Trial results forced out of drug company support the concept that cholesterol may not ’cause’ cardiovascular disease

Last Monday’s blog featured an article which revealed evidence of ‘publication bias’ (basically, the publication of positive studies and the junking of negative ones) in the area of antidepressant therapy. Not only that, but this study revealed that many negative studies are reported by their authors in a way that makes them look positive. The end result, of course, is that antidepressant drugs have ended up looking significantly more beneficial than they really are.

But don’t imagine for a moment that this sort of bias is only an issue in this area: it probably pervades most, if not all, areas of medical research. Take, for instance, the cholesterol-reducing medications known as statins. Last year one of my blogs revealed the results of a review [1] which found that drug company funded studies were more than TWENTY TIMES more likely to report positive results than independently funded studies. Some of the reason for this relates to drug companies designing studies in a way that makes it more likely to get the desired result. But publication bias is likely to play a big part here too. Oh, and this study also found that drug-company funded studies were more than 30 times more likely to report positive findings in the conclusion of these studies than independently-funded studies. Seems to me like there’s at least some element of ‘he who pays the piper calls the tune’at work here.

The good news is that the medical ad research community is wise to publication bias, and increasingly it’s becoming standard practice for studies to be registered before they are done. That way, it makes it harder for anyone to ‘bury’ disappointing results that might affect our perception about the effectiveness of a drug and a manufacturer’s bottom line.

One such registered trial pitted two cholesterol-reducing medications known as ezetimibe (Zetia) and simvastatin (Zocor) against just one (simvastatin). The trial, known as the ENHANCE trial, lasted for two years. The researchers tracked the thickness of the main artery supply blood to the brain (technically known as the carotid artery intima media thickness) in the study participants.

Controversy around this study started to emerge when it transpired that the drugs companies that make ezetimibe (Merck and Schering-Plough Pharmaceuticals) seemed none to keen to publicise the findings of the ENHANCE study. Two years after the study was completed, the results were still not in the public domain. It seems it’s taken a US Congressional enquiry to get the manufacturers to cough up their data. Given this background, I don’t suppose anyone was too surprised when it turned out that ezetimibe and simvastatin was no better than simvastatin alone. You can read about the results of this study here.

The fact that political intervention was required, it seems, to extract this data is concerning. However, on the plus side, in the olden days perhaps you and I would not have known the study had even taken place.

Part of the reason for talking specifically about this study is its specific results: the study showed that those taking the two drugs actually saw a significant drop in cholesterol levels (supposedly ‘unhealthy’ LDL cholesterol dropped by 58 percent compared to 41 percent in the single-drug group). Interestingly though, the amount of plaque progression was about twice in the two-drug group than the mono-drug takers (although this was not statistically significant).

So, while two drugs pushed the cholesterol lower, the tendency was to build up plaques (also known as ‘atheroma’) more quickly. Now, if cholesterol causes atheroma, this finding does not make sense. However, if cholesterol doesn’t cause atheroma, then what does?

Last December, I reported on a study [2] that found no association between cholesterol levels and risk of death due to stroke (the vast majority of which are caused by atheroma in the vessels supplying blood to the brain). There’s no getting away from the fact that this findings asks serious questions about the supposed role of cholesterol as an artery-clogger.

I first learned about the findings of ENHANCE trial from a new article in this week’s British Medical Journal [3]. The item includes a picture which (I think) depicts some atheroma in a carotid artery. Beneath the picture reads ‘Cholesterol causes atheroma plaques’. Personally, I wouldn’t be too sure about that.

References:

1. Bero L, et al. Factors Associated with Findings of Published Trials of Drug-Drug Comparisons: Why Some Statins Appear More Efficacious than Others. PLoS Med 2007 4(6): e184 doi:10.1371/journal.pmed.0040184

2. Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 33000 vascular deaths. Lancet 2007;370:1829-1839.

3. Lenzer J. Unreported cholesterol drug data released by companies show drug is ineffective. BMJ 2008;336:180-181

3 Responses to Trial results forced out of drug company support the concept that cholesterol may not ’cause’ cardiovascular disease

  1. Neil 29 January 2008 at 9:19 pm #

    Things will change John, but the cholesterol hypothesis is a juggernaut which such momentum that it can only change direction slowly.

    Had a quick look at British Heart Foundation website and found the following gem.

    “Cholesterol is a waxy substance which is mainly made in the body. The liver makes it from the saturated fats in food”

    I’d love to see that ‘proved’ in a biochemical pathway. But of course that is impossible as its just not true. But its been repeated so often that its in the realms of ‘everybody knows that..’ facts.

    Shame we went so far down the wrong path

  2. Rosina 1 February 2008 at 10:52 pm #

    I’d like to echo and amplify Neil’s comments. I think his comments are so true, that it won’t turn around until after the end of my life. People’s first reactions to info other than the ‘party line’ is defensive, so getting past that is as monumental as ‘Doctors prefer Camels’; recalling that gives me perspective on other issues. Though when that changed, it changed very completely–the embarrassment of the medical establishment figured into that.

  3. Dennis 2 May 2008 at 2:57 pm #

    “However, if cholesterol doesn’t cause atheroma, then what does”???
    Only have 50 % flow in right & 100% blockage in left neck, sure would like to know. Have survived 3 mild heart attacks also, 4 stents of which 2 are blocking again!!!!

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