How do statin proponents deal with debate? They stifle it - Briffa

How do statin proponents deal with debate? They stifle it.

By Dr John Briffa on 4 July 2014 

 

Last month, one of my blog posts featured a letter written by a group of doctors, expressing their concerns about the mooted expansion of statin therapy. The letter detailed six major objections to the plan, including the mass-medicalization of millions of healthy individuals, the unreliability of the evidence regarding the adverse effects of statins, and the facts that almost all the evidence is industry-funded and that multiple conflicts of interest exist on the ‘expert committee’ that is adjudicating on the statin issue. The letter received widespread coverage in the press and other media, and I think it did much to stoke the flaming debate that some have described as the ‘statin wars’.

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
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Statin drug found to impair learning and memory in animals

By Dr John Briffa on 26 September 2013

 

One of my blogs last week focused on the potential impact statins have on the development or symptoms of dementia. Interest in this area is an example of the growing recognition that statins have the ability to affect brain functioning. As I briefly mentioned last week, even the Food and Drugs Administration in the US has recognised the potential for statins to induce symptoms such as memory loss, forgetfulness, and confusion.

There is no doubt that statins have the potential for toxicity. However, any direct affects on the brain has generally been believed to be related to the ability of statins to cross what is known as the ‘blood-brain-barrier’. An agent’s ability to breach the blood brain barrier is traditionally thought to be related to several factors, including its affinity to fat or water. Substances that have a high affinity for fat are described as ‘lipophilic’ and have traditionally been believe to cross the blood brain barrier relatively easily. On other hands, conventional wisdom tells us that substances with a high affinity for water (‘hydrophilic’ compounds) do not cross the blood brain barrier readily.

It is known that some statin drugs such as atorvastatin (Lipitor) are lipophilic, white others such as pravastatin (Pravachol) are hydrophilic. In theory, atorvastatin would be expected to be more likely to have adverse effects on the brain compared to pravastatin.

This week saw the publication of a study in which rats were treated for 18 days with one of two statins: pravastatin (Pravachol) or atorvastatin (Lipotor) [1]. Before during and after treatment, the rats were subjected to a learning test. This was adversely affected by pravastatin but not atorvastatin. The animals were also subjected to a memory task, which was also adversely affected by pravastatin but not atorvastatin. The adverse effects induced by pravastatin were ‘reversible’ (resolved on discontinuation of the drug).

These results are the perhaps the opposite of what one might expect from the theory of the propensity of different statins to gain access to the brain. However, the authors of the study point out that pravastatin tends to distribute itself more widely in the body than atorvastatin, and this may ultimately increase pravastatin’s ability to gain entry to the brain.

As to how statins may impair brain function, the researchers suggest one potential mechanism directly relates to lowered cholesterol levels. Cholesterol is required, among other things, for the formation of the fatty sheathes (myelin sheathes) that surround nerves, and any disruption in this may impair neurological functioning. Cholesterol also contributes to the functioning of ‘synapses’ – the tiny gaps between cells via which nerves communicate with each other.

I suspect we have much to learn about the potential for statins to disrupt brain function, and this recent animal study is only a small piece in the puzzle. However, it does support the idea that different statins can pose different risks here, and suggests that the conventional wisdom on lipophilic statins being more hazardous than hydrophilic ones may not actually hold true.

References:
1. Stuart SA, et al. Chronic Pravastatin but Not Atorvastatin Treatment Impairs Cognitive Function in Two Rodent Models of Learning and Memory. PLoS ONE 8(9): e75467

Research finds ‘raised’ cholesterol to be associated with a reduced risk of death - Briffa

 

By Dr John Briffa on 23 August 2013   

 

In the UK and Europe generally, it is recommended that levels of cholesterol in the blood should not be above 5.0 mmol/l (= about 190 mg/dl). We are given the impression that having levels above this puts us at increased risk of heart disease – a major ‘killer’. However, if this is true, it does not tell the whole story. Because while having a ‘raised’ cholesterol may be associated with an increased risk of heart disease, it might also be associated with a reduced risk of other conditions.

 

It is known, for instance, that higher levels of cholesterol are associated with a reduced risk of cancer. And even last week I wrote about some research which suggests that putting downward pressure on cholesterol levels increases the risk of death due to suicide, accidents and violence.

For these reasons, when assessing the relationship between any lifestyle factor and health, it pays to take as wider a view as possible. This is best done by focusing on the relationship the factor has with overall risk of death.

Such a study published recently in the Scandinavian Journal of Health Care makes for some interesting reading, I think [1]. Here, researchers assessed the levels of cholesterol and risk of death in almost 120,000 adults living in Denmark.

The researchers found that having higher than recommended levels of total cholesterol was associated with a reduced risk of death. For instance, in men aged 60-70, compared with those of total cholesterol levels of less than 5.0 mmol/l, those with total cholesterol levels of 5.00-5.99 had a 32 per cent reduced risk of death. For those with levels 6.0-7.99 mmol/l, risk of death was 33 per cent lower. Even in individuals with levels with 8.00 mmol/l and above, risk of death was no higher than it was for those with levels less than 5.0 mmol/l.

The results were similar for women too. In women aged 60-70, levels of 5.0-5.99 and 6.0-7.99 were associated with a 43 and 41 per cent reduced risk of death respectively.

In individuals aged 70 and over, the results were similar, except here, levels of total cholesterol of 8.00 mmol/l or more were associated with a reduced risk of death too (in both men and women).
Cholesterol in the blood stream is made up of two main types: LDL-cholesterol and HDL-cholesterol, dubbed ‘bad’ and ‘good’ cholesterol respectively. In this study, higher levels of LDL-cholesterol (above 2.5 mmol/l) were consistently associated with a reduced risk of death, irrespective or age or sex.

Together, these findings suggest that the current total cholesterol and LDL recommendations advised by doctors and other health professionals are way off beam. The authors of this study concluded that: “These associations indicate that high lipoprotein levels do not seem to be definitely harmful in the general population.”

Some have suggested that low cholesterol is a marker for ‘frailty’ in the elderly. However, this concept is contradicted by evidence finding that the association between low cholesterol levels and enhanced risk of mortality occurs in younger individuals too [2].

It has also been suggested the relationship between low cholesterol and enhanced risk of mortality is the result of ‘reverse causality’ i.e. that chronic conditions such as cancer can cause lowered cholesterol, rather than the other way round (sometimes referred to as ‘Iribarren’s hypothesis’).
However, evidence refuting this concept comes in the form of a long-term study which found that individuals with a low serum cholesterol maintained over a 20-year period had the worst outlook in terms of overall risk of death [3]. The authors of this study write: “Our present analysis suggests that this [Iribarren’s] hypothesis is implausible and is unlikely to account for the adverse effects of low cholesterol levels over twenty years.”

In the Danish study, the relationship between blood fats known as triglycerides and risk of death was also assessed. In women aged 50-60, higher triglyceride levels were consistently found to be associated with increased risk of death. This was somewhat true for women aged 60-70.

This does not mean that higher triglyceride levels cause heart disease – only that these two things are associated with each other. However, the major driver of triglyceride levels is dietary carbohydrate. And previous studies have found that swapping certain carbohydrates for fat in the diet is associated with an increased risk of cardiovascular disease [4,5].

All-in-all, I’d say this research should cause us to pause before recommending individuals aspire to current cholesterol recommendations. And, I think, we should be particularly wary about recommending that people adopt a lower-fat diet richer in carbohydrate to achieve these goals. There is at least some evidence which suggests that this is likely to do more harm than good.

References:
1.  Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: A population-based register study. Scandinavian Journal of Primary Health Care 2013;31(3):172-180
2.  Ulmer H, et al. Why Eve is not Adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality. J Womens Health 2004;13(1):41-53
3. Schatz IJ, et al. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet 2001;358(9279):351-5
4. Jakobsen MU, et al. Intake of carbohydrates compared with intake of saturated fatty acids and risk of myocardial infarction: importance of the glycemic index. Am J Clin Nutr 2010;91(6):1764-8
5. Jakobsen MU, et al. Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr 2009;89(5):1425-32
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British Heart Foundation does not want to engage with the troubling science on sterols - Briffa

The medical director of the British Heart Foundation does not want to engage with the troubling science on sterols

By Dr John Briffa on 9 August 2013  

 

Last month, I wrote a blog post about how there was no evidence that cholesterol-lowering ‘stanols’ and ‘sterols’ (found in some margarines and other ‘functional foods’) have benefits for health. In fact, the National Institute for Health and Care Excellence explicitly states that they should not be used. Yet, the British Heart Foundation (BHF) recommends the use of stanols and sterols, though I wondered if this might have something to do with the fact that one of its corporate partners is Flora pro.activ (a brand of sterol-enriched foods made by Unilever).

On the 17th July, I emailed the BHF about this. Here’s my email to them:

The National Institute for Health and Care Excellence has this to say about dietary stanols and sterols: “People should not routinely be recommended to take plant sterols and stanols for the primary prevention of [cardiovascular disease].”
We are also advised by NICE that: “There is a need for trials to test both efficacy and effectiveness of plant sterols and stanols in people who are at high risk of a first CVD event.

 These trials should test whether plant sterols or stanols change lipid profiles and reduce CVD events under best possible conditions. Randomised controlled trials are needed to test the effectiveness of advising people who are at high risk of experiencing a first CVD event to include food items containing plant sterols or stanols in a low-fat diet. The trial should last for at least 2 years and should consider appropriate outcomes.”

Yet, I notice that the BHF advocates stanols and sterols. Can someone explain the discrepancy, and whether the BHF believes the fact that Flora pro-avtiv is a corporate partner of represents a financial conflict of interest?
 

On the 30th July, I got a reply from Professor Peter Weissberg, the medical director of the BHF. Here are the highlights from his email:

• They are not suggesting that plant sterols/stanols can prevent a heart attack
• They do help to reduce LDL cholesterol, which is a risk factor for heart disease
• Their information reflects this and has not been altered by their fundraising partnership with Flora pro.activ.
• The BHF  has a very clear set of principles on the basis of which they work with commercial organisations.
• The amount of money they take from Flora pro.activ is a tiny percentage of their overall budget.

The same day, I emailed Professor Weissberg again, this time questioning the presumed benefit of LDL-cholesterol reduction, but also to draw his attention, should he not be aware of it already, of the considerable body of evidence which suggests sterols have the potential for harm. Here’s my email:

 

Dear Professor Weissberg
Thank you for getting back to me.

As you allude to, sterols/stanols have never been demonstrated to have clinical benefit, and it appears your support of them rests on their ability to reduce LDL-cholesterol levels (which you say is a risk factor for heart disease). Unfortunately, as I’m sure you’ll know, reduction of LDL-cholesterol most certainly does not assure clinical benefit. Ezetimibe – which has a similar mechanism of action to sterols/stanols – is a case in point.

Also, if arsenic and cyanide were found to be effective LDL-cholesterol reducing agents, it still would not make sense to recommend them for people for the reduction of cardiovascular disease risk, right?

The reason that I use this example is because, as you may know, there is a considerable body of evidence which suggests that sterols/stanols may have adverse effects on health. These are very well summarized in a paper published in the European Heart Journal in 2009 [Weingartner O, et al Controversial role of plant sterol esters in the management of hypercholesterolaemia. Europlean Heart Journal 2009;30:404-409]. If you have not already read it, I urge you to.

In this paper, the authors cite evidence linking the presence of sterols in the blood with an increased risk of cardiovascular disease. For example:

…there is evidence that elevated levels of plant sterols are associated with an increased cardiovascular risk. Glueck et al [Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives. Metabolism 1991;40:842–848] were the first to report that elevated plant sterols might be a risk factor for coronary heart disease. In a study with 595 hypercholesterolaemic patients, they found that slightly elevated plasma levels of plant sterols were a heritable marker for an increased cardiovascular risk.

Rajaratnam et al [Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women. J Am Coll Cardiol 2000;35:1185–1191]…found that in postmenopausal women, plant sterols were independently associated with coronary heart disease in a multivariate analysis. These findings were confirmed by Sutherland and his team in a study involving both sexes over all age groups [Association of plasma noncholesterol sterol levels with severity of coronary heart disease. Nutr Metab Cardiovasc Dis 1998;8:386–391].

The Scandinavian Simvastatin Survey Study (4S study) also identified a subpopulation of coronary artery disease patients with low endogenous synthesis of cholesterol and high absorption of cholesterol and plant sterols. The subjects of this subpopulation had the highest levels of plant sterols and the highest risk of recurrent coronary events despite lower levels of serum cholesterol due to simvastatin ingestion [Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. Finnish 4S Investigators. BMJ 1998;316:1127–1130]

Larger epidemiological studies reported similar data. Results of the PROCAM-study showed that patients afflicted with myocardial infarction or sudden cardiac death had increased plant sterol concentrations [Plasma sitosterol elevations are associated with an increased incidence of coronary events in men: results of a nested case-control analysis of the Prospective Cardiovascular Munster (PROCAM) study. Nutr Metab Cardiovasc Dis 2006;16:13–21]. Upper normal levels of plant sterols were associated with a three-fold increase of risk for coronary events among men in the highest tertile of coronary risk according to the PROCAM-algorithm.

Similar data are available for the plant sterol campesterol from the MONICA/KORA-study. In this prospective study, campesterol correlated directly with the incidence of acute myocardial infarction [Abstract 4099: elevated campesterol serum levels–a significant predictor of incident myocardial infarction: results of the population-based MONICA/KORA follow-up study 1994–2005. Circulation 2006;114:II_884].

This is all epidemiological evidence, of course, but it supported by several animal, in vitro and clinical experiments that, I think, give us genuine cause for concern. Again, from the European Heart Journal paper [Weingartner O, et al Controversial role of plant sterol esters in the management of hypercholesterolaemia. Europlean Heart Journal 2009;30:404-409]:

Current experimental findings from our own research group show that a diet supplementation with plant sterol esters that is equivalent to a commercially available spread induces endothelial dysfunction and leads to an increase of ischaemic stroke size in wild-type mice [Vascular effects of diet supplementation with plant sterols. J Am Coll Cardiol 2008;51:1553–1561].

…in a clinical study, we demonstrated that patients who were consuming plant sterol ester enriched margarine had increased concentrations of plant sterols in cardiovascular tissue [Vascular effects of diet supplementation with plant sterols. J Am Coll Cardiol 2008;51:1553–1561].

Further mechanistic data suggest that vascular deposits of sterols, when compared with cholesterol, result in increased oxidation and release of oxygen radicals [Oxidized plant sterols in human serum and lipid infusions as measured by combined gas-liquid chromatography-mass spectrometry. J Lipid Res 2001;42:2030–2038].

…the induction of apoptosis is not limited to tumour cells, but extends also to vascular cells. Recent in vitro experiments demonstrated that the plant sterol sitosterol exerts a strong cytotoxic propensity inducing apoptosis in human endothelial cells, revealing detrimental effects on the vasculature [Beneficial or harmful influence of phytosterols on human cells? Br J Nutr 2008;100:1183–1191].
In fact, the first experimental study reporting negative cardiovascular effects dates back to the year 2000. Ratnayake et al.  [Vegetable oils high in phytosterols make erythrocytes less deformable and shorten the life span of stroke-prone spontaneously hypertensive rats. J Nutr 2000;130:1166–1178 reported that increased serum levels of plant sterols increase rigidity of erythrocytes and shorten the life span of stroke-prone spontaneously hypertensive (SHRSP) rats.

These findings were the reason for Health Canada, the federal department responsible for helping Canadians maintain and improve their health, to raise significant safety issues and not to allow functional foods enriched with plant sterol esters to be sold in Canada.

I am sure you must be very busy, but please take some time to consider this evidence. From what I can see from the research, we have no evidence at all that sterols/stanols improve clinical outcomes, and considerable evidence linking them with potential for harm. Until we have positive evidence regarding outcomes, wouldn’t the most prudent and safety-conscious thing be to not recommend sterols/stanols (as NICE does)?

Thank you for your explanation regarding your corporate partners. If the funds derived from this relationship are so low, why not sever the link and have no conflict of interest at all, here?
I look forward to hearing from you.
Kind regards
John Briffa
 

On the 6th August, I got this response from Professor Weissberg:

Dear Dr Briffa
Thank you for your further email on this subject. I am aware of a large number of publications, of varying quality and validity, on the subject of plant stanols and sterols and their potential benefits and harms. I would prefer not to enter into a debate on any one of them since they all have their strengths and weaknesses.

So, as with so much in science, interpretation of the data is not as straightforward as is sometimes presented. Nevertheless, we are agreed that, ideally, one would like to see appropriately designed outcome trials to test their role in protection against cardiovascular events. In the absence of such data (and I doubt they will ever be produced), it is a matter of judgement as to whether or not plant stanols should be included as part of a wider strategy to reduce cardiovascular risk, and different national bodies have come to different conclusions.

In drawing this correspondence to a close I would conclude by saying that the BHF only enters into partnerships after careful consideration of all the pros and cons of so doing. As discussed previously, the main objective of the partnership with Unilever is to utilise their considerable reach to help us highlight the risk of CVD to women.

I thank you for your interest in this project and assure you we take seriously all feedback we receive.
Yours
 

Notice here how Professor Weissberg makes no comment at all on the specifics of the studies, nor puts up one scrap of evidence to refute the concerns raised. And what are we to glean from his writing: “In drawing this correspondence to a close…” To me, that gives the impression Professor Weissberg wants to hear no more from me (or perhaps anyone else) on the matter. Case closed!
I think we deserve better to be honest. I genuinely believe that, based on the evidence, there is a case to answer regarding the health effects of sterols, and it’s simply not good enough for Professor Weissberg to dismiss the evidence based on rhetoric to do with, supposedly, the evidence being of ‘varying quality and validity’. This is true of all science, so is Professor Weissberg suggesting we just go back to the dark ages and believe what suits us?

How many people do you imagine look to the BHF as being a reliable and credible organisation dedicated to our heart health? Lots, I would imagine. How do you think they would feel to know that when legitimate concerns are raised about products they recommend (some of which are made by a company the BHF partners with), their medical director just flatly refuses to engage with the science?
There is absolutely no evidence that sterols benefit health, but it seems the BHF is going to recommend them anyway, even in light of significant evidence suggesting they have the potential for harm.

Professor Weissberg seems to claim that the BHF’s relationship with Unilever does not compromise them. In fact, Unilever is helping them raise awareness about the risk of cardiovascular disease in women! I wonder how many of these women will be concerned enough to put their faith in utterly bogus food products enriched with sterols?
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Licence for another unproven cholesterol drug - Briffa

The FDA grants licence for another unproven cholesterol drug

By Dr John Briffa on 8 May 2013

 

Ezetimibe is a drug that lowers cholesterol levels by blocking its absorption from the gut. The drug is available under the brand name Zetia. Doctors can also prescribe ezetimibe in combination with the statin drug simvastatin. This combination medication is sold under the name Vytorin. Both Zetia and Vytorin have racked up billions of dollars in sales. What a shame, then, that neither of them has been found to have any benefit at all in terms of reducing the risk of heart disease, heart attacks, strokes or risk of death.

Zetia and Vytorin are licenced on the basis of their impact on cholesterol levels. The thinking is that LDL-cholesterol must be bad, so anything that reduces it must be good. However, we know from experience that many things that ‘improve’ cholesterol do not bring broad benefits to health. And besides, it’s simply not good science or medicine to assume that a drug has benefits for health based on its impact on what is known as a ‘surrogate marker’ such as cholesterol. I mean, if arsenic reduced cholesterol it still would not make sense for us to swig back arsenic each day, would it?

This seems like perhaps an extreme analogy, but it should be borne in mind, I think, the Vytorin use has in some studies been associated with an increase (not statistically significant) in the thickening of the arteries compared to simvastatin alone. Also, there was some early evidence the Vytorin increased the risk of death from cancer, though some more recent evidence is said to have allayed fears here.

While some doctors continue to prescribe Zetia and Vytorin it’s difficult (for me) to justify this. There is some evidence that since 2008 (when we saw the first of a few negative studies on Zetia/Vytorin emerge) sales of these drugs have fallen considerably, though profit remains considerable. Make no mistake, though, the fact that Zeta/Vytorin is still on the market and was licensed in the first place is seen by some doctors and researchers as testament to the ability of drug companies to bamboozle regulatory authorities such as the Food and Drugs Administration (FDA) in the US. Either that, or the FDA is perhaps putting the needs of drug companies above those of patients.

Against this background, it is interesting to note that Merck (manufacturer of Vytorin) has been for some years attempting to get another similar drug combination passed by the FDA. The drug combines ezetimibe with the statin atorvastatin and has the brand name Liptruzet. As with Vytorin, there exists no evidence that Liptruzet benefits so-called ‘clinical’ outcomes such as incidence of heart disease and stroke.

Now, given all the controversy around Vytorin and the lack of evidence for the benefit of this product, you might imagine the FDA would be keen not to repeat its mistake by granting Liptruzet a licence. Astonishingly, though, the FDA did just this last week.

Now, normally, when a new drug hits the market the press reports parrot the drug company rhetoric about, say, the benefits of the drug and the lives it could save. What is interesting about the press reports on the licensing of Liptruzet is how many of them report scepticism regarding the wisdom of this decision expressed by doctors and researchers. See here for an example.

The piece quotes Steven Nissen, chairman of cardiology at the Cleveland Clinic in the US. According to Dr Nissen, the FDA’s decision to approve the Liptruzet “just doesn’t make any sense.” He is quoted as saying:

I find it astonishing that after all the controversy about ezetimibe the FDA would approve another combination product with a drug that has been on the market for a decade and has not been shown to improve cardiovascular outcomes. It seems like the agency is just tone deaf to the concerns raised by many members of the community about approving drugs with surrogate endpoints like cholesterol without evidence of a benefit for the disease we are truly trying to treat – cardiovascular disease.

And what does Merck have to say for itself? According to spokeswoman Pamela Eisele, Merck is “confident in ezetimibe and in the established relationship between lowering LDL cholesterol and reducing cardiovascular events.”

Merck can be confident all it likes in ezetimibe and its products Zetia, Vytorin and Liptruzet, but the fact is, none of these have been shown to lower ‘cardiovascular events’. My personal opinion is that either Merck is full of idiots or is taking us for idiots. The good news is that the sort of rhetoric spouted by Merck is immediately being recognised by some as having a distinct whiff of b.s. about it.
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‘Patient Powered Health’ - Briffa

Patients are the new doctors

By Dr John Briffa on 23 April 2013

 

I regularly see patients who, rather sheepishly, tell me that they have ‘googled’ their symptoms to try and work out what might be wrong with them. They often add something like ‘I know shouldn’t have”. Finding useful health advice on the internet can be a bit of a lottery, but I personally have no issue with patients googling their symptoms and looking for information. My experience in practice tells me that they will very often find something that is of genuine use to them and their health practitioner (if open-minded enough).

The rise of the internet has seen medical and research information become much more available to individuals. And boy have people seized the opportunity to access this information in an effort to understand better how to overcome illness and enhance health. Not uncommonly I see patients who know far more about some health matter than I. I like to embrace this, personally, as it usually means that person is likely to progress faster down the path to health than if they hadn’t bothered to or been able to educate themselves. And I have generally have no issue at all (quite the reverse, actually) with a patient educating me about some health matter.

Another trend I’ve noticed is just how much people have been able to tap into the collective experiences and wisdom of others. I see this quite commonly in diabetics, for instance. I’ve seen quite a few diabetics who have found controlling their blood sugar levels difficult on the low-fat, high carbohydrate diet often recommended to diabetics (go figure!). Many of these diabetics go looking for or stumble across a forum like this one where individuals can swap stories and idea relating to low-carbohydrate eating.

Some will feel sufficiently convinced to give this type of eating a try and will usually see a significant improvement in their blood sugar control and a reduction in medication requirement as a result. Some will run the idea past their doctor or diabetologist first, but some will not. In effect, those in the latter group have made a self-directed decision about their diet and healthcare based on the experiences and advice of, not healthcare professionals, but ‘ordinary’ individuals with experiences and ideas to share.

I’ve heard many healthcare practitioners express horror that this sort of thing going on. For example, dieticians or dietician bodies very often warn about the supposed perils of taking ‘a whole food group’ (e.g. starchy carbs) out of the diet. The idea here is that somehow such a person is being reckless and risking a diet deficient in key nutrients. In my view, this person is unlikely to be exhibiting any recklessness at all, and there’s nothing found in these starchy carbs that cannot be found more healthily (in my opinion) elsewhere in the diet. And let’s not forget that this particular dietary change is often accompanied by an improvement in not just blood sugar control, but improvements in a range of disease markers.

I was motivated to write about this on reading a recent piece form the deputy editor of the British Medical Journal [1]. Entitled ‘Patient Powered Health’, this piece explores the notion that the internet can be a source of useful information from the lay public that can inform patients and help direct their care in ways that supersede conventional medical care.

The same edition of the journal contains an account from someone – Dave deBronkart – who was diagnosed with advanced kidney cancer, and who’s doctor suggested he take a look at acor.org, an online resource for individuals with various forms of cancer. deBronkart posted a message on the site, and within two hours he: “got facts and practical advice that to this day don’t exist in any journal article or establishment website,” including information about the best treatments and side effects from those who had already experienced them.

The editor’s piece goes on to say: “The internet and online communities are often rightly criticised as sources of misinformation and bad advice. But deBronkart’s story illustrates the contribution that informed and engaged patients can make to the complexities of medicine.” deBronkart is quoted as saying: “The value delivered by skilled clinicians is still there, but now we can see that it’s no longer the only source,” he writes. “Please, let patients help improve healthcare. Let patients help steer our decisions, strategic and practical. Let patients help define what value in medicine is.”
The BMJ has a long-running ‘Patient’s Journey’ series which is partly designed to achieve this end (letting patients help define value and quality in medicine is). The BMJ’s patient editor, Peter Lapsley, adds: “There is no privileged vantage point from which to decide who is right and who is wrong.”

That’s right, I think. We doctors no longer have a monopoly in health information and advice. Patients now have the potential to learn much from the experiences and wisdom of other patients. I don’t think we doctors should be threatened by this: I think we should embrace it, partly because it can benefit patients, and partly because our patient’s experiences and ideas can benefit we doctors too.

References:
1. Jackson T. Patient powered health. BMJ 2013;346:f2255
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Read the complete article here.

Links: ACOR, Association of Cancer Online Resources - http://www.acor.org/
BMJ, British Medical Journal Patient's Journey - http://www.bmj.com/content/346/bmj.f1988?sid=92bca820-ea7c-400b-9a9e-1198c3987b0c
 

Side effects of statins are likely to be much more common than official statistics suggest

Some reasons why the side effects of statins are likely to be much more common than official statistics suggest

By Dr John Briffa on 7 March 2013

 

I saw a patient recently who suffered from mental symptoms (poor memory and inability to find his words) quite soon after commencing statins, and his symptoms resolved quite soon after discontinuing the drugs. He might be imagining his issues or suffering from a ‘nocebo’ response (the opposite of a placebo response), but he and I reckon the most likely thing is that his brain has suffered from the side effects of statins.

When side effects appear to come on quickly after taking a drug, and resolve quite quickly on stopping it, it’s generally easy to work out what’s likely to be going on. However, the side effects of drugs can take some time to manifest, and this is certainly true for statins. A recent piece of research makes the point that some statin side effects can take even years to become apparent. The authors of this study make the point that for a given number of people taking statins, the total number of people suffering from side effects creeps gradually upwards.

I was interested to read about a recent review in which the frequency of adverse effects from statins was assessed over time [1]. The authors of this study make the point that when side effects occur, these can often come on quite soon after therapy is commenced (just as in the man referred to above). However, they also point out that side effects can be delayed for several years too. The relatively short duration of studies leads the authors to conclude that it is: “…impossible to determine with certainty the frequency of long-term side effects with these drugs.”

In reality, though, there’s a pretty good chance those who start statins will not be taking them in the long term. That’s because about three-quarters of people who start statins promptly stop them within a year. And last year, a poll conducted by drug company Eli Lilly discovered that the most common reason for people discontinuing their statin was side-effects. In fact, 62 per cent of people cited this as the reason. By my reckoning, it seems that getting on for half of people will stop their statin within a year of starting because of side effects.

Despite this sort of data, we are often assured that the side-effects from statins are ‘rare’. In fact, if you look at the studies in which people are treated with statins, this generally appears to hold true. However, there’s a number of ways in which the design of studies can downplay the risk of side effects. Here’s a few:

1. short duration and ‘early termination’ of studies (this also tends to exaggerate benefits)

2. screening out those susceptible to side effects before the study begins

3. logging side effects only if there’s extreme deviation from normal biochemistry (some studies only log side effects once biochemical markers are several times the upper limit of normal)

4. not looking for certain side effects in the first place

 

These devices help explain the disparity between what studies show in terms of statin side effects, and our apparent experience in the real world. My own experience (and that of many doctors I speak too) tells me that statin side effects are much more common than official statistics would have us believe.

References:
1. Huddy K, et al. Do the frequencies of adverse events increase, decrease, or stay the same with long-term use of statins? Curr Atheroscler Rep. 2013;15(2):301

Could statins be adding to the epidemic of heart failure? - Briffa

Could statins be adding to the epidemic of ‘heart failure’?

Jan, Fri 4th, 2013 By : Dr John Briffa

 

Statins are drugs that reduce cholesterol by inhibiting an enzyme in the liver known as ‘HMG-CoA reductase’ which ‘drives’ cholesterol production (most of the cholesterol in the bloodstream is made in the liver and does not come directly from the diet). But HMG-CoA reductase also facilitates the production of a substance known as ‘coenzyme Q10’ which itself participates in the production of what is known as ‘adenosine triphosphate’ (ATP) – the most basic unit of energy ‘fuel’ in the body. The major biochemical process which involves CoQ10 that drives ATP and energy production in the body is known as ‘oxidative phosphorylation’.

