More evidence that ‘modifying’ cholesterol does not necessarily have broad benefits for health

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Higher levels of so-called ‘HDL-cholesterol’ is associated with reduced risk of cardiovascular issues including heart disease and stroke. This finding has led to the widespread view that raising HDL levels has benefits for health, particularly with regard to cardiovascular risk.

There are three main classes of agents that are known to boost HDL levels: the B-vitamin niacin (vitamin B3), fibrates, and inhibitors of what is known as ‘cholesteryl ester transfer protein’ (CETP-inhibitors). Recently, a review of the impact of these agents on health was published in the British Medical Journal [1].

The review assessed data from studies which had compared the impact of these agents on their own, or when added onto treatment with statins.

When added to statins, none of the agents brought any benefits in terms of endpoints such as non-fatal heart attack, fatal heart attack or overall risk of death (overall mortality).

When not taken in conjunction with statins, however, niacin and fibrates were found to reduce the risk of non-fatal heart attack (but there were no mortality benefits). CETP inhibitors did no good in any setting, and one CETP (torcetrapib) actually increased the risk of death (it has been withdrawn from sale).

An accompanying editorial [2] from the head of cardiology at Sydney University suggests that we should not give up on HDL modification just yet. The editorial suggests that there is some evidence that HDL may be genuinely protective for cardiovascular disease through mechanisms that include the removal of cholesterol from cells involved in the early stages of atherosclerosis (foam cells), immune modulation, and amelioration of diabetes.

However, even if HDL is genuinely protective for cardiovascular disease, that does not mean that something that raises HDL levels will automatically be beneficial for health: if arsenic and cyanide were found to boost HDL levels, that would not be an argument for taking arsenic and cyanide each day.

While the author of the editorial may not want to give up on HDL as a potential marker for cardiovascular disease and a target for therapy, he does concede that: “…it probably is time to abandon our assumption that fibrates, niacin, or CETP inhibitors will improve clinical outcomes in contemporary populations taking statins simply because they have favourable effects on surrogate lipoprotein biomarkers.”

This is a key point: we cannot judge health effects of pharmaceutical agents on their effect on so-called surrogate markers such a cholesterol levels. The only important thing is their effect on overall health. What a shame, then, that we still have regulatory agencies like the Food and Drug Administration in the US and the National Institute for Health and Care Excellence in the UK recommending the use of drugs based solely on their impact on surrogate markers (the drug ezetimibe is a case in point).

It is lamentable that those whose job it is to provide reliable guidance on medical treatments are so stupid and/or corrupt as to recommend doctors prescribe treatments which have no proven benefits and may in fact do considerable harm.


1. Keene D, et al. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117 411 patients. 2014;349:g4379

2. Kritharides L, et al. Not so “good” cholesterol. BMJ 2014;349:g4664 (Published 18 July 2014)

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