Eminence based medicine defends the status quo on statins

by Jerome Burne

Last week I was called by a friend who opened the conversation by saying: “So you were wrong about statins.” He was referring to the correction that the British Medical Journal (BMJ) has had to make in two papers that claimed statins have a high level of side effects. But I certainly haven’t recanted and started popping those pills.

Given the huge amount of attention this has attracted, the actual point being “corrected” is remarkably small. It is the kind of thing that would normally be dealt with by publishing a response to the article in the journal. I’ll come to the specifics in a moment but first a bit of context.

Even though statins have been used for about 20 years there is still a big dispute as to your chance of suffering a side effect and that matters because if it’s bigger than is commonly claimed, then the balance between risk and benefit changes.

The complaint about the two papers was made by Professor Sir Rory Collins, a very senior medical researcher, the author on a number of respected, detailed papers showing that statins are effective and have few side effects.

Why RCTs can be unreliable

In recent weeks Sir Rory has given media interviews containing widely different estimates of side-effect risk. He’s put serious muscle problems at 1/10,000 and he’s said the overall risk is 1/100. In contrast the claim made in the two BMJ papers was 1/5. Interestingly the patient leaflet for the most lucrative statin ever – Lipitor – says that: “common side-effects may affect 1/10. So experts disagree but knowing which side is more accurate is important with the proposal to put another 7 million on the drugs.

So how good is Sir Rory’s evidence? It is based on large randomised controlled trials (RCTs), generally considered the evidence gold standard. But in recent years there has been growing criticism of the reliability of these trials, especially when it comes to assessing side effects. Here are some of the factors that can lead to side-effects being under estimated:

Firstly they are virtually all paid for by the drug companies which have little interest in checking carefully for possible side effects. For instance diabetes is now recognised as a risk but just three out of 29 statin trials reported on new cases of diabetes.

Second, many trials don’t give any details about how side-effect reports were actually collected or how often.

Third, some trials exclude patients with disorder such as severe diabetes, kidney failure or hypertension, many of who would be likely to be given statins in the real world.

Fourth, people who volunteer for trials are often chosen because they are enthusiastic and so may be less likely to report side effects and less likely to stop taking the drugs than real world patients.

Fifth, many trials start with a period when all subjects get the drug. Those that show a reaction to the drug can be excluded.

It’s a scandal we can’t see full trial data

For this reason it is important that other researchers are able to get access to the full data collected in during any trial – known as the Clinical Study Report. (CSP) The CSP’s for statins however are considered a commercial secret and not made available to independent researchers. See recent HealthInsightUK post[Link].

This is not an eccentric view of mine, among those concerned about the reliability of RCTs is Mark Wilson of the Cochrane Collaboration, a body dedicated to establishing an evidence base for treatments: “It is a scandal that we still do not have access to all trials’ data so that we can be confident in our conclusions,” he said last year.

It also relevant here that a declaration of interest form, published on Zoe Harcombe’s site’here, shows that Sir Rory together with another top statin researcher received £91 million pounds from Merck and an associated company, makers of simvastatin along with other funding. There is no suggestion of impropriety but funding has not been publicly known before.

So with that background what was the problem with the two papers? Both referred to the same paper – a review of the medical records of more than 107,000 patients taking statins over 8 years, which reported that 17.4% had a ‘statin related event documented’.

Is this a joke?

And what had they got wrong? One said that “side effects of statins occur in about 18 -20% of cases” while the other claimed there were: ‘unacceptable side effects… in 20% of participants.’

Can you see what they got wrong? The actual figure was 17.4%. I am not joking. The further charge is that the statements did not take ‘sufficient’ account of the fact that this was not a RCT but an ‘observational’ study – considered less reliable because a various factors – age, social class, existing health – could all affect the outcome.

It seems frankly incredible that this narrow statistical point, the sort of thing that is the bread and butter of responses to articles in hundreds of journals every day, now needs a committee to decide if the each of the two articles should be withdrawn rather than corrected. (Dr John Briffa has written an angry satirical response to this on the BMJ site here)

This is despite the fact that it’s admitted that in neither case did the correction change the main argument of the article. One was challenging a big study done by the organisation headed by Sir Rory (the CTT in Oxford). It argued that the study didn’t show that giving statins to patients without heart attacks cut the rate at which they died. The other article challenged the accepted wisdom that saturated fat was a cause of heart disease and recommended much greater awareness of the benefits of the Mediterranean diet.

This could cause unnecessary deaths

That leaves the other part of the charge – that both articles failed to mention the shortcomings of observational trials, which given that they had been written for a professional audience, might be thought unnecessary.

But even if it were appropriate, then surely warnings about the considerable shortcomings of RCTs should be part of any claims about statins’ lack of side effects that are based on published results from RCTs?

Such caveats were certainly not part of Sir Rory’s interviews with the media. Here’s one example from the Mail: “We have really good data from over 100,000 people that show that the statins are very well tolerated. There are only one or two well-documented [problematic] side effects.”

He went onto confidently assert that the BMJ had overstated the dangers of taking statins by 20 times – his figure of 1% of patients suffering side effects vs the 20% from the BMJ’s papers. Not only was this a “huge error” but it could “cause unnecessary deaths.”

Statins make some less likely to exercise

This is eminence based medicine, which is quite different from the evidence based version. The data from the trials, at best, has a big question mark over it, even the drug companies themselves admit to a 10% risk and clinicians regularly report a much higher figure. This is not the cut-and-dried issue that Sir Rory aggressively presents.

In fact there is a randomised controlled trial of the side effects of statins published in 2012 in the Archives of Internal Medicine. It involved over 1000 patients compared reports of fatigue between those on statins and those getting a placebo. Not only did 20 to 40% of those on statins report fatigue but this affected their level of activity which “could lead to an increase in cardiovascular events”.

The high-powered attack on the authors and the BMJ seems to have little to do with constructing an evidence based picture of the risk and benefit of statins but rather to defend the status-quo by publicly denigrating any researcher who disagrees, in remarkably offensive terms.

“I would think the papers on statins are far worse in terms of the harm they have done,’ declared Sir Rory “than the paper on the MMR vaccine by Andrew Wakefield.” Interestingly this is a phrase that Sir Rory used when criticising a draft of the Cochrane report on statin use on healthy patients several years ago, suggesting he regards it is an effective debating point.

However Sir Rory is not the only one using heavy-handed tactics to intimidate critics of statin benefit. The same thing as been going on in Australia in recent months and there are some striking similarities – challenges to both statins and to official dietary advice as well as a critique on a minor point. It involved a TV science reporter for ABC (Australia Broadcasting Corporation) called Dr Maryanne Demasi who had made two programs for the science program Catalyst; they aired at the end of October beginning of November.

Not a single charge was upheld

The station was deluged with complaints from professional bodies claiming that the two programs had broken cardinal principles of balance and fairness. A committee was set up to assess them.

Earlier this month, after committee had produced at 49-page report, ABC decided that both programs should be withdrawn. So she’d got something really wrong, right? Well again no. It’s worth pointing out just what a challenge it is to maintain a balance while explaining disputed and quite complicated science and make a lively TV program.

And for the saturated fat program that is just what Demasi did. Not one of numerous charges made by her critics was upheld. The verdict on the statin program was equally impressive. The committee had examined 17 charges of violating standards of fair and honest broadcasting and upheld just one of them.

The criticism that was accepted, like the one against the BMJ authors, was narrow. It was a failure to make it clear that statins for patients who already had heart disease has wider benefits, even if it doesn’t make them live longer.

Repressing intelligent and informed debate

What this ignores is that without full knowledge of the trial data (unavailable) such an overview of statins risk and benefit can’t be done. However that single point was sufficient to have both programs withdrawn, leaving the popular impression that low fat diet and widespread statin use had triumphed. For a far more detailed account of this saga see Dr Malcolm Kendrick’s latest blog

What’s on display here is an authoritative system attempting to repress an intelligent and informed critique in the name of science. The flexibility of the way this ‘science’ was wielded in both the UK and Australia is illustrated by how the rules were relaxed for the establishment.

Sir Rory felt no need to issue caveats about his own research model while the National (Australian) Heart Foundation, which uses observational trials to support its advice on low fat seemed happy to use belief to support its position. The Committee’s evidence included this comment: “Notwithstanding the lack of definitive proof… the NHF believes there is enough good quality evidence to recommend a diet low in saturated and trans fats.”

Science relies on questioning and testing not eminence based bullying, I for one will continue to view statins with a sceptical eye.

Jerome Burne

Jerome Burne

Jerome Burne is the editor of HealthInsightUK. He is an award-winning journalist who has been specialising in medicine and health for the last 10 years and now works mainly for the Daily Mail. His most recent book “10 Secrets of Healthy Ageing” was written with nutritionist Patrick Holford. He blogs at “Body of Evidence” – jeromeburne.com. 2015: Finalist for 'Blogger of the Year' award from Medical Journalists' Association.

28 Comments

  • First, I would like to add a sixth item to your list of criticisms of drug trials – they simply don’t go on long enough!

