This episode centred around the claims made in the BMJ papers that regarding the adverse effects of statins. Professor Collins maintains that the papers overstated the hazards and, as a result risked putting people off taking statins, which (according to him) ‘risked lives’.

One line of attack taken by Professor Collins is the fact that while some claim that muscle problems appear to be quite common in those who take statins, randomised controlled trials fail to support this. In fact, these studies typically find that muscle damage is very rare.

Professor Collins was the lead investigator in a huge statin study (known as the Heart Protection Study) which found that ‘myopathy’ was only found in 0.05 per cent of people taking a statin. Here you will find Professor Collins quoting this figure in support of the safety of statins.

0.05 per cent is a stunningly low rate (just 5 in 10,000 people treated). Does it reflect reality?

First of all, take a look at this table from the Heart Protection Study. It gives the rates for myopathy with and without ‘rhabodomyolysis’ (a condition where the damage is so bad the muscles basically go into meltdown).

Rate of myopathy without rhabodomyolysis is 0.05 per cent, but with rhabodomyolysis the rate is also 0.05 per cent. This means that the rate of myopathy is actually 0.1 per cent (0.05 + 0.05 per cent) – precisely double what Professor Collins claims it to be.

I think it’s interesting to consider first of all how myopathy is defined in Professor Collins’ study. When muscle is damaged, it can liberate a substance known as creatinine kinase into the bloodstream. So, elevated levels of creatinine kinase point to muscle damage. Whether levels of a biochemical marker are considered normal or not depends on ‘normal ranges’ that generally encompass about 95 of the population. What this means, in effect, is that for someone to have a ‘raised’ creatinine kinase blood levels would have to be in about the top 2-3 per cent of the population. However, in the HPS study, myopathy was only diagnosed when creatinine kinase levels were more than 10 times the upper limit of normal.

Here you will see the normal range for creatinine kinase cited as 55 – 170 units/litre for men. In other words, using this normal range quoted above, myopathy would only be diagnosed once creatinine kinase levels were above 1,700. Wow – that sets the bar pretty high. What about lesser degrees of muscle damage? What about muscle symptoms (including muscle fatigue) where no elevation in creatinine kinase is seen (possible)?

But is there anything else about the Heart Protection Study that means it would be unlikely to pick up problems that may occur more frequently in the general population?

In the Heart Protection Study study, a total of 20,536 people were randomly assigned to take statin (simvastatin) or placebo. However, a total of 32,145 were recruited into the study to begin with. What happened to the 11,609 people who did not make it into the study proper?

The Heart Protection Study employed a ‘run-in period’ which all 32,145 people were entered into. For 4 weeks, individuals were given a placebo which, according to the researchers, allowed assessment of biochemistry including creatinine kinase. After this, individuals were treated with simvastatin for 4-6 weeks. This was, according to the researchers, “to allow a prerandomisation assessment of the LDL-lowering “responsiveness” of each individual.” This makes it sound as though if simvastatin did not have the ‘desired’ effect on someone’s cholesterol level, they would be removed from the study. If so, I’d say that is not the most scientific way of assessing the impact of this drug in the general population.

But, elsewhere in the paper we are told that: “36% [11,609 people] were not subsequently randomised: 26% [8,358 people] chose not to enter the trial or did not seem likely to be compliant for 5 years…” But there is no detail given here. Why would people decide not to enter a trial after participating in a run-in period? One reason could be that they suffered unacceptable side-effects. And side-effects might also be the reason someone seems unlikely to be compliant for 5 years.

Whatever the facts of the matter here, one thing that is clear is that the run-in period in the Heart Protection Study had the potential to screen out many people who suffered from adverse effects from simvastatin including muscle symptoms. In short, the study was designed in a way which makes any extrapolation to the population at large completely inappropriate. Any attempt to generalise its findings to the wider population is, I think, either a sign of gross scientific naivety or outright intellectual dishonesty.

Previously, I have written about the attempts by Professor Sir Rory Collins to have two articles in the BMJ withdrawn. Both of them cast considerable doubt on the effectiveness of statins, particularly for those at relatively low risk of cardiovascular disease. However, both pieces also misquoted a piece of research finding that statins were associated with adverse effects in 17.4 per cent of those who take them. Both articles rounded this figure up to 18-20 per cent, and also implied that statins caused the adverse effects seen (the study – ‘observational’ or ‘epidemiological’ – type did not allow this inference to be made).

Once alerted to the issue, the BMJ promptly withdrew the comments about adverse effects. But Professor Collins was not happy, and insisted that the BMJ retract both articles in their entirety. However, to my knowledge, neither Professor Collins not anyone else had countered the main thrust of the articles (one was principally about the ineffectiveness of statins, and the other was the lack of association between saturated fat and heart disease).

The editor-in-chief of the BMJ – Dr Fiona Godlee – convened a committee to look into the matter, and to rule whether there were grounds for the one or both of the articles to retracted.

Elsewhere in the BMJ, one of Professor Collins’ previous collaborators – Professor Peter Sever – referred to Professor Collins’ detailed case for retraction. I emailed Professor Collins asking if I could see his detailed arguments. I was particularly interested to read what Professor Collins’ had to say about the claims that statins are, on the whole, quite ineffective. To his credit, Professor Collins replied, but only to tell me I would need to wait until the committee issued their report and all the documentation.

Well, last week, the committee published their report. It found no grounds whatsoever for retraction of either of the articles. You can read the report here, and here is a list of all the relevant documentation.

I read four (SP17-20) letters Professor Collins submitted to Fiona Godlee to make his case. Each letter, I think, has a similar theme: the claims about statins side effects were inaccurate and overblown, and as a result people may be discouraged from taking them or continuing them (exposing them to increased risk of cardiovascular disease). However, these issues had been acknowledged by the BMJ and the authors of the articles, and the statements had already been withdrawn.

However, on the subject of the effectiveness (actually, ineffectiveness) of statins, Professor Collins has nothing much to say. My guess is that Professor Collins would prefer not to engage with this critically important area, because erhaps he knows statins are extremely limited in their effectiveness in the vast majority of people who take them. Better, I suggest, to bang on and on about some other topic that maybe provides a convenient diversion.

