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.