    I took Simvastatin for 3 years before it gave me severe cramps in my polio leg. I was so surprised that this wonder drug could be responsible that I started and stopped 3 times so as to confirm beyond all doubt that Simvastatin was the culprit! How many trials would detect a problem of that sort?

    Secondly, if I were indeed a 1 in 10000 exception, and only spoke to about 15 people about my experience, I’d expect to speak to nobody with a similar experience (probability 0.9985) – in fact about half had similar experiences or knew others who had problems! How would Sir Rory answer that?

    My experience also suggests that statins don’t attack the body’s muscles uniformly, so the symptoms can easily look like something else.

    You efforts on this website are greatly appreciated!

  • I do not think ‘exerting undue eminence’ to ‘pervert the course of science’ ranks as a crime, at least not yet, but the experience of patients like you David, their number, then understanding the importance of cholesterol and the mevalonate to human (and animal physiology), allied with the clumsy and indiscriminate way statins act, make it plain to people with the balanced view that Sir Rory has overstepped the mark. That various parties have given in to his ‘eminence’, and to that exerted by others, upon mere technicalities as opposed to the truly important issues, is severe blow for much needed exposure and debate.

    The results at the BMJ, those allegedly brought about by Rory Collins interference in what ought to be the bread and butter process of publication and response through the more usual channels associating with the publication, have stifled the kind of debate medical professionals and consumers ought to see and hear reported without bias or sensationalism.

  • .. knowing which side is more accurate is important with the proposal to put another 7 million on the drugs.

    Dear Jerome Burne,

    Who is that is proposing to have another 7 million patients on statins and how? May I take it that you have read the announcement issued through NICEs web-pages? The mention of 7 million takers was a mere estimate, and the mention of cost of £285 annually to the public purse for these marvels were NICEs own figures inserted into their announcement.

    NICE are not proposing to put another 7 million on statins, and in their announcement they used the term ‘thousands more could be offered … statins’. NiCE have not issued ‘proposals’ they announced the release of a consultation document and published new guidelines on lipid modification in draft. In this document they inform that statins are so effective and so safe the the threshold that computes from the QRISK2 calculation tool and that qualifies a patient for statin prescription should be halved.

    The QRISK2 calculation tool is a sophisticated algorithm applied to several well accepted risk factors (only one of which is the measurement of a persons cholesterol levels) and drops out a number. Compared to present guidelines NICE the qualifying number should be halved.

    Halving of the number (the threshold) does not automatically mean double the number of people will qualify. It could be more than double or it could be less than double. To establish how many more people will qualify you would need to have a lot of statistics (data) and be able to plot a distribution curve for the incidence rate and distribution of QRISK2 results. Then it is possible to read from the curve to return how many people would fall within the former and the new threshold. Even NICE were not sophisticated enough to have done this in their extensive documentation, and so I wonder where do you get your figures from?

    We should all strive for the highest editorial standards at all times, my man, and it is clear that the impression you have given that 7 million more are to be put upon statins is a misrepresentation for not having been computed properly, nor even computed at all. Since you have demonstrably fallen short of the kind of standards that should be upheld at all times I insist you remove your article, along with the comments that follow, from your second rate website. People might read this nonsense and think statins are not for them, and that would be disastrous.

    Yours sincerely.

    Sir Richard-complete-lack-of-experience-in-clinical-pratice-Clever-Dick.

  • Professor Sir Collins (I think we should adopt John Briffa’s way of referring to him) has not only stifled debate on statins, he has also deflected attention from his own refusal to open the study data to scrutiny. Abramson & co were not deflected though – in their Authors’ Response in the BMJ they said;

    If the Cochrane Reviewers have requested and been denied access to the patient-level data from the statin studies, we believe they should do what the reviewers of oseltamivir have done: publicly declare their inability to perform a responsible evaluation and retract conclusions that are based on published data only. The entire world is relying upon third party representations of data that the manufacturers should make readily available to Cochrane Reviewers and other academic researchers.

    Revelations such as this could also be frankly embarrassing to, let’s say, Pfizer, at a time when they were trying to pull off a tricky adjustment of their tax status by buying Astra Zeneca.

  • Your reading of the data from the original paper which has been misquoted by Malhotra and Abramson et al in the BMJ is wrong.

    It’s got nothing to do with 17.4% and 20% being different. It’s got to do with the fact this figure was not a percentage of patients who had side effects. If you actually read the paper you would know this too.

    The 17.4% of people quoted was the number of people on statins who had a “statin related event” – of all these people, 59% actually stopped the statin at least temporarily (ie. 40% never stopped), and of the 59% who did stop the statin temporarily, 73% of them were back on a statin 12 months later.

    So the issue is that Malhotra claimed 20% had unacceptable side effects requiring cessation of therapy. This is clearly just wrong.

    Abramson said 18% of patients had discontinued therapy (at least temporarily) due to side effects when 10% stopped therapy temporarily due to a statin event and 3/4 of these went back on a statin within 12 months.

    There are other issues that were challenged by presenting this data. Because there was no control group, the percentage of people with “events” could not be compared. Several randomised trials have shown that a reasonable proportion of placebo patients report muscle aches and other symptoms. Some trials, like the HPS, found the same frequency of side effects in both statin and control patients.

    I completely agree that diet and exercise should be the cornerstone for prevention of disease, but I also think statins have a vital role to play in treating and preventing vascular disease in patients at a high enough risk.

    It’s worth noting that Abramson has been making a living on being anti-statins for decades now and certainly garners a lot of media attention for his controversial views.

    Molhotra is a cardiology registrar who argued in his paper that cholesterol levels have nothing to do with heart disease. Such a sweeping statement is rubbish. We can graph all the randomised statin trials and show that for every 1 mmol/L LDL cholesterol reduction achieved, vascular events are reduced by 20%, irrespective of what level cholesterol you start with. This proves a linear relationship between cholesterol levels and heart disease risk.

    Regarding your comments about the ABC Catalyst program in Australia, I’d be interested to know if you saw that too. Maryanne Demasi presented one of the most biased pieces of television journalism Australia has seen. Most of the people interviewed had undeclared financial interests in products designed to be taken instead of statins. She presented the anti-statin viewpoint for about 80% of the program and heavily edited interviews with the 2 medical professionals who were defending statins. It was absurdly biased reporting and this was the conclusion of the ABCs investigation.

    It’s one thing to mouth off about evil pharma, but I’d recommend you look a bit more closely into what “facts” you are challenging because on these points you are regretfully not right at all.

    I declare I am a cardiologist undertaking PhD research on the benefits and adverse effects of statins and receive no commercial funding from any body.

    • Just so long as they sit in the light cast by conventional wisdom the points you raise are good ones, Jordon.

      However the light cast by conventional wisdom on fat and cholesterol does not shine its light upon the evidence that matters most. The evidence that matters most indicates that oxidised cholesterol brings about the degeneration of certain cells that subsequently results in the development of atheromas. It is not a quantitative concern that results in the development of atherosclerosis, instead atherosclerosis results from a qualitative event in which cholesterol can be subjected to oxidative stress and thus be converted to oxidised cholesterol.

      Conventional wisdom has it:

      #1 .. that the case for lipid modification (lowering cholesterol) is a strong one and evidence based.

      #2 .. that statins are a good way to achieve lipid modification.

      #3 .. that low fat is better and low saturated fat better still.

      #4 .. the lipid profile test is a sophisticated tool.

      By acting upon mevalonic acid through inhibiting the enzyme HMG-CoA reductase statins are actually very indiscriminate in the way they act. They inhibit biosynthesis of at least five other known biochemicals that fulfil important physiological functions. Indeed cholesterol fulfils several crucially important physiological functions itself – which explains why cholesterol is so ubiquitous in physiology and within biology.

      It was established almost forty years ago the cholesterol becomes atherogenic and produces results in smooth muscle cells that lead into atherosclerosis only when it becomes oxidised [1]. Oxidised cholesterol is an atherogen; cholesterol is not. The fat/cholesterol hypothesis in its’ present incarnations takes no account of this fact.

      Sufficient fats in the diet encourage hormonal adjustments that discourage over-feeding. Carbohydrates in the diet encourage hormonal balances that encourage over-feeding. Once ingested fats in the diet may place an order for additional cholesterol to be supplied to the digestive track (with bile) .. .. but all fats would signal this request. Then after digestion all fats ingested must be bundled with cholesterol into lipoprotein parcels called chylomicrons. Chylomicrons are the largest members of the lipoprotein family.

      Chylomicrons don’t enter the blood until they have divested themselves of much of their constituency. Through having done aspects of their ‘job’ they shrink and wind up, in the jargon ‘more dense’. Once passed from the digestive track chylomicrons go through a cycle at the end of which it is a mere remnant, and the remnant will cease to conform to the description of a chylomicron.

      A lipid profile test cannot report upon chylomicrons because chylomicrons enter the lymph system. The lipid bloated chylomicrons that may be the postprandial consequence of eating a fry-up cannot be detected by the lipid profile blood test. All fats, and not saturated fats alone, may call for more cholesterol, but whether the lipid profile test can discern the postprandial consequence is a moot point.

      Contrary to conventional wisdom low-fat is actually ‘bad’ because low-fat diets high in carbohydrate (or even protein) encouraged lipogenesis and sequestration of body fat. Including sufficient fat in the diet encourages a shift towards ketosis and permits the kind of hormonal balance that will tolerate lipolysis (release of body-fat for burning). If these swings between metabolic modes (be that a flow of fat for storage of energy, or a flow of energy being released from body-fats) can have bearing upon lipid profiles I would not be surprised. If anything people who add fat back to their diet report their lipid profiles are restored to the kind balance that is considered ‘good’, which is a result that surprises those who side with conventional wisdom.

      Too much attention is paid to the lipid profile test. The biggest failing of the test is that it attempts to describe the risk of an event that is the result of a qualitative variable (oxidation of cholesterol) with recourse to quantitative analysis. LDL is incidental to the process of forming atheromas. Even the methodology that derives the test results is suspect for being ‘circular’. The application of the test has resulted that people (and GPs) confuse cholesterol with lipoproteins.

      Cholesterol only becomes an atherogen when it becomes subject to oxidative stress. That oxidised cholesterol can reside in lipoproteins is not in doubt. That oxidised cholesterol can be ingested and conveyed to the site of atheromas is not in doubt either, and the striking influence is that oxidised cholesterol can be conveyed within the constituency of lipoproteins as they cycle through our arbitrary incarnations as chylomicron through to LDL. In English a person could have high cholesterol while that cholesterol remains ‘pure’ and uncontaminated by oxidation. The business of atherogenicity requires some cholesterol molecules to be converted to oxycholesterols. LDLs direct involvement extends only to the fact LDL gets close enough to the site(s) to deliver the atherogens.

      There exists an emerging and likely successor to the fat/cholesterol hypothesis upon which conventional wisdom is built. The fat/cholesterol hypothesis reveals its weakness when it is tested against the facts. In contrast the likely successor to the fat/cholesterol hypothesis reveals its strengths when held aloft in the light of the evidence.

      The evidence that casts the greatest light is as follows:

      #1, Imai et al [1] established that cholesterol is not an atherogen after all.

      #2, The effect fats in the diet might have upon lipid profiles (cholesterol) is a moot point.

      #3, Saturated fats in the diet would not have exclusive influence over lipid profiles.

      #4, In 1953 Keys produced a study branding saturated fat as being angiotoxic. Dr Ancel Keys abuse of data, and the second rate standard of data he used, was exposed by Yerushalmy and Hilleboe in 1957 [2]

      #5, 2, 3, & 4 in this list are unimportant because oxidative stress commuted to cholesterol results in the conversion to oxidised cholesterol, and oxidised cholesterol better accounts for atherogenicity than does cholesterol itself.

      #6, The evidential basis backing the practice of lipid modification is not nearly so strong as conventional wisdom would have it. The war being fought upon cholesterol is phoney and without mandate.

      #7, Even if the war on cholesterol numbers were justified (recall it is not) recourse to statins is a crude methodology. Remember statins act as HMG-CoA reductase inhibitors which places mevalonic acid in short supply which risks placing all six known derivatives in short supply too.

      #8, There is no real justification to wilfully impede synthesis of cholesterol from mevalonic acid.

      #9, When we impede synthesis of mevalonic acid there is every risk CoQ10, dolichol, tau protein, seleno-protein, and nuclear factor-kappa B will be in short supply too. All are purposeful biochemicals.

      #10, Elephants need cholesterol too, we ought not forget that.

      #11, That elephants need mevalonic acid and dolichol is implied by biology and the level of ‘empathy’ elephants exhibit amongst species. That elephants grieve is evidence they have need of dolichol, more say than a crocodile.

      #12, Through being so indiscriminate in the way they act statins risk physiological side-effects in 100% of takers.

      #13, Through targeting a phantom and quantitative cause (high cholesterol) statins and any other class of lipid modifying intervention miss the qualitative process (oxidation of cholesterol) that is actually the cause of atherosclerosis. Any benefits of statins are truly incidental to their intended action.

      #14, Knowing that oxidative stress commuted the way of cholesterol is the cause responsible for development of atheromas paves the way for a fresh look at physilogy.

      #15, CVD is multi-factorial. Something conventional wisdom cannot explain is ‘convergence’. Just how do lifestyle and other epi-physiological risk factors commute to one physiological process (atherogenicity) in common? I’ll give you a clue. Think about a notional axis of cortisol, homocysteine, and oxy-cholesterol (CHO-axis), then next think about the process of methylation and how compromise to the process of methylation might bear upon this notional CHO-axis. With a bit of work epi-physiological risk factors can be shown to converge upon aspects of the CHO-axis, and mostly via added demand for methylation, or through compromise to capacity to supply detoxifying methyl (CH3) donations.

      #16, That epi-physiological risk factors, the better of them anyway, can be shown to converge upon the balance of mathylation and thence have bearing upon the CHO-axis, satisfying the need to describe ‘convergence’, is amongst the best of the ideas to emerge in this current century. Everybody knows ‘stress’ causes heart disease. That glucorticoids may be a drain upon methyl donors, and that homocysteine levels may rise as a result, is certainly a seam worth exploring.

      There Jordon, that ought to have your PHD research track along the right lines.

      In the light of the evidence Malhotras piece, despite it missed some salient points by a country mile,was essentially correct and a breath of fresh air. Abramson et als critique of intentions to half the QRISK2 threshold was entirely justified because the evidence does not support even the present guidelines issued by NICE upon lipid modification. Catalysts broadcasts were essentially correct, directing concern where concern ought to be directed. In two instances ‘eminence’ was allowed to nobble the ‘evidence’. Those attempting to express dissent are being expected to do so to far higher standards than was ever the case along the way of establishing a very errant consensus in the first instance. It is an outrage.

      Notes:
      1, Imai, Wetherssen, Taylor & Lee “Angiotoxicity and arteriosclerosis die to contamination of USP-grade cholesterol.” Archives of Pathology and Laboratory Medecine 100:565-572, 1976.
      http://legacy.library.ucsf.edu/documentStore/n/k/r/nkr20a00/Snkr20a00.pdf

      2, Garth Lane, “Heart of the Matter.” The Actuary Magazine, August 2011.
      http://www.pensionsfirst.com/media/11323/TheActuaryAugust2011.pdf

      Footnote: Jordon do get in touch. There are three pdfs that could save you a lot of heartache and which I would willingly share. One especially casts light upon the merit of the most likely and promising successor to the ailing fat/cholesterol hypothesis.

      email: cjpalmer [at] talktalk [dot] net

      • Editorial

        Many thanks for your hugely well-informed and generous-spirited contribution – just the kind of involvment in a debate HIUK was set up to enable. It has been suggsted to me that most medics understanding of the metabolic and homronal changes linking cardiovascular and lipid physiology is not that good. “They do it in year one and then forget it,” remarked an Oxford professor who is currently researching ketosis.

        • Thank you Jerome, that is just the kind of encouragement I needed. The folks around me simply cannot conceive how big a drain it is to work alone and not be able to discuss matters with a person of equal concern and comparable advances.
          The ‘dots’ that are in my possession were all supplied in books and stuff written by others, but I feel I recognised ‘dots’ in the amassed body of their work they had not ‘joined’ and I managed to join some of them.
          In the event I think the proponents of homocysteine theory have now trended to perceive homocysteine as more as a conveyor of oxidative stress than as an outright atherogen. In vivo and in vitro homcysteine produces consistent atherogenic results, but seems to do so by oxidising cholesterol. The question is open to when and where?
          While the likely successor to the fat/cholesterol hypothesis is something I figured for myself (at least in the scratchiest of sketches) a chap named Stanford Field figured it better and sooner than I.
          Fiona Godlee has inidcated willingness to meet with Dr John Briffa, ‘rapid responses’ to the BMJ http://www.bmj.com/content/348/bmj.g3306?tab=responses reveal a bit of indignation and people power, and so the smoke is rising.
          Professor Sir Collins actions and exertion of undue eminence may have backfired, and now this spat is set to escalate. The outcome will be, and we sceptics must make it thus, that more somke rises and more people gain a sense that there ain’t no smoke without fire. Imais paper says the guidelines on lipid modification amount to fraud. Garth Lanes actuarial analysis says Keys committed a fraud.
          The link to Lanes article is returning the 404 exception. Lucky I have a copy.
          Jordon can be grateful. We’ve all but written his thesis, at least in outline. but if Jordon insists on writing up his thesis in the ‘faithful’ style he risks a very real prospect it will soon be rendered worthless by a seas change in public and medical opinion.

    • Editorial

      Apologies for slow reply – was away for a long weekend and then events got in the way. So thanks for taking the time to write such a detailed response, although I disagree with most of it. Some of my points overlap with your post today but will respond to this one first.

