Category Archives: Cholesterol & Statins

Cholesterol lowering – proven or not?

Repatha

Just before I head off on holiday for a couple of weeks, I thought I should make a quick comment on the Repatha trial (PCSK9- inhibitor). I have written much about this new class of cholesterol lowering drugs, and I have been highly skeptical that they would have any benefits on cardiovascular disease. [Mainly on the basis that I don’t believe raised LDL causes CVD, and these drugs have one action – to lower LDL].

As many of you will be aware, the data from a clinical trial on Repatha has just been released. It was reported by the BBC thus

‘Huge advance’ in fighting world’s biggest killer.’

An innovative new drug can prevent heart attacks and strokes by cutting bad cholesterol to unprecedented levels, say doctors. The results of the large international trial on 27,000 patients means the drug could soon be used by millions.

The British Heart Foundation said the findings were a significant advance in fighting the biggest killer in the world. Around 15 million people die each year from heart attacks or stroke. Bad cholesterol is the villain in the heart world – it leads to blood vessels furring up, becoming easy to block which fatally starves the heart or brain of oxygen.

It is why millions of people take drugs called statins to reduce the amount of bad cholesterol . The new drug – evolocumab – changes the way the liver works to also cut bad cholesterol. “It is much more effective than statins,” said Prof Peter Sever, from Imperial College London.

He organised the bit of the trial taking place in the UK with funding from the drug company Amgen. Prof Sever told the BBC News website: “The end result was cholesterol levels came down and down and down and we’ve seen cholesterol levels lower than we have ever seen before in the practice of medicine.”

And so on, and so forth. So, the Repatha trial was a huge success. Obviously, it certainly lowered LDL to levels never seen before. Or, maybe it was not quite such a huge success. Michel de Logeril, a professor of cardiology in France – who set up and ran the famous, and successful, Lyon Heart Study sent me this comment.

‘This is just junk science.

The calculated follow-up duration required to test the primary hypothesis was 4 years as written by the authors themselves (but only in the second last paragraph before the end of discussion…) but the actual median duration of follow-up has been 2.2 years; it is thus a biased trial (a similar bias as in JUPITER: 1.9 years instead of 4 years): early stop!

In addition, contrary to the misleading claims in the medias, there was no effect on both total [444 deaths with evolocumab vs. 426 with placebo] and cardiovascular [251 vs. 240] mortality; which is not unexpected with a so short a follow-up.

They pretend that they are differences for non-fatal AMI and stroke but there is no difference in AMI and stroke mortality… Very strange… It would be critical to get access to the raw clinical data to verify the clinical history of each case in both groups.

Well, in my opinion and given the present state of consciousness among US doctors, FOURIER is a flop!

Best

Michel’

What he is saying, is that there was a reported reduction in non-fatal heart attacks and stroke. And less need for revascularization procedures e.g. PCI/stents. As you may gather Professor de Logeril would like to see the raw data to verify this. There is very little chance that this will be made available.

Anyway, that was the upside.

The downside is when you look at cardiovascular deaths.

  • The total number of deaths from cardiovascular disease in the Repatha group was 251
  • The total number of deaths from cardiovascular disease in the placebo group was 240
  • So, 11 more people died of cardiovascular disease in the Repatha group

The overall mortality data

  • The total number of, overall, deaths in the Repatha group was 444
  • The total number of, overall, deaths in the placebo group was 426
  • So, there were 18 more deaths in those taking Repatha.

The differences here are not large enough to be statistically significant. However, there were more, not less, deaths in the Repatha group, and more, not less, CV deaths. This study was also terminated early, which is extremely bad news for any clinical trial, and casts enormous doubt on any findings. It was supposed to last four years, but was stopped at 2.2 years. Why? Were the mortality curves heading rapidly in the wrong direction.

Alongside this, should be set the knowledge the Pfizer also had a PCSK9-inhibitor undergoing clinical trials, and they pulled the plug, right in the middle of it all.

Pfizer Ends Development Of Its PCSK9 Inhibitor

‘November 1, 2016 by Larry Husten

Immune issues and diminishing efficacy doomed the new drug.

Pfizer announced on Tuesday that it was discontinuing development of bococizumab, its cholesterol-lowering PCSK9 inhibitor under development.

“The totality of clinical information now available for bococizumab, taken together with the evolving treatment and market landscape for lipid-lowering agents, indicates that bococizumab is not likely to provide value to patients, physicians, or shareholders,” the company explained.

Pfizer said that it would halt two very large ongoing cardiovascular outcome studies with bococizumab, the 17,000 patient SPIRE 1 trial and the 10,000 patient SPIRE 2 trial. The trials were fully enrolled.’

Pulling the plug when 27,000 patients had been fully enrolled. What on earth did they see. Something more than slightly worrying. I guess we will never really know, but that is one hell of a write off.

It is also interesting to note that Amgen – the company selling Repatha, has announced that:

‘Amgen to refund cholesterol drug if patients suffer heart attack

Pledge aims to convince insurers to pay for $14,000-a-year medicine.2

As reported in the Financial Times.

This is a big vote of confidence … not! I think, perhaps, we are looking at a doomed drug. Probably a doomed class of drugs. Has the cholesterol hypothesis been verified, or contradicted? I know I am biased, but I know what I think.

1: http://cardiobrief.org/2016/11/01/pfizers-ends-development-of-its-pcsk9-inhibitor/

2: https://www.ft.com/content/34154cdc-0a86-11e7-ac5a-903b21361b43

High cholesterol low heart disease – The Sami

(Of course, it is a paradox…. Paradox number 112, or thereabouts)

As a nod to a regular contributor to this blog, who lives not far from the area, I thought I should write about the Sami. When I was younger we would probably have called the Sami ‘Eskimos’ – because anyone who lived north of the Arctic circle and dressed in fur was, clearly, an Eskimo. This term is now, I believe, a dread insult. A bit like calling a Scotsman an Englishman, or an Austrian a German. Or, I believe, a Canadian an American. Wars have been fought over less.

The Sami, unlike the Inuit, who reside mainly in North America, live in the North of Scandinavia: Northern Sweden, Norway and Finland and suchlike. In what used to be called Lapland. However, we now call the Lapps, the Sami (please keep up), so do they live in Samiland?

What I know about the Sami is that they obviously enjoy the cold, eating reindeer and smoking. They must do other things too, but I am not entirely sure what. This makes them very similar to the Inuit, who also enjoy: the cold, eating seals, caribou, and smoking. Neither the Sami, nor the Inuit, have the least interest in eating vegetables. I suppose there may be the occasional frozen carrot – or suchlike – from Iceland (that is a UK based joke).

Apart from not eating vegetables, smoking, and eating lots of fat, the Inuit and the Sami have one other thing in common. You can probably guess what it is. Yes, they both – those that live a traditional lifestyle anyway – have a very low rate of death from heart disease.

