Cholesterol researchers make up the rules as they go along

There is a well-established paradigm in medicine that ‘raised’ levels of cholesterol cause heart disease and that reducing cholesterol levels has broad benefits for health. Yet, despite how firmly these concepts are entrenched in the psyche of doctors and their patients, these assertions fail to tell the whole story regarding cholesterol and its management.

One, I think glaring, issue with the whole cholesterol debate is just how commonly doctors, researchers and drug companies focus on things like heart attacks and strokes (cardiovascular disease). However, a broader and more appropriate measure of the impact of cholesterol reduction is ‘overall mortality’. One reason for this is that low cholesterol levels are associated with an increased risk of potentially fatal conditions including cancer and something known as ‘haemorrhagic stroke’. Haemorrhagic stroke is caused by bleeding in the brain (the other major type of stroke – termed ‘ischaemic stroke’ – is caused by blockages in brain blood vessels).

We hear repeatedly the assertion that cholesterol-reducing drugs known as statins can reduce the risk of cardiovascular disease and even death due to cardiovascular disease. However, in essentially healthy people (those without pre-existing cardiovascular disease), statins do not reduce overall mortality.

What this means is that the great majority of people who take these drugs will not enjoy any life extension as a result. And of course such drugs are not without risk. Statin therapy is associated with enhanced risk of several major side effects including muscle weakness and/or pain (myopathy), liver damage , kidney failure and cataracts. In a British Medical Journal study published in 2010 the risks/benefits of statin therapy were assessed [1]. Here, in summary, are the findings of this study:

 

For every 10,000 women at high risk of CVD treated with statins, we would expect approximately 271 fewer cases of cardiovascular disease, 8 fewer cases of oesophageal cancer, 23 extra patients with kidney failure, 307 extra patients with cataracts; 74 extra patients with liver dysfunction; and 39 extra patients with myopathy.

 

For every 10,000 men at high risk of CVD treated with statins, we would expect approximately 301 fewer cases of cardiovascular disease, 9 fewer cases of oesophageal cancer, 29 extra patients with kidney failure, 191 extra patients with cataracts; 71 extra patients with liver dysfunction; and 110 extra patients with myopathy.

This study actually focused on data relating to individuals deemed to be at high risk of cardiovascular disease. Many individuals who take statins are actually not at high risk of cardiovascular. For these, benefits are likely to be significantly lower than those elucidated in this study (while risks are likely to be about the same).

There are a number of ways in which researchers can make the effects of cholesterol-reduction appear better than they are in reality. One way is simply not to publish negative results (known as ‘publication bias’). You can read more about this here. Publication bias has been made harder by new guidelines which require trials to be registered prior to completion (otherwise, the authors may find it difficult to get major journals to published them). It is perhaps interesting to note that cholesterol-reduction studies prior to these rules were overwhelming positive. However, since the rules, the results of relevant studies have been generally very poor. Previous publication bias may explain how cholesterol reduction appeared so very beneficial at one time, but more recently seems much less beneficial.

Another way researchers can give a skewed view on the effects of cholesterol reduction is, as I’ve alluded to above, focus on a defined set of outcomes. After all the data is in, researchers (some of whom may have close financial ties to the drug industry) get to slice and dice the data in endless ways to end up with the very best possible result for the drug or drugs being tested. This practice has also been made more difficult by the new rules, as investigators are required when they register a trial to declare what ‘primary outcomes’ will be assessed.

All this needs to be borne in mind as you read now about a curious turn on events regarding a cholesterol-reduction study. The study in question is testing the effect of simvastatin (a statin) and ezetimibe (another type of cholesterol-reducing agent) in individuals with kidney failure. Originally, the investigators declared that the primary outcomes would be “major vascular events”. The trial finished in August, and now the investigators have declared that the primary outcome is going to change. They’re going to leave a couple of things out, including haemorrhagic stroke.

Why the change of mind? Here’s what one of the lead investigator Dr Colin Baigent is quoted as saying: “…we wanted an end point that would be as sensitive as possible to any real benefit”. This does not make sense to me. If it’s ‘real benefit’ we’re looking to discern, then I suggest we should take as broad a look at outcome as possible. Let’s look at, for instance, not only things that appear to have been helped, but things that haven’t, and perhaps things that appear to have been adversely affected too.

This shifting of the goalposts is troubling. What it suggests is that the original primary outcomes didn’t look so good, and the researchers then set about massaging the data to get a positive result.