      As I said originally the claim that “side effects of statins occurred in 18 -20% of people” was retracted. I also mentioned the criticism that it didn’t reflect “necessary caveats” or the “uncontrolled nature of the study.” Malhotra in a “reply to some responses” has pointed out that “initial rate for discontinuation for all causes” was …”far higher at 53.1%” and while accepting that the great majority of those who went back on the drug were still on it after a year, he points out that “the majority were either on a different statin or a lower dose”. In other words the drug was most likely still having an impact.

      However disagreements over percentages in Zhang is really a distraction. It was only mentioned in passing in both papers. It was not relevant to the key point of Abramson’s – that the 2012 Lancet paper did not demonstrate a reduction in overall mortality in healthy patients – and that saturated fat was not a major contributor to heart disease in the case of Malhotra’s.

      The relevance of Zhang is that it just one among many studies that illustrates there is a genuine uncertainty about the level of side effects and so about the risk/benefit of drugs given to millions.

      The precise level of side-effects was also not central to my post which was about the unscientific way Professor Collins had attempted to have the work of both men withdrawn. I was not making a statement about the level of side-effects, although I think Collin’s figure is very unrealistic, I was objecting to the way he went about responding to his critics.

      Like Rory Collins, you pointed out that Zhang’s study had various shortcomings, such as “no control group”, as if they had not already been acknowledged. I had referred to then in the original article and asked, if the problems with observational trials needed to be acknowledged, why not the numerous shortcomings of RCTs? A point you chose not to deal with.

      Instead you chose to pick up on the fact that commercially funded RCT trials had found a similar rate of side-effects in control and treatment arms. In the original article I set out a number of reasons why RCTS were unreliable sources of side effect data and also pointed out that in the case of the big statin trials held by the CTT, no independent researchers were allowed to access them, making conclusion from them even more unreliable. Also points you chose not to acknowledge.

      You say statins play a vital role in “patients at high enough risk” – a phrase that skips lightly round the crucial question, raised by the issue of unreliable RCTs: just how high does a risk have to be to be worth treating?

      Your observation that Abramson has been “making a living being anti-statins” is untrue and insulting. He is a lecturer on Lecturer on Health Care Policy at Harvard who has published one book on the serious flaws in drug research – Overdosed America – and published a relatively small number of articles that relate to drugs, health guidelines and evidence; his area of expertise. Contrast that with the 90 million pounds that Collins has received from one drug company to do research on their product. I don’t think the point you “think is worth making” carries any weight at all.

      You then turn to Malhotra and assert that his claim that cholesterol levels have nothing to do with heart disease is “rubbish”. Malhotra’s rejection of the cholesterol hypothesis is closely connected to his successful publicising of the weak evidence for the claim that saturated fat causes heart disease.

      This is a complex area with a lot of disagreement but it is certainly not settled by pointing to the very dubious claim that the more you lower cholesterol the more you risk of heart diseases goes down. It doesn’t apply to the elderly, for instance, and there are many examples of the “French paradox” where raised cholesterol is linked with fewer heart attacks.

      The original claim that statins would cut cardiac disease by 30 per cent has not been supported and the number of sufferers has increased from about eight per cent of the adult population in 1995 to 12 per cent today. Statins may have cut the number of subsequent heart attacks in patients with heart disease but so has other factors like a reduction in stenting and improved cardiac treatment.

      And what about that remarkable drug ezetimibe, which is very effective in lowering cholesterol – we spent 60 million a year on it in England alone – but it has never been shown to reduce risk of heart attacks?

      But your comments seem most error prone when it comes to your description of the Catalyst programs – curiously since they were made in Australia in the city where you work. There were two programs – on statins and on saturated fats – which you described as – “one of most biased pieces of television journalism” and raise, again, the issues of “undeclared financial interests”.

      The vested interests claim is odd since the two groups who attacked the programs most fiercely were those linked with statins and those linked with large food companies that have benefitted hugely from the low fat hypothesis. Statins are of course now mostly off patent but just how many new, and very expensive cholesterol drugs, do you think are waiting in the wings?

      Your “absurdly biased” allegation just doesn’t stand up as my post made clear. The committee set up to investigate the avalanche of criticism that greeted the program putting the case against low fat found no grounds at all for the claims that journalistic standards had been violated. The investigation of the allegations against the statin program upheld just one – out of 17.

      Your claim here is pure rhetoric just like your reference to me as “mouthing off about evil pharma”. My post never mentioned “evil pharma”. The problem is not evil pharma but senior academic figures making claims about the benefits of the drugs using data gathered by the companies that is not available to anyone else. Points you have perhaps understandably ignored.

      • In the interests of being more specific I might address some of your points in turn, bearing in mind that even in my original post I was only challenging some, by no means all, of what had been said.

        You wrote:

        “Malhotra in a “reply to some responses” has pointed out that “initial rate for discontinuation for all causes” was …”far higher at 53.1%” and while accepting that the great majority of those who went back on the drug were still on it after a year, he points out that “the majority were either on a different statin or a lower dose”. In other words the drug was most likely still having an impact.”

        This interpretation is not valid. When anyone on a statin complains of a symptom that even might be caused by it, the first thing that happends is it is stopped. Presuming symptoms resolve most doctors will then either start a lower dose or start another statin. This does not prove the statin caused the symptom. This is why randomised trials matter so much here. Like I said previously in PROSPER, as an example, the incidence of muscle aches and pains was the same in the placebo group as the statin group. Lots of people get aches and pains but if they have aches and pains on a statin many manyt doctors will just stop it and change statin or lower the dose later. This is cautious and sensible medicine. Who wants to be the guinea pig who gets put back on the same dose of the same drug just to see if it was responsible? This is why observational studies like Zhang’s are unreliable and why you can’t infer that the statin actually caused the problem that resulted in the cessation rates published by Zhang. Yes the statin might have caused the problem. It also might not have. I reccognise you have acknoweldged the shortcomings of this trial type but you can’t infer causality based on the associations in this single arm observational study, particularly the magnitude.

        You wrote:

        “It was not relevant to the key point of Abramson’s – that the 2012 Lancet paper did not demonstrate a reduction in overall mortality in healthy patients …”

        This is what Fiona Godlee wrote to defend her position. It is not the main purpose of his article at all. His clear argument is that the benefits of statin therapy in lower vascular risk do not outweigh the risks. When Abramson misquoted Zhang’s work he was distorting the magnitude of risk which alters the benefit/risk arguments he presents. The mortality finding in the CTT analysis is one of many interpretations of data he presents, it is not the chief message.

        It might also be worth noting that the information Abramson used to calculate his mortality analysis was wrong – not because he didn’t have access to it – but because he never read the figure legend or checked out the comprehensive web appendix. He missed out several hundred other deaths that could not be classified into vascular or not vascular. If he had read the web appendix he could have found the actual values to use. It is embarassing that he attempts to collate published data and can’t even read the it accurately enough to get the numbers right. If you do look at the CTT paper Webfigure 8 has the actual numbers he should have used.

        I agree with you there is some uncertainty about some of the possible side effects of statin therapy, particularly rates of myalgia which are no doubt the most common side effect and the best estimate is up to 10%. This is as opposed to myopathy, which has a clinical definition related to CK muscle enzyme levels and rhabdomyolysis, both of which are rare and have been well documented to be rare in all the statin RCTs.

        You wrote:

        The precise level of side-effects was also not central to my post which was about the unscientific way Professor Collins had attempted to have the work of both men withdrawn. I was not making a statement about the level of side-effects, although I think Collin’s figure is very unrealistic, I was objecting to the way he went about responding to his critics.

        Professor Collins acutally approached the BMJ in late November and presented the editor with a detailed powerpoint presentation in December. It was in response to the complete inaction taken by the journal in rectifying the misquotations made that he took his actions further. I think the real problem in this whole debate is the inordinately long time it took a journal to rectify this problem. It should not take 6 months to identify and fix such errors.

        You wrote:

        “if the problems with observational trials needed to be acknowledged, why not the numerous shortcomings of RCTs? A point you chose not to deal with.”

        Yes there will be shortcomings of RCTs. Agreed. Hopefully a meta-analysis of 27 such trials should have ironed out individual trial shortcomings. There will be generally far fewer shortcomings from an RCT than a single arm observational study.

        You wrote:

        “…I set out a number of reasons why RCTS were unreliable sources of side effect data and also pointed out that in the case of the big statin trials held by the CTT, no independent researchers were allowed to access them, making conclusion from them even more unreliable. Also points you chose not to acknowledge.”

        The “big statin” trials are not held by the CTT. The CTT holds only the trial data that was requested and uniformly available for almost all the trials in order to perform meta-analyses. Outcomes specific to only a few of the trials are not held by the CTT at all. In addition the CTT is not industry funded. Some of its members were responsible for conducting some of the statin trials. The insitutions they represent – the Universities of Oxford and Sydney – and their respective clinical trials units do not receive industry funding for any of these analyses. And if you seriously consider the results from a meta-analysis of 170,000 trial participants with individual patient data from 27 separate RCTs as unreliable then you must have no faith in any evidence based medicine. These findings are amongst the strongest and most definitive modern medicine has. They don’t answer every question but the questions they do answer are as good an answer as you will get and most results are pretty definitive.

