as muscle pain or weakness. This is especially true if it takes weeks or months for problems to develop. In some cases, even years.

Even if patients do report symptoms, doctors do not record many, if any, of the adverse effects. Which is true of all drugs, not just statins. The US does have an adverse drug reaction reporting system. But less than 1% of adverse reactions are captured by it¹:

As the article confirms: ‘Underreporting significantly delays the dissemination of critical information about such reactions.’ You don’t say.

In the UK, we have a yellow card system, specifically designed to make it a complete pain to report any problems. If you do fill in a yellow card, you find yourself bombarded with requests for masses of additional information. Past medical history, drug history, days and dates of starting the medication, exact adverse effect, lab tests etc. etc. This can all take many, many, unpaid, hours to gather. Which means that doctors rarely bother to use the system, and patients have never even heard of it.

The issues of adverse effect reporting has many other complexities. A few years ago, an interesting study caught my eye. It was not large, but telling. I have not seen the same research done, before or since. I may have missed it. It can be tricky to keep up with all the research done. Seventy-five patients were taking blood pressure lowering tablets – anti-hypertensives. They were asked the following questions:

Did their quality of life improve on medication?
Did it stay the same?
Did it get worse?

Two other groups, the patient’s doctor, and the patient’s closest relative/partner were asked the same questions … about the person taking the tablets.

A little background. High blood pressure causes no symptoms. Because of this, hypertension is often referred to as the ‘silent killer’. Anti-hypertensives, on the other hand, are well known for causing a number of unpleasant effects. Therefore, you would probably expect that taking anti-hypertensives would have a negative effect on quality of life. Or, at best, it would remain about the same. Here is how the three groups answered.

Doctors: Quality of life improved: 100% agreed

Patients: Quality of life improved: 50% agreed

Patient’s relatives: Quality of life improved: 0% agreed

Possibly most telling is that seventy-four out of seventy-five of the patient’s relatives reported that the quality of life worsened ². What can we learn from this? Well, I might start by giving the doctors involved a good slap. I wouldn’t learn anything, but it might be a good lesson in humility for them. ‘Stop seeing what you want to see, and start seeing what is.’

The point here is that if there is a significant bias in the reporting of adverse effects, the bias is heavily weighted towards not reporting them. Not by patients, and certainly not by the doctors – remember that 1% figure. Which means that nothing is recorded for posterity. See no evil, hear no evil, speak no evil.

Another issue in play here, specifically, is that the authors of the Lancet paper do not appear to have heard of the placebo effect:

The placebo effect is a phenomenon where a person’s physical or mental health improves after receiving an inert, “dummy” treatment (like a sugar pill or saline injection). Triggered by the belief in, and expectation of, improvement, the brain induces real, measurable physiological changes—such as releasing endorphins or dopamine—that reduce symptoms like pain, fatigue, and anxiety.

One of the main reasons why we have such massive, complex, double-blind placebo-controlled trials is precisely because of the placebo effect. The drug could initially appear brilliant, but it may be achieving nothing; it may be that the ‘placebo effect’ is doing the heavy lifting.

Because of this significant ‘confounding factor’ clinical trials need to be ‘controlled’ by giving everyone a pill, or an injection. A percentage get the active drug, the rest get the dummy placebo. It is a major reason why clinical trials are so huge, complex, and costly.

However, the impact of taking an unknown ‘placebo’ is far less than being handed a real tablet by a doctor. Who will likely inform you, with great enthusiasm, that it is going to do you good³. Especially if they add, as they do with statins. ‘And it will stop you dying from heart disease.’ Or words to that effect. [And if you dare stop taking it, you will die].

Strangely, it appears to have escaped the attention of the CTT in Oxford that there is such a thing as the placebo effect. For them, the only bias that exists with statins is that you read about nasty effects, then suffer from them. The Nocebo effect. Why did they not mention the placebo effect? Which does the exact opposite – far more powerfully. I leave it to you, dear reader, to decide on that matter.

Some evidence of causality

It is very difficult to know what the true rate of adverse effects with statins may be. So much heat, so very little light. I cannot possibly cover all adverse effects in this blog. Instead, I will focus primarily on muscle pain and damage. This is probably the most common problem, and the most easily explained and understood.

I want to make it exceedingly clear that, far from being an imagined problem, we have a well-established biochemical pathway that directly links from statins to muscle damage, pain and weakness. With all steps proven, multiple times, in multiple studies.

In its simplest form, the pathway goes like this. Statins block an enzyme known as HMG-CoA reductase. This inhibits an early step in the long and complex – thirty-six step process – that ends up with the synthesis of cholesterol. This mainly takes place in the liver, which synthesizes around five grams of cholesterol, per day. About twenty eggs worth.

However, if you block HMG-CoA reductase this is not the only pathway you inhibit. You are also blocking the production of many other highly important compounds at the same time. You can perhaps think of cholesterol synthesis as a tree that grows from the ‘root’ of a chemical compound called Acetyl CoA.

As the chemical reaction ‘tree trunk’ grows upwards it starts to branch out, leading to the creation of many other, vital, substances. Such as dolichols, Heme A, prenylated proteins, co-enzyme Q10 etc, etc. Don’t worry there won’t be a test at the end.

Forgetting the others, important though they are, I will focus on Co-enzyme Q10 here. Which is also known as ubiquinone. This co-enzyme is critical in the synthesis of Adenosine Triphosphate (ATP). This molecule is, in turn, the power source that drives everything in our bodies. When ATP is broken down to ADP, energy is created, and used. This is how we work. From ‘professor’ Wikipedia:

‘ATP (adenosine triphosphate) is the primary energy carrier and “molecular currency” of the cell, storing and transferring energy to power essential processes like muscle contraction, nerve impulses, chemical synthesis, and active transport.’