I don’t know, but I have a sense that Professor Collins’ crusade to have the papers retracted was as much about censoring the truth about statin effectiveness as writing any wrong to do with adverse effects. And I am delighted to say he did not get away with it.

In fact, I suspect rather that Professor Collins’ ‘shock and awe’ tactics have spectacularly backfired. I think he has come across as bullying and aggressive (and wrong). But there is worse in store for him: The committee ad the editor of the BMJ have drawn our attention to the fact that the data held my Professor Collins and his colleagues at the CTT is for their eyes only. No-one else can have access to it nor is in a position to verify their conclusions about statins. In the interests of transparency and scientific integrity, they are calling for this data to be made public.

My personal opinion is that Professor Collins and some of his colleagues have done considerable damage to the reputation of medical and research fraternities. I’d say his actions will have contributed to the growing mistrust members of the public appear to have for ‘experts’. Being eminently credentialed does not guarantee that someone will always seem keen to uphold the basic tenets of good medicine and good research.

This week saw the publication of a study that aimed to assess the impact of NHS health checks [1]. The researchers compared in outcomes general practices that undertook screening, with those in patients from practices where health checks were not routine. The researchers focused on five conditions: high blood pressure, heart disease, kidney disease atrial fibrillation (a type of heart rhythm disturbance) and diabetes.

This 3-year study found that the rates of these conditions was no higher in screened patients than in those who received normal care. In other words, health checks did not pick up an additional health issues that would not have been picked up in the normal course of events. By the way, in this study the total number of screens performed was 16,669. Think of all the time, effort and resources that went into these screening endeavours, only for them to prove to be a complete dud.

More important than this finding, I think, is the impact of health checks not on the apparent prevalence of a condition, but on actual health. Do health checks translate into a reduced risk of disease or death?

The impact of health checks on health outcomes was assessed by researchers from the so-called Cochrane Collaboration (specialising in performing ‘meta-analyses’ of health interventions) [2]. The review pooled together the results of 14 studies where the health outcomes of people who underwent a health check were compared with those of people who didn’t.

Here are the results:

Risk of death from cancer – no benefit

Risk of death from cardiovascular disease – no benefit

Overall risk of death – no benefit

The authors concluded that:

General health checks did not reduce morbidity [illness] or mortality, neither overall nor for cardiovascular or cancer causes, although they increased the number of new diagnoses. Important harmful outcomes were often not studied or reported.

Yet, despite this, the NHS Choices website continues to promote health checks and makes quite grand claims about the ‘expected’ benefits in terms of lives saved and cases of disease prevented. The NHS Choices does not provide the evidence that backs up these claims (which, remember, run counter to the evidence presented here).

Should you get an invite for a health check, it’s perfectly legitimate to attend. It’s also perfectly legitimate, though, to ask your doctor for the evidence that supports this initiative. It’s high time we doctors were made more accountable for the recommendations we make and services we offer, including those sanctioned by our Government.

References:

1. Caley M, et al. The impact of NHS Health Checks on the prevalence of disease in general practices: a controlled study. BJGP 2014;64:625 e516-e521

2. Krogsbøll LT, et al. General health checks in adults for reducing morbidity and mortality from disease: Cochrane systematic review and meta-analysis. BMJ 2012;345:e7191.3

However, blood sugar control is a spectrum: between what are thought to be ‘healthy’ blood sugar levels and type 2 diabetes exist states which are not extreme enough to be called diabetes, but are associated with enhanced risk of developing this condition.

For example, if the glucose concentration 2 hours after the glucose load is 7.8-11.1 mmol/L (140-200 mg/dL), then a diagnosis of ‘impaired glucose tolerance’ is made. The term ‘Impaired fasting glucose’ is also used to define individuals with fasting blood glucose levels of 6.1-6.9 mmol/L (110-125 mg/dL) (according to the World Health Organization).

Another relatively newly-coined term is ‘pre-diabetes’. This diagnosis is based on a measurement known as the HbA1c which gives an indication of the overall blood sugar (glyaemic) control over the preceding 3 months or so. One of the supposed advangates of this test is that it does not require fasting nor an oral glucose load. According to the American Diabetes Association, a HbA1c of 5.7%-6.4% indicates ‘pre-diabetes’, though some bodies have recommended a slightly higher threshold for this condition. The basic thinking here is that by identifying pre-diabetes, individuals may be helped with interventions including drug therapy.

While this all may seem eminently sensible on the surface, there are a number of problems with this approach. These are explored in quite some detail in a paper published this week in the British Medical Journal co-authored by Professor John Yudkin from University College London and Professor Victor Montori from the Mayo Clinic in the US [1].

The article explains that the relationship between glycaemic control and health risks are a continuum, and where we begin to diagnose pre-diabetes is utterly arbitrary. If we apply the criterion recommended by the ADA, then apparently half the Chinese population (that’s almost half a billion people) have pre-diabetes. The authors question whether we even have the resources to treat vast swathes of the population according to these arbitrary criteria.

Of course a stronger case might be made for those arguing for population treatment if this had been tested. But as the authors point out, there simply is no evidence that earlier intervention based on the ADA’s criteria leads to either improved health or a reduced risk of death.

What we do know if that certain interventions appear to be able to delay the onset of diabetes by about 2-4 years. The real effects in terms of reducing healthcare costs or disease burden, though, are unknown.

And even if genuine benefits exist, let’s not forget that applying a diagnosis of ‘pre-diabetes’ to someone is not without risk. We have risks associated with medication, say, but also there may be issues with self-image, health and life insurance (particularly in the US).

One of the first-line drugs used to treat pre-diabetes is metformin. The authors point out that data suggest that using this drug may reduce the risk of developing type 2 diabetes by about 31 per cent. However, as the authors point out, what this means is that treating pre-diabetes in this way means individuals now have a “100% chance of using metformin with the goal of reducing by 31 per cent their risk of developing a condition that might require them to use metformin.”

