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?
To some extent, as long as the statins were working, few people worried too much about why they were helping. But statins are not for everyone. Some people cannot tolerate the drugs’ side effects, including muscle pain and, more rarely, liver damage. Others cannot lower their LDL levels enough simply by taking a statin. In addition, at least one in five people whose LDL levels are well controlled by their medications still experience heart attacks or strokes. “What are we going to do with these people?” asks Christie Ballantyne, chief of cardiovascular research at Baylor College of Medicine.
Thus, by the late 1990s the search was on to find drugs that could supplement the use of statins. One approach was to lower LDL levels using nonstatin drugs such as ezetimibe, which was approved by the U.S. Food and Drug Administration for its cholesterol-lowering ability in 2002. Studies had shown that ezetimibe reduces LDL levels in the body by a different molecular pathway than any that the statins use. Theoretically at least, the combination of a statin and ezetimibe should reduce LDL levels more than either alone. Another option was to raise HDL levels using a drug such as niacin, which is one of the B vitamins. Here again the idea was that a combination of drugs—one to lower LDL and one to raise HDL—should work better at reducing heart disease risk than any single medication.
Crucially, however, neither drug—ezetimibe or niacin—had yet been rigorously tested to see whether it actually reduced the number of heart attacks or strokes in a given population. That kind of investigation is more complicated and takes longer to conduct than does a test of how much LDL or HDL levels change in response to treatment. To determine if a drug actually reduces heart risk or stroke, researchers have to wait until enough study participants develop heart attacks or strokes to make a statistically valid comparison between those who took the trial drug and those who did not.
Clinicians were therefore eager to see the results of a 2008 study named ENHANCE, which compared a combination of ezetimibe and one particular statin drug, simvastatin, against simvastatin alone in people with familial hypercholesterolemia. To everyone’s surprise, ENHANCE found no benefit from the combination treatment, at least with respect to the thickness of the trial participants’ artery walls (thickened walls being a sign of advancing atherosclerosis and another potential indicator of heart disease). This result occurred despite the fact that the LDL levels of the combination therapy group dropped, on average, an extra 51 mg/dL.
Needless to say, the results generated more questions than answers. Did the ezetimibe produce a second effect that negated the beneficial effect of lowered levels of LDL? Or do statins trigger a beneficial anti-inflammatory effect that is the true reason for their benefit? Is LDL lowering as important as most people still think it is? The answers to such questions may become clear in 2013, when results are expected to be released of another study, which is specifically designed to determine whether an ezetimibe-statin combination works better than a statin alone in reducing heart attacks and strokes in test subjects. The clinical results for niacin, the HDL booster, looked more promising at first. A 2009 trial that compared adding either ezetimibe or niacin to standard statin treatment in people with heart disease found that niacin worked better than ezetimibe to reduce trial participants’ artery thickness. Results from this study, combined with those of the ENHANCE trial, looked like bad news for ezetimibe and good news for niacin until this May, when the National Heart, Lung, and Blood Institute stopped its own clinical trial of niacin because researchers found no difference in the numbers of heart attacks and strokes suffered by trial participants taking niacin and a statin compared with participants taking a placebo and a statin.[break]
A similar study, being run by the University of Oxford, is exploring whether niacin has an effect on heart disease or stroke cases in a broader selection of cardiac disease patients. Its results are expected in 2013.
So far, then, only the statins have been shown to safely reduce the number of heart attacks and strokes in the average person with high cholesterol, and the reasons for their success are not fully understood. To Steven Nissen, who chairs the department of cardiovascular medicine at the Cleveland Clinic, the recent disappointing results with other medicines means one thing: if researchers want to know whether a new drug reduces the number of heart attacks in a given population, they must design a study that measures the number of heart attacks in that population. “Changing a biochemical marker is not the same as improving the outcome for patients,” Nissen insists. As much as physicians and their patients might wish it otherwise, cardiovascular disease has complex causes, and changing one or two factors that contribute to it will not always be enough to guarantee good health. In the meantime, in addition to taking prescribed medicines, Baylor’s Ballantyne says, people at risk for heart disease and stroke would be wise to use all the weapons at their disposal—such as exercising, if their doctors approve of it—and watching what they eat.