You could think of ATP as the fuel in our car, or the battery in an EV. ATP doesn’t’ last long, and is being constantly replenished within the mitochondria – the little energy factories that live inside our cells. But without ATP, everything stops, and you die.

So, you could say it is kind of important. And, yes, statins have a significant and detrimental effect on the production of coenzyme Q10 (CoQ10), and then on ATP production. If you want some ‘real’ boring science about what this does. Read this paper:

‘Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes ⁴.’

‘These data demonstrate that simvastatin induces myotube atrophy and cell loss associated with impaired ADP-stimulated maximal mitochondrial respiratory capacity, mitochondrial oxidative stress, and apoptosis (death) in primary human skeletal myotubes, suggesting that mitochondrial dysfunction may underlie human statin-induced myopathy (muscle damage and pain).’

Paper highlights – taken from the paper itself:

Statins can induce muscle weakness/myopathy.
In culture, simvastatin induced dose dependent atrophy of human myotubes.
Statin exposure decreased mitochondrial respiratory function and increased ROS (reactive oxygen species…ROS = ’bad’) production.
Activation of apoptosis (muscle cell death) also evident.
Findings suggest mitochondrial dysfunction underlies statin-induced myopathy.

It all sounds pretty damned unpleasant, does it not. The primary problem is that, without sufficient CoQ10 mitochondria cannot make enough ATP. This, in turn, ‘impairs ADP-stimulated respiration’ which leads to mitochondrial dysfunction then activation of apoptosis. Apoptosis means cell death.

In short. If the mitochondria can’t make enough ATP, the cell does not have enough ATP/energy to survive, and may commit suicide. Which is what ‘activation of apoptosis’ means.

You think the pharmaceutical companies didn’t notice this… this (imaginary) muscle cell destruction and death? Of course they did. They may be many things, most of which are far too rude to print here, but they are very good at science, and they certainly do notice stuff.

They knew very early on that statins block CoQ10 synthesis, and then ATP synthesis. Not entirely, but up to a fifty per-cent reduction. At one point it looked as if this could be such a significant problem that Merck took out two patents outlining how to neutralise it. The first was US4933165A:

Key Aspects of US4933165A

Assignee: Merck & Co., Inc.
Inventor: Michael S. Brown (Note: The patent is often associated with the work of Dr. Karl Folkers regarding CoQ10, though the listed assignee in the 1990 publication is Merck).
Purpose: The invention describes a method for reducing the side effects of HMG-CoA reductase inhibitors (statins) by combining them with Coenzyme Q10.
Mechanism: Statins work by blocking the HMG-CoA reductase pathway. This same pathway is used by the body to produce CoQ10. The patent addresses the depletion of CoQ10 caused by statins, which can lead to muscle pain (myopathy) and potential heart damage.
Scope: The patent covers the combination of CoQ10 with various statins, including lovastatin, simvastatin, and pravastatin.

They didn’t act on this patent. Perhaps it wasn’t seen as a great sales idea to stuff the antidote into the same packet as the statin. ‘These are perfectly safe, you say. So, what it this other tablet here for – precisely?’

One man who did take out a patent with regard to the muscle damage caused by statins was none other then Professor Sir Rory Collins himself, in 2009.

A leading Oxford medical researcher who says statins are safe is at loggerheads with a company that makes “misleading” claims about the drugs’ side effects to sell a diagnostic test he invented.

More than 6m people take statins — drugs which reduce cholesterol and save an estimated 7,000 lives a year — but there is a fierce debate about the benefits and side effects.

Sir Rory Collins, a professor of medicine and epidemiology at Oxford University, led a review into statins, published in The Lancet earlier this month, which found that not more than one in 50 people will suffer side effects.

Collins, who believes millions more Britons could benefit by taking statins, is also co-inventor of a test that indicates susceptibility to muscle pain from them.

In 2009, he and three co- inventors filed the patent for a genetic marker that identifies patients at increased risk of myopathy (muscular pain). The patent says the incidence of myopathy is around one in 10,000 patients per year on a standard statin dose*.

The test, branded as Statin–Smart, is sold online for $99 (£76) on a website that claims 29% of statin users will suffer muscle pain, weakness or cramps. The marketing material also claims that 58% of patients on statins stop taking them within a year, mostly because of muscle pain.

Oxford University said Collins had raised his concerns “several times” about “misleading” marketing claims made by Boston Heart Diagnostics, the American company granted the exclusive licence for Collins’s patent by the university⁵. [Lois Rogers was health editor for the Sunday Times].

*Muscle pain and myopathy are not quite the same thing. Myopathy is a serious adverse effect – assocatied with a significant rise in an enzyme called creatine kinase (CK). When muscles are damaged and/or, die they – usually – release enzymes, with CK being the main one. Myopathy can be the precursor to rhabdomyolysis (very widespread muscle death) which has an extremely high fatality rate. And yes, all statins can cause rhabdomyolysis – albeit rarely.

I think of it this way, as a spectrum.

Muscle pain = Moderate muscle damage/death ± moderate rise in CK

Myopathy = Severe muscle damage (often, not always, a rise in CK)

Rhabdomyolysis = Catastrophic muscle damage, CK through the roof

Myopathy may be considered relatively rare 1:10,000 per year (according to Collins). But the diagnosis is not straightforward, and it is heavily reliant on the finding of raised CK levels. But…here is a small study looking at patients with severe myopathy, and no rise in CK. ‘Statin-associated myopathy with normal creatine kinase levels.’

‘Four patients with muscle symptoms that developed during statin therapy and reversed during placebo use… Muscle biopsies showed evidence of mitochondrial dysfunction…These findings reversed in the three patients who had repeated biopsy when they were not receiving statins. Creatine kinase levels were normal in all four patients despite the presence of significant myopathy⁶.’

So, we have a condition that is considered rare … but which may not be as rare as you think it is. Because you are relying on a blood test that may, or may not, actually diagnose it. You may get a lot of false negative tests. [A test which says you do not have a condition, when you do]. And when does muscle pain transform into myopathy? It is arbitrary.

Enough of this, I think.

What do we now know? We know that statins block CoQ10 production, and this reduces the amount of ATP being manufactured by the mitochondria – by up to fifty per cent. This is a well-researched, and inarguable, scientific fact. It will be a particularly significant problem in cells that have a high energy requirement e.g. skeletal muscle, or heart muscle, or neurones.

In truth, the adverse effect issue mainly boils down to this. Do you have the reserves to overcome the mitochondrial damage that statin cause … or not. If you do have the reserves, you may not notice much, if anything. If you don’t, you could end up stuck in a chair, hardly, able to rise. Which I have seen happen to several patients. And my father-in-law. An early statin user.

One lady I was looking after in an elderly care unit was judged to be so physically and mentally incapacitated that she was going to be admitted to a nursing home with frailty and dementia. I stopped the statins, and she walked out of the unit two weeks later, bright as a button. The nurses were stunned. I got a letter from her GP a week later, condemning me for stopping her life saving medication. That was just one of many patients where I had very similar results. She was just the most dramatic.

Do I have other terrible tales about statins? Of course. I recall another lady with such severe abdominal pain that she ended up having a laparoscopy (sticking a camera into the abdominal cavity to have a look around). Nothing was found, a mystery. She stopped the statin, on my recommendation, and the pain went away. Completely and forever.

Yes, I am biased, yes these are ‘anecdotes’, easily dismissed – and, boy, they will be. But I have seen so very many. Far more cases of rhabdomyolysis, for example, than I should ever have seen in my career …statistically. And so many more have written to me, telling me how they have suffered, and then been dismissed by their own doctors.

Here is one such. I could dredge up a thousand more, given a couple of days.

‘Thank you, Dr. Kendrick. I am one of the many unfortunates who suffered permanent muscle damage from a needless prescription of simvastatin from 2008 to 2012. No monitoring, but my CK reading of 20 x normal was discovered by chance and the alarm was raised. When referred to NHS specialists their attitude was very strange, complete denial and hostility. Now permanently disabled on the right side of my body.’ Georgina H (Reproduced with consent).

Before I finish this blog. I would like to return to my court case, and all the interesting documents that emerged, blinking into the light. Barney Calman was the Health Editor of the Mail on Sunday which ran the defamatory article against me. He put out a call for case histories from people who had stopped taking statins, then suffered a major event e.g. heart attack, or stroke, or suchlike. What he got was the following:

From: Barney Calman Sent: Tue, 26 Feb 2019 08:44:40 +0000From: “Barney Calman” To: “Fiona Fox” , “Rory Collins” , “Colin Baigent” , “samanin@bhf.org.uk” , “Sever, Peter S” , “Liam Smeeth” CC: “Greg Jones” Thread To: Fiona Fox Rory Collins Cc: Greg Jones Sensitivity: Normal Colin Baigent samanin@bhf.org.uk Sever, Peter S Liam Smeeth

Yes, he was ‘inundated’ with stories of people who felt far better having stopped their statins. The only two case histories he had managed to get hold of, at this point, were two people who took statins which then (almost certainly) caused liver failure, then death. [Statins are known to cause liver failure leading to, in extreme cases, death].

One would hope, in an ideal world, that if an investigative journalist was running a story on the unrivalled benefits of taking statins, and the harm that would befall those who stopped taking them … then. Then, when he found himself literally, his word, ‘inundated’ with stories of people who felt far better after stopping statins, and two cases of people who were almost certainly killed by statins then … Then you may pause to wonder if you are grabbing the right end of the stick.

But no, he did not let this put him off in the slightest. He had his eyes on the prize.

Next, a few surprising facts about statins and the unpleasant effects they can cause. Before finally, my direct criticism of the Lancet paper. And the nonsense that it is.

1: https://www.ncbi.nlm.nih.gov/books/NBK599521/

Click to access jroyalcgprac00086-0041.pdf

2: jroyalcgprac00086-0041.pdf

3: Unraveling the mystery of placebo effect in research and practice: An update – PMC

4: https://www.sciencedirect.com/science/article/abs/pii/S0891584911011130

5:Statins expert in row over level of risk to patients – Lois Rogers

6: Statin-associated myopathy with normal creatine kinase levels – PubMed

The latest Lancet paper on statin adverse effects – Part One

49 Replies

‘A lie is halfway round the world, before the truth has a chance to get its boots on.’ A quote used most famously by Winston Churchill.

A few of you may have noticed a recent paper in the Lancet written by the Oxford Cholesterol Treatment Triallists Collaboration (CTT). Much to no-one’s great surprise it fully supported their long-held contention that statins have, virtually, no adverse effects [Often inaccurately called side-effects, as side-effects can be harmful or beneficial].

The central message of the paper is as follows. The reason why people report that they are suffering aches and pains, or other symptoms, is because they have heard about them, or read about them. In other words, they are imagining them. The so-called ‘nocebo’ effect.

The authors suggest that the main culprit for the disinformation causing this comes from the patient information leaflets themselves. Which can be found inside the tablet packaging, and are legally required to be there.

The authors have gone so far as to state that, based on the findings of their study: ‘ .there is a pressing need for regulatory authorities to require revision of statin labels and for other official sources of health information to be updated.’ My imagined scene.

Patient: ‘I’m sure I am getting muscle pains since starting on statins.’

Professor X: ‘No, you are not. You are imagining it. For the recent paper at the CTT has proved that all but four adverse effects are entirely imaginary. Please read this incomprehensible paper, full of clever statistics that you are, sadly, too imbecilic to comprehend and, by the way, ignore the leaflet.’