Now that we have the potted biochemistry lesson over, we can see that statins have the potential, by lowering CoQ10 levels, to put a break on oxidative phosphorylation and ATP production in the muscles. The end result may be fatigue? Muscle pain is another potential consequence.

In a study published this week in the Journal of the American College of Cardiology (JACC), Danish researchers measured CoQ10 levels in individuals taking simvastatin (a commonly-prescribed statin), and compared them with those not taking statins [1]. The levels in those taking the statin were significantly lower.

Now, studies such as this one are what is termed ‘epidemiological’ in nature, which means it looks at associations between things, but cannot prove that one thing is causing another. However, of relevance here is other evidence which finds that giving statins to people does indeed have the capacity to lower levels of CoQ10 in the body [2].

What was also interesting about the JACC study is that it found that those treated with statins had lower levels of oxidative phosphorylation than those not taking them. They also had reduced ‘insulin sensitivity’. This is relevant for a number of reasons, including the fact that insulin facilitates the uptake of nutrients such as glucose into the cells. Lowered insulin sensitivity can therefore ‘starve’ the cells of essential nutrients. Reduced insulin sensitivity is also the underlying fault in type 2 diabetes. It is perhaps worth bearing in mind that statin use has been proven to increase the risk of type 2 diabetes.

Another thing worth bearing in mind here, I think, is the fact 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’ (also known as ‘congestive cardiac failure’). I think the ‘benefits’ of statins are vastly overstated, generally speaking. However, if someone is to take statins, I think it’s a reasonable safeguard to take CoQ10 on a daily basis. 100 mg a day is a decent dose, I think, though higher doses are likely to better when symptoms of statin toxicity are present.

In researching this article, I came across an interesting review of the evidence for statin-inducted CoQ10 depletion in both humans and animals [3]. Here’s what the authors of this review have to say in their concluding remarks:

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.

References:
1. Larsen S, et al. Simvastatin Effects on Skeletal Muscle – Relation to Decreased Mitochondrial Function and Glucose Intolerance. J Am Coll Cardiol. 2013;61(1):44-53
2. Passi S, et al. Statins lower plasma and lymphocyte ubiquinol/ubiquinone without affecting other antioxidants and PUFA. Biofactors 2003;18(1-4):113-24.
3. 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.
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Read the complete article here.

Drug company kills off another cholesterol-modifying drug - Briffa

Drug company kills of another cholesterol-modifying drug

Dec, Fri 14th, 2012

 

I rarely meet someone who has not heard of cholesterol and does not believe it to be a largely dangerous substance. And increasing number of people seem to be aware of the conventional wisdom regarding the different forms of cholesterol, specifically low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C). Actually, these names are a bit misleading, as these particles are not cholesterol (though they do contain cholesterol). But, anyway, the conventional wisdom is that LDL-C dumps cholesterol on the inside of our arteries while HDL-C clears cholesterol. As a result, LDL-C and HDL-C are often dubbed ‘bad-’ and ‘good-’ cholesterol.

The most commonly prescribed cholesterol drugs are known as statins, and their main mechanism of action is to lower LDL-C levels. However, other types of cholesterol-modifying drugs exist, including a relatively new class known as cholesterylester transfer protein inhibitors (CEPT inhibitors), which the conversion of supposedly healthy HDL-C into supposedly unhealthy LDL-C. If you believe the conventional wisdom on cholesterol (I don’t), then this should translate into benefits for health with regard cardiovascular disease (e.g. heart disease and stroke).

All this theory is meaningless, however. The only important thing is not the effect drugs (or anything else) have on cholesterol levels, it’s the impact they have on health. Some years back the drug company Pfizer spent in the region of $800 million developing a CEPT inhibitor by the name of torcetrapib. It had ‘positive’ effects on LDL-C and HDL-C levels, but also turned out to kill people. Pfizer promptly and quite rightly ceased development of the drug.

The crashing failure of torcetrapib has not stopped other drug companies seeking to find a commercially viable CEPT inhibitor of their own. More recently, drug company Roche invested in the development of a drug known as dalcetrapib. However, in the middle of this year Roche abandoned plans for further development, and a recently-published study shows us why [1].

In this study, published in the New England Journal of Medicine, almost 16,000 patients who had suffered from ‘acute coronary syndrome’ (e.g. angina or heart attack) were treated with dalcetrapib or placebo for an average of about two and a half years.

These are just the sort of patients one would expect to benefit most from an intervention because, as a group, they would generally be at high risk of future problems. Also, the number of subjects here is huge, and therefore more than big enough to detect any real benefit the drug may have.

The researchers assessed the effects of dalcetrapib using a ‘composite endpoint’ – which essentially means lumping several outcomes together. The composite outcome included death from heart disease, non-fatal heart attack, ischemic stroke (strokes due to blockage of blood vessels rather than bleeding), unstable angina (angina that can come on at rest), and cardiac arrest with resuscitation. The use of composite endpoints ups the odds that a ‘statistically significant’ benefit for a drug will be found (compared to when only one single outcome is chosen).

Biochemical analysis revealed that dalcetrapib did, as expected, have considerable HDL-boosting effect. But the study showed that this drug had no benefits for health at all.

Another interesting thing about the study was that dalcetrapib was found to increase markers of inflammation – a process which is believed to play a key part on the development of heart disease and stroke.

This study was originally designed to run for longer but was terminated early once these results were in. Early termination of studies is known to generally inflate the benefits of drugs and downplay their risks. Who knows what may have happened if they’d continued.

Of course you’re unlikely to hear about the dalcetrapib study because it wasn’t announced with the blaze of publicity usually afforded to more ‘positive’ studies about cholesterol-reducing drugs. But this is often the way with cholesterol-related research in particular: positive results are spun in a way which gives medication seeming miraculous properties, while negative results and inconvenient truths are swept under the carpet.

References:
1. Schwartz GG, et al. Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 29 November 2012 (epub)
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Read the complete article here.

Do statins really reduce the risk of cancer? - Briffa

Do statins really reduce the risk of cancer?

Nov, Fri 9th, 2012 By : Dr John Briffa

 

Yesterday saw the on-line publication of a study in the New England Journal of Medicine (NEJM) that concerns statins and is getting more than its fair share of media attention. The study, conducted in Denmark, analysed the rates of death from cancer in individuals taking statins, and compared them to those in individuals not taking these drugs. Those taking statins were found to be at a statistically significant reduced risk of dying from cancer. Some seem keen to claim that statins may not only be an answer to heart disease, but our cancer woes too. Take this headline for example which you can find here: ‘Statins cut mortality in cancer patients’. The wording of this title on a website dedicated to the education of doctors strongly suggests that statins actually reduce the risk of death from cancer.

But, not so fast. The NEJM study is what is known as ‘epidemiological’ or ‘observational’ study. The study tells us that statin use is associated with a reduced risk of death from cancer, but it can’t tell us whether or not statins actually cut cancer risk.

One fundamental problem with studies of this nature is that they are subject to what is known as the ‘healthy user effect’. Basically, what this means is that healthier, often more health-conscious individuals are more likely to end up on statins than less healthy, not so health-conscious individuals. Because of this, it’s possible that the apparent benefits of statins with regard to cancer (or anything else) are not to do with the drugs themselves, but the health characteristics of those more likely to take statins.

