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See Inside November 2011

Cholesterol Conundrum

Changing HDL and LDL levels does not always alter heart disease or stroke risk



Gilles Podevins/Corbis

Most people who are even a little bit concerned about their cholesterol know that there is a “good” kind—known as HDL—and a “bad” kind—known as LDL. Research has shown that the higher the amount of HDL and the lower the amount of LDL in the blood, the less likely a person is to suffer a heart attack or stroke. As for the one in six Americans with unhealthy cholesterol levels, well, they can always hope to change their luck with a cholesterol-changing medication or two. Or can they?

Two major clinical trials in the past three years have greatly complicated the picture for these and perhaps other folks. The first study, from 2008, shows that lowering LDL levels does not always decrease the risk of having a heart attack. Similarly, results from the second study, released in the spring of this year, show that raising HDL levels does not always translate into fewer heart attacks or strokes.

These perplexing findings do not mean that people should stop taking their cholesterol drugs. The results have, however, underscored the danger of indulging in a common logical shortcut in medical thinking—assuming that artificially producing normal test results in a patient is the same as conferring good health on that patient. For one thing, drugs typically do not mimic normal conditions perfectly. For another, heart attacks and strokes occur after a complex series of processes that may take years to unfold. Simply altering one of these processes does not necessarily fix the whole problem.

Good vs. Bad Cholesterol
Still, researchers and physicians, knowing the roles of LDL and HDL in the body, had good reasons to suspect that manipulating the levels could protect against heart attacks and strokes. Despite its bad reputation as a clogger of arteries, the cholesterol molecule is an irreplaceable component of many key parts of the body, from cell membranes to sex hormones. Indeed, this fatty, waxy substance is so important to life that evolution has produced several different mechanisms for transporting it through the bloodstream. Just as oil and water do not mix, neither do waxy cholesterol and watery blood, so cholesterol needs a kind of protective vehicle to surround it and carry it around the body. Two of the most important vehicles for the job are LDL (low-density lipoprotein), which delivers cholesterol to the various cells of the body, including the walls of arteries, and HDL (high-density lipoprotein), which removes cholesterol from the blood. HDL may also act as an antioxidant that reduces unhealthy inflammation in the arteries.

The trouble begins when too much LDL-carried cholesterol winds up in the arterial lining and contributes to the buildup of fatty material, or atherosclerotic plaque. Much of the time the plaque stabilizes without creating too many immediate problems, but sometimes it bursts, triggering blood clots that lead to heart attacks and strokes if the clots prevent blood from delivering critical oxygen to heart or brain tissue. Without oxygen, the affected tissue dies.

People with high LDL levels may form arterial plaques that are more likely to burst. Some people develop extremely high LDL levels because of a genetic disease called familial hypercholesterolemia that severely limits their ability to clear cholesterol from their blood. They suffer heart attacks in their thirties or forties, which is several decades earlier than the average for the general population. On the positive side, those who maintain normal cholesterol levels (LDL less than 100 milligrams per deciliter of blood and HDL cholesterol levels greater than 40 mg/dL) throughout their life without medication are much less likely to suffer heart attacks or strokes.

A Shortcut in Logic
With all this evidence linking cholesterol levels to heart disease risk, it is no wonder that researchers in general and pharmaceutical companies in particular reached a fairly straightforward, if simplistic, conclusion: anything—such as a medication—that reduces LDL levels and raises HDL levels must also reduce heart disease risk. By the 1980s the drug industry began marketing a whole family of cholesterol-lowering drugs called the statins, which work by blocking a liver enzyme that is essential for forming cholesterol. Clinical studies proved that statins do in fact reduce the number of heart attacks in people with high cholesterol. But is it the medications’ cholesterol-lowering effect or some other aspect of how the drugs affect the body—such as its anti-inflammatory properties (inflammation is strongly suspected of contributing to atherosclerosis)—or even a combination of both that does the trick?

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