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 . 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 10,000omen 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.
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