If we really want to know if statins reduce the risk of cancer death then we need to look to what are known as ‘intervention studies’ in which, usually, roughly equivalent groups of individuals are given statins or placebo. These studies, the gold standard of which are ‘randomised controlled trials’ do have the potential of discerning the true effects of drugs and other treatments.

Single studies such as these can provide useful data, but sometimes it makes sense to amass data from several studies to get a decent overview of the impact of a drug or class of drugs. Such grouping of studies together are referred to as ‘meta-analyses’.

One meta-analysis published in 2009 found that statin use was not associated with a reduced risk of cancer [2]. A more recent meta-analysis published this year found the same thing [3]. Meta-analyses of intervention studies are not perfect, but they are much better than (crappy) single epidemiological studies like the one currently doing the rounds. And it’s perhaps worth bearing in mind that there as been at least some concern about the impact statins might have on cancer risk in the elderly. In one study, statin use (compared to placebo) increased the risk of cancer by 25 per cent (statistically significant) [4].

Put in this context, the frothing enthusiasm exhibited by some regarding this latest study seems inappropriate. And for a website dedicated to the education of doctors to proclaim that ‘Statins cut mortality in cancer patients’ is downright negligent.

References:
1. Nielsen SF, et al. Statin Use and Reduced Cancer-Related Mortality. NEJM published online 8 October 2012
2. Brugts JJ, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:b2376.
3. Cholesterol treatment trialists’ collaboraton. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One 2012;7(1):e29849. Epub 2012 Jan 19.
4. Shepherd J, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360(9346):1623-30
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Read the complete article here.

New cholesterol-lowering drug is licensed despite no evidence of benefits for health - Briffa

 Another new cholesterol-lowering drug is licensed despite no evidence of benefits for health

I was reading here that there’s a new cholesterol-lowering drug in the pipeline. The Food and Drugs Administration in the US has approved the injectable agent mipomersen for the treatment of ‘homozygous familial hypercholesterolaemia – a genetic cause of raised cholesterol levels associated with cardiovascular disease developing early in life. Mipomersen has been shown to reduce low density lipoprotein (LDL) levels by about a quarter. The hope is that this will help reduce the risk of individuals suffering premature death from, most likely, heart attack.

I’ve used the word ‘hope’ in the preceding sentence but, in reality, the FDA panel that has ratified mipomersen has no idea whether it has health benefits or not. That’s because the studies used to assess this drug were not large enough in scope to detect change in ‘clinical endpoints’ such as risk of heart attack or death. In other words, the licensing of this drug has been on the basis of its impact on ‘surrogate endpoints’ (in this case, cholesterol levels), rather than clinical endpoints (the thing that really matters).

And I’m not splitting hairs either, as we already have examples in the not-too distant past of drugs that promised a lot in terms of their impact on cholesterol, but failed to deliver in terms of actual health. For example, the drug ezetimibe is a proven cholesterol-lowerer, yet not one single study to dates demonstrates it has benefits in terms of clinical endpoints. Also, the drug torcetrapib looked at one time to be a new hero of cholesterol management, until appropriately designed studies found it was killing people (it’s since been dropped).

But the principle that something that benefits cholesterol does not necessarily benefit health does seem to have been somewhat lost on the FDA. And worse still, it seems the panel may have put their faith in cholesterol modification above some quite troubling data. Here you can read how the FDA’s own review of mipomersen revealed a number of concerns about this drug. Here’s an excerpt from the article:

Serious adverse events of cardiac disorders occurred in 3.8% (10/261) of patients in the mipomersen group compared with 3.1% (4/129) in the placebo group. The reviewers concluded that “the possibility that mipomersen therapy increases the risk for cardiovascular events cannot be excluded.”

Other concerns were raised by the finding that mipomersen increased the levels of ‘liver enzymes’ and increased the amount of fat in the liver (both signs of damage to the liver). Here’s another except:

The FDA reviewers said they did not know whether long-term use of mipomersen could cause irreversible liver damage, but warned that patients could be at risk for cirrhosis and liver-related death if the observed liver changes progressed.

And perhaps worse still, there’s even concern that mipomersen might have cancer-inducing potential:

According to the review, during clinical testing neoplasms, both benign and malignant, were detected in 3.1% (23/749) of patients who received mipomersen compared with 0.9% (2/221) of patients who received placebo. However, the FDA clinical reviewer noted that there was a diversity of malignant neoplasms and that two out of nine mipomersen patients who developed a malignancy had been on mipomersen for less than a month, “making it highly unlikely that mipomersen played a role.” The review concluded that ”there are several confounding factors that make it difficult to conclude that mipomersen is playing a dominant role in this cancer imbalance.”

Forgive me, but personally I detect a hint of ‘sweeping the issue under the carpet’ here. The same thing, by the way, happened with ezetimibe, which has been shown to increase the risk of death from cancer, an effect which researchers put down to chance (even though the effect was statistically significant and therefore highly unlikely to be due to chance). See here for more about this.

The FDA panel’s vote on mipomersen was relatively close (9 v 6), so at least some members of the panel had their doubts. It is said that the severe nature of homozygous familial hypercholesterolaemia was a major determining factor in swaying the vote. That’s laudable, perhaps, but I don’t think it excuses the fact that this drug has been licensed despite an absence of data that it benefits health, as well as the presence of data which points very much in the opposite direction.
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Read the complete article here.

Bread – the staff of life or the stuff of nightmares? - Briffa

Bread – the staff of life or the stuff of nightmares?

Sep, Fri 21st,  Dr John Briffa

 

I was away for most of this week and, as a result, this on-line article (and several similar ones) passed me by. It focuses on the ‘research’ conducted by Dr Aine O’Connor of the British Nutrition Foundation and published in its ‘journal’ – the Nutrition Bulletin [1]. I’ve not read the article itself, but here’s the abstract (summary).

Despite being a staple food in the UK for centuries, bread consumption has fallen steadily over the last few decades. Average consumption now equates to only around 2–3 slices of bread a day. As well as providing energy, mainly in the form of starch, bread contains dietary fibre and a range of vitamins and minerals. The National Diet and Nutrition Survey (NDNS) of adults suggests that it still contributes more than 10% of our daily intake of protein, thiamine, niacin, folate, iron, zinc, copper and magnesium; one-fifth of our fibre and calcium intakes; and more than one-quarter of our manganese intake. Therefore, eating bread can help consumers to meet their daily requirements for many nutrients, including micronutrients for which there is evidence of low intake in some groups in the UK, such as zinc and calcium. This paper gives an overview of the role of bread in the UK diet, its contribution to nutrient intakes and current consumption patterns in different population groups.

The tone of the articles spawned by this research and the (likely) press release that accompanied, people who have eschewed bread in search of better health are deluded idiots. Plus, they’re putting themselves at perilous danger of nutritional deficiencies. And this has to be right, of course, because it comes from a ‘nutrition scientist’.

So, let’s get a few things straight. First of all, bread is not a particularly nutrient dense food, and it also contains things (like digestion inhibitors and phytates) that impair our ability to absorb nutrients from it anyway.

The fact that: “The National Diet and Nutrition Survey (NDNS) of adults suggests that it still contributes more than 10% of our daily intake of protein, thiamine, niacin, folate, iron, zinc, copper and magnesium; one-fifth of our fibre and calcium intakes” may sound impressive, but these figures exist only by virtue of the fact that, although declining, bread consumption is still relatively high. The fact remains that there’s nothing in bread that cannot be had more healthily elsewhere in the diet. Superfood it ain’t.