        You wrote:

        “You say statins play a vital role in “patients at high enough risk” – a phrase that skips lightly round the crucial question, raised by the issue of unreliable RCTs: just how high does a risk have to be to be worth treating?”

        The CTT addressed this question in their 2012 paper examining outcomes in patients at different levels of vascular risk. The short answer is that statins work in everyone at every risk level, but it’s a relative effect. If you have a lower absolute risk to start with your absolute risk reduction with statin therapy will be smaller.

        As you are aware the issue of exactly what risk level we should recommend statin treatment is under debate. For your reference the AHA/ACC/ASA recommend treatment with a 10 year risk >7.5% ; The Europeans recommend treatment with a “SCORE” level of 5%, which equates to a 10 year risk of a vascular event of about 15% depending on gender. The NICE guidelines previously recommended treatment at a 10 year risk >20% but currently proposed revisions under consideration recommend 10 year risk >10%.

        You wrote:

        “Your observation that Abramson has been “making a living being anti-statins” is untrue and insulting. He is a lecturer on Lecturer on Health Care Policy at Harvard who has published one book on the serious flaws in drug research – Overdosed America – and published a relatively small number of articles that relate to drugs, health guidelines and evidence; his area of expertise.”

        You have left out that he acts as a medical witness in court cases taken out by people against statins. He has a strong and vested interest in driving this controversy.

        You wrote:
        “Contrast that with the 90 million pounds that Collins has received from one drug company to do research on their product. I don’t think the point you “think is worth making” carries any weight at all.”

        I would appreciate a reliable reference indicating he has received 90 million pounds from pharma please. It seems far fetched.

        You wrote:

        “Malhotra’s rejection of the cholesterol hypothesis is closely connected to his successful publicising of the weak evidence for the claim that saturated fat causes heart disease.”

        Malhotra’s article is akin to an opinion piece in so much as it is bereft of references in multiple instances where there should have been.

        You wrote:

        “This is a complex area with a lot of disagreement but it is certainly not settled by pointing to the very dubious claim that the more you lower cholesterol the more you risk of heart diseases goes down. It doesn’t apply to the elderly, for instance, and there are many examples of the “French paradox” where raised cholesterol is linked with fewer heart attacks.”

        You shouldn’t really be pointing to subgroups like the “elderly” and the “French paradox” to support your argument that cholesterol lowering does not lower heart disease risk. If it’s not true you should be pointing to large trials from large numbers of people. In addition there is evidence in the elderly. Look at PROSPER and 4S. The graph showing the relationship between LDL lowering and reduction in vascular risk can be found in the CTT paper in the Lancet in 2005. Not really dubious. I think it’s pretty robust evidence actually.

        You wrote:

        “The original claim that statins would cut cardiac disease by 30 per cent has not been supported and the number of sufferers has increased from about eight per cent of the adult population in 1995 to 12 per cent today. Statins may have cut the number of subsequent heart attacks in patients with heart disease but so has other factors like a reduction in stenting and improved cardiac treatment.”

        I don’t know who owns this “original claim” and why it carries so much weight, but for each 1 mmol/L LDL cholesterol reduction, major vascular events are reduced by 20%. So if you lowered your LDL cholesterol by 1.5mmol/L then major vascular events are reduced by 30%. If you lower it by 2mmol/L it will be 40%.
        Heart disease has increased because heart disease risk is influenced by blood pressure, diabetes, smoking, depression, obesity, kidney disease and most importantly age. People are older now. There is more heart disease. This doesn’t mean statins didn’t reduce their relative risk by 20% or 30% or 40% or whatever. We aim to treat all risk factors to prevent heart disease, not just one. Statin therapy is just one component of it.

        You wrote:

        “And what about that remarkable drug ezetimibe, which is very effective in lowering cholesterol – we spent 60 million a year on it in England alone – but it has never been shown to reduce risk of heart attacks?”

        Agreed. There is some weaker evidence for ezetimibe but it isn’t anywhere near as compelling. If statins are truly unique and their actions have nothing to do with LDL cholesterol lowering we will find out very soon when the PCSK-9 inhibitor trial results come out. They lower LDL-cholesterol by extremely large amounts (50-60%) so we will have answers on this fact soon. It doesn’t change the evidence that statins reduce vascular events.

        You wrote:
        “But your comments seem most error prone when it comes to your description of the Catalyst programs – curiously since they were made in Australia in the city where you work. There were two programs – on statins and on saturated fats – which you described as – “one of most biased pieces of television journalism” and raise, again, the issues of “undeclared financial interests”.

        The vested interests claim is odd since the two groups who attacked the programs most fiercely were those linked with statins and those linked with large food companies that have benefitted hugely from the low fat hypothesis. Statins are of course now mostly off patent but just how many new, and very expensive cholesterol drugs, do you think are waiting in the wings?”

        The program was attacked because it was biased. I saw both episodes. The National Heart Foundation of Australia attacked it for good reason – it was a scare campaign which basically said statins don’t work in primary prevention but the message was so distorted droves of people stopped their statins who have heart disease. I know one of the two doctors interviewed as part of the limited time offered to “defend” statins and he indicated his interview had been hacked to pieces with editing to imply indecision and uncertainty in his answers. The chief medical advisor for the ABC publicly stated the program was damaging to patient health.

        You wrote:

        “Your “absurdly biased” allegation just doesn’t stand up as my post made clear. The committee set up to investigate the avalanche of criticism that greeted the program putting the case against low fat found no grounds at all for the claims that journalistic standards had been violated. ”

        I copy for you a summary of the ABC’s findings. At contention was nothing to do with “low fat” – something which I think this blog keeps confusing – at issue was the biased presentation of the evidence for statins. You don’t have to agree with the “cholesterol hypothesis” not to acknowledge the blinding evidence that statins lower vascular disease. These were the committee findings, as reported in the Australian newspaper:

        ——————
        “The AC&A reported “flaws with the programs presentation did result in a finding that editorial standards had been breached as the program’s treatment of the use of statins “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,” the AC&A reported. “This perspective was necessary to a fair understanding of the pros and cons of statin use in this group.

        “Furthermore, by omitting a principal relevant view – held by the National Heart Foundation and other experts – that statins are useful in primary prevention if carefully targeted, the program had the effect of unduly favouring the perspective that statins are ineffective in primary prevention.

        “Our findings in relation to the second episode are necessarily different because a principal relevant perspective about the effectiveness of statins – a topic central to the program – was not presented.”

        —————————

        You wrote:

        “Your claim here is pure rhetoric…”

        Based on above I disagree.

        You wrote “…just like your reference to me as “mouthing off about evil pharma”

        Agreed you did not use the words “evil pharma”. But you have implied the data from the trials they conducted is so untrustworthy that a meta-analysis of 27 trials cannot be trusted either and that they have paid Prof Collins 90 million pounds which is why he is witholding critical statin information from the public (presumably in his lair). It is hard not to think there are conspiracy theories afoot.

        I hope I have acknowledged enough of your points to at least partially refute your repeated insinuations that I was cherry picking. I realise little of this may change your mind but I hope others may realise there is more to this debate.

        One final point – statins work in both primary and secondary prevention – this has been shown on several occasions – just like in secondary prevention they reduce major vascular events by 20% per 1mmol LDL cholesterol reduction. They also reduce all cause mortality in primary prevention – although already presented in JACC in 2012 you will see more definitive data published in the near future.

        • Editorial

          Re Malhotra and discontinuation of statins:
          Your claim that the: first thing a doctor does when a patient complains is to take them off it, doesn’t square with the real world – as is so often the case with the statin story when based on clinical trials. Studies by Golomb for instance show that responses like “at your age what do you expect” are far more likely.

          As for going on a lower dose my understanding is that the bulk of trials involve higher dose statins, so it is essentially a pragmatic response.
          There is some interesting research by Dr David Healy at Rxisk on what can be done to get far better reporting on patient reports of side effects and doing a challenge, re-challenge is one way of generating data which has a bit more weight than the “anecdotal” report of side-effects.

          Re Abramson’s paper and overall mortality.
          I’ve put your comments to him and this is his response to the point that includes Fiona Godlee:

          “Dr. Fulcher is not correct. The main point of the article was to show that statins do not provide an overall mortality benefit or reduction in the risk of serious illness in people with less that 20% risk of stroke or heart attack over the next 10 years. Therefore ANY risk of side effects associated with statins tips the equation in the negative direction—not to mention the cost of statins in money and opportunity to focus on healthy lifestyle changes that do, in fact, reduce the risk of heart attack and stroke.”

          You claim he used the wrong information to calculate mortality. This is what he replied:

          “Calculations based on the figure we cited in the article show statins provide no reduction in mortality for people with less than 20% risk of cardiovascular disease. That figure reported vascular and non-vascular deaths. Webfigure 8 summarizes all deaths and includes some patients whose cause of death could not be classified as vascular or non-vascular. Based in either figure, CTT data show that statins do not reduce the risk of death in people with less than 20% 10-year risk. Further, Webfigure 8 shows that statins do not even reduce the risk of death from heart attack or stroke or both combined. Dr. Fulcher would provide a far greater public service if he would focus on the CTT’s data showing no mortality benefit overall or for cardiovascular deaths than on which figure was cited (both show the same result for overall mortality).”

