Is Raising HDL Cholesterol A Good Idea After All?

A new HDL hypothesis

HDL cholesterol
HDL cholesterol. Images

For a couple of decades, it has been virtual dogma that HDL cholesterol is the "good" kind of cholesterol, that the higher your HDL levels the lower your cardiac risk, and that raising HDL cholesterol levels is a very good idea. But disappointing results from several recent clinical trials have called that dogma into question.

Why HDL Is Considered “Good”

HDL cholesterol is thought to scour excess cholesterol from the walls of the blood vessels, thus removing it from where it can contribute to atherosclerosis.

Furthermore, in epidemiological studies involving over 100,000 individuals, people whose HDL cholesterol levels are below about 40 mg/dL had a substantially higher cardiac risk than those with higher HDL levels. This is the case even when LDL cholesterol ("bad" cholesterol) levels are low. Higher HDL levels have also been associated with a reduced risk of breast, colon and lung cancer.

From such studies comes the belief that taking steps to increase HDL levels is a good idea. This is the so-called HDL hypothesis: the higher your HDL levels, the lower your cardiac risk.

How Can HDL Levels Be Increased?

HDL levels appear to be strongly influenced by a mixture of genetic and environmental factors. Women tend to have higher HDL levels than men (by an average of 10 mg/dL). People who are overweight, sedentary, or have diabetes or metabolic syndrome tend to have low HDL levels.

Alcohol appears to increase HDL by a small amount; trans fats in the diet reduce it.

Drugs commonly used to reduce LDL cholesterol have relatively small effects on HDL levels. Statins, the most commonly used cholesterol-reducing drugs, increase HDL only minimally. Fibrates and niacin increase HDL by a moderate amount.

For the most part, because there are no drugs that reliably produce a marked increase in HDL, recommendations on increasing HDL cholesterol have centered around controlling weight and getting plenty of exercise, with a smattering of dietary recommendations thrown in.

Throwing Water On The HDL Hypothesis

Because increasing HDL levels is thought to be such a beneficial thing, and because there is no easy or reliable way to do so, developing drugs that substantially raise HDL levels has become a major goal for several pharmaceutical companies. And indeed, several of these drugs have been developed, and have led to clinical trials to demonstrate their safety and efficacy.

So far, these studies have been disappointing to say the least. The first major trial (concluded in 2006) with the first CETP inhibitor drug - torcetrapib (from Pfizer) - not only failed to show a reduction in risk when HDL was increased, but actually showed an increase in cardiovascular risk. Another study with another CETP inhibitor - dalcetrapib (from Roche) - was halted in May 2012 for lack of effectiveness. Both of these related drugs significantly increased HDL levels, but doing so did not result in any clinical benefit.

Another disappointing study (AIM-HIGH) was published in 2011, assessing the benefit of adding niacin (to increase HDL levels) to statin therapy.

This study not only failed to show any benefit from increasing HDL levels with niacin, but also suggested that the risk of stroke was increased among patients taking niacin.

Finally, an investigation appearing in Lancet in 2012 evaluated the potential benefit of having one of several genetic variants that increase HDL levels. The researchers were unable to show that people who had such variants enjoyed any reduction in cardiac risk.

The results of these studies have everyone (even scientists who have devoted their careers to HDL research) doubting whether the HDL hypothesis is accurate.

A New HDL Hypothesis

At the very least, it appears that the simple HDL hypothesis (that increasing levels of "HDL cholesterol" is invariably a good thing) has been disproven. When HDL cholesterol has been successfully increased by CETP-inhibitors, by niacin, or by several genetic variants, no benefit has been demonstrated.

HDL researchers are in the process of revising their simple HDL hypothesis. It turns out that when we measure "HDL cholesterol," we are actually measuring several different kinds of particles. Notably, there are large HDL particles and small ones, which represent different phases of HDL metabolism.

The small HDL particles consist of the lipoprotein ApoA-1, without much cholesterol. Thus, the small HDL particles can be thought of as “empty” lipoproteins, that are on their way to scavenge excess cholesterol from the tissues. In contrast, the large HDL particles contain a lot of cholesterol. These particles have already done their scavenging work, and are just waiting to be taken back up by the liver.

Under this newer understanding, increasing the the number of large HDL particles would result in higher blood HDL levels - but would not improve our “cholesterol scavenging capacity.” On the other hand, increasing the small HDL particles should improve the removal of excess cholesterol from blood vessel walls.

In support of this revised hypothesis is the fact that CETP inhibitors (the drugs that failed in clinical trials) seem to result in an increase in big HDL particles, and not the small ones.

New Targets For HDL Therapy

The new HDL hypothesis points to the need to increase the small HDL particles.

To this end, synthetic forms of ApoA-1 are being developed and tested in humans. This approach, unfortunately, requires intravenous infusion of the ApoA-1 -- so it is being targeted to acute conditions, such as acute coronary syndrome. Early studies have been quite encouraging, and human trials are ongoing.

Also, an experimental drug (so far referred to as RVX-208 - Resverlogix) has been developed that increases the body's own production of ApoA-1. This oral medication is also being tested in human trials.

Additionally, work is being done to create drugs that stimulate ABCA1, the enzyme in tissues that encourages the transfer of cholesterol onto HDL particles.

Thus, researchers are turning their attention to find ways to increase, or improve the function of, the small HDL particles that (under the new hypothesis) are responsible for reducing cardiac risk.

In The Meantime

While we wait for the scientists to sort this all out, and to develop and test new approaches to increasing the "right kind" of HDL, we can all continue doing the things that we know both increase HDL cholesterol and reduce our cardiac risk. All of these things are reasonable, safe and effective.


Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: A Mendelian randomization study. Lancet 2012; DOI:10.1016/S0140-6736(12)60312-2.

Roche, Inc. Roche provides update on Phase III study of dalcetrapib [press release]. May 12, 2012.

Michos ED, Sibley CT, Baer JT, et al. Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events. J Am Coll Cardiol 2012; DOI:10.1016/j.jacc.2012.01.045.

Vergeer M, Bots ML, van Leuven SI, et al. Cholesteryl ester transfer protein inhibitor torcetrapib and off-target toxicity. A pooled analysis of the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials. Circulation 2008; DOI: 10.1161/CIRCULATIONAHA.108.772665.

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