The issue of wheat sensitivity needs dealing with too, because repeatedly we are told by people like Dr O’Connor that it’s a minor and rare concern. Often this view is based on the prevalence of coeliac disease (sensitivity to gluten). However, research suggests that it is possible to be sensitive to gluten but not have coeliac disease. In other words, even if tests exclude coeliac disease, that does not mean that person will have no ill effect from eating gluten. Over the years, I have seen literally hundreds of patients who, on reduction or elimination of wheat from their diets, have seen significant improvement in a range of symptoms including abdominal bloating, other digestive symptoms including indigestion. Of course, some people (maybe Dr O’Connor) will tell us that such improvement can only be in their heads. They might be right, but the consistency of the improvement seen on elimination of wheat suggests to me there’s something in it.

Another potential problem with bread is that it’s made mainly of starch, and starch is sugar (starch is comprised of chains of glucose molecules). Now, the extent to which bread disrupts blood sugar levels is about the same as table sugar (also known as sucrose, which is half glucose and half fructose). So, munching down on a sandwich at lunch, for instance, is quite likely to induce quite a sugar high, that may well get the body pumping out insulin, the effect of which can be to drive blood sugar levels to sub-normal levels in the mid-late afternoon. The end result can be fatigue, mental lethargy, and perhaps a desire to raid the biscuit tin or take a trip to the vending machine.

When people take bread out of their lunch, the usual end result is for people to feel significantly more energised and productive through the afternoon. I say ‘usual’, but actually it’s hardly ever not the case. Again, perhaps it’s all in their heads and a major placebo response is going on. However, once again, the predictability and consistency of the improvement suggests to me that it’s something that deserves our consideration and has validity.

As I said earlier, I haven’t read Dr O’Connor’s article, but her scientific credentials lead me to suspect at least some of her line of argument will be ‘where’s the evidence’ for the harmful effects of bread? In my experience, the evidence is all around and evident to those who:

1. have benefitted from the removal of bread/wheat from their diets
2. see patients who consistently benefit from bread/wheat from their diets and are prepared listen to what their patients tell them

By the way, I fall into both categories. When I eat wheat the usual response in very noticeable digestive discomfort and fatigue.

I don’t feel inclined to wait for evidence that smashing someone in the face with a polo mallet causes pain and suffering, and I feel pretty much the same about bread.

I suppose it should not go unremarked that the British Nutrition Foundation is supported by various factions within the food industry, and this organisation is sometimes less than transparent about where it gets its money from and the obvious conflicts of interest here. See here for more on this.

References:
1. O’Connor A. An overview of the role of bread in the UK diet. Nutrition Bulletin 2012;37(3):193–212
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Read the complete article here.

Read an additional article titled "The Threat of CSIRO’s GM Wheat Revealed at Press Conference"
Quote:  “What we found is that the molecules created in this wheat, intended to silence wheat genes, can match human genes and through ingestion these molecules can enter human beings and potentially silence our genes.”

Supposed Perils Of Eating Eggs - Briffa

 Supposed Perils Of Eating Eggs

Aug, Wed 15th,  By : Dr John Briffa

 

Someone recently sent me a link to this report of a study which warns us of the supposed perils of eating eggs. The study on which the report is based [1] looked at the association between the amount of egg yolks people ate and the amount of ‘atherosclerotic plaque’ in the main arteries supplying blood to the head (the carotid arteries). The authors tells us that an association was found, even when other potential ‘confounding’ factors were taken into account such as smoking and body mass index. By their own admission, though, the authors suggest they should have perhaps included some other confounding factors too, including exercise and waist circumference. Nevertheless, the end result is the authors warning us off eating eggs. Is there concern and advice justified?

OK, let’s get something straight from the start: this study is what is referred to as an epidemiological study, which looks at associations between things, but can’t be used to determine causality (in this case, that eating eggs accelerates atherosclerosis). One relevant factor here is that eggs have suffered from an unhealthy reputation for years now, and it may be that those who eat eggs are less health-conscious on-the-whole, and perhaps are more likely to engage in genuinely life-threatening behaviours such as filling up on processed food or being very sedentary. I actually wrote about these issues most recently here, in a post entitled ‘Note to medical journalists: correlation does not prove causation’. It seems some researchers need to be reminded of this too, hence the title of this blog post.

Another fundamental problem with research of this nature as it relies on individuals reporting how much and/or often they eat of specific foods. As a patient remarked to me yesterday, most people find it difficult to recall what they ate even a couple of days ago. Self-reporting of diet is generally recognized to be hopelessly prone to error.

So, let’s summarise here the essentials of this study:

1. it found an association between egg eating and the amount of atherosclerosis in the carotid arteries
2. it controlled for some relevant confounding factors but not others
3. it relied on self-reported dietary data which is very prone to error
4. even if the study was really well done and the dietary reporting accurate, it’s still epidemiological in nature which tells us, in the end, little or nothing

Now, bear this in mind when you read this quote from the one of the study authors – Dr J David Spence – as it appears in the report I link to above:

What we have shown is that with aging, plaque builds up gradually in the arteries of Canadians, and egg yolks make it build up faster…

This stance clearly gives the impression that eating eggs yolks cause atherosclerosis, but this claim simply cannot be made on the basis of this study.
Here’s another quote from Dr Spence:

In diabetics, an egg a day increases coronary risk by two to five-fold

He’s referring to other epidemiological research here, and again his assertion is indefensible.
But maybe we shouldn’t be too surprised, here, because Dr Spence has form in this area. In a previous blog post here I detail how he, along with a co-author, makes strong claims about eggs eating based on weak evidence. What would cause a ‘scientist’ to overstate the relevance of his or her research? Many things, but here’s two:

1. Ego
Look, researchers generally like to publish ‘impactful’ stuff. Too bad that Dr Spence engages in ‘research’ that simply can’t be very impactful on the basis of it epidemiological nature. Even unconsciously there can be a tendency to ‘over-egg’ (sorry, couldn’t resist) one’s findings.

2. Conflicts of interest
As I detail in the blog post I link to above, Dr Spence has been rewarded financially in a way that gives him a vested interest in keeping the ‘cholesterol is bad’ theory alive.

References:
1. Spence JD, et al. Egg yolk consumption and carotid plaque. Circulation epub 31 July 2012
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Read the complete article here.

Doctors criticise plans for cholesterol screening in children

Doctors criticise plans for cholesterol screening in children

Back in November 2011, a panel of experts assembled by the National Heart, Lung and Blood Institute (NHLBI) in the US published recommendations regarding cholesterol screening in children. The panel recommended that all children aged 9-11 should be screened, and that more targeted testing (in those deemed to be at high risk) should be used in 2-8 year-olds and 12-16 year olds.

These recommendations risk making millions of American children into patients with their diagnosis of ‘dyslipidemia’ (disordered blood fat levels). Many may end up on cholesterol-reducing medication, of course, which is not without risk. And what evidence is there that this strategy will reap dividends in the long term?

The problems inherent in the NHLBI panel recommendations were made plain this week in an on-line article penned by three doctor-researchers at the University of California in San Francisco which appeared on-line in the journal Pediatrics [1]. In the piece, the authors draw our attention to the fact that the guidelines are simply a matter of opinion, albeit supposedly ‘expert’ opinion. The fact of the matter is that there has been no proper study which assesses the benefits (or otherwise) of screening children or the recommendations that may come out of this screening.

Not only this, but there has been simply no effort to quantify the costs of such an endeavour. So, in addition to not knowing whether the proposed strategy would even work, we have no idea what it would cost and are therefore unable to determine if it offers value for money (and if that money might be better spent elsewhere).