This came to my attention during an e-mail discussion I was having about whether the human brain required any glucose – at all. Those taking part were the usual suspects, Richard Feinman, Gary Fettke, Nina Teicholz, Jimmy Moore, Jason Fung, Tim Noakes etc. [Yes, good bit of name dropping there].

The consensus was that the human brain could use Ketone bodies for much of its energy requirement. However, there was an absolute need for about forty grams of glucose per day. The final statement on this matter, the one everyone seemed to agree on anyway, was as follows:

1)     The brain requires no dietary glucose. It has a requisite use of 40 grams/day, but these grams can easily be provided from glycerol, and normal ingestion of not particularly high amounts of protein in a high fat, zero carbohydrate diet.

2)     But this is a time dependent situation. Short term fasting will not be a problem for most otherwise healthy people. However, more prolonged starvation will eventually kill you as the brain will pirate 40 grams of glucose/day from protein and lipid, until you have neither fat stores, nor adequate diaphragm or heart muscle left to survive.

Don’t worry, there were about a thousand papers quoted in creating these statements, so the science seems robust. This discussion started because I had an interest in how hunter gatherers, who ate no carbohydrates, kept their brains going. What was the mechanism by which the Massai, Inuit and Sami, power their brains with glucose, if they don’t eat any carbohydrates?

Well, it seems that you can get a certain amount of glucose from fat. Fat is made up of triglycerides, and each triglyceride contains three fatty acids and one glycerol molecule. Two glycerol molecules stuck together (by the liver) makes one glucose molecule.

In short, pure fat does contain some glucose, which can be used to power the brain. However – assuming you are eating no carbs – the brain requires more glucose than can be provided by the glycerol held in triglycerides. Thus, you still need to convert some dietary protein into glucose. If you are not eating any food at all, the body will need to break down muscle to get at the protein required to synthesize glucose.

To cut a very long story short, the end point of the discussion was an agreement that you do not actually need to eat any carbohydrates to remain heathy. The body, and the brain, can get all the glucose it requires from glycerol and dietary protein.

The reason why I was interested in this issue was that ‘the absolute need for carbohydrates’ is a ‘fact’ that is thrown at me from time to time by ‘experts.’ I have always known they were wrong, because there are people e.g. the Massai, who never eat any carbohydrates, and remain far healthier than any expert I have ever cast my eyes upon. However, I wanted to be sure of the facts.

Anyway, time to return to the Sami. For, during this lively discussion, someone posted up two papers on the Sami that I had not seen before. Both papers noted that the Sami, despite having very high cholesterol levels, a high level of smoking, a high fat diet and almost zero carbohydrate intake – and suchlike – had a very low rate of cardiovascular disease.

This was particularly interesting for a couple of reasons. Firstly, most of the Sami live in Finland, and the Finns – at one time – had the highest rate of heart disease in the world. Not only that, but the Sami live in an area of Finland, North Karelia, which had the highest rate of heart disease in Finland. The worst of the worst.

In addition, the Sami had considerably worse ‘traditional’ risk factors for heart disease than the surrounding population. Higher cholesterol and LDL, high fat diet, far more smoking etc.

‘The finding of high cholesterol and high prevalence of smoking the Sami area are compared with the reference rate, and high cholesterol in the Samis and Finns in the north, conforms with similar observations. in studies performed previously. As the classic risk factors indicate a high risk of CHD in the north, other factors, possibly the antioxidants, are important in the low CHD mortality there.’1

[Antioxidants and their impact on CHD were studied in the Heart Protection Study (HPS), and found to have no effect on CHD whatsoever. Whilst this study was done by Rory Collins, and has many issues, the data on the lack of impact of antioxidants on CHD appear robust].

Other researchers have also tried to establish why the Sami have such a low rate of CHD/IHD. As noted in the paper ‘‘Low mortality from ischaemic heart disease in the Sami district of Finland’:

An exceptionally low mortality from IHD was found here in the Sami district of Finland and an exceptionally high mortality in a neighbouring Finnish area, a 2-3-fold contrast or even wider, depending on age and time. No difference in IHD of this magnitude between areas located so close to each other has previously been described in the literature.’2

Of course, they looked for the reasons.

‘Reasons for the rarity of IHD in the Sami district of Finland

Our current knowledge of cardiovascular risk factors cannot explain the low mortality from IHD in the Sami district of Finland. Serum cholesterol is, in fact, relatively high in the far north of Finland, and it is higher in the Sami than the Finns, the same being true of the prevalence of smoking, while the low blood pressure frequently found in the far north and among the Sami would be insufficient to cause any substantial reduction in the risk of IHD. Similar differences in serum cholesterol, blood pressure and smoking have also been found between Norwegian Sami and Norwegians of Finnish ancestry. Serum high density lipoprotein cholesterol (HDL)is usually similar in both ethnic groups, although a Finnish study found even lower HDL-total cholesterol ratios in the Sami, which would indicate an elevated risk of IHD… The high serum cholesterol in the Sami can be attributed to their fatty diet.’

In short, the Sami live in area of Finland that had the highest rate of heart disease in the world. Their risk factors were worse than the surrounding population (LDL 4.45mol/l on average), yet their heart disease rate remained very low. It was postulated that this was due to a high intake of antioxidants, but the impact of antioxidants on heart disease has been subjected to large double blind placebo controlled trial, and antioxidants were found to have no impact on heart disease.

At this point you may cry, enough of finding populations that eat a high fat diet, have high LDL levels and low rates of heart disease. It is like shooting fish in a barrel. Not that the experts pay the slightest attention to such contradictory facts. They merely label such findings a ‘paradox’ and move on. But I thought it was interesting. Another nice shiny nail in the cholesterol hypothesis. ‘You call it a paradox, I call it a contradiction… let’s call the whole things off.’

Next, my series on what truly does cause heart disease continues.

1: ‘High serum alpha-tocopherol, albumin, selenium and cholesterol, and low mortality from coronary heart disease in northern Finland’: P. V. LUOMA, S. NAYHA, K. SIKKILA & J. HASSI. Journal of lnternal Medicine 1995; 237: 49-54

2: Simo Nayha: ‘Low mortality from ischaemic heart disease in the Sami district of Finland.’ Soc. Sci. Med. Vol. 44 No. 1, pp. 123-131, 1997

P.S. I am feeling much better, thanks for those who were concerned over my welfare.

Buy this new book

Fat and Cholesterol Don’t Cause Heart Attacks

There is a group of doctors, scientists and researchers called the International Network of Cholesterol Skeptics (THINCS) www.thincs.org. I am a member, and recently a number of us have contributed chapters to a new book called Fat and Cholesterol Don’t Cause Heart Attacks And Statins are Not the Solution.