This approach with metformin or some other drug may have some sections of the drug industry rubbing their hands with glee, I suppose, but it’s certainly true that overall benefit is not assured, and there is even considerable potential for harm.

The authors are sceptical regarding any supposed benefits, and also warn that we risk deflecting from the real issues with diabetes and pre-diabetes relating, for instance, to diet and exercise. The article ends with three points that doctors should discuss with patients. These are:

• A diagnosis of pre-diabetes does not mean that you will develop diabetes. In fact, of 100 people like you, fewer than 50 are likely to develop diabetes in the next 10 years

• There are ways of reducing your risk of developing diabetes that involve changing your diet and being active. These can result from efforts you make as well as changes in your environment (food supply, workplace conditions, education, and other social determinants of health)

• There are drugs to delay diabetes, but these are the same drugs you will need if you do develop diabetes, and the value of starting them before you have developed diabetes is unknown

The footnotes to the article state that: “The authors are clinical academics with a shared interest in patient centred diabetes care and shared decision making.” And this comes loud and clear in their article, I think. Their focus really does seem to be on taking an objective look at the data and giving patients the very best information on which a truly informed decision can be made.

The article also states that it is: “…part of a series on overdiagnosis looking at the risks and harms to patients of expanding definitions of disease and increasing use of new diagnostic technologies. The underlying message here is that more medicine is not necessarily better (and may in fact be a bad thing). We need more articles like this, and we need more high profile medical journals willing to publish them.

References:

1. Yudkin JS, et al. The epidemic of pre-diabetes: the medicine and the politics. BMJ 2014;349:g4485

It seems I’m not the only one to have noticed distinct lack of evidence for the supposed benefits of these compounds, either. Here you see find a story concerning France’s food standards agency (ANSES). It has recently issued its opinion of foods ‘enriched’ with stanols and sterols. It, like the EFSA, acknowledges the fact that these foodstuffs can reduce cholesterol, but otherwise remains very unenthusiastic about them. In its report, it points out that:

• Higher levels of stanols in the bloodstream (this can happen as a result of eating stanols) have ‘unquantified cardiovascular consequences’ and further study is required. Studies have, by the way, linked higher levels of sterols in the bloodstream with heightened risk of cardiovascular disease.
• That these products are not recommended for children, though the products are available to children.
• That sterol/stanols consumption should be accompanied by an increase in fruit and vegetables consumption, to compensate for the fact that stanols and sterols can lead to a reduction in levels of nutrients known as ‘carotenoids’ in the body.
• That reducing cholesterol levels in the bloodstream does not necessarily translate into a reduction in risk of heart disease.

And in summary, ANSES tells us that: “…as regards public health, the available data do not make it possible to consider foods fortified with phytosterols/stanols as a suitable way of preventing cardiovascular disease.” You can find a pdf of the full report here. Perhaps not surprisingly, Unilever (manufacturers of sterol-enriched Flora pro.activ) has retorted that French position is counter to “the current scientific consensus and all regulatory approvals already obtained.”

However, regulatory approvals regarding these foods are based on their ability to lower cholesterol, the assumption being that this translates to benefits for health. But, as we know, this is an assumption too far (dietary reduction of cholesterol and several cholesterol-reducing drugs have been shown to be ineffective for the purposes of enhancing health, and some drugs have even been found to kill people). By focusing on cholesterol, rather than health, the food (and pharmaceutical) industry has been able to divert our attention away from what is truly important (health). My personal opinion is that ratification of these food products has been the result of regulatory agencies being too stupid or corrupt (or both) to do the right thing.

The French position, I think, is an example of what happens when individuals refuse to swallow food company rhetoric whole without thinking, and focus on the most important thing of all: not the impact stanols/sterol-enriched foods have on cholesterol, but on health.

Those strongly supportive of the plans to widen statin prescriptions are hardly going to go away without a fight, though. And this week six professors convened a press briefing at the Science Media Centre to put forward their arguments. The briefing was reported in the British Medical Journal this week [1].

Two of the ‘usual suspects’ were Professor Sir Rory Collins (head of the Cholesterol Treatment Trialists collaboration) and Professor Peter Weissberg (medical director of the British Heart Foundation).

One of Professor Collins’ gripes was, apparently, that “misrepresenting the evidence” will have a negative impact on people who are at high risk of cardiac events. He is quoted as saying: “It’s perfectly reasonable to debate whether patients at lower risk should get statins or not, but it’s inappropriate to misrepresent the evidence.”

He redoubled his assertion that rates of ‘myopathy’ are much lower than some people state. However, he is referring to the incidence of muscle problems where the threshold of ‘abnormal’ is when levels of the enzyme used to assess muscle damage (creatinine kinase) is at least 10 times the upper limit of normal. Professor Sir Rory Collins is apparently disinterested unless muscles are in near-meltdown. We can, I suppose, just ignore those poor unfortunates with less biochemical aberrations even though their symptoms are real and often debilitating. I think it’s clearly business as usual for Rory Collins, who makes claims that some are misleading the public while I think he, ahem, continues to mislead the public.

Professor Weissberg tells us that the “…the critics are wrong. They’ve retracted, they’re wrong.” Except, that the only thing that has been retracted were the misleading representations of statin side-effects as reported in one piece of research. All the major objections detailed in the original letter stand until someone properly disputes them.

With regard to these, Professor Weissberg calms any concerns about industry involvement in the evidence base, because drug companies only paid people to do the studies, rather than the drug companies doing the studies themselves. So, nothing to concern ourselves with here.

He adds that: “The biggest threat to good medicine is prejudice and anecdote.” I have some sympathy for this view, but boy would I like to see Professor Weissberg stay away from prejudice and anecdote myself. It was not so long ago that he made claims to support statins using data that did not support the use of statins at all.

And perhaps the most telling thing of all are the comments that come from Fiona Fox, director of the Science Media Centre. Apparently, only pro-statin experts were invited to the briefing. In defence of this tactic, Ms Fox tells us that the “vast majority” of cardiac and statin experts believed that the evidence was overwhelming, and that it was not the centre’s job to provide a platform to a minority who did not and thereby project a false image that the debate was in equipoise (when it was not).

