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For a couple of decades now, 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.
The notion that HDL cholesterol is "good" comes from several epidemiological studies involving over 100,000 individuals.
These studies clearly show that, even in people whose LDL cholesterol ("bad" cholesterol) has been reduced to very low levels, those whose HDL cholesterol is below about 40 mg/dL have a much higher cardiac risk than those whose HDL is above 40. 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.
What Makes HDL "Good?"
LDL cholesterol delivers cholesterol to the walls of the blood vessels, where it is taken up and helps to produce atherosclerosis. In contrast, HDL cholesterol is thought to scour excess cholesterol from the walls of the blood vessels, thus removing it from where it can do damage. Therefore, HDL cholesterol is doing good things -- and the more HDL, the better.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 an HDL-raising 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 HDL-raising drug -- 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 demonstrated clinical benefit. At least one other drug in the same category as torcetarapib and dalcetrapib is being developed, but enthusiasm for this family of drugs (the so-called CETP-inhibitors) has been generally dampened.
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) strongly doubting whether the HDL hypothesis is accurate.
Is There Any Life Left In The HDL Hypothesis?
At the very least, it appears that the simple form of the HDL hypothesis (that increasing levels of "HDL cholesterol" is 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.The HDL hypothesis is not altogether dead, however.
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. It now appears likely that not all of the HDL particles are "good." Increasing the "wrong" kind of HDL particle might increase the measured HDL levels without improving cardiac risk. So the HDL hypothesis is not really dead -- perhaps it merely needs to be refined.
HDL Metabolism, Greatly Simplified
The following explanation of HDL metabolism may not meet with the approval of experts, as it greatly oversimplifies things. We all wait with great anticipation for the experts to supply us with a coherent explanation of the complexities of HDL metabolism that is understandable by regular folks. In the meantime, here is a reasonable way of looking at it.Think of a coal-burning electrical plant. The plant dispatches empty dump trucks to a coal mine. Workers at the coal mine shovel coal into the truck. When the truck is overflowing with coal, it is driven back to the plant where it is emptied and the coal is burned. The empty truck is then dispatched back to the mines for another load of coal.
Consider the electrical plant as being analogous to the liver, the coal mine as analogous to the lining of the blood vessels, and the coal as analogous to cholesterol. The empty dump trucks are the protein backbone of HDL cholesterol, or apolipoprotein A-1 (ApoA-1). The ApoA-1 gathers excess cholesterol from the blood vessels, and returns it to the liver, where it is removed and metabolized. The remaining cholesterol-poor HDL particles (essentially, the ApoA-1) then go back for another load of cholesterol.
When we measure "HDL cholesterol," we are measuring all the dump trucks as they drive back and forth on the roads between the coal plant and the coal mine. Dump trucks that are empty or only partially full are analogous to "small" HDL particles, and dump trucks overflowing with coal are analogous to "big" HDL particles. Both kinds of particles (both kinds of dump trucks) are lumped together in our measurement of HDL, and we cannot distinguish one from the other.
In this analogy, the empty or partially full dump trucks are "good cholesterol," because they still have the capacity to remove excess cholesterol from the blood vessels. The overflowing dump trucks are already filled to capacity and are not capable of taking on any more cholesterol from the blood vessels -- so increasing these big particles cannot be expected to do much good. When we increase "HDL cholesterol," we may be increasing the empty dump trucks (small HDL particles), or the full dump trucks (big HDL particles), or both. But only increasing the small HDL particles can be expected to increase the removal of cholesterol from the blood vessels, or to improve clinical outcomes.
Our current understanding of HDL metabolism suggests that a "new" HDL hypothesis needs to be formulated. Under this new hypothesis, increasing small HDL particles (the nearly empty dump trucks), and not just "HDL levels," ought to become the new target for therapy.
Why Recent HDL Studies Have Been Disappointing
If the new HDL hypothesis turns out to be correct, it will not be surprising that some of the recent studies on increasing HDL have been disappointing. The major disappointment has been the apparent failure of the CETP-inhibitors to improve cardiac risk. But as it happens, the CETP-inhibitor drugs seem to result in an increase in big HDL particles, and not the small ones.
Also, in the recent, disappointing genetic study mentioned above, the genetic variants that were assessed generally produced only minor increases in HDL levels; and furthermore it is unclear which "kind" of HDL was increased.
So, while these studies have been helpful in disproving the original HDL hypothesis, they leave the "new" HDL hypothesis intact.
New Targets For HDL Therapy
The new HDL hypothesis points to the need to create "empty dump trucks" that are capable of receiving excess cholesterol from the blood vessel walls.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. (This would result in the "empty dump trucks" being filled more efficiently.)
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 reaonable, safe and effective.Sources:
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.