This was written in honour of the founder of THINCS, Uffe Ravnskov, a Swedish doctor and researcher who has been arguing against the current die-heart/cholesterol hypothesis for many years. He has written several books, many, many, research papers, and had the dubious honour of having one of his book burned, live, on television. [Finland 1992, the book was The Cholesterol Myths]. He has also been ruthlessly attacked, both professionally and personally. Yet he has never given up.

Ravnskov, like all of us in THINCS, started looking at heart disease, or cardiovascular disease (CVD) and recognised that the widely accepted views were simply wrong. Something recognised by many people over the years, including Professor George Mann (who helped to start up and run the Framingham study).

‘Saturated fat and cholesterol in the diet are not the cause of coronary heart disease. That myth is the greatest scientific deception of this century, perhaps of any century.’

George Mann, like many others was silenced. Kilmer McCully, who discovered the role of homocysteine in CVD, and suggested that it could be more important that cholesterol was also attacked. Funding for his research disappeared, leading to the loss of his laboratory. His hospital director told him to leave and ‘never come back’. His Harvard affiliation and tenure were terminated.

Another contributor to this book, Professor Michel De Logeril, set up and ran the seminal Lyon Heart Health Study. Possibly the seminal work on the ‘Mediterranean Diet.’ Yet he is a trenchant critic of the diet-heart hypothesis, and believes that statins do more harm than good. He is, again, attacked ruthlessly.

Yes, there is a pattern here. Dare to criticise the current dogma that saturated fat in the diet raises cholesterol, which then goes on to cause CVD, and your chances of progression in the research world are, precisely, zero. Your chances of getting anything published are, pretty close to zero. You will be attacked both personally and professionally. You will be accused of killing thousands of people by putting them of taking statins – and suchlike.

However, those in THINCS have never given up in their efforts to get the ‘truth out there’ and never will. This book is a further way to help inform the public about the true facts. There are chapters on competing hypotheses as to the cause(s) of CVD, there are chapters outlining the flaws in the current ideas. Some chapters are technical, others not.

Everything is held together by Paul Rosch, a brilliant researcher, writer and editor, clinical professor of Medicine and Psychiatry and New York Medical College, Chairman of the Board of the American Institute of Stress, and a great, deep thinker, on many subjects. Would that there were more like him.

thincs-coverart-frontcover-sm

You can get a copy direct from the Publishers here…

Or if you prefer to support Amazon, it’s on Amazon UK here and Amazon USA here


Amazon.co.uk
Amazon.com

Medical censorship in the twenty first century

“If liberty means anything at all, it means the right to tell people what they do not want to hear.” George Orwell.

Many of you may be aware of an article published in the Lancet on the eighth of September. ‘Interpretation of the evidence for the efficacy and safety of statin therapy.’1 It caused a media stir, and I was asked to appear on a few BBC programmes to argue against it – tricky in two minutes. At one stage I was cut off when I attempted to bring up the issue of financial conflicts of interest amongst the authors. The lead author of this paper was Professor Sir Rory Collins.

In truth, I have been awaiting this article for some time. In fact, I am going to reproduce here a blog I wrote on February 16th 2015, predicting exactly what was going to happen, who was going to be involved, and (in broad terms) exactly what they were going to say:


A humiliating climb down – or a Machiavellian move?

Some of you may have seen a headline in the Sunday Express Newspaper ‘Statin, new safety checks.’ The subheading was ‘Oxford professor who championed controversial drug to reassess evidence of side effects.’

Those of you who read this blog probably know that the professor in question is Sir Rory Collins. He, more than anyone, has championed the ever wider prescription of these drugs. He has also ruthlessly attacked anyone who dares make any criticism of them.

You may remember that last year he tried to get the BMJ to retract two articles claiming that statins had side effects (correctly called adverse effects, but I will call them side-effects to avoid confusion) of around 18 – 20%.

He stated that these articles were irresponsible, worse than Andrew Wakefield’s work on the MMR vaccine, and that thousands would die if they were scared off taking their statins by such articles. Ah yes, the old ‘thousands will die’ game. A game I have long since tired of.

Is this story ringing any bells yet? The truth was that both articles quoted a paper which stated that 17.4% of people suffered adverse effects. So, yes, a pedant would say that the 18 – 20% figure was wrong – although not very wrong. Certainly not worth a demand of instant retraction, and apology, which is a very drastic step indeed.

Anyway, below is a short description of the findings of an independent panel set up by Fiona Godlee, editor of the BMJ, regarding the Rory Collins attacks:

“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. Although The BMJ issued a correction for both papers for inaccurately citing an earlier publication and therefore overstating the incidence of adverse effects of statins, this response did not satisfy Collins. He repeatedly demanded that the journal issue a full retraction of the articles, prompting The BMJ’s editor-in-chief, Fiona Godlee, to convene an outside panel of experts to review the problem.

The report of the independent statins review panel exonerates The BMJ from wrong doing and said the controversial articles should not be retracted:

“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.””1

To provide a bit more context at this point, you should know that for a number of years, people have been trying to get Rory Collins to release the data he and his unit (the CTT), holds on statins. [The CTT was set up purely to get hold of and review all the data on statins, it has no other function].

He has stubbornly refused to let anyone see anything. He claims he signed non-disclosure contracts with pharmaceutical companies who send him the data, so he cannot allow anyone else access. Please remember that some of the trials he holds data on were done over thirty years ago, and the drugs are long off patent. So how the hell could any data still be ‘confidential’ or ‘commercially sensitive’ now?

[The concept that vital data on drug adverse effects can be considered confidential, and no-one is allowed to see it, is completely ridiculous anyway. But that is an argument for another day.]

Now, amazingly, after running the CTT for nearly twenty years, Collins claims that ‘he has not seen the full data on side-effects.’ In an e-mail to the Sunday Express 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.

Let that statement percolate for a moment or two. Then try to make sense of it. So, they have got the data, but not bothered to look at it? Or they have not got it – which surely must be the case if he hasn’t even seen it. Give us a clue. Either way, Collins states he has not assessed it.

Despite this, he still managed a vicious attack on the BMJ for publishing articles, claiming statins had side effects of around 20%. This was an interesting stance to stake, as he now claims he has no idea what the rate of side effects are? In which case he should make a grovelling apology to Fiona Godlee immediately.

What is certain, and must be reiterated, is that Rory Collins has consistently refused to allow anyone to see the side effect data, or any other data, that that the CTT may, or may not, hold. See e-mail below from Professor Colin Baigent to the ABC producer MaryAnne Demasi (she was trying to get the CTT to confirm that they would not release data, Colin Baigent is, or was, deputy to Rory Collins)

From: colin.baigent@xxxxxxxxxxx

To: maryannedemasi@xxxxxxxxxxxx

Subject: RE: URGENT COMMENT NEEDED PLEASE: ABC TV AUSTRALIA

Date: Tue, 24 Sep 2013 17:02:23 +0000

Dear Maryanne

The CTT secretariat has agreement with the principal investigators of the trials and, in those instances where trial data were provided directly by the drug manufacturers, with the companies themselves, that individual trial data will not be released to third parties. Such an agreement was necessary in order that analyses of the totality of the available trial data could be conducted by the CTT Collaboration: without such an agreement the trial data could not have been brought together for systematic analysis. Such analysis has allowed the CTT Collaboration to conduct and report all of the analyses on efficacy and safety that have been sought directly or indirectly by others (eg by Dr Redberg in her papers on the efficacy and safety of statins in primary prevention, and in questions raised by the Cochrane Collaboration). Hence, the CTT Collaboration has made available findings that would not otherwise have emerged.

I would be very happy to ring you at whatever time is convenient for you in order to help you to understand our approach, and then address in writing any residual concerns. It would be a shame if we were not able to speak as this would be the most effective way of explaining things.

Please let me know where and some times when I can reach you, and I will endeavour to telephone.

Colin Baigent.

I put the word safety in bold in this copied e-mail. You will note that Professor Colin Baigent does not say that that the CTT do not have these data on safety. He just says that the CTT won’t let anyone else see any data.

If they do have it, why have they not done this critically important review before, as they have had much of the data for over twenty years. If they don’t have it, how exactly is Rory Collins going to review it – as he states he is going to? Sorry to keep repeating this point, but I think it is absolutely critical.

Picture the scene in a lovely oak panelled office in Oxford, the city of the dreaming spires….

Professor Collins:             ‘Hey guys, you’re just not going to believe this, but a researcher just found a big box in the airing cupboard, and guess what, it has all the safety data in it….phew.’

Professor Baigent:           ‘Ahem… Why that’s lucky Professor Collins, now we can do the safety review.’

Professor Collins:             ‘Ahem… Indeed, Professor Baigent, we can. So, let’s get cracking shall we?’

And lo it has come to pass that after all these years Professor Collins has deigned to look at the safety data. This review shall, in Collins own words ‘be challenging.’ But you know what. I really don’t think they should bother, because we all know exactly what they are going to find….

That they were right all along, statins have no side effects. Hoorah, pip, pip. Nothing to see here, now move along.

A.N.Other Researcher:                    ‘Please sir, can anyone else see these data that you hold, to ensure that you are being completely open and honest?’

Professor Collins:                               ‘Don’t be ridiculous, these data are completely confidential.’

At this point I feel that I should ask how much do you, gentle readers, believe you can trust a review by Collins, on the data that Collins holds, on behalf of the pharmaceutical industry. Data that no-one else can ever see. [And the data from clinical trials on side effects is totally inadequate anyway].

Were I to be given the task of finding someone to review the safety data on statins, Professor Sir Rory Collins would not be the first person I would ask. He might even be the last.

1: http://www.forbes.com/sites/larryhusten/2014/08/02/no-retraction-for-you-review-panel-exonerates-medical-journal-in-statin-kerfuffle/

P.S. Actually, he would be the last.


I do not claim to be Nostradamus here. What was going to happen was obvious. The script had been written a long time ago. It was only a question of when, not if, it happened.

However, whilst the article itself is nothing new… and believe me, there is nothing new here. Just the same data stretched into three hundred references, and mind-blowing statistical obfuscation. It does, however, contain a few new Alice in Wonderland statements, such as the following:

‘If information on a particular outcome is not available from a randomised trial because it was not recorded, that would not bias assessment of the effects of the treatment based on trials that did record that outcome.’ How can this statement be made? For the first twenty years of trials on statins, no-one had noted that statins increase the risk of type II diabetes. It was not, as far as could be seen at the time, a problem.

Then, in a later study, JUPITER, all of a sudden it was found that there was a significant increase in type II diabetes. Now, it turns out that all statins increase the risk of type II diabetes. Had JUPITER not recorded the incidence of type II diabetes, this would never have been noticed. The cynics among you might say that they recorded this in the hope that the incidence would actually go down.

Here we have a perfect example of an outcome not recorded in the vast majority of statin studies. Had it been, it would have significantly biased the assessment of treatment. We also find that after two trials, 4S and HPS, found an increase in non melanoma skin cancer2, this outcome was not recorded, ever again, in statin trials. Outcomes certainly cannot make a difference if you do not record them. But if you did bother record them – who knows what might have happened.

This type of logic litters this Lancet paper, along with straw man argument after straw man argument. However, the purpose of this blog was not to discuss the evidence, such as it is, such as we are allowed to see, but to highlight why this paper was written and published. For this I shall turn to the editorial, accompanying the paper, written by Richard Horton. Who is the editor of The Lancet.

Read this, and be afraid, for it is the most frightening thing you will read this year. Possibly this decade and maybe the entire century as is a direct attack on human freedoms. Whilst couched in the usual life destroying scientific prose, what he is saying is that any who questions current accepted medical dogma should be very tightly controlled, and probably should not be allowed to publish anything at all.

The entire editorial is an exercise in trying to silence any dissent with what some might view as threats and bullying. This, I think, is the key paragraph (my emphasis in bold).

‘The debate about statins, as for MMR, has important implications for journals. Some research papers are more high risk to public health than others. Those papers deserve extra vigilance. They should be subjected to rigorous and extensive challenge during peer review. The risk of publication should be explicitly discussed and evaluated. If publication is agreed, it should be managed with exquisite care.’

Now that, when you strip it down, is basically censorship.

Despite the seriousness of what Richard Horton is proposing, it is amusing to know what his published views on peer review might be, consider his statement that ‘Those papers deserve extra vigilance. They should be subjected to rigorous and extensive challenge during peer review’:

‘The mistake, of course, is to have thought that peer review was any more than a crude means of discovering the acceptability — not the validity — of a new finding. Editors and scientists alike insist on the pivotal importance of peer review. We portray peer review to the public as a quasi-sacred process that helps to make science our most objective truth teller. But we know that the system of peer review is biased, unjust, unaccountable, incomplete, easily fixed, often insulting, usually ignorant, occasionally foolish, and frequently wrong.’ https://en.wikipedia.org/wiki/Richard_Horton_(editor)

Anyway, you can read the editorial in full here (http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)31583-5.pdf). In addition to the paragraph highlighted above, I would like to draw your attention to a couple of other very worrying statements in the closing parapgraphs:

The Committee’s [Committee on Publication Ethics COPE] decision [not to investigate statin critics as demanded by ‘concerned’ scientists] points to a serious gap in UK science—the lack of a central institution where scientists who wish to question the actions or ethics of other scientists or scientific institutions can go. Allegations of research misconduct are best investigated by the institution where the original research took place. But that principle does not apply for some organisations, such as scientific or medical journals.