The authors of the article also draw our attention to the fact that there were significant financial conflicts of interest to be found in the NHLBI panel. The website sciencedaily.com reports here that:

The authors [of the article] note that the panel chair and all members who drafted the lipid screening recommendations disclosed an “extensive assortment of financial relationships with companies making lipid lowering drugs and lipid testing instruments.”  

Some of those relevant relationships include paid consultancies or advisory board memberships with pharmaceuticals that produce cholesterol-lowering drugs such as Merck, Pfizer, Astra Zeneca, Bristol-Myers Squibb, Roche and Sankyo.

“The panel states that they reviewed and graded the evidence objectively,” said Newman [Thomas Newman – one of the authors of the article]. “But a recent Institute of Medicine report recommends that experts with conflicts of interest either be excluded from guideline panels, or, if their expertise is considered essential, should have non-voting, non-leadership, minority roles.”

Evidence is needed to estimate health benefits, risks and costs of these proposed interventions, and experts without conflicts of interest are needed to help synthesize it, according to Newman. He said that “these recommendations fall so far short of this ideal that we hope they will trigger a re-examination of the process by which they were produced.”

Pediatrics also published on-line this week a rebuttal to this article co-written by several of the panel members, including its chairman Dr Stephen Daniels [2]. Here Dr Daniels (who has worked as a consultant or advisory board member for several cholesterol drug manufacturers including Abbott Laboratories, Merck and Schering-Plough) is quoted as saying that he feels industry ties did not influence the debate among panel members. He can say what he likes, but common sense suggests otherwise, as does the distinct lack of rigour in the panel’s recommendations.

In the linked article, the NHLBI’s acting director and the person who convened the panel, Dr Susan Shurin, tells us that there are few qualified specialists which have no industry relationships. This perhaps goes to show just how the effective the industry can be in sewing up an area and ensuring it gets the ‘expert’ opinion it wants.

“We got the best people in the country to do this,” Dr Shurin is quoted as saying. What a shame the ‘best people’ come with so many of conflicts of interest attached, and that their recommendations are set to convert millions of kids into patients despite there being simply no good evidence that this will benefit them or society in general.

References:
1. Newman TB, et al. Overly Aggressive New Guidelines for Lipid Screening in Children: Evidence of a Broken Process. Pediatrics Published online July 23, 2012(
2. McCrindle BW, et al. Guidelines for Lipid Screening in Children and Adolescents: Bringing Evidence to the Debate. Pediatrics Published online July 23, 2012
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Read the complete article here.

Drug company survey suggests statin side-effects are common and the most common reason for people stopping their medication

Drug company survey suggests statin side-effects are common and the most common reason for people stopping their medication
Jul, Fri 13th, 2012  By : Dr John Briffa

Statins are a runaway success in modern medicine, though it should perhaps be borne in mind that for the great majority of people who take them, they do nothing to prevent disease or delay death. Plus, there is growing awareness that these drugs are not without risk, and have genuine potential to cause adverse effects that include diabetes and damage to the muscles, liver and kidneys.

The hazards of statins is not something that the pharmaceutical industry likes to shout about, of course. In fact, industry sponsored studies sometimes look as though they’ve been designed to ensure the real risks of statins remain unseen. One tactic, for instance, is to screen out those most susceptible to side-effects before the study even begins. Another is to detect and log damage to organs only once blood test results are several times the upper limit of normal. For more on this, see this blog post from earlier this year.

So, sometimes it can be difficult to gauge the true risk of taking statins. And one thing I have noticed quite commonly is that many doctors believe the side-effects associated with statins appear to be, in practice, much higher than ‘official statistics’ suggest. Plus, it’s well known that about 75 per cent of people who start statins stop again within a year. Could side-effects be a major reason why individuals default in such large numbers?

Recently, the drug company Eli Lilly issued a press release regarding a survey was called ‘Understanding Statin use in America and Gaps in Education’ (‘USAGE’). The USAGE survey was an attempt, on the face of it, to better understand the reasons for why so many individuals stop taking their statins. More than 10,000 people were polled, and the results are in.

It turns out that off all of the reasons individuals might stop their statin medication, ‘side effects’ was the most commonly cited reason. According to the survey, a full 62 per cent of respondents cited side effects as the reason for stopping their medication. The two next most common reasons cited were ‘cost’ and ‘lack of effectiveness’ at 17 and 12 per cent respectively. You can see from these statistics that problems with side effects was the standout ‘winner’.

One might ask what it was about this drug company that led to a moment of uncharacteristic candour regarding statin side-effects. Well, it turns out that Eli Lilly, in conjunction with Kowa Pharmaceuticals America, markets a statin by the name of pritavastatin (Livalo). This statin is not widely prescribed, but it is sometimes said that it puts individuals at lower risk of side effects.
It seems to me that Lilly is keen to grab a bigger slice of the statin market. However, in so doing, it has revealed to us evidence which supports the idea that, in the real World (rather than the more manipulated and controllable environment of clinical studies), statin side effects are a much bigger problem then some would have us believe.
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Statins shown not to save the lives of women, even those at high risk of cardiovascular disease-Briffa

Statins shown not to save the lives of women, even those at high risk of cardiovascular disease

Jun, Tue 26th,  By : Dr John Briffa

Statins reduce cholesterol, and this is said to be the primary mechanism through which they reduce the risk of ‘cardiovascular’ events such as heart attacks and strokes. When used in clinical practice, statins can be given to people with or without prior history of cardiovascular disease. Giving statins to people with a history of cardiovascular disease (e.g. a prior heart attack or stroke) is known as ‘secondary prevention’ and generally gets better results than giving it to people with no such history (known as ‘primary prevention’). For example, statins in secondary prevention have been shown to reduce overall risk of death, while in primary prevention they have not.

A review published this week looked again at data from secondary prevention studies [1]. The purpose of the review was to pool the results of several (11) studies to see if there was any difference between the results obtained in women compared to men. There were statistically significant reductions in the risk of things like heart attacks, strokes and overall risk of death in men.

But in women, the results were different: there was no significant reduction in the risk of stroke nor overall risk of death. Even in the secondary prevention setting where results are generally best, no woman appeared to have her life saved by taking statins.

Now, one reason for this result might be that there were not enough women in the studies used in the analysis to detect a change. That might be true and we can’t tell one way or the other, unfortunately. Another explanation is, of course, is that statins don’t save lives in women, even in those at high risk of cardiovascular problems.

There’s a very interesting commentary that accompanies this review, written by two researchers from the London School of Hygiene and Tropical Medicine [2]. The researchers are keen to persuade us that statins work just as well in women as in men. They cite two meta-analyses which show benefit in terms of heart events (such as heart attacks) and ‘vascular events’ (total number of events such as heart attacks and strokes). However, the quoted data cannot tell us anything about risk of stroke alone, and crucially does not tells us anything about the key matter in hand: whether statins actually save women’s lives.

The researchers then go on to draw our attention to a study which was excluded from the most recent analysis (the so-called Heart Protection Study). The researchers add this into the data and appears to improve the results. The thing is, though, even when they put in this study, overall risk of death in women was (again) not reduced by a statistically significant amount.

But that does not matter to the researchers, because they maintain that statistical significance is not important. With this stance, these researchers cut themselves adrift from a central tenet of the scientific method and the interpretation of results. It seems some scientists, in order to positive spin on unexpected or undesirable results, will take a distinctly unscientific stance.

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
2. Taylor F, et al. Statins Work Just as Well in Women as in Men: Comment on “Statin Therapy in the Prevention of Recurrent Cardiovascular Events”. Arch Intern Med. 2012;172(12):919-920
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