          You also made a point about myalgia to which Abramson replied:

          “The definition of myopathy is not the issue. CTT defines the word narrowly to include CK enzyme elevations (reporting 0.5 cases per 1000 patients over 5 years). A paper in the Cleveland Clinic Journal of Medicine titled “Statin myopathy: A common dilemma not reflected in clinical trials” uses the term “myopathy” to include the full range of muscle symptoms: from muscle soreness to elevated muscle enzyme levels, to muscle symptoms with CK enzymes at least 10 times the upper limit of normal. The important point for people to understand is that statins cause some amount of muscle symptoms, and given their lack of net risk reduction in the low risk population ANY amount of side effects tips the balance. This is the secondary point of our paper. Squabbling about whether the number is 5%, 10%, 20% or more does not change the benefit to risk equation from being dominated by the latter.”

          You claimed he had a vested interest in driving the statin controversy because he has acted as a medical witness. He replied:

          “I have, in fact, been retained as an expert in litigation involving a statin. This is long after I have written that the 2001 and 2004 U.S. guidelines exaggerated the benefits of statins for low risk women and people over 65. Dr. James Wright and I published a paper in the Lancet in 2007 (6 years before my involvement with statin litigation) showing the lack of evidence to support the U.S. Guidelines. In fact, the 2013 U.S. guidelines finally admitted that there was not evidence to support the recommendations for women made in 2001. In 2010, I was a co-author on a paper that examined unresolved epidemiological questions in the prematurely stopped JUPITER trial, 3 years before I was retained as an expert in litigation involving statins.”

          This is how Abramson summed up his position and his response to such attacks.

          “The primary issue is whether or not statins provide more benefit than harm to people with less than 20% risk of cardiovascular disease over the next 10 years. Based on CTT data, statins provide no net benefit, and the evidence is incontrovertible that statins carry some risk of side effects. This is the public health issue. Dr. Fulcher and others are attempting to vilify me and my co-authors as well as the BMJ for framing the question in the terms that affect real people. If they would focus more on the public health debate and less on nitpicking researchers who are trying to engage in a full and open debate the public would be far better served.”

          Your defense of Collin’s actions is that the BMJ took long to respond and that he offered a detailed power point presentation. That actually just reinforces my “eminence” point. It is my understanding that he was offered the chance to respond in the normal way via a rapid response to the articles and he was also offered a slot for an article. He rejected both and continued to demand special treatment. I would humbly suggest that your experience of journalism is limited if you think any editor would welcome the chance to view a detailed power point from every reader to took issue with an article.

          Re who hold what and who gets paid for what at CTT
          Your reply is yet more of the “trust me I’m a statin researcher response”. You may be giving an accurate account but no one can verify it because the whole operation is shrouded in secrecy. I gather that the relevant companies (stakeholders) send representatives to annual meetings to decide what to analyse each year. Exactly what you have there is not remotely transparent. You sound as if we all have good reason to trust drug company results. The evidence from a host of books and publications suggests that is not the case.

          At no point in your responses have you dealt with the way that RCT’s can be manipulated in ways to produce favourable results – was there none of that in these in any of those trials? You also consistently use relative benefit. How many people with a 10% risk would have to be treated for one to benefit. And what change in the (under-reported ) side effect rate would reverse the risk/benefit ratio?

          Re the Abramson vested interest point – see above

          I’ll come back later on the lower cholesterol = less heart disease risk later.

          Re the Catalyst program on statins there seems a lot of special pleading. It was one program putting forward a view that gets a tiny fraction of the coverage given to the claim that statins for all is the way to go. The question of whether the official view got enough air time was a judgment call. Just one of the allegations they didn’t was accepted.

          Re low fat –
          There is no confusion here. One of the programs was about the poor evidence that saturated fat is a risk factor for heart disease – and that fear is closely linked with the cholesterol hypothesis and with the disastrously erroneous advice to eat a low fat diet.

          Re The AC &A report
          This simply repeats what I said in a more detail; it is still one point accepted out of 17 and the wildly exaggerated response to it mirrors the response by Professor Collins to the BMJ articles.

          Re the money and the CTT data.
          The point is not that I know the data is fudged but it is not an unreasonable assumption that trials have been designed to produce favourable results – you surely can’t be unaware of the large amount of evidence showing that drug companies do this frequently. Why should they suddenly become squeaky clean when trialing statins? It is for that reason that greater transparency is essential.

          And you misrepresent my point about the drug company funding. I have nowhere claimed Professor Collins was personally was “withholding critical information”. I am merely making the, surely uncontroversial, point that being in receipt of 90 million pounds could create a conflict of interests. After all you claim that getting fees for expert testimony in court – surely small change by comparison – could be driving a critical approach to statins.

          I also do not believe he is withholding information as an individual but because that is the nature of the deal done with the companies back in the early nineties and the ownership of the data still lies with the companies – something that was acceptable them but which is viewed with considerably more distrust now. If that is the sign of a “conspiracy theory” then you would have to include in it the BMJ, the EMA and many senior doctors. Really?

          • I thank you for putting these points to Dr Abramson and for both of your responses.

            The one thing that I would say is that Abramson places a lot of emphasis on overall mortality when dealing with primary prevention trials. It should be understood by everyone that the duration over which the statin trials were conducted was, in the end, a mean of 4.9 years. These trials did show a significant reduction in major vascular events which is made up of major coronary events, stroke and coronary revascularisation. The same significant reductions are seen in people with a 10 year risk under 20%.

            The number of deaths in both groups (statin or placebo) was relatively small, and whilst the same relative risk reduction estimate was observed in overall mortality, the upper confidence interval does exceed 1 for this subgroup (<20%). These group sizes were just not large enough to produce an independently significant result. This is the alternate way to interpret the statistics Abramson is challenging, and is generally more widely accepted.

            The other more important point is that If someone does have a heart attack, stroke or need a stent or bypass, is this not a benefit?? Would you rather reduce your risk of suffer a permanently disabling stroke than have a 10% risk muscle pains? Moreover it follows that these serious cardiovascular events carry with them a much higher risk of recurrence and ultimately death. The duration of the primary prevention trials was not long enough to generate all the deaths needed to produce a significant mortality reduction in all subgroups. This is why the long term analyses of the statin trials have been conducted and show extended long term mortality benefits (overall) in those patients who took statins in those trials, all those years ago. The benefit from being randomised to a statin in those trials produced a long term mortality benefit a decade after the trials ended. Several of these trials have been published already.

            Regarding the fact Sir Collins was able to meet with the editor of the BMJ is an indication of the fact his contribution to medical research is considered so profound his input into this area is highly desirable because he is considered a world expert. Of course the toilet cleaner should not be given the same default opportunity, unless they are also a world expert on statins. I would hope world experts are allowed the opportunity to express views on topics within their expertise. This was not inherited expertise. It was earned through a lifetime of work and contribution. At real issue is that the misquotation in the BMJ were not difficult to pick up. Anyone could do it if they read Zhang's article. The correction of these misquotations was embarrassingly untimely.

            Finally the CTT annual meetings do not involve industry heavyweights deciding what should be analysed. This is just not true. The decision on what to analyse comes from the CTT.

            Again I appreciate the contribution of all concerned in these discussions.

          • Editorial

            RCT’s too short
            You use this as an argument to cast doubt on Abramson’s conclusion that the statins don’t affect overall mortality. It could just as well fit with my original point that RCT’s have value in answering specific questions but to rely on them to provide the proof that trumps every other sort of evidence is unwise. A key reason for performing RCTs is to gain a licence (do you still only need two favourable ones?) and for many drugs few trials are longer than six months. Questions about the balance between patient’s interests and commercial interests hover over these trials.

            Isn’t a bit of muscle pain better than a stroke?
            This again shows you don’t really get the implication of the fact that statin critics are not as sanguine about both the benefits showing up in the trials (for reasons already extensively covered) as you are and they are certainly not convinced by your claims about side-effects. How many healthy primary patients at the new 10% level have to be treated to prevent one having a stroke? And what is the corresponding Numbers Needed to Harm figure for risk of diabetes plus muscle pain plus cataracts etc etc?

            Sir Rory
            Sorry but each time you seek to defend Sir Rory and his Eminence based medicine approach you make things worse. He is of course a highly respected world expert etc. but no one is claiming that that a toilet cleaner should have the same access as him to a medical journal. But surely what counts in science is your arguments and your evidence not your awards. So it is reasonable to expect him to behave like any other expert and follow the normal rules and discuss and debate in rapid responses or in an article. Not to rush in with special power point presentations and then go round newspaper and other media giving interviews that accuse those criticising his data of killing people. I’m surprised none of his critics have contacted a lawyer.

            CTT meetings and drug companies
            You say there are no drug company representatives present I have been reliably told there are. They may not make a decision but it seems very likely that they are present. After all they “own” that information. But we have no way of deciding because of the secrecy shrouding this organisation.