Patient: ‘Oh, OK, sorry. I will keep taking them.’

Professor X: ‘Yes, quite. I hate to say it, but you are stupid and easily led. Like most people – other than me, of course.

You can perhaps understand my joy at this article, and the worldwide headlines it created. I knew it would be jargon filled, full of complex statistics, and written in such a way as to make it virtually impossible to understand. Here is how the BBC reported its findings:

‘Cholesterol-lowering drugs called statins, used by millions, are far safer than previously thought, a major review has found.

Leaflets in packs should be changed to reflect this and avoid scaring people off using the life-saving pills, say the authors.

Statins do not cause the majority of the possible side effects listed, including memory loss, depression, sleep disturbance, weight gain and impotence, says the team funded by the British Heart Foundation. Meanwhile, they can slash a person’s risk of heart attacks and strokes.’

‘Slash a person’s risk of heart attacks and strokes’ – well that’s a scientific statement if ever I saw one.

All the other mainstream media outlets reported this study in very much the same way. Which I would define as, unquestioning acceptance. A long line of nodding dogs. There has been no real investigation into their claims, and certainly no criticism of any sort. What ended up in the media was, effectively, a summary of the press release.

‘Statins do not cause the majority of the conditions that have been listed in their package leaflets, including memory loss, depression, sleep disturbance, and erectile and sexual dysfunction, according to the most comprehensive review of possible side effects. The study was led by researchers at Oxford Population Health and published in The Lancet.’ Beep, message ends.¹

This is all most people will ever hear, or remember. However, I believe that a far more in-depth critique of this paper is needed.

What I hope to explain, in three blog posts, is that this may be one of the most highly manipulated and misleading studies I have ever come across, and I have seen some belters in my time. The assumptions they made are … contentious, to say the least. And they have not a scrap of evidence to support their conclusions.

So, as briefly as possible, I hope to highlight:

The massive conflicts of interest at the CTT. Which is why they are the last organisation on earth who should have done this research. They set out trying to prove a point – and, surprise, surprise, they did.
The games played to allow the researchers to come to their conclusions. Potentially, very dangerous games indeed.
Why the data they used itself is enormously, and I would argue, fatally biased.

The first two blogs provide background and context. The final blog applies a microscope to the data, insofar as this is possible [As they won’t let anyone else see the data they used].

The massive conflicts of interest at the Cholesterol Treatment Triallists (CTT) Collaboration?

This paper emerged from The Cholesterol Treatment Triallist Collaboration (CTT). A group based at Oxford University in the UK. It was not written by Oxford Population Health, as stated in their press release. It is true that the CTT group sits within Oxford Population Health (OPH) … sort of. This is the explanation that will be used if they are questioned about it. ‘Don’t be so picky.’

However, I believe there is an important reason why the press release chose to highlight Oxford Population Health, not the CTT, and I think you will understand that reason after reading this blog. In truth, pretty much everything about his paper is misleading, even stating who did it.

This may seem a very minor issue to highlight, but details matter, and they can be very damning. I would allege that this press release represents a clear tactic to distract attention away from the organisation who actually did the study. This matters, because most people will not look beyond the press release and will therefore not link the study to the CTT. This has certain benefits, for reasons that should become clear.

You think I am being oversensitive and unreasonable? Then why did the press release fail to mentionthis study was done by the CTT? Did they not want to take the credit for it? Or were they trying to hide something.

Just in case you are wondering. Here is the title of the paper, with its affiliation, copied directly.

‘Assessment of adverse effects attributed to statin therapy in product labels: a meta-analysis of double-blind randomised controlled trials.’

Cholesterol Treatment Trialists’ (CTT) Collaboration²

The important point I want to make is that the CTT has long and, some would say, inglorious history in this area. Over the years they have attacked anyone who has dared suggest that statins carry a significant burden of potentially damage effects. Including in the British Medical Journal (BMJ). As far back as 2013 there was a major bust-up over two papers published in the BMJ which suggested that statins had more adverse effects than were reported in clinical trials.³

Professor Collins demanded that the BMJ remove, and then apologize for, the articles published. Such was the kerfuffle he created that an independent review panel was formed to decide if the articles should be taken down. The panel found Professor Sir Rory Collins’ criticisms were not valid.

An independent review panel has rejected a demand by a prominent researcher that The BMJ retract two controversial articles. The report largely exonerates the journal’s editors from any wrongdoing.

As previously reported Rory Collins, a prominent researcher and head of the Cholesterol Treatment Trialists’ (CTT) Collaboration, had demanded that The BMJ retract two articles that were highly critical of statins.²

“The panel were unanimous in their decision that the two papers do not meet any of the criteria for retraction. The error did not compromise the principal arguments being made in either of the papers. These arguments involve interpretations of available evidence and were deemed to be within the range of reasonable opinion among those who are debating the appropriate use of statins.”

In fact, the panel was critical of Collins for refusing to submit a published response to the articles:

“The panel noted with concern that despite the Editor’s repeated requests that Rory Collins should put his criticisms in writing as a rapid response, a letter to the editor or as a stand-alone article, all his submissions were clearly marked ‘Not for Publication’. The panel considered this unlikely to promote open scientific dialogue in the tradition of the BMJ.””

The panel also had this to say.

“The panel did have one final comment. It became very clear to the panel that the fact that the trial data upon which this controversy is based are held by the investigators and not available for independent assessment by others may contribute to some of the uncertainty about risks and benefits. Different investigators may come to different conclusions with the same data … The panel strongly believes that the current debates on the appropriate use of statins would be elevated and usefully informed by making available the individual patient-level data that underpin the relevant studies”

Yes, you read that right. The CTT hold all the data on the major statin trials done by various pharmaceutical companies. And they will not allow anyone else to see it. Science, where art though.

