Two reviews reveal the lack of evidence for HDL-boosting agents

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Cholesterol is transported in the bloodstream packaged with protein in the form of ‘lipoproteins’. There’s two main forms of lipoprotein in the blood: so-called ‘low density lipoprotein’-cholesterol (LDL) and ‘high density lipoprotein’-cholesterol (HDL). Traditionally, LDL has been said to be chiefly responsible for the depositing of cholesterol on the inside of the arteries and the development of cardiovascular diseases such as heart disease and stroke. HDL, on the other hand, has often been said to be a marker for the clearing of cholesterol from the inside of the arteries. Higher levels of HDL have traditionally been thought of as a good thing and indeed have been linked with better cardiovascular health outcomes.

The pharmaceutical industry has not been slow out of the blocks in its attempt to develop HDL-boosting therapies. After all, if higher HDL levels are associated with improved health, then raising HDL levels in the blood should be good for health, right? While sometimes persuasive, this logic is flawed on more than one level.

To begin with, just because HDL is associated with improved health outcomes, that doesn’t mean that it’s actually responsible for those outcomes. It might be that HDL is not so much a protective factor in cardiovascular disease, but a marker for protection.

We know, for instance, that high-carbohydrate diets can push up blood sugar levels and induce changes such as raised triglyceride levels, inflammation and ‘oxidative stress’ (free radical damage) that likely increase the risk of cardiovascular disease. High carbohydrate diets also tend to lead to lower HDL. So, not surprisingly, lower carbohydrate diets tend to raise HDL levels, and lower triglyceride levels, inflammation and oxidative stress. In people eating a low-carb diet HDL may be pleasingly on the high side.

But are the improved health outcomes associated with this down to the HDL or other markers associated with low-carb eating? We don’t know, I think, and that means we cannot be too sure that a drug or agent that pushes up HDL levels are necessarily a good thing. Also, a drug or agent may have untoward effects. So, even if cyanide turns out to be a good HDL-boosting agent, on balance one might judge that it’s overall effects on healthy are negative.

What all this boils down to is that what we really need is studies that judge the impact of drugs not on ‘surrogate’ markers such as HDL levels, but on health.

In recent years, there has been focus on two main types of HDL-raising therapy: niacin (a form of vitamin B3) and what are known as CETP inhibitors. In the current edition of Current Opinions in Cardiology, two papers take a look at the state of the evidence in the area of HDL-raising therapy.

One of these papers comes from researchers based in Manchester, UK [1]. In their paper, the authors acknowledge work which suggests that in those with acceptable LDL levels, low levels of HDL is associated with elevated risk of cardiovascular disease. However, the authors also point out the presence of three recent ‘randomised controlled trials’ which find that neither niacin nor the CETP inhibitor dalcetrapib improved health outcomes. The authors of this paper make the point that, in the future, drugs will be required that actually have benefits for health (and don’t simply raise HDL levels).

The other paper comes from a researcher at the Mayo Clinic in Minnesota in the US [2]. The author of this study reviews, in essence, the same evidence as the authors of the first paper, and draws the same conclusions regarding the benefits (none). The author also draws our attention to the fact that niacin has been found to induce side-effects, and that the CETP inhibitor torcetrapib was found to increase the risk of death.

This review also draws our attention to the fact that two other CETP inhibitors (anacetrapib and evacetrapib) are being trialled but that the results will not be known for some years. Right now, though, given the overall adverse effects seen with HDL-boosting agents to date, I’d say that all bets are off.


1. Schofield JD, et al. High-density lipoprotein cholesterol raising: does it matter? Curr Opin Cardiol. 2013;28(4):464-74

2. Wright RS. Recent clinical trials evaluating benefit of drug therapy for modification of HDL cholesterol. Curr Opin Cardiol. 2013;28(4):389-98

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