          • Editorial

            To jordan:
            put your point re mortality data for primary patients that trials weren’t run for long enough for benefits to show up to Abramson and he responded:

            “This is the story of claiming orphan’ s benefits after killing your parents. Statins have been on the market since 1987, all trials have commercial funding. Nothing stopped manufacturers from running longer-term trials, except the risk that the outcomes wouldn’t be as desired when sales were already maxed out without the information.”

        • Jordan Fulcher wrote:
          “Would you rather reduce your risk of suffer a permanently disabling stroke than have a 10% risk muscle pains?”

          I get sick of seeing statin side effects described using this euphemism, which sounds as if it were dreamed up by a drug salesman!

          I know this is primarily a place for dispassionate medical discussion, but I think it is worth describing things as they really were.

          Before my problem with Simvastatin began, I would enjoy long walks and cycle rides in the hills round here. Now that I have been free of statins for over a year, I can do exactly the same, but when things were really bad, I recall parking and walking about a mile, gently up hill. Normally I would have gone much further, but the pain and weakness in my leg made that seem inadvisable. I rested for a bit, and walked back to my car, where I rested some more before I felt ready to drive home! My leg was also liable to cramp in a very painful way when I first got out of bed, or if I bent over to fasten my shoe laces.

          I have talked to a number of people who have had problems with statins, and there are other accounts you can read on the internet, and nobody described their experience in the terms you use (so I am not, I think, describing some particularly horrible interaction between statins and polio).

          Dr Kendrick summed this up nicely by observing that taking a statin won’t make you live 15 years longer, but you may feel as if you had!

          One of the reasons I stopped and started Simvastatin 3 times, was that the symptoms I was experiencing didn’t seem remotely like mere “muscle pains” – which sound as though they would merge with everyday tiredness.

          There is, of course, a much rarer statin side effect, rhabdomyolysis, but I wonder if this problem would be more common if it were not for the fact that people search the internet or talk to friends and are warned off statins before it is too late. I certainly didn’t feel I had experienced all that Simvstatin had in store for me!

  • Jordan Fulcher wrote
    “Molhotra is a cardiology registrar who argued in his paper that cholesterol levels have nothing to do with heart disease. Such a sweeping statement is rubbish. We can graph all the randomised statin trials and show that for every 1 mmol/L LDL cholesterol reduction achieved, vascular events are reduced by 20%, irrespective of what level cholesterol you start with. This proves a linear relationship between cholesterol levels and heart disease risk.”

    As I non-medical person with a science background, I find it hard to square that statement with this analysis of the paper ” Corti MC et al: Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons.”

    http://drmalcolmkendrick.org/2013/07/23/proving-that-black-is-white/

    This was a total eye-opener to me, because it (i.e. Corti’s paper) took a study which showed that those with higher cholesterol levels get slightly less CHD, and adjusted it until it showed the exact opposite!

    This seems a terrible way to perform research. If the original study was so flawed that it could produce completely the ‘wrong’ answer, which would then need ad-hoc adjustments to ‘correct’ it, it should not have been run in that form.

    If there really is an answer to the criticisms of the entire saturated fat/cholesterol/CHD hypothesis, it would be best to focus in detail on what your opponents have written, rather than throw in another statistic, which (for all I know) may have been produced by the same tortuous route described in the above link.

    It might also help to address the, presumably undeniable, fact that the saturated fat hypothesis was based originally on Ancel Keys’ cherry picked graph of heart disease plotted by country against national saturated fat consumption, which omitted most of the available data because it didn’t fit his hypothesis!

    Your discussion about the side effects of statins, really illustrates how little is knows about this subject. Since Simastatin has been in use for over 20 years, isn’t it time we actually had some reliable (and long term – see my earlier comment) data about side effects? Stating that 3/4 of people who stopped statins, returned in 12 months, tells us very little, because people are under enormous pressure to conform with their doctor’s advice.

    I would be really interested to see a detailed point-by-point rebuttal of the information in Dr Kendricks book, “The Great Cholesterol Con” (most of which is technical).

  • I think there may be some crossing of lines in the arguments being presented.

    1. Some of what is discussed here challenges the notion that simple measures of cholesterol are not entirely accurate / predictive of CVD and that excessive emphasis is placed on its importance when discussing CVD risk.

    On matters of biological action of cholesterol I will by no means profess to be an expert, and the points made by Christopher Palmer are not being challenged. There is no doubt in my mind issues of oxidation are paramount to atherogenesis, and yes it is acknowledged that there are other lipid markers which are better predictors of atherosclerotic risk than straight LDL cholesterol.

    2. Even if we accept this, what I don’t think can be dismissed is the current collection of 27 randomised control trials which demonstrate that the relative risk of cardiovascular events is reduced proportionally to the amount of LDL lowering with statin therapy. If you don’t believe LDL cholesterol plays a direct role in atherogenesis in itself, its reductions by statins are directly correlated with reductions in vascular events in a clinically useful way to measure treatment effects. Even if Malhotra was correct in saying statins work because of their anti-inflammatory properties, we can measure the magnitude of cardiovascular protection acheived by measuring the amount someone’s LDL cholesterol has been reduced.

    Figure 3 in this paper shows individual trial LDL reductions and vascular event reductions and it’s a pretty convincing linear relationship. David should look at this since you asked me to provide some evidence…

    Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.[erratum appears in Lancet. 2005 Oct 15-21;366(9494):1358]. Lancet. 2005; 366(9493): 1267-78.

    Another figure to look at is figure 4 of the following reference, which shows that irrespective of the starting LDL cholesterol reduction, lowering of LDL cholesterol by 1mmol/L produces the same relative risk reduction in vascular events. This should not be confused with absolute reduction, which is lower at lower LDL starting cholesterol reductions as the figure shows.

    Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet. 2010; 376(9753): 1670-81.

    The highest form of evidence is currently considered to be a meta-analysis of randomised controlled trials. These meta-analysis were performed on individual patient data – not published data – and I think if people want to dismiss their findings you might as well believe that all medical trials are corrupt and none can be trusted. It is rare to find such an enormous database of trial information, and I should point out that the publication of these papers is via funding from the Clinical Trials Units in Oxford and Sydney University and have received no industry funding for their collation.

    I won’t dispute that individual trials funded by industry are not ideal, although in nearly all cases the trialists performed their research without industry involvement. In addition a certain practicality has to be applied here. Who should pay for them? Do taxpayers want to be slogged money to pay for a massive trial that may or may not make a company money in the chance it might work? This is beyond the scope of the purpose of this message really, but simply viewing all medical and scientific trials funded by the company that made the medication as unreliable is naive. Of greater importance is the relationship between funding body and the research group and what independence there was. I would hope in this case that the results of 27 separate randomised trials might be considered sufficient evidence that statins prevent CVD.

    3. If you want an example of a paper that is absolutely full of unreferenced assertions, look no further than Malhotra’s piece. He makes multiple assertions with no backing references for evidence.

    4. The issue Rory Collins has taken with the BMJ is that he notified them of the blatant errors made in Malhotra’s and Abramson’s papers back at the end of November and the editor made no moves to correct these errors in a timely fashion. It should not take the BMJ 5 months to work out these obvious errors and make them public. His issue is that the failure to correct them quickly has allowed the false claims about the magnitude of statin side effects to influence public opinion and dissuade people from taking statins. There can be no disputing that both these papers falsely represented the findings of Zhang’s paper, and in a debate about the pros and cons of statin therapy allowing these errors through even the review process is an embarrassment to the integrity of the BMJ.

    5. The Cholesterol Treatment Trialist’s collaboration is not witholding data. I can say that categorically because I know what data they have. When most of the statin trials were performed people were entirely focused on the big picture – do statins prevent vascular events and deaths ; and do they cause cancer, clinical myopathy, rhabdomyolysis? There is data presented for all these things already. What some trials did, and most did not, is collect more detailed data on reports of muscle pains (which is entirely different to myopathy as a clinical definition) and several outcomes. Some trials looked at cognitive function. Some looked at LFT derangements and other specific adverse events. Some looked at new diabetes. None of them used consistent definitions and hence when the individual trial data was collated by the CTT data for these outcomes was not collated because of the much lower numbers of patients in whom data was recorded and the variable definitions used. What I can say is that myopathy and rhabdomyolysis were slightly increased from a very very low incidence – myopathy at 0.1% and rhabdomyolysis much rarer still. No effects on cognitive function were found. No serious effects on LFT derangement were found. The rates of intracranial haemorrhage might be very slightly increased (evidence still not clear) but overall strokes are significantly reduced by a vastly greater number. The incidence of new diabetes diagnosis might be increased by about 10% but again the people who sustained these diagnoses had multiple metabolic syndrome risk factors and their vascular risk level was so great that the question of them overall net benefiting from statin therapy in preventing vascular events is without doubt.

    Should this information be examined? Yes. It actually has been by other trialists who collated specific data from a smaller number of trials where it was available – and these results have been published. And the CTT is currently attempting to uniformly collect data on other adverse events where possible, right now.