But how could Collins have known, in 2013, that the articles were misleading? Here is a quote from the man himself in 2015, made to the Sunday Express newspaper:

Head researcher Prof Collins admitted he had not seen the full data on side effects. In an email to this paper he stated that his team had assessed the effects of statins on heart disease and cancer but not other side effects such as muscle pain.

Klim McPherson, professor of public health at Oxford University, said: “We know these drugs have side effects but we do not know if these have been assessed properly by the drug companies who carried out the trials.’⁴

So, by his own admission, in 2013, Collins did not have any data on the adverse effects of statins. Yet he attacked the BMJ on this very same issue. In fact, the CTT’s position on statins has been consistent for many decades now. Basically, they are fantastically beneficial drugs, and have almost no adverse effects. Various members of the CTT have stated this repeatedly. Extraordinarily, they even managed to make these claims, before they had the data to support it.

Sometime between 2015, and now, the CTT must have got hold of the missing data. Although the paper does not explain how, or from who, or exactly what these data were. It is … obscure. I think I know, but I am not sure.

At this point, a question to you, gentle reader. Do you believe that anyone working for the CTT – where Collins and Baigent are the leading members – could be considered unbiased. When it comes to the issue of statin adverse effects?

I would argue that even if there were no financial considerations at play, we are staring straight at massive intellectual bias. Collins, Baigent and the rest of those working for the CTT, have staked much of their status, and their reputations, on this matter. A touch of cognitive bias might be in play?

‘Cognitive biases in medical research are systematic errors in thinking that skew study design, data interpretation, and clinical decision-making, often leading to faulty evidence. Key forms include confirmation bias (seeking supporting evidence), anchoring (relying too heavily on early information), and publication bias (ignoring negative results).’

I believe that all three forms of Cognitive Bias are on full display here.

And, of course, there are financial issues to be considered here. Very significant ones indeed. The Cholesterol Treatment Triallists Collaboration was set up within Oxford University. It receives no direct funding from the pharmaceutical industry, something they are very keen to emphasise – repeatedly.

However, the CTT was established by Collins, and Baigent et al. alongside the already existing Clinical Trials Research Unit (CTSU) in Oxford. It is made up of exactly the same people.

Indeed, if you try to contact the CTT, you are actually referred to the CTSU site. Here is the e-mail address for the CTT. Email (Specific Research/Database): ctt@ctsu.ox.ac.uk. Yes, the CTT ‘at’ the CTSU.

I asked Google AI about contacting CTT, and this is what it brought up:

Any claim that these organisations can act independently of each other, in some strange way, is one hundred per cent pure … Don’t get it on your shoes.

Why is this an issue? Because the CTSU receives very large sums of money from the pharmaceutical industry to run clinical trials. Many of these involve cholesterol lowering agents, including simvastatin – as used in their initial HPS study. How much money are we talking about here?

The next section has been taken from a piece by Zoe Harcombe on the same Lancet article. She agreed to let me use it – because she has written about this many times, and I didn’t want to look it all up again, or tread on her toes.

Her section starts with the declaration that the CTSU had, by 2014, received ‘grants’ of £268 million for commercially funded research. How much have they earned since …who knows? No more declarations have been forthcoming……

[From Zoe Harcombe] The May 2014 declaration of funding (c. £268 million at that time, as above) was titled “Grants to Oxford University for any Clinical Trial Service Unit (CTSU) trials or other commercially-funded research over the past 20 years…”

‘My best guess as to how the CTT can try to claim no grant funding, given the self-declared grant funding, is that semantics have been relied upon between Oxford University, the CTSU and the CTT Collaboration. I’m open to any other explanations that may be on offer. I searched the latest CTT paper (the Lancet paper) for “Clinical Trial Service Unit” or “CTSU” and it appeared once – at the corresponding address “Correspondence to: Clinical Trial Service Unit…”

Whatever the semantics, the latest CTT paper focused on five statins. The manufacturers of the five statins chosen are Pfizer (atorvastatin), Novartis (fluvastatin), Bristol Myers Squibb (pravastatin), AstraZeneca (rosuvastatin), and Merck (simvastatin). The author declarations of interest took up over a page in the paper. Pfizer appeared 5 times, Novartis appeared 11 times, Bristol Myers Squibb appeared 3 times, AstraZeneca appeared 11 times, and Merck appeared 7 times.

Oxford University has strategic research alliances with several pharmaceutical companies including Pfizer, Bristol Myers Squibb and AstraZeneca. It has research partnerships with Novartis and Merck (Ref 21).

– “Pfizer has a longstanding research relationship with the University of Oxford” (Ref 22).

– “The Oxford-Bristol Myers Squibb alliance was established in 2015 … Oxford’s alliance with Bristol Myers Squibb continues to grow year on year, the total of Oxford-Bristol Myers Squibb Fellows is now 34 and many other collaborative projects are currently running” (Ref 23).

– “AstraZeneca (AZ) and Oxford have a long history of collaboration” (Ref 24).

While Novo Nordisk was not one of the companies helped by this paper, I noticed that “The alliance between Novo Nordisk and Oxford … has seen Novo Nordisk establish a presence onsite at the University of Oxford, with the Novo Nordisk Oxford Research Centre (NNRCO) employing up to 100 researchers between 2017 and 2021” (Ref 25).

Wow – 100 researchers – and how many people have been employed as a result of the few hundred million given to Oxford University for the CTSU or other commercially funded research?