First of all, I wouldn’t be too sure that the evidence is overwhelming or that the pro-statin camp is in the great majority.  And even if there things were true, is that a reason to stifle debate and allow no right of reply?

Do these tactics suggest that Professors Collins and Weissberg and the rest of their merry band of men have true confidence in their position? I personally doubt it, and believe that their attempt to shut down debate suggests they may be desperate not to have the weakness of the data and their arguments revealed in front of their very own eyes.

References:

1. Hawkes N, et al. Six professors back NICE guidance on extending use of statins. BMJ 2014;349:g4380

1. Commercial sponsors of clinical trials may not be motivated to search exhaustively for potential side effects..

2. Many trials do not state clearly how and how often adverse effects were assessed. Because of this, it far from certain that all adverse events have been recognised and logged appropriately.

3. Trial volunteers tend to be enthusiastic individuals, and may therefore be less likely to report side effects than patients in routine clinical practice.

4. Many trials have a ‘run-in’ period where individuals are given a placebo to help ensure adequate compliance with medication. This can cause studies to be ‘enriched’ with highly motivated individuals who, again, may be less likely to complain of side-effects.

5. One major statin trial (The Heart Protection Study) employed a run-in period which subjected all potential participants to the active drug. Individuals with evidence of adverse events were excluded, which obviously means a higher percentage of ‘statin tolerant’ individuals made it into the study proper.

6. Several studies are of short duration and, worse still, may have been subject to early termination (something which tends to downplay harm and exaggerate benefits).

7. In many trials, adverse effects are only deemed to have occurred if there’s been extreme deviation from normal biochemistry (for example, judging that myopathy has occurred only when creatinine kinase levels are 10 times the upper limit of normal or higher). Setting the bar this high obviously works to depress side effect rates.

8. Many studies exclude types of individuals who exist in the real world and may take statins, including older patients, patients with other conditions or on other drugs that may make them uniquely sensitive to adverse effects from statins.

9. Published accounts of clinical trials in medical journals generally report only a minority of adverse events compared to full ‘clinical study reports’.

Plus, it should be borne in mind that statins reduce cholesterol by inhibiting an enzyme in the liver known as ‘HMG-CoA reductase’. This enzyme ‘drives’ cholesterol production but it also facilitates the production of a substance known as ‘coenzyme Q10’ – an essential player in the production of what is known as ‘adenosine triphosphate’ (ATP) – the most basic unit of energy ‘fuel’ in the body. We know that giving statins to people does indeed have the capacity to lower levels of CoQ10 in the body [1].

Depletion of CoQ10 is thought to be a major reason for why statins can reduce energy production (and therefore provoke fatigue) in muscles. However, it’s worth bearing in mind that the heart is a muscle, and depleting it of CoQ10 may be hazardous for cardiac health. Specifically, it may weaken the heart and lead to what is known as ‘heart failure’. Previously, researchers have noted the ability for statins to induce CoQ10 depletion in both humans and animals [2]. In this particular review, the authors concluded that:

Statin-induced CoQ10 deficiency is completely preventable with supplemental CoQ10 with no adverse impact on the cholesterol lowering or anti-inflammatory properties of the statin drugs. We are currently in the midst of a congestive heart failure epidemic in the United States, the cause or causes of which are unclear. As physicians, it is our duty to be absolutely certain that we are not inadvertently doing harm to our patients by creating a wide-spread deficiency of a nutrient critically important for normal heart function.

In a recent study, the effect of supplementing individuals with CoQ10 was tested in a group of individuals who were also given statins [3]. In this study, 62 individuals with heart failure were put on one of two regimes for 4 months.

1.    a statin (atorvastatin 10 mg a day) plus 100 mg of CoQ10, twice a day

2.    a statin (atorvastatin 10 mg a day) plus placebo, taken twice a day

The individuals in the study were subjected to a range of measurements including the heart’s ‘ejection fraction’ (basically, how much blood the heart pumps with each beat), and levels of the substance ‘N-terminal B-type natriuretic peptide’ (higher levels are generally found in worsened heart function). Compared to the placebo group, those taking CoQ10 were found to have better ejection fractions and lower levels of N-terminal B-type natriuretic peptide.

My conclusion, that CoQ10 depletion is a genuine potential issue in those who take statins, and that CoQ10 supplementation should at least be considered by those who take statins or have taken them (particularly if they suffer from heart failure or other symptoms linked to CoQ10 depletion).

References:

1.    Passi S, et al. Statins lower plasma and lymphocyte ubiquinol/ubiquinone without affecting other antioxidants and PUFA. Biofactors 2003;18(1-4):113-24

2.    Langsjoen PH, et al. The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications. Biofactors 2003;18(1-4):101-11

3.    Pourmoghaddas M, et al. Combination of atorvastatin/coenzyme Q10 as adjunctive treatment in congestive heart failure: A double-blind randomized placebo-controlled clinical trial. ARYA Atheroscler. 2014;10(1):1-5

Soon after graduating from medical school, I bumped into someone who had graduated a year before me. She waxed lyrical about a lecture tour of the US she was about to embark on to discuss the ‘exciting’ new medical research she had been involved with as part of a PhD. I forget the details, but I remember asking how this research would translate into improved patient outcomes. Her response was that it wouldn’t. Then she laughed. This is a rather extreme example, I think, of how researchers (and those who fund research) can sometimes forget what medicine is for.

In the past, I think one of the problems is that the medical and research fraternities viewed ‘ordinary people’ as lacking the skills required to understand and contribute positively to research. If that was the case in the past, this is clearly much less of an issue now. And that’s because there are growing numbers of individuals who have, in effect, educated themselves on matters such as the scientific method and the relevance of different types of study. I honestly believe that ‘complete amateurs’ often have a much better grasp of the issues than the ‘professionals’.

Let me give you an example. On the BMJ website recently I watched a brief video in which a US-based researcher was talking about research in which a high cereal fibre diet was found to be associated with better outcomes after a heart attack. The researcher confidently stated that patients should be told to up their fibre intake as this will help them. Except that the nature of this study (epidemiological) does not allow him to be so confident about the relevance of his findings and it appropriateness to patient care. On the other hand, there are many people with no background in research at all who would be able to spot this researcher’s error in an instant, and might be happy to make their views known too.

I was delighted this week to get an email from a frequent commenter here (Chris Palmer) to a BMJ blog about a very patient-centred initiative which you can read here.

The BMJ recognises that ‘evidence-based medicine’ has some serious issues. For example, the evidence base for some drugs is very skewed (I’d say the evidence on statins is a prime example). Also, ‘benefits’ that may be statistically significant may not be very important clinically. The suggestion is to make medicine more ‘patient-centred’, and use clinical judgement to apply the evidence to the individual, perhaps releasing doctors from the tyranny of ‘clinical guidelines’ and ‘protocols’.

But the BMJ has taken a bolder step in planning the involvement of patients in the review of studies being considered for publication (so-called ‘peer review’). The article I link to above includes a short video which explains how someone can sign up as a ‘peer reviewer’ with the BMJ. If you feel sufficiently moved, then please do sign up. And, if you so feel inclined, please do whatever you can to promote and support this initiative. I applaud the BMJ for remembering those for whom medicine should primarily exist.

The editor has convened a committee headed by Dr Iona Heath to judge whether there are good grounds to retract the papers (or not).

The BMJ has a ‘rapid response’ service, where individuals can submit on-line responses to articles and people. The editorial about this issue has, at the time of writing, received 64 responses (that is a lot for the BMJ, and in fact, the article is currently by far the most commented on piece in the journal). Take a look at the responses and you will see that the vast majority of them are supportive of the BMJ and its editor (Fiona Godlee). Many people feel strongly that the articles should not be withdrawn.

I wrote a response in which I called into question the validity of the data so often used by Professor Sir Rory Collins (and people of his persuasion) to state that ‘statins are safe’. My position is that Professor Sir Rory Collins and others have misled us (wittingly or unwittingly) about the safety of statins and the trustworthiness of the data (potentially putting people at risk of health issues caused by statins). Readers can vote on rapid responses with an ‘up-vote’. There has clearly been some support for my position in that my response has over 850 up-votes (I have never seen such a high number for any response in the BMJ). Perhaps you voted. If you did – thank you!

Not everyone who has commented is supportive of the BMJ. One malcontent is Professor Peter Sever, who is a colleague of Rory Collins, and has run one big industry-funded trial that (among other things) tested the effectiveness of the statin atorvastatin (known as the ‘ASCOT’ trial, published in 2003).

Here’s a link to Professor Sever’s response , but to make it easy for you I’ve reproduced it below. Professor Sever rams home the point (with righteous indignation, I think) that the original papers misled us on the findings of the statin side-effect paper, and gives full backing to Professor Sir Rory Collins’ calls for retraction. Judge for yourself…

Dear Dr Heath,

In your role as chairman of the panel set up by the BMJ to consider the question of whether a full withdrawal of the Abramson and Malhotra papers, relating to side effects of statins, should be expedited, I write to you to provide my full support of the detailed case made by Rory Collins that these 2 papers are examples of bad science, in that the authors misrepresent the truth and sensationalise a variety of side effects claimed to be due to statins, the consequence of which, is that for the wrong reasons patients, whose future morbidity and mortality from cardiovascular disease would have benefited substantially from statin therapy, will be dissuaded from taking the drugs or discontinuing them if they are already receiving treatment.

The BMJ has taken a strong position on scientific integrity and its detailed review and condemnation of the Lancet’s publication of the Wakefield MMR scandal was well received. The same principles should apply over the critical reviews of these two statin papers and the misrepresented claims of Zhang et al, that statins were causally related to side effects in 20% of statin users.

As the Co-chief Investigator of ASCOT, a trial that was independently designed and lead, and where the executive committee held the data base, analysed the results and published the papers independent of the funder, Pfizer, I strongly refute the implications of authors of the 2 recent studies implying that trial sponsors could have influenced the results and downplayed the side effect profiles of the drugs.

In ASCOT, side effect profiles were identical on those taking placebo and statin.

Interestingly, in the blood pressure arm of ASCOT we detected drug related side effects of the ACE inhibitor (cough) and the calcium channel blocker (ankle oedema) with incident rates not dissimilar from those experienced in clinical practice. So if statins were to be causally related to myalgia/ myopathy, why did we not detect this in a trial of 10,000 subjects ?

I would like to remind you that in a recent study published in Archives, a rechallenge of patients previously withdrawn from statin because of muscular side effects, yielded the return of identical symptoms in 80% of patients. Problem was the rechallenge was a placebo !

We are dealing with a very serious issue here, and editors of major international journals have a duty to publish good science and not popularize bad science which is regrettably the prerogative of the lay press.

The retraction of these two papers will go some way towards damage limitation, but do not underestimate the huge impact these publications will have had and the disastrous consequences for the vulnerable patient population who stand to benefit enormously from their statin treatment.

Peter Sever

Professor of Clinical Pharmacology

National Heart and Lung Institute

Imperial College London

May 24th 2014

Competing interests: Recipient of grants to Imperial College from Pfizer Inc for conduct of ASCOT Recipient of honoraria for speakers bureau- Pfizer Inc

Let me cut to the chase here and say that I believe Professor Sever’s response to be verging on hysterical, and actually a great example of misinformation and sensationalism. I think it employs the same ’eminence-based’ and bully-boy tactics I suspect Professor Sir Rory Collins deployed when he ‘forced’ a meeting with the BMJ’s editor without formally tabling his objections.

So, taken aback was I by Professor Sever’s response, that responded to him with a detailed analysis of his assertions, and several questions of my own (including questions about the reliability of his own research, as well as that of Professor Sir Rory Collins. Also, I respectively point out to Professor Sever that nothing in his response in anyway counters the central claims of the papers he wants retracted.

To see my response, click this link. Again, there’s an opportunity to lend your support for the arguments with an ‘up vote’.