    But the notion that Sir Collins is sitting on a treasure trove of vital information from trials that is being deliberately witheld to deceive the public is completely and utterly false, and is akin to a conspiracy theory of no veracity.

    Remember we are only in this position, where the small rates of side effects from statins really matter – because the strength of evidence for their use to prevent vascular disease is so strong now that it is suggested they be used in primary prevention patients at increasingly lower levels of vascular risk. The question to be answered is at what level of risk do the benefits outweigh the risks. When people deliberately distort the risks like Malhotra and Abramson they distort the answer to this question.

    6. Finally David the long term effects of statin therapy have now been published in 7 separate legacy effects trials. These include long term follow ups of WOSCOPS, PROSPER, HPS, 4S, LIPID, ASCOT-LLA and ALLHAT-LLT. Mortality and CVD benefits are sustained over the original placebo groups and none have identified an excess of long term adverse events to date. I would dispute most people are “forced” to take statins, although perhaps some are.

    Do I think statins are perfect? Absolutely not. I think the evidence shows they reduce vascular events, and the real question is at what risk level do the benefits outweigh the risk. Perosnally I believe a 10 year risk level > 10% appears to be the best cut-off. The evidence for aspirin shows a similar cut-off due to its bleeding risks. And the emphasis on actual cholesterol levels takes a secondary priority to overall vascular risk, because as many people have pointed out, multiple risk factors contribute to this, and they should all be factored in when considering statin treatment.

  • Once again, thanks for responding.

    Jordan Fulcher wrote:
    “Figure 3 in this paper shows individual trial LDL reductions and vascular event reductions and it’s a pretty convincing linear relationship. David should look at this since you asked me to provide some evidence… ”

    Unfortunately, I don’t seem to be able to get beyond the abstract. This is very frustrating, because I clearly am not going to take out an expensive journal subscription to pursue this. However, I guess the key question is whether a person’s natural cholesterol level is linked to cardiovascular events.

    As I understand it the ‘alternative hypothesis’:

    Statins have a small benefit in reducing CV events in those who have already had one, but this is not the result of lowering LDL. Furthermore, overall mortality is not lowered even in these individuals!

    This would imply that LDL levels would correlate with CV events purely because LDL levels correlate with statin levels.

    I’d love to read the original paper(s). I would also love to see an open debate between supporters and opponents of statin treatment and indeed the whole cholesterol hypothesis, taken at a reasonably detailed level. I am sick of “Eminence Based medicine”.

    Do you have a view regarding Ancel Keys’ famous graph?

    It would also help if you can indicate the percentage reduction in CV events in those studies, because I can assure you that statins do cause huge problems for some people, and I would not want to take any drug long term if the gain was less than (say) a 10% reduction in my chance of suffering a CV event.

    ******Everyone should know the actual percentage gain they will obtain from taking statins – both in CV events and total mortality. ***********

    It would also help if ALL the relevant studies were published on the internet without restriction, because there are plenty of non-medical people who can follow graphs and statistics about outcomes, etc.

    I very much hope that Jerome will also jump back into this debate.

    David

  • Jordan Fulcher wrote:

    “This interpretation is not valid. When anyone on a statin complains of a symptom that even might be caused by it, the first thing that happends is it is stopped.”

    This was not my experience. In my case I had been taking Simvastatin for 3 years before there were problems, and it was only because I remembered that muscle problems were a side effect of statins that I suggested stopping to my GP. Maybe what you say is true if the side effects start in the first few weeks.

    My main concern is that there may be some people suffering severe statin side effects, who are still taking the drug!

    • Hi David,

      I’d be happy to email you any of the PDFs I have made mention of in my posts.

      Your personal situation was far from ideally managed and I share your concerns about what occurred. There’s not much medical defence for someone not considering a statin might be causing muscle pains. As you say people are more attuned to looking out for this early on but we are well aware that muscle symptoms related to statins can arise well down the track. The fact that you re-tried it 3 times is a slam dunk case of a side effect and no one could dispute that.

      The other point to make is that there is evidence that simvastatin in high doses associates with a higher risk of more serious muscle complications (myopathy and rhabdomyolysis) than other statins which is why in the US it is essentially no longer recommended (there are some fineprint caveats to this which can be found on the FDA website). Ordinarily current best practice medicine would suggest you should have been re-trialled on another statin, not returned to simvastatin.

      When it comes down to it we are all using medications which are rarely completely understood. We use them because we recognise that the evidence says they work in treating or preventing disease. That someone might experience an adverse reaction or side effect is always a possibility. Our ongoing aim is to identify an accurate benefit/risk profile as best we can. It is the frequency and seriousness of these side effects and the magnitude of what benefits the medication brings that is the question every patient and doctor must weigh up. This balance is always shifting slightly based on what we know. In the case of statins what started as a medication to treat heart disease patients alone has so much strong evidence that we believe it will help prevent heart disease from developing, which in the end is a far better outcome than waiting for the heart attack or stroke to occur. Most doctors are advocates for their patients and are not in the business of deliberately harming their patients.

      The problem we really face now is conducting a randomised trial with statins where it is not considered unethical by giving a placebo dose. The only feasible way in my mind would be to run such a trial in patients with virtually no predicted vascular risk at all (ie. young, very healthy) and focus on side effects in both groups.

      • Jordan,

        I would be happy to read whatever you think would be helpful, in particular:

        The paper containing the correlation between CV events and the reduction of LDL levels using statins that contains the figure 3 that you referred to. I particularly want to observe the size of the effect, because from what I have read elsewhere, it is negligible. As I said, if the gain is small enough, it can’t possibly make sense to take a powerful drug for the rest on one’s life!

        For example, one statistic I read, was that if an extra 10,000,000 people were treated with statins 50000 lives would be saved! That sounds impressive until you realise that the gain to an individual is just 0.5%!

        I’d also love to see the evidence that saturated fat increases CV events – particularly since Ancel Keys’ evidence seems to be utterly broken (did he even retract his paper?)

        I’d certainly not want to blame my GP, because I am sure all GP’s are bombarded with gushing reports about statins, and they only get a few minutes per patient.

        Your comments about Simvastatin surely highlight the point that side effect data absolutely needs to be collected (in normal practice) and published – I mean that drug has been in use for 20 years! In fact I knew it was an old drug when I started it, and thought that was desirable – that its side effects would be fully understood!

        I also really wish that you would read Malcolm Kendrick’s “The Great Cholesterol Con”, and write some sort of detailed rebuttal of his case, if you still think he is wrong after you finish!

        dave at dbailey dot co dot uk

  • Jordon Fulchers email address links him to the Clinical Trials Centre at the University of Sydney. Small wonder that he is so offended by a critique of RTCs.

    Jordons latest post to the thread (30th May) has a different tone and style to his earlier ones, do you think? It reads like a well drafted statement, grammar better, spelling errors less evident, and better proofed. I even wonder if a legal professional has cat their eye upon it.

    The mere fact that Jordon is connected with a clinical trials centre means that’s where his interests lie. Irrespective of whether he is aware of it in himself his in in a placement that lends bias. Jordons attention majors upon trials data, and yes, it is entirely possible Jordon and the team about him are fully committed to the highest standards of diligence and honesty. But this placement does not encourage curiosity for the causes of heart disease. It encourages an assumption that the fat/cholesterol hypothesis is valid, and it is not. And even if Jordon had some notion of the form of the likely successor to the fat/cholesterol hypothesis his attention will be on trialling the efficacy of some treatment or other. People in situations like Jordon cannot see the pertinence and attraction of avoiding a health condition by avoiding all contact with its cause.

    People might see virtue in the coming link. Jordon may see virtue in the coming link, but we have to wonder if he’d be interested in taking up with its directions.

    http://www.svhi.com/lateschmart/methylmagic.pdf

    Declaration of interest:
    I hold a vocational driving license and not much more. I work as a professional truck driver. The pay is lousy and it is my only source of income. I have yet to make a penny from upwards of twenty thousand thousand hours of study and contemplation undertaken since 2009. I follow certain blogs and leave comments beneath them. I think it is fair to say I am free from conflicting interests, yet nonetheless it does feel like I’m out on a limb through holding views that are removed from those of my my peers.

  • Jordon.

    Can I inquire what are your thoughts on zeta potential of RBCs (red blood cells) as may have bearing upon risk of cardiovascular events?

    Also, if I was trialist participating in an RCT testing efficacy of statins how might I detect an effect on CoQ10, how might I report that, and what lengths might an RCT go to measure effects upon CoQ10?

    Does a side-effect have to manifest itself in physical or mental symptoms to count or might detectable (or even undetectable) physiological changes rank as side-effects? In my my they must. They are the fisrt step on route to manifestation of outward symptoms, surely, or am I revealing how little I know?

    It would not be easy for a trialist to notice diminution of supply of CoQ10 without the physical symptom manifests itself. The physical manifestation of CoQ10 deficiency is CHF (congestive heart failure). After CHF the window of oppurtunity for a patient (or trial volunteer) to report it as a side-effect is a bit late in the day might we say?

    You are a really interesting guy, and your comments truly interesting.

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