There can be little doubt that relationships between Oxford University and pharmaceutical companies are of great mutual benefit. There can also be little doubt that it is inconceivable that any research would emanate from Oxford University that is critical of any drug made by any alliance companies. On the contrary, the higher the number of positive papers that can be published, the stronger the mutual alliance. [End Zoe Harcombe]

Yes, hundreds of millions in commercial funding. And that was twelve years ago. This figure will have grown considerably. In addition, hundreds of researchers have also been paid for by various pharmaceutical companies. Total cost? One hundred researchers at an employment cost of, at least, fifty thousand is five million, per year – minimum.

To claim, as they do, that the CTSU/CTT has no financial conflicts of interest is …what is the correct word here? Let me think.

At this point I will declare my own conflict of interest here – which has clear relevance to the discussion. Six years ago, I sued The Mail on Sunday for an article they published, way back in March 3^rd 2019. I was accused, along with Zoe Harcombe and Aseem Malhotra, of being responsible for thousands of unnecessary deaths.

This was because we had ‘claimed’ that statins have more adverse effects than are widely reported. Also, that they were significantly less beneficial. With positive effects boosted by various forms of statistical manipulation.

The Mail on Sunday article stated that our talks, and blogs and publications had led to hundreds of thousands of people stopping their statins, leading to many thousands of excess heart attacks and strokes as a result. As one third of heart attacks are fatal, the implication, though not directly stated, is that many, excess deaths occurred. Hundreds, thousands?

Having, effectively, been accused of mass murder, I sued, along with Zoe Harcombe. And, yes, we won. [Which is why you cannot see the article anymore]. The libel case took over five years from start to finish. There was no evidence to support the central accusation of increased heart attacks and strokes. This accusation was based on a modelling study which had no outcome data on morbidity, or mortality. None.

Behind the scenes, Rory Collins and Colin Baigent were very active. They advised Barney Calman, the health editor on what to say. They even edited the paper. Here is one statement that Collins provided to Calman, which was in the article itself:

‘Professor Sir Rory Collins, the British scientist behind pivotal research into statins, says the potential consequences far outweigh that of the infamous MMR vaccine scandal, in which disgraced paediatrician Andrew Wakefield fabricated evidence to support his idea that the jab triggered autism in infants, leading to a decline in vaccination uptake and the resurgence of measles.’

Yes, Collins and Baigent, and various other Professors from the British Heart Foundation, were advising Calman on the best lines of attack. Collins and Baigent even congratulated him warmly after the article was published.

Below are just three of the hundreds of e-mails sent between the various players [All e-mails are on file. I am considering releasing the whole lot – as they are no longer confidential]. The first one here is from Barney Calman, health editor of the Mail on Sunday, to Rory Collins and Colin Baigent, among others, thanking them for ‘all their input’ into the article. [It includes Professor Nilesh Samani, medical director of the British Heart Foundation at the time].

Also named in the e-mail trail is Professor Liam Smeeth who was the lead author of the modelling study mentioned above. He has written widely on the fact that statins have no adverse effects. There is also Professor Peter Sever on the e-mail trail. And he is …stop right here Kendrick, libel goes both ways. A bit more info on Liam Smeeth…

‘Professor Liam Smeeth and Professor Sir Rory Collins are both prominent British academic experts in epidemiology and cardiovascular health who have closely intersected through high-profile, collaborative research on statins.’ From Google AI.

E-mail: From: Barney Calman To: Fiona Fox; Colin Baigent; Rory Collins; Professor Nilesh Samani; Sever, Peter S; Liam Smeeth Subject: [EXTERNAL] MOS/Statins Dear all, please find below our piece.

Thank you again for everything you’ve done to help so far. If you each separately send me back any amendments you have in tracked changes or some other trackable way, that’d be great. All comments welcome. BC by BARNEY CALMAN Health Editor

That was one e-mail proving that members of the CTT were commenting on, and even editing, the article.

After it was published, Rory Collins wrote this e-mail to Barney Calman:

E-mail From: Rory Collins Sent: Sun, 3 Mar 2019 18:07:05 To: Barney Calman Cc: Colin Baigent Subject: RE: all changes made Sensitivity: Normal External Sender:

Dear Barney: What a pleasure to see such a hard-hitting evidence-based article on fake news related to statins … and the page 2 article with Matt Hancock’s very direct comments was an unexpected bonus. Best wishes. Rory

Fake news …indeed. Twelve minutes later, Colin Baigent wrote this:

E-mail From Colin Baigent: Subject: Re: all changes made Sensitivity: Normal External Sender

Dear Barney: I’d like to echo Rory’s praise for your article. Thanks very much for taking the trouble to understand the issues, and also for your willingness to address last minute concerns, as I think the final product was admirable. Best, Colin

‘An admirable article’ … Although, as it turns out, it was also a libellous article. And you guys helped him to write it. Good job.

I knew where, and from whom, Calman was getting his information right from the start. Before the article had been published. To me, it was glaringly obvious that it had the CTT’s fingerprints all over it. Shortly before the article was published, Calman wrote to me, asking for my comments on the article (which he did not include in the e-mail), giving me twenty-four hours to respond to the various points he was making.

I then sent this e-mail on 28^th February 2019 to others who share my views on statins:

On Thu, Feb 28, 2019 at 12:05 PM, malcolmken@doctors.org.uk [thincs] wrote:

Dear all,

The Mail on Sunday have contacted me about an article they plan to run, attacking me, and us. It is the usual Rory Collins attack.

I have been given until tomorrow to reply. Does anyone have any good, concise ammunition?

Regards

Malcolm

Yes, these guys work tirelessly behind the scenes to destroy the reputation of anyone who dares to question statins. This time their activities, normally unseen, were exposed in documents that were required to be released to the court before the libel case was heard.

I think that is enough information about the conflicts of interest at play here. You may still feel that the CTT is fully independent, and their objectivity remains beyond question. If so, then I do not suppose that anything I write, nor any other evidence, could convince you otherwise.