Citation: https://buyshares.co.uk/online-casinos/

Here’s the wording of the complaint I was able to submit:

I stated in the blog that I had not had a response to the piece after 2 months. I tweeted to this effect, and was assured by one of the editors of NHS Choices that I had been sent a reply. When I questioned this, it turned out no response had been sent. The confusion was put down to ‘Human error’.

Shortly after, I did get a response, which I posted as an addendum to the blog. I felt the response was inadequate. The Managing Director of NHS Choices (Jonathan Carr-Brown) agreed, and eventually got back to me with a more fulsome response on 25 February, which I have pasted below. I’ve also added my response to the points Mr Carr-Brown makes.

Response from NHS Choices

My Response to NHS Choices

I got an almost immediate response from Mr Carr-Brown, who suggested we discuss the issues when we meet. I said I’d like a formal response, and that the complaint should be escalated to what is known as the ‘Clinical Information Advisory Group’. We shall see what comes of this in due course.

In the meantime, as for the suggestion that I syndicate NHS Choices content on my own site, I think I’ll pass: Disseminating unscientific, non-evidence-based, misleading and potentially dangerous dietary advice is not a business I want to be in.

The fight went up a notch last week when the editor of the British Medical Journal announced that remarks made in two BMJ articles about the side-effects of statins had been withdrawn [1]. One of the articles was written by Dr John Abramson from Harvard Medical School and colleagues, and principally questioned whether extending statin use to those at lower risk (as has been suggested by the National Institute of Health and Care Excellence) will save lives [2].  According to their analysis, it won’t. The other piece was written by UK cardiologist Dr Aseem Malhotra, and principally questioned the role of saturated fat in heart disease [3].

In both articles, the authors referred to a study [4] that found that 17.4 per cent of people taking statins had adverse effects as a result attributed to statins. In the articles this figure was expressed as 18 per cent or ‘about 20 per cent’ which, apparently, was the first error. However, other issues, according the BMJ, was that the authors claimed that the 17.4 figure related to the percentage of people who stopped statins (at least temporarily) due to side-effects – this is not correct (it represented the percentage of people who had adverse effects). Also, the study in question was ‘observational’ in nature, which means that we don’t know if the adverse effects are due to statins or are the result of the ‘nocebo’ effect (like a placebo effect, only with negative effects rather than positive). The Editor of the BMJ, Fiona Godlee, tells us in her editorial that the caveats concerning the observational nature of these findings should have been made.

Both the articles made it through the peer-review process, so how did these errors come to be picked up? Well, apparently, they were brought to the attention of Fiona Godlee by Professor Sir Rory Collins, who heads up what is known as the Cholesterol Treatment Trialists (CTT) collaboration based in Oxford, UK. The CTT holds data on statin studies and periodically assesses it to tell us that statins are safe and very effective.

However, the CTT has in the past made grand claims about the effectiveness of statins that are based on the extrapolation of data (rather than actual data). Plus, as some have pointed out, the CTT refuses to release its data for independent inspection. The CTT can basically say what it likes about the effectiveness and safety of statins, but no-one can challenge what it says because no-one else has access to its data.

Apparently, Professor Sir Collins was invited by Fiona Godlee to put his concerns in writing for publication but he refused. He and Fiona Godlee met, and this set the ball rolling which culminated in the withdrawal detailed above. However, apparently this is not enough for Professor Sir Collins: he is demanding retraction of both articles, even though he has not challenged the main points raised in the articles. Fiona Godlee has set up an investigation to determine whether or not the articles should be retracted.

I have written to the BMJ in the form of an online ‘rapid response’ that was posted yesterday. You can read my response here.

In my response I accept that errors were made, but ask if a simple correction might have done.

Professor Sir Collins bases his assertions regarding the safety of statins on data from randomised controlled trials, like the ones analysed by the CTT. However, there are many reasons why randomised controlled trials may not adequately identify and report adverse effects from statins. Fiona Godlee acknowledges this herself and lists some of the issues, and I add to that list in my response. In all, there are about a dozen reasons why randomised trials stand to ‘miss’ adverse effects.

I also raise the issue of a recent study which appeared to confirm the safety of statins [5]. The study also detailed many reasons why results from clinical trials are an unreliable assessor of side effects. The study was reported in the BMJ [6], but the report included none of the caveats listed in the paper (or any other ones). As I explain to the Editor, these omissions may lull individuals into a false sense of security, and put people at unnecessary risk of adverse effects of statins, some of which can be serious.

One might argue that the ‘crime’ committed by the BMJ is roughly equivocal to the ones perpetrated by Drs Abramson and Malhotra. I point this out to Fiona Godlee in my response, and request a meeting with Fiona Godlee to discuss my concerns. After all, why should I not be afforded similar privileges as Professor Sir Collins”

You can read the response in full here. If you agree with the sentiments expressed in it, please click on the ‘thumbs up’ symbol to the right of the response to log your agreement.

References:

1.    Godlee F. Adverse effects of statins. BMJ 2014;348:g3306

2.    Abramson JD, Rosenberg HD, Jewell N, Wright JM. Should people at low risk of
cardiovascular disease take a statin? BMJ2013;347:f6123

3.    Malhotra A. Saturated fat is not the major issue. BMJ2013;347:f6340

4.   Zhang H, et al. Discontinuation of statins in routine care settings. Ann Intern Med 2013;158:526-34

5.    Finegold JA, et al. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. European Journal of Preventive Cardiology 2014;21(4):464-74

6.    Wise J. Statins may have fewer side effects than is claimed, meta-analysis finds BMJ 2014; 348:g2151

This documentary was preceded by another episode of the same title, this one questioning the conventional wisdom regarding saturated fat – specifically the role this fat supposedly has in heart disease.

There was quite some uproar after the shows aired, particularly with regard to the second show. The main accusation appeared to be that the programme did not provide a balanced view of the effectiveness of statins, and might ‘frighten’ people into not taking their statins, with the result that some may die.

My blog post in December explored this claim.  As I explained, the risk here, even for people who have had a previous heart attack or stroke (‘secondary prevention’) individuals, is very small. In primary prevention (for those who have no previous history of cardiovascular disease), the risk is even smaller and, in fact, may pose no risk at all (some research finds that statins do not reduce risk of death in primary prevention).