Should we be surprised? Not really. After all, it seems that some researchers (perhaps not these ones) will do whatever they can to get the result their paymasters want them to get. And let’s also bear in mind that the combination of simvastatin and ezetimibe has been associated with adverse effects including increased arterial narrowing compared to placebo (though not statistically significant) as well as increased risk of death due to cancer. Despite the fact that this latter finding was statistically significant very unlikely to be due to chance, prominent researchers put it down to chance all the same. See here for more about this.

I know that many scientists like to cultivate an image of detached objectivity when it comes to research. But believe me when I tell you quite a few make up the rules as they go along.

References:

1. Hippisley-Cox J, et al. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database BMJ 2010;340:c2197

5 Responses to Cholesterol researchers make up the rules as they go along

  1. Chris 7 October 2010 at 4:32 pm #

    Money is scarce Dr Briffa, we’re each trying to get a slice of a cake that the system does not so readily pass around. The scarecity makes us very competitive and makes some more compliant to do what each of the paymasters want, willing to cheat if you like. The process(es) you recount above is tanatmount to fraud but masquarade as science, research and development, and the ‘conspiracy’ would be exccedingly difficult to prove in a court of law. It has that in common with ‘securitisation’, the process by which the banks converted home loans, the sub-prime ones in particular, into instruments to be traded and treated as further assets. Securitisation, so it would seem, circumvented the normal limits imposed by the fractional reserve system, flooded the market with money that wasn’t there, caused a bubble in house prices (prices are not sitting on a satisfactory price/income ratio), and , in the name of compeptive business practice, eroded (certain) bank liquidity ratios. And I’m not grinding an axe here, the scarcity arises from asymmmetry, let me illustrate.

    Some contemporaneous events reported in the media are thus. Lord Saisbury donates £25million to the British Museum, Warren Buffet aand Bill Gates, two people who like Lord Sainsbury do not have to worry about their future pension or next car repair bill, jet accross to China to address an invited delegation of Chinese dollar millionaires upon the virtues of philanthropy. There are a reported 60 native dollar billionaires in China today. Yet, Greeks cannot afford retail food prices, nations agonise over budget deficits including Greece, Ireland, and UK. Austerity measures, and what they will mean are foremost in our minds. There’s clearly money about, but not, so it would seem, where it is needed. It is very asymmetrical.

    Might I suggest the greater extension of such asymmetry, being capital accumulation on the one hand and debt proliferation on the other, is the very origin of various crises of capital; one of which you describe above. Cyclically the extension becomes super-extended and unsustainable. My humble, not learned, opinion is that we are at that point now. Hitherto the correction to the extended asymmetry has involved collateral damage in a process that some term ‘creative destruction’.

    For those who see the cholesterol as a ‘con’ then they may see the relationship of Pharma to Health as being, well, quite creative. Innovation creates a new market which, as instances illustrate, the suppliers are hell-bent on preserving, even in the light of adverse consequence.

    Have taxpayers and patients been the real ‘philanthropists’ here? Do they fund the cost of the nations drugs bill promoting the accumualtion of capital (and corresponding debt proliferation). And is such promotion in favour of this illusory and fallaceous ‘monetray capital’ at the expense of a real one, their HEALTH? Part of the answer lies in the balance of merit over adverse effect. Another part can be found in how scarcity and asymmetry is, for the present, hard-wired. See (here) and (here). Incredulous?

    Sources; several, but two titles pivotal.
    1, The Future of Money, Creating New wealth, work, and a Wiser World; Bernard Lietaer.
    2, The Enigma of Capital; Professor David Harvey.

  2. Michael Allen 8 October 2010 at 2:04 am #

    Dr Briffa’s latest post is distressing, but not remotely surprising. This kind of thing has been going on for many decades, and was criticised by Adelle Davis in the 1960s. Professor John Yudkin also condemned it in his final revision (1986) of Pure, White and Deadly (his book on sugar). In fact, to the layman, the sugar industry appears to be the worst enemy of objectivity. Plus ca change.

  3. Chris 8 October 2010 at 11:25 am #

    ” .. .. distressing, but not remotely surprising.”

    Mishael thanks, I agree, economic determinism is universal. Your sources are helpful. Davis was not on my radar. Yudkin was but had dropped of the screen. Thanks again. :)

  4. Richard Feinman 9 October 2010 at 4:19 pm #

    The researchers who “wanted an end point that would be as sensitive as possible to any real benefit” evaluate diet studies by trying to think of an end point that would be as sensitive as possible to something that they can say is harmful.

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