Summary

The CTT, members of whom wrote the Lancet paper, have been aggressively attacking anyone who suggests that statins carry a significant burden of adverse effects for many years. Even when, by their own admission, they did not actually have the data on adverse effects.
The CTT, who also have all the data from the statin trials, will not share it with any other researchers. Claiming commercial sensitivity/confidentiality.
The CTT is intimately related to the CTSU, is part of the CTSU, and the CTSU has gained hundreds of millions of pounds in funds for running clinical trials on behalf of the pharmaceutical industry.
My own conflict of interest is that individuals within the CTT have attacked me directly, and indirectly, many times over the years. Their behind-the-scenes activities were laid bare in court disclosure documents.

I think it is important for everyone to understand this background before moving on. And I feel the need to repeat that this was not a study led by Oxford Population Health. It was a study by the Cholesterol Treatment Triallists collaboration. A group with a very long history in this area, which they may not have wished to publicise. I believe the CTT are far too conflicted to have carried out unbiased research on statins.

1: https://www.ox.ac.uk/news/2026-02-06-statins-do-not-cause-majority-side-effects-listed-package-leaflets

2: Assessment of adverse effects attributed to statin therapy in product labels: a meta-analysis of double-blind randomised controlled trials – The Lancet

3: https://www.bbc.co.uk/news/health-28602155

4: Rory Collins wants to see safety checks made for statins | UK | News | Express.co.uk

Disruptive science – part one

76 Replies

I read an article in Nature magazine a couple of years ago which has nagged at me ever since. It highlighted the sobering fact there has been a collapse in disruptive science.

‘Disruptive’ science has declined — and no one knows why

04 January 2023

The proportion of publications that send a field in a new direction has plummeted over the past half-century.

I recently watched the film Oppenheimer where scientists argued about new ideas. Debating, pushing forward their thinking in exciting new ways. Niels Bohr, Heisenberg, Einstein, Van Neumann, Oppenheimer himself. They seemed like true intellectual giants whose names still echo through history.

In the same era Isaac Asimov was developing new ideas in his novels – the three laws of robotics. Foundation and Empire. Then there was Philip K Dick, Harlan Ellison, Ursula K Le Guin. Where are these giants now? Where is the new thinking? Why has it all got so … dull?

As a child I watched the Apollo moon landings, but when was the last time I woke up to the news that something earth shattering had just taken place in a scientific field? Some form of major disruption. Everything we thought we knew just got turned upside down. New directions …

Although it could seem a little on the trivial side, for me it was with graphene. Two scientists in Manchester were, essentially, larking about in the lab, trying to find out how thin a layer of graphite they could create by wrapping Sellotape round pencil lead. Turns out, you could get a monolayer of graphite. Allowing me to misquote Asimov who reckoned that the most exciting phrase in science is. ‘Well, I never expected that.’

I fully believe that graphene will change the world in many different ways, mainly for the better. A completely unexpected breakthrough in material science. I love this type of thing.

Medical science

Unfortunately, in my world of cardiovascular disease, you could go back fifty years and find almost exactly the same ideas remain in use, about virtually everything. It is hard to think of anything remotely disruptive, or even remotely novel. Cholesterol causes heart disease, check. Diabetics should eat a high carbohydrate diet, check…

Looking specifically at raised blood pressure. What causes it? In ninety-five per cent of people we have no idea. We didn’t know then, and we don’t know now. We still call it “essential hypertension” as we always did, which means – in plain English – a raised blood pressure of no known cause. The proposed management then, and now is … Lower it. Sorted. And we call this progress? Ahem (I say). No disruption here …check.

In this blog I want to look at one, specific area. The use of salt/sodium restriction to lower blood pressure and reduce the risk of dying early? An idea that has been around since before the second world war. Bonkers then, bonkers now. Unchanged …check.

Once some proper scientists managed to fully establish the neurohormonal system that controls blood pressure. Including the renin, angiotensin, aldosterone system (RAAS), it should have become clear to anyone with a functioning brain that restricting salt intake could very well do far more harm than good. An area that is both complicated and fascinating. But this new knowledge had no effect. Nothing was disrupted.

What about the evidence on salt intake. Below, I give you a graph of overall mortality [all cause death] vs. sodium intake ^1.

I do love a graph, but I know a lot of people don’t. So, I shall attempt to explain it in a little more detail.

The bars that rise, and fall, from left to right, represent the percentage of people consuming different amounts of sodium. With most people it falls around the two-to-four-gram mark, or thereabouts. [Which is approximately the same as four to eight grams of table salt, sodium chloride. Most of our sodium intake comes from ‘salt’ but not all].

The solid line, heading down from left to right, shows the risk of death associated with different levels of sodium intake. The shaded area, around the line, represents the spread of ‘probability’. Or, to put it another way, the likelihood that the risk of death at various levels represents a statistically significant finding – at increasing levels of sodium intake. Got that? There will be an exam at the end of this blog.

In essence, though, this graph is very simple to understand. Namely, the more salt you eat, the longer you will live. And, or course, vice-versa. Which is the exact opposite of everything you are constantly told.

I shall repeat this to emphasize the point:

If you eat more salt, you will live longer.

And this benefit continues right up to twenty grams of salt a day. I don’t think they could find anyone who consumed more than that. Although me, swimming in a choppy sea on a sunny day, might manage.

I know what you may be thinking. I have cherry picked one study to make a point. Well yes, this is just one study. However, it is the biggest and longest ever done. It represents one small part of the National Health and Nutrition Examination Survey (NHANES).

And, although it is only a small part, it represents very nearly ‘one-million-person years’ of observation. Of course, like all nutritional studies it has its weaknesses, but you will find nothing bigger, longer, or better than this. And if you want to find one that contradicts it – feel free – and good luck.