So great was the controversy surrounding the documentary that ABC’s own Audience and Consumer Affairs Unit (ACA) carried out an investigation into the two programmes. Its report (which you can access here Catalyst Heart of the Matter FINAL ACA Report) clears the first documentary (on saturated fat) of any bias. However, the ACA concluded that in two instances, the second documentary demonstrated bias.

The two issues appear to be:

1.    That the documentary did not put enough emphasis of the benefits of statins in secondary prevention (see page 40 of the report).

2.    That the documentary omitted information regarding the use of information relating to primary prevention. Some claim that statins can reduce mortality in those in the primary prevention category who are at relatively high risk of cardiovascular disease. The makers of the Catalyst programme argued there is no evidence for this stance. But, according to the ACA, they should have included it anyway so that viewers could ‘make up their own minds’. Here’s the actual wording (see page 45):

Catalyst has also explained that the stratified risk approach was omitted because it is ‘erroneous’ and lacks an evidential basis. However, the effect of excluding this issue was that viewers were not given the opportunity to hear both sides of the argument, and were not left in a position to make up their own minds.

Two days ago, Mark Scott, the managing director of ABC TV published a statement in which he announces the removal of both documentaries from the ABC website. His reason is that the second documentary “breaches ABC standards on impartiality”, and goes on to explain that the first documentary will also be removed “[b]ecause of the interlocked nature of the two programs…”.

I am sceptical about the role of saturated fat in heart disease and the value of statins in the prevention of cardiovascular disease. My scepticism is based on the published research. I’ve documented contemporary research relevant to the issues many times. Obviously, I have a bias towards Dr Demasi’s programmes and their broad sentiments.

However, when I attempt to put my own bias aside and focus on the facts, I am still left with the belief is that Dr Demasi did, overall, a very good job of highlighting the misinformation that abounds in this area. It is my opinion that Dr Demasi’s work was an example of good, responsible journalism. Read through the ACA report, though, and you’ll see that the content of the programmes was fundamentally sound.

Somehow, I feel like Mark Scott’s action to remove these documentaries is inappropriate and wholly disproportionate. If all documentaries (whatever the subject) were subjected to the level of scrutiny seen here, and then judged because of the omission of information (which one could argue is inevitable), then I suspect no documentaries would be deemed fit for transmission.

I am also left wondering what sort of pressure Mark Scott felt he was under to capitulate in such a spectacular fashion. If you’re wondering the same thing, or simply would like to express your support or otherwise for his decision, you may care to email Mr Scott at scott.mark@abc.net.au.

In its statement, Diabetes UK informs us that “while the NHS is spending £10 billion per year on diabetes care, this money is too often being used ineffectively, with the vast majority spent on treating complications that could often have been prevented if the person had received good healthcare in the first place.”

Diabetes UK bases its claims on a report it commissioned, which I have not read, but have no reason to doubt either.

However, when I hear anyone talking the good management of diabetes, my mind very often goes to dietary approaches first. Diabetes is principally a condition of impaired ability to handle glucose in the bloodstream. While the body can liberate glucose into the bloodstream (particularly from the liver), much of the sugar in the bloodstream tends to find its way there from the food we eat. Sugar is an obvious source, but another major potential provider of glucose is starch (because starch is basically made up of chains of glucose molecules).

I can categorically state here that when individuals with diabetes cut back on carbohydrates, they almost always see significant improvement in their blood sugar control. They usually lose weight, and see improvements in markers of disease too. I’m most certainly not the only person to have noticed this. Just yesterday I met a most wonderful general practitioner who has come to the low-carb approach quite late in his career, but has used it to utterly transform the health of his patients. He showed me a variety of graphs from several patients pre- and post-adoption of a lower carbohydrate diet. He relayed a few stunning anecdotes too of people who believe eating a lower-carb diet has given them their health and their lives back.

None of what he told me surprised me, but it did not fail to warm my heart, either.

Beyond me and my GP friend, though, we have the collective experience of literally thousands of individuals with diabetes who have often seen comprehensive improvement in their condition and general health by scaling back the carbohydrate. Many type 2 diabetics them have been able to scale back their medication too, or even dispense with it entirely. Type 1 diabetics will very often report the need for much less insulin.

The generally better blood sugar control these people enjoy will, by rights, lead them to suffer less in the way of diabetic complications. In its statement this week, Diabetes UK highlighted the foot-related complications that diabetics can suffer, one potential end-result of which isamputation.

I do not doubt Diabetes UK’s desire for diabetic care to be better, and I also do not doubt the ability of lower-carb diets to help diabetics control their blood sugar better and improve their general health. So, excuse me for being a little aghast at the dietary advice given to diabetics here. Here’s a screenshot of Diabetes UK’s dietary advice for diabetics regarding starch in the diet:

Yes, that’s right, according to Diabetics UK, a third of a diabetic’s diet should be made up of foods that are essentially concentrated glucose (many of which, by the way, are known to be highly disruptive to blood sugar). Note that the charity recommends diabetics eat up to fourteen portions of starchy foods each day.

I won’t mince my words and state here that I believe these recommendations are utterly mad. My experience tells me they will generally just entrench diabetics in their condition and the need for medical care. Compared to a lower-carbohydrate diet, the regime advocated by Diabetes UK stands to worsen blood sugar control and increase the need for medication and risk of complications. If Diabetes UK is serious about helping diabetics, I suggest it starts by ceasing to recommend a diet that, in my view, is utterly unsuitable for diabetics.

This week, I came across an interesting piece in the New York Times. The article questions the wisdom of women taking statins. It details some of the ‘under-whelming’ results of research demonstrating that statins don’t work as well for women as for men. In fact, statins have not been found to save women’s lives – even women deemed to be at high risk of cardiovascular issues such as heart attack and stroke.

One thing that caught my eye in this piece concerned comments made by Dr C. Noel Bairey Merz, director of the Barbra Streisand Women’s Heart Center in Los Angeles. According to Dr Bairey Merz,

We haven’t shown that we can prevent deaths, because we just haven’t enrolled enough women, and that’s a crime,

going on to add,

But the absence of data is not the same as negative data.

