(Some) doctors suggest that lower cholesterol levels may not be better after all

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About a month ago, I reported on a study (known as the ENHANCE trial) which found that two cholesterol agents (simvastatin and ezetimibe) were no better than one (simvastatin) in terms of reducing the narrowing of arteries in the body. This blog post was based on data that had to be, it seems, forced out of the manufacturers of these drugs by a congressional hearing in the US. The results finally came to light a full two years after the study had been completed. And on Sunday the study results were formally published on-lined in the New England Journal of Medicine [1]. Bearing in mind the fact that some ‘negative’ studies are not even published, I suppose we should be thankful for small mercies and at say ‘better late than never’.

The results of the study were also discussed last weekend at a meeting of the American College of Cardiology meeting in Chicago, US. The conclusion of an expert panel was, in essence, that there is no evidence that simvastatin and ezetimibe is better than taking a statin alone, so doctors should ‘turn back to statins’ [alone] in their management of raised cholesterol.

Rather predictably, I suppose, the manufacturers of ezetimibe ” Schering-Plough – went on the offensive. Dr. Robert Spiegel, chief medical officer at Schering-Plough told Reuters news agency: “We were very disappointed in the ACC panel. We had expected a balanced discussion and we really didn’t think the panel today served patients well”. I’m wondering how patients could have been better served than to be told that the addition of one drug to another doesn’t seem to work. And also, how did it ‘serve’ individuals to take ezetimibe for two years while its manufacturer sat on the results of a negative study?

Schering Plough issued a joint statement with Merck (manufacturers of simvastatin) in which it is claimed that the most likely explanation for why individuals on double-barrelled therapy did not do any better than those on simvastatin alone was because the patients in the study had already been aggressively treated with statins, and there are limits to how much more they could improve.

Of course, this ‘explanation’ (if that’s what it is) seems to neatly dodge the fact that the two drugs led to a significantly lower cholesterol level than simvastatin alone. So, if cholesterol causes a gumming up of the arteries, how come lower cholesterol did nothing to help in this respect.

In my first post about this I put forward theory that one explanation for this finding is that cholesterol doesn’t actually ’cause’ cardiovascular disease. This may seem a rather radical stance, but it is supported by the results of this study. And consistent with this notion is that fact that statins may lower cholesterol, but also have a number of mechanisms of action that may explain the fact that they reduce the risk of cardiovascular disease.

Now, I’m not expecting a big rush of doctors and scientists denouncing the cholesterol hypothesis and suggesting that cholesterol does not cause cardiovascular disease. Such a move would, I dare say, cause the sky to fall in. However, the ENHANCE study has at least led to some interesting murmurings. The ENHANCE trial is accompanied by an editorial in which the cholesterol mantra ‘lower is better’ is at least questioned, and that can only be a good thing, I think.

However, the authors of this editorial would not be the first to suggest that current vogue to drive cholesterol levels ever lower may be flawed: a review published in the Annals of Internal Medicine in 2006 concluded that achieving the current cholesterol targets has not proven to be either ‘beneficial or safe’.


1. Kastelein JJP, et al. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia NEJM [epub 30th March 2008]

2. Brown G, et al. Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe? NEJM [epub 30th March 2008]

3. Hayward RA, et al. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Int Med 2006;145:520-530

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