With no independent tribunal to consider allegations of research or publication malpractice, a damaging dispute has been allowed to continue unresolved for 2 years, causing measurable harm to public health.

The debate about statins, as for MMR, has important implications for journals. Some research papers are more high risk to public health than others. Those papers deserve extra vigilance. They should be subjected to rigorous and extensive challenge during peer review. The risk of publication should be explicitly discussed and evaluated. If publication is agreed, it should be managed with exquisite care.

Authors and editors should be aligned on the messages they wish to convey, and every eff ort must be made to avoid misinterpretations and misunderstandings in the media. Editors also have to separate their roles as gatekeepers and campaigners. It is tempting to publish science that confirms pre-existing beliefs, especially if those beliefs underpin a campaign. Two ongoing campaigns—against Too Much Medicine and for Statin Open Data—continue to imply that statins are overused and that hidden harms remain to be exposed. As the Review we publish makes clear, the best available evidence indicates that neither statement is true.

Would this be the same Richard Horton, editor of the Journal, the Lancet,  who wrote? ‘Journals have devolved into information laundering operations for the pharmaceutical industry.’3

Would this be the Richard Horton who said? “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.”4

And would this be the same man who followed it up with?

‘The apparent endemicity of bad research behaviour is alarming. In their quest for telling a compelling story, scientists too often sculpt data to fit their preferred theory of the world. Or they retrofit hypotheses to fit their data. Journal editors deserve their fair share of criticism too. We aid and abet the worst behaviours. Our acquiescence to the impact factor fuels an unhealthy competition to win a place in a select few journals. Our love of “significance” pollutes the literature with many a statistical fairy-tale. We reject important confirmations. Journals are not the only miscreants. Universities are in a perpetual struggle for money and talent, endpoints that foster reductive metrics, such as high-impact publication.’4

Couldn’t have put it better myself. Yet, despite the fact that Richard Horton knows that much of the research is flawed and distorted by ‘flagrant conflicts of interest’ he still seems to believe that the statin studies, uniquely in history, are perfect – and cannot be questioned in any way. “Doublethink means the power of holding two contradictory beliefs in one’s mind simultaneously, and accepting both of them.” (George Orwell).

What do other editors think of this latest paper? Well, we have the thoughts of Fiona Godlee (editor of the BMJ), and Rita Redberg (editor of the Journal of the American Medical Association). I will supply a few quotes from them in an article published in Medpage Today (http://www.medpagetoday.com/cardiology/cardiobrief/60122):

‘More generally, Godlee and Redberg lamented the absence of independent verification of the statin data. Redberg said that “none of the CTT data has been made available to other researchers, despite multiple requests.” “No one has seen these data except the trialists.” Godlee agreed. “Ideally all clinical trial data should be available for third-party scrutiny,” she said.

Godlee’s also noted that “this is not an independent review, this is a review by the trialists.” Redberg went further, saying that “the long declaration of interests is telling. The Oxford Clinical Trials Unit receives hundreds of millions of pounds of support from the pharmaceutical industry.”

Godlee said that the need for independent review is especially pressing in this case, given the public health implications of the call for widespread use of statins for primary prevention. Redberg went even further and observed that “all of this data is from industry-sponsored studies, with concern for bias.”

As they went on to say

‘Redberg also pointed out some unintended consequences of statin usage. “Data shows that people on statins are more likely to become obese and more sedentary over time than non-statin users, likely because people mistakenly think they don’t need to eat a healthy diet and exercise as they can just take a pill to give them the same benefit (Sugiyama et al. JAMA IM 2014). So it seems this review affirms that many healthy people who feel perfectly well can take a pill every day, not live any longer, suffer any number of adverse effects, all to treat the ‘disease’ of LDL. I maintain the best way to reduce cardiac risk is to eat a Mediterranean-style diet, get regular physical activity, don’t smoke, and enjoy yourself.”

Godlee also emphasized the limitations of primary prevention. “Evidence about poor adherence to statins has long been known,” said Godlee. “People don’t want to take a drug forever. The problem didn’t arise with the BMJ study.”

It also seems likely that the Lancet paper exaggerated the benefits of primary prevention. The long-term benefits of primary prevention in the paper were based on modeling. The calculated benefits might have been a best-case scenario.’

In short, they did not think much of this paper, and Fiona Godlee was particularly concerned about the censorship element:

‘Godlee rejected the comparison of the BMJ papers to the Lancet Wakefield paper and objected to the idea that it’s too dangerous to publish papers critical of statins. “Where do you stop and where does that begin?” she wondered. She also pointed out that public concern over statins in the U.K. became elevated, not after the publication of the BMJ papers, but after Collins brought attention to the papers in a public denunciation of the papers on the BBC.

“We have to allow debate, I don’t know where you would draw the line,” she said. “In terms of public debate, the statin debate is fascinating and deserves airing.”

So, thank goodness for them. I shall stop now, although there is much still to say, because this blog is already very long and people may fall asleep reading it. However, I think this is such an important issue – potential censorship in medical research – that I felt I absolutely had to write something. So, here it is.

I shall finish on two things. Firstly, to state the Uffe Ravnskov, who has been a long-term campaigner against the cholesterol hypothesis, and statins, had one of his books, burned, during a live television debate. I do not have any footage, but here is my attempt to replicate the scene using a photograph from the past.

pic1

Secondly, here is a list of some of the conflicts of interest of the authors of the paper.

Declaration of interests

JA, CB, LB, RC, JE, RP, DP, and CR work in the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU) at the University of Oxford. The CTSU has received research grants from Abbott, AstraZeneca, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Schering, and Solvay that are governed by University of Oxford contracts that protect its independence, and it has a staff policy of not taking personal payments from industry (with reimbursement sought only for the costs of travel and accommodation to attend scientific meetings). RC is co-inventor of a genetic test for statin-related myopathy risk, but receives no income from it. DP has participated in advisory meetings for Sanofi related to PCSK9 inhibitor therapy in his previous employment. The CTT Collaboration, which is coordinated by CTSU with colleagues from the University of Sydney, does not receive industry funding. JD has received research grants from, and served as a consultant to, Merck and Pfizer. GDS hast twice received travel and accommodation funding and honoraria from Merck; DD receives compensation for serving on data monitoring committees for clinical trials (including of statins) funded by Abbvie, Actelion, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck, Sanofi , and Teva. NW and ML are inventors of a combination formulation for the prevention of cardiovascular disease that includes a statin, covered by patents licensed to Polypill in which they both hold shares and which owns the website polypill.com. SMac has received research grants for research on statins and polypill development from Bristol-Myers Squibb and BUPA. SMar is co-inventor on a pending patent for a LDL cholesterol estimation method, and has served as an advisor to Sanofi, Regeneron, Quest Diagnostics, Pressed Juicery, and Abbott Nutrition. NP has received research grants and honoraria for participating in advisory meetings and giving lectures from Amgen, Lilly, Menorini, and Merck. PR has received investigator-initiated research grants from Amgen, AstraZeneca, Kowa, Novartis, and Pfizer. PSa has received research grants and honoraria for consultancies from Amgen and Pfizer. LS has undertaken advisory work unrelated to statins for AstraZeneca and GlaxoSmithKline. SY has received a research grant from AstraZeneca through Hamilton Health Sciences. AR declares that George Health Enterprises, the social enterprise arm of The George Institute, has received investment to develop combination products containing statin, aspirin, and blood-pressure-lowering drugs. JS has received grants from the National Health and Medical Research Council, Australia; Bayer Pharmaceuticals; Roche; and Merck Serono. RB, SE, BN, IR, and PSa declare no competing interests.