She’s right on the second point, but is she right on the first?

Well, she is completely correct when she concedes that statins have not been shown to reduce the risk of death in women. In a review of secondary prevention studies (studies of people who have had a previous heart attack or stroke who are generally at high risk of further problems), statin therapy was found not to reduce the risk of death in women [1].

Now, a potential reason for finding no benefit here is that the total number of women involved in these studies was not large enough to detect a difference, as Dr Bairey Merz alludes to. However, in this review, a total of more than 4,500 women were involved in the studies in which mortality was reported. If no mortality benefit was found in this quite large group, then this does suggest that if any mortality benefit exists, it’s going to be quite tiny.

So, what about Dr Bairey Merz’s, though, that “We haven’t shown that we can prevent deaths, because we just haven’t enrolled enough women…”?  She’s not entitled to claim this, I think, for the simple reason she cannot possibly know that. This is not science, it is speculation. She may as well start her claim with the words “When I look into my crystal ball…”

The New York Times piece notes Dr Bairey Merz’s funding from several drug companies, and I suppose her speculation stated as fact may have something to do with these conflicts of interest.

Perhaps like many observers here, I am growing slightly weary of conflicted ‘opinion leaders’ making unfounded claims about statins or some other treatment. I’m half-considering devoting a section on this blog to such instances, and am inclined to call it ‘Experts who make shit up’.

References:

1. Gutierrez J, et al. Statin Therapy in the Prevention of Recurrent Cardiovascular Events: A Sex-Based Meta-analysis. Arch Intern Med. 2012;172(12):909-919

Richard Horton seems very taken with the results (perhaps this has something to do with the fact that the study was published in his journal). However, there are a few things about the review that I think are perhaps worth bearing in mind.

Its authors (from the Cholesterol Treatment Triallists collaboration) essentially concluded from their data that more intensive statin therapy produced better outcomes. They extrapolated their findings to conclude that if LDL-cholesterol were to be reduced by 2-3 mmol/l, then risk would fall by 40-50 per cent.

Are these conclusions founded in good science?

Firstly, the ’40-50 per cent reduction’ claim is an extrapolation. It’s not based on actual data, just on a projection the authors make from existing data. In other words, it’s not very scientific at all.

But also, statin drugs have a number of different mechanisms (including an anti-inflammatory effect) that might allow them to reduce cardiovascular disease risk in ways that have nothing to do with cholesterol reduction. Now, when we intensively lower cholesterol with statins, non-cholesterol-related effects (e.g. anti-inflammatory action) will generally be increased too. The bottom line is we cannot assume that any additional benefits from more intensive statin therapy come from more intensive lowering of cholesterol per se.

In this ‘meta-analysis’, the results of a large number of studies was pooled. The problem is, these studies used a range of different drugs at different doses. Sometimes, the drugs were being tested against placebos, and sometimes they were being tested against other drugs. A more scientific way of determining if higher doses of statins really are better is simply to compare the effects of two doses of the same statin. You’d be surprised how rarely such studies are done.

One such example, though, is the so-called TNT study [2]. Here, individuals with heart disease (very high risk of future vascular events) were given either 10 or 80 mg of atorvastatin for an average of about 5 years. The higher dose did lead to lower LDL levels and lower risk of death due to heart disease. The absolute reduction in risk was 0.5 per cent, by the way, which meansrisk of dying from heart disease fell by about 0.1 per cent per year (so nothing to get too excited about).

Also, the higher dose of statins (a full 8 times the lower dose) did not lead to a reduction in overall risk of death. In other words, taking 8 times the lower dose of atorvastatin did not extend life by a single day.

The idea that the anti-inflammatory effects of statins (and not their cholesterol-reducing effects) may be at the heart of their benefits has been bolstered by work focusing on an inflammatory marker known as C-reactive protein (CRP). Statins are known to have the capacity to reduce CRP levels.

In one study assessing the relationship between statin therapy and cholesterol and CRP levels, it was discovered that “Patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol.” [3] (emphasis mine).

In another study, statin therapy and cardiovascular disease risk assessed using ultrasound scanning of the inside of the coronary arteries [4]. It was found that “atherosclerosis regressed in the patients with the greatest reduction in CRP levels, but not in those with the greatest reduction in LDL cholesterol levels.”

So, despite what the authors of the Lancet review would have us believe, there is evidence that statins primarily work through mechanisms that are independent of their cholesterol-reducing effects.

But, I’d also like to focus a little on other findings from this review, specifically the impact of statins on overall mortality. First of all, it’s worth bearing in mind that for people who do not have a history of heart attacks or strokes (so-called ‘primary prevention’) statins do not reduce the risk of death overall.

They do appear to reduce the risk of death in those with a history of cardiovascular disease (so-called ‘secondary prevention’). In the Lancet review, overall risk of death was found to be reduced by 10 per cent (a result that was statistically significant). However, this relative risk reduction needs to be taken in the context of overall risk. It turns out, that over the course of a year, risk of dying was reduced from 2.3 per cent to 2.1 per cent. In other words, the absolute risk reduction per year was 0.2 per cent – not exactly earth-shattering.

There’s another measure that is useful in gauging the effectiveness of a treatment: the ‘number needed to treat’ or ‘NNT’. We can use the data to calculate, for example, the number of people needed to be treated with statins for a year to prevent one death. The answer is 500.  The NNT for deaths due to cardiovascular disease is even higher: 1,000.

Bearing in mind the relatively high risk of serious side-effects (the best estimates comes in at around 20 per cent), one would have to wonder on what the enthusiasm many doctors, researchers and medical journal editors have for statins is really based. Only they can possibly know.

References:

1. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 9 November 2010 [epub ahead of print]

2. La Rosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-35

3. Ridker PM, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352(1):20-8

4. Nissen SE, et al. Statin therapy, LDL cholesterol, C-reactive protein and coronary artery disease. N Engl J Med. 2005;352(1):29-38