But if you would like some more data. Here is the Scottish Heart Health Study. In this case the researchers looked at twenty-seven factors associated – in one direction or another – with cardiovascular disease [although they only mentioned 26?].

They also incorporated overall mortality (risk of dying of anything), and I reproduce their graph, for men, below. The graph for woman was pretty much identical. This was the first time I noticed that increased sodium intake may be beneficial, not harmful ².

Again, a little more explanation is probably required to make sense of this chart. The numbers at the bottom 0 – 4 represent the Hazard Ratio (HR). A hazard ratio of one means the risk of a ‘factor’ is neither raised nor lowered. It is average. Two means risk is doubled, three means risk is trebled etc.

At the top of this chart lies ‘Previous myocardial infarction’ [Previous heart attack]. No surprise to find that having had a heart attack is a pretty good indication of serious problems and a potentially much-shortened lifespan.

There is another thing I need to explain here. You will notice that ‘Previous myocardial infarction’ is ranked +01 – the 01 = the most important factor. The plus sign in front of 01 means that risk of death is increased. If you go down to number five ‘Urine Potassium’, you will see – 05 (minus 05). The minus sign means risk is reduced…ergo, the hazard ratio is reduced. [I shall cover potassium at some point in the future].

If you keep going down the list, you arrive at sodium, at number eleven. As you can see, greater sodium excretion, which is directly related to greater sodium intake, is protective. Sitting at -11. And these researchers actually did a measurement – urinary sodium. Rather than asking people how much salt they consumed each day, because who has any idea about that?

As a further aside if you keep going down you will see the letters NS and NL.

NS = not statistically significant (probably not important one way or the other)

NL = non-linear (there is no consistent association at different levels – risk goes up and down randomly. Definitely not important)

Amongst the NS and NL ‘risk factors’ we find the following:

High Density Lipoprotein (HDL) a.k.a. ‘good’ cholesterol
Triglycerides (now considered a form of ‘bad’ cholesterol)
Total Cholesterol a.k.a. ‘bad’ cholesterol
Body mass index
Weight
Energy intake
Alcohol
Blood glucose

None of these things were found to have any effect on the risk of death. Sorry, possibly a bit too much disruptive evidence in one graph for easy digestion. In truth, I could talk about this graph all night, and still have time for more. But I do want to loop back to the start.

‘Disruptive’ science has declined — and no one knows why.’

Both of the studies here could have been, should have been, extremely disruptive. However, they have had no discernible impact whatsoever. Nothing has changed. Here, for example, is what the British Heart Foundation continues to say about sodium:

‘Some food labels call salt, sodium instead. Salt and sodium are measured differently. Adults should have less than 2.5 grams of sodium per day.’ [Approx 5 grams of ‘salt’]

Here is what the CDC has to say, as of today:

‘The CDC recommends that adults and teens consume less than 2,300 mg of sodium per day, which is about one teaspoon of salt.’

[There are many different salts. The one we generally call ‘salt’, table salt, is sodium chloride. NaCl. This is the form of salt from which we obtain most of our sodium. Sodium makes up, very close to, one half of the weight of ‘salt’. So, five grams of salt is around two and a half grams of sodium. No-one eats sodium alone, and it is certainly not recommended. There would be a rather large explosion].

Reading the CDC recommendation did cause my irony meter to reach its maximum recorded level, then break. How so? Because the NHANES graph that I showed earlier comes from research that is funded by, and run by, the Centres for Disease Control and Prevention (the CDC).

Yes, their very own study utterly contradicts their very own advice. Despite this, the CDC continue to harangue us to consume less sodium. Which is not merely health neutral, it is actively damaging. Why don’t they advise people to start smoking while they’re at it?

‘Our studies tell us cigarette smoking damages health. We advise cigarette smoking for all adults. At least ten a day should be tickety boo.’

Sound crazy? Yup.

Now, I know that it is bloody difficult to change an idea. And this has always been the case. To quote Leo Tolstoy from many moons ago:

‘The most difficult subjects can be explained to the most slow-witted man if he has not formed any idea of them already. But the simplest thing cannot be made clear to the most intelligent man if he is firmly persuaded that he knows already, without a shadow of doubt, what is laid before him.’

But science, if it is to be about anything, is the acceptance of new ideas. Disruptive evidence should not be attacked and silenced. Or, in this case, simply ignored. It should be welcomed with open arms. It is the very ground upon which science rests. To quote AI Google on Richard Feynman.,

‘Richard Feynman’s quote, “Science is the belief in the ignorance of experts,” means that genuine science is a process of constant questioning and scepticism, not a blind acceptance of authority. It emphasizes that knowledge is provisional and that experts, while valuable, are limited by their current understanding and should be questioned rather than treated as unquestionable authorities.’

Yes, every ‘scientist’ nods sagely when you say things like this. They then rush off to slam the doors in their minds and carry on regardless.

Were things this bad in the past? I don’t believe so. My sense is that disruptive science has been declining the last fifty years or so …. ‘And no-one knows why?’ But is it true that no-one knows why. Or is that almost everyone does know why, but no-one wants to say it out loud. Or even admit it to themselves. For myself, I believe the answer is, as is usually the case, staring us in the face.

It is money. Or to be more accurate, disruptive science is dying a death due to the enormous effect that financial considerations now have on research. Directly, or in the case of salt, indirectly.

I use the word indirectly because, as you have probably recognised, the impact of money cannot be straightforward with salt. The salt industry, if there is such a thing, can hardly be pushing for a reduction in salt consumption, and who else could get rich from this? So, why do we continue to be bombarded with anti-salt messages. And how can this possibly relate to money?

Next, let me take you on a long and winding golden paved road.

1: https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-023-17582-8

2: ‘Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish heart health study:cohort study.’ BMJ 1997;315:722