[This list is far from complete. Paul Ridker, for example was (and may still be) a board member of Merck Sharp and Dohme, the maker of simvastatin at the time. Something he failed to report in a paper entitled: ‘Association of LDL Cholesterol, Non-HDL Cholesterol and Apolipoprotein B level with risk of cardiovascular events among patients treated with statins: A meta-analysis.’6 And something he has not mentioned here either.]

 

1: http://www.thelancet.com Published online September 8, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31357-5

2: Hung SH, Lin SC, Chung SD. Statins use and thyroid cancer: a population based case-control study. Clin Enodocrinol (Oxf) 2014 published online 30 July 2014,doi:10.111/cen.12570

3: Richard Smith. “Medical journals are an extension of the marketing arm of pharmaceutical companies.” Public library of Science. (May 17, 2005).

4: http://www.thelancet.com Vol 385 April 11, 2015

5: http://www.medpagetoday.com/cardiology/cardiobrief/60122

6: Correction. “Unreported Financial Disclosures in: Association of LDL Cholesterol, Non-HDL Cholesterol, and Apoliprotein B levels with risk of cardiovascular events among patients treated with statins: a Meta-analysis.’ JAMA. (April 25, 2012].

Greater Cholesterol lowering increases the risk of death

Sorry to get distracted from my series on what causes heart disease, yet again. However, I felt the need to blog about this article published in the BMJ on the 12th April 2016.

A group of researchers went back through the data from the Minnesota Coronary Experiment run between 1966 and 1973 in the US – on many thousands of participants. They were, in part stimulated to do this because they had previously looked at the Sydney Diet Heart Study 1966 – 73. In their own words:

‘Our recovery and 2013 publication of previously unpublished data from the Sydney Diet Heart Study (SDHS, 1966-73) belatedly showed that replacement of saturated fat with vegetable oil rich in linoleic acid (a polyunsaturated fat) significantly increased the risks of death from coronary heart disease and all causes, despite lowering serum cholesterol. Our recovery of unpublished documents and raw data from another diet-heart trial, the Minnesota Coronary Experiment, provided us with an opportunity to further evaluate this issue.’1

To make this clear. The Sydney Diet Heart Study (SDHS) was set up to show that replacing saturated fat with unsaturated fat would reduce the risk of heart disease The original researchers who set up and ran the SDHS did not fully publish their data at the time (one can only speculate as to why this may be so).

When this current group of researchers finally managed to get hold of the full data from the SHDS, it was found that replacing saturated fat with polyunsaturated fat did lower cholesterol, however:

REPLACEMENT OF SATURATED FAT SIGNIFICANTLY INCREASED THE RISK OF DEATH FROM CORONARY HEART DISEASE AND ALL CAUSES.

I am not normally a great fan of capitalisation, and using bold, but I think this statement needed that treatment.

Now, a few years later, the researchers who re-analysed the Sydney Diet Heart Study decided to try and find all the unpublished data from the Minnesota Coronary Experiment (MCE). (One can again only speculate as to why the original researchers did not reveal all of their data). The main points from this re-analysis were the following

  • Though the MCE intervention lowered serum cholesterol, this did not translate to improved survival
  • Paradoxically, MCE participants who had greater reductions in serum cholesterol had a higher, rather than lower, risk of death
  • Results of a systematic review and meta-analysis of randomized controlled trials do not provide support for the traditional diet heart hypothesis

I shall paraphrase their findings:

THE MORE THE CHOLESTEROL WAS LOWERED THE GREATER THE RISK OF DEATH

The Minnesota Coronary Experiment (MCE), a randomized controlled trial conducted in 1968-73, was the largest (n=9570) and perhaps the most rigorously executed dietary trial of cholesterol lowering by replacement of saturated fat with vegetable oil rich in linoleic acid. The MCE is the only such randomized controlled trial to complete post-mortem assessment of coronary, aortic, and cerebrovascular atherosclerosis grade and infarct status and the only one to test the clinical effects of increasing linoleic acid in large prespecified subgroups of women and older adults.

Those who have read my ramblings over the years will not be in least surprised by this finding. Because, as you may know by now. I believe that raised cholesterol has nothing whatsoever to do with the heart disease. So, this finding is not a paradox to me. It is simply further confirmation of many, many, other studies which utterly contradict the cholesterol hypothesis.

I would not, however, hold my breath waiting for this study to make any difference to anything. My current favourite comment on this study comes from an opinion leader from the British Heart Foundation. It is, as follows:

‘Professor Jeremy Pearson of the British Heart Foundation commented: “This is an interesting study which shows that decreasing your intake of saturated fat can have a positive impact in helping lower cholesterol. More research and longer studies are needed to assess whether or not eating less saturated fat can reduce your risk of cardiovascular death.’

Read and weep gentle readers. Here is a man so completely and utterly convinced of the dangers of saturated fat consumption and raising blood cholesterol that he is incapable of grasping what this paper is saying. Max plank said that ‘Science advances one funeral at a time.’ There is at least one funeral, currently, that I can think would help to move science along.

Perhaps time from a quote from Professor John Ioannidis, who wrote a rather sad article recently, entitled Evidence-based medicine has been hijacked: a report to David Sackett.

‘This is a confession building on a conversation with David Sackett in 2004 when I shared with him some personal adventures in evidence-based medicine (EBM), the movement that he had spearheaded. The narrative is expanded with what ensued in the subsequent 12 years. EBM has become far more recognized and adopted in many places, but not everywhere, for example, it never acquired much influence in the USA. As EBM became more influential, it was also hijacked to serve agendas different from what it originally aimed for. Influential randomized trials are largely done by and for the benefit of the industry. Meta-analyses and guidelines have become a factory, mostly also serving vested interests. National and federal research funds are funnelled almost exclusively to research with little relevance to health outcomes. We have supported the growth of principal investigators who excel primarily as managers absorbing more money. Diagnosis and prognosis research and efforts to individualize treatment have fuelled recurrent spurious promises. Risk factor epidemiology has excelled in salami-sliced data-dredged articles with gift authorship and has become adept to dictating policy from spurious evidence. Under market pressure, clinical medicine has been transformed to finance-based medicine. In many places, medicine and health care are wasting societal resources and becoming a threat to human well-being. Science denialism and quacks are also flourishing and leading more people astray in their life choices, including health. EBM still remains an unmet goal, worthy to be attained….

He concludes

“David, I was a failure when we started this conversation and I am an even bigger failure now, almost 12 years later. Despite my zealot efforts, my friends and colleagues have not lost their jobs. The GDP devoted to health care is increasing, spurious trials, and even more spurious meta-analyses are published at a geometrically increasing pace, conflicted guidelines are more influential than ever, spurious risk factors are alive and well, quacks have become even more obnoxious, and approximately 85% of biomedical research is wasted . I still enjoy science tremendously, focusing on ideas, rigorous methods, strong mathematics and statistics, working on my weird (and probably biased) writings alternating with even more desperate poetry, and learning from young, talented people. But I am also still fantasizing of some place where the practice of medicine can still be undeniably helpful to human beings and society at large. Does it have to be a very remote place in northern Canada close to the Arctic? Or in some isolated beautiful Greek island where corpses of unfortunate refugees are found on the beach or floating in the water almost every day, as I am writing this commentary, although no naval battle has been fought? Is there still a place for rational thinking and for evidence to help humans? Sadly, you cannot answer me any longer, but I hope that we should not have to escape to the most distant recesses of geography or imagination. Twenty-five years after its launch, EBM should still be possible to practice anywhere, somewhere—this remains a worthwhile goal.”2

David Sackett, the founder of Evidence Based Medicine, is now dead. I presume he is spinning in his grave at what has happened to medicine and medical research. Which is, currently, not based on any evidence at all. If the evidence does not fit with the currently dogma it is simply not published.

Does anyone in the higher reaches of the medical establishment actually give a stuff about this? It seems that they do not. Meanwhile the shelves of our supermarkets groan under the weight of the super-healthy polyunsaturated fat products that we are encouraged to eat, by the likes of the British Heart Foundation.

Yet, here is what the uncovered evidence from the largest study done in this area is screaming at us:

Greater cholesterol lowering, using polyunsaturated fats, increases the risk of death

So, British Heart Foundation, the question must be asked… are you killing people with your advice on saturated fat consumption? Perhaps you ought to think about changing it, before more people die.

Here is what the BHF currently say about saturated fats:

‘Swap these for unsaturated fats. Eating too much saturated fat increases the amount of cholesterol in your blood.’3

Do you have any actual evidence to base this advice on… any at all? If so, let’s see it. If not, change it.

References
1: http://www.bmj.com/content/353/bmj.i1246

2: http://www.jclinepi.com/article/S0895-4356(16)00147-5/fulltext

3: https://www.bhf.org.uk/heart-health/preventing-heart-disease/healthy-eating/fats-explained

Lowering cholesterol has no effect on heart disease

Yes, if anyone is interested, I enjoyed my holiday. Mountains, snow, skiing, food, France. What more could you ask for?

Whilst away I kept an eyes on a whole series of stories on cholesterol and statins and adverse effects of statins, and suchlike, unfold across various newspapers. Many of you were kind enough to send me said various articles and stories. Some of which were easy to follow. One, in particular, was completely incomprehensible.

HOPE-3, was a study done by Astra Zeneca looking at the use of rosuvastatin vs. placebo. Actually, it was a study done using rosuvastatin alone vs. antihypertensive medication vs. rosuvastatin and antihypertensive medicine vs. double placebo (a term I have never come across before). Double placebo has twice the power of a single placebo? Yes, its ‘Double Placeboman’ playing at a cinema near you.

I have read the HOPE-3 article, and given up several times. I just cannot understand it. Professor Michel de Lorgeril (who ran the Lyon heart health study) also had a go at making it easier to understand. Below is part of his simplification which (I am afraid) is not terribly simple. But it may give you some gist. There is a prize for anyone who gets to his final point:

  1. No effect on all-cause mortality.
  1. No effect on cardiovascular mortality.
  1. As cardiovascular disease is a serial killer, we could conclude that rosuvastatin is shown useless in that trial (as in the previous trials). We could stop the analysis at this point.
  1. Since the authors do suggest that rosuvastatin was protective, it means that these patients are as “deaths cured”’ or “death prevented”, which is probably not what they expected when taking the pills.
  1. All this despite the LDL reduction that was close to 30%.
  1. HOPE 3 investigators curiously examine the effects of rosuvastatin on two “combined primary endpoints” (called “first and second co-primary outcome” as shown on Table 2, below) suggesting that there were two primary hypotheses. This is not “in line” with basic Methods in clinical trial sciences [one trial, one primary hypothesis]. That strange and novel strategy should have been presented long before starting the trial. In any case, the probability of a difference between rosuvastatin and placebo for the first co-primary outcome [the only one to be considered] should have been adapted, a kind of Bonferroni correction; p should have been much lower than 0.05 to be significant; which is not “clinical significance”.
  1. HOPE 3 investigators present the comparison of rosuvastatin with placebo (Table 2, below) as if there were only two randomized groups. In fact, there were 4 groups as there was a second randomization to test an antihypertensive treatment; and also the combination of cholesterol lowering and blood pressure lowering. In summary, these investigators tested many more than two primary hypotheses. They say that they can pool the data from all the patients taking rosuvastatin (plus antihypertensive) to make the comparison with all the patients taking a placebo, including those taking antihypertensive; thus comparing two groups of about 6300 patients rather than 4 groups of about 3100 patients each) because there was no interaction between treatments. This is not exactly true as we see a clear interaction between treatments for at least two components (myocardial infarction and stroke) of the two co-primary outcomes (see Table S20 in the supplementary materials, below). It would have been therefore imperative to present data and full statistics for the 4 groups together to examine the effects of rosuvastatin vs. placebo. It is a mistake not to do that. 6- HOPE 3 investigator also say that there were fewer heart attacks; but after almost 6 years and with about 13,000 patients randomized, there were only 114 heart attacks (45 vs 69 in a simplistic analysis of 2 groups only, Table 2 below).
  1. In fact, things are not so clear when looking at Table 2: they report for the first co-primary outcome (CV deaths + myocardial infarction + stroke) 304 events in the placebo group and 235 in the rosuvastatin group, thus numbers different from the sum of 171+69+99 (total 339, placebo group) Michel de Lorgeril 2016 and 154+45+70 (total 269, rosuvastatin) according to the numbers given in Table 2. This means that they do not use the same numbers in the Table and in the statistics. This is a way of misleading the readers.

Ahem. Perhaps not as simple as you may expect, but I hope you get the general drift. All I did, rather than Lorgeril, was attempt to pull out the figures of greatest interest, to me. Which should be the figures of greatest interest to everyone taking rosuvastatin. The absolute difference in number of deaths between those taking rosuvastatin and double placebo.

  • After five years of treatment, in 3,181 people taking rosuvastatin, there were 171 deaths (of all causes)
  • After five years of taking double strength placebo, in 3,168 people, there were 178 deaths (of all causes)

This represents a difference of 7 deaths over 15,905 years of treatment. Or, one death delayed for every 2,272 years of treatment. This is both statistically, and clinically, insignificant. It is well within the limits of a chance finding. It is a difference that can simply be ignored.

Of course, it was hailed as a triumph, and further proof of the cholesterol hypothesis.

Of more interest, in many ways, and coming out at almost exactly the same time as HOPE-3 was the ACCELERATE trial. Which looked at the use of evacetrapib on lowering LDL (‘bad’ cholesterol), and raising HDL (‘good cholesterol) on the risk of CVD. It was reported thus…

‘Cleveland Clinic researchers studying evacetrapib have shown that despite reducing levels of low-density lipoprotein (LDL, or “bad” cholesterol) by 37 percent and raising levels of high-density lipoprotein (HDL, or “good” cholesterol) by 130 percent, the drug failed to reduce rates of major cardiovascular events, including heart attack, stroke, angina or cardiovascular death.

The phase 3, multi-center clinical trial was discontinued in October 2015, on the recommendation of the independent Data Monitoring Committee after preliminary data suggested the study would not meet its primary endpoint of a reduction in major cardiovascular events. The research is being presented at the American College of Cardiology’s 65th Annual Scientific Session

“Here we have a paradox. The drug more than doubled HDL and lowered LDL levels by as much as many statins, but had no effect on cardiac events,” said Steve Nissen, M.D., chairman of Cardiovascular Medicine at Cleveland Clinic. “These findings illustrate the importance of performing large, high-quality outcome trials. Just looking at the effects a therapy has on cholesterol levels doesn’t always translate into clinical benefits.”

The ACCELERATE trial involved more than 12,000 patients at more than 540 sites who were at high risk for serious cardiovascular problems. They were randomized to receive either 130 milligrams of evacetrapib or a placebo daily, along with standard medical therapy throughout the trial. Study participants either had an acute coronary syndrome 30 days to one year before enrolling, had cerebrovascular atherosclerotic disease, had peripheral vascular disease, or had both diabetes and coronary artery disease.’

In HOPE3, LDL was lowered 30%, had some (very slight) impact on CVD, and was hailed as a triumph for cholesterol lowering. In ACCELERATE LDL was lowered 37%, HDL raised 130%, with no effect whatsoever on CVD. Aha, but, there is an answer…

The ACCELERATE trials was, you’ve guessed it. A paradox. [Question, how many paradoxes can a hypothesis sustain before it collapses in a smoking ruin?]

Karl Popper would call such a thing a black swan. Which is a refutation of your hypothesis. Karl Popper, as we all – ahem – know ‘proposed falsification as a solution to the problem of induction. Popper noticed that although a singular existential statement such as ‘there is a white swan’ cannot be used to affirm a universal statement, it can be used to show that one is false: the singular existential observation of a black swan serves to show that the universal statement ‘all swans are white’ is false—in logic this is called modus tollens. ‘There is a black swan’ implies ‘there is a non-white swan,’ which, in turn, implies ‘there is something that is a swan and that is not white’, hence ‘all swans are white’ is false, because that is the same as ‘there is nothing that is a swan and that is not white’.

One notices a white swan. From this one can conclude:

At least one swan is white.

From this, one may wish to conjecture:

All swans are white.

It is impractical to observe all the swans in the world to verify that they are all white.

Even so, the statement all swans are white is testable by being falsifiable. For, if in testing many swans, the researcher finds a single black swan, then the statement all swans are white would be falsified by the counterexample of the single black swan.’2

Here is another ‘white swan’ hypothesis

Researchers, looking at those living in Framingham, in the US, found that younger men with high cholesterol levels were more likely to die from CVD. From this they concluded. Raised cholesterol causes CVD. ACCELERATE clearly falsifies their simplistic hypothesis. It is a black swan. Thank you, and goodnight.

Next, part XII as to what causes heart disease.

References:
1: http://www.dddmag.com/news/2016/04/evacetrapib-impacts-cholesterol-doesnt-reduce-cardiovascular-events

2: https://en.wikipedia.org/wiki/Falsifiability

Cholesterol goes up heart disease goes down

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

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

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

Lowering cholesterol – an urgent Christmas appeal

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Kerching!

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

Sanofi:                     Exclusive conference sponsor

Amgen:                   Sponsored symposia 1

Sanofi:                    Sponsored symposia 2

Amgen:                   Privileged sponsor…etc.

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

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

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

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

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

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

Attacking those who criticise statins – again

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

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

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

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

Changing the definition of Familial Hypercholesterolaemia

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

3: golowcholesterol.com/tag/amgen/

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

At one point they go on to say…

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

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

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

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

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

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

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

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

We can draw the following conclusions:

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

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

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

As they say that odds are, as follows

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

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

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

The Augean Stables – part II

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The Augean stables

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

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

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

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

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

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

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

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

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

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

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

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

Pharmaceutical companies have been asked to register trials since 2005.

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

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

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

Do you think this is too strong?

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

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

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

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

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

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

Here they come – take cover

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  • Statin hype
  • Cost
  • Injectable
  • No outcome data

Statin hype

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

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

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

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

Cost

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

Injectable

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

No outcome data

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

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

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

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

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

You have been warned.

You’re killing my patients (again)

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

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

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

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

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

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

However, all of this was represented as follows:

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

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

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

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

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

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

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

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

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

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

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

The authors wrote:

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

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

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

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

The study authors wrote:

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

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

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

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

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

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

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

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

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

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

Statins and cancer

(Ho hum, not again)

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

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

by up to 50% reveal major studies

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

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

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

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

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

Not randomised controlled studies

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

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

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

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

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

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

Relative not absolute risk

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

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

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

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

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

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

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

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

CL-vs-CR

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

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

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

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

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

Can I return to my slumbers on this issue now?

 

References

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

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

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

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

Hoorah

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

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

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

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

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

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

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

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

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

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

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

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

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

The dog that did not bark in the night

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

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

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

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

And so on and so forth.

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

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

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

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

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

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

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

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

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

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

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

A does not → C

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

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

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

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

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

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

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

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

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

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

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

Hats off to the Japanese

(Raised cholesterol is good for you)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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