Lown Cardiovascular Research Foundation

Harvard Heart Letter | April 2008

Trial fails to enhance cholesterol drug’s reputation
Vytorin comes under fire after trial shows it works no better than a statin.

The media firestorm that torched the cholesterol-lowering drug Vytorin in January 2008 showed just how hot the topic of new drugs is today. Trial results showing that the FDA-approved drug was no better than a generic statin at keeping artery-clogging plaque in check had some commentators calling for a moratorium on the use of the drug. Headlines such as “Cholesterol drug bombs” and “Vytorin May Increase Risk of Heart Attack or Stroke” prompted thousands of worried Vytorin takers to call their doctors.

The less-than-promising results may bear a message for stockholders of Merck and Schering-Plough, the companies that make Vytorin. But exactly what they mean for people with high cholesterol is a bit murky.

A good idea in search of support

Vytorin combines two cholesterol-lowering drugs — ezetimibe (Zetia) and simvastatin (Zocor, now also available as a generic) — into a single pill. Packaging them together seems like a good idea since they control cholesterol in different ways. Zetia prevents cholesterol in food from crossing the intestinal wall and getting into the bloodstream. Zocor blocks an enzyme in the liver that helps make cholesterol.

Clinical trials show that this double whammy lowers cholesterol better than either drug alone. Ten milligrams (mg) of Zetia plus 20 mg of Zocor lowers LDL by 50%, as much as 80 mg of Zocor alone. What wasn’t known is whether Vytorin’s impressive reduction in cholesterol yields fewer heart attacks and strokes and longer lives.

Merck and Schering-Plough have funded several studies to test Vytorin’s ability to prevent heart attack and other cardiovascular problems. The first of these so-called outcomes trials, dubbed ENHANCE, included 720 men and women with heterozygous familial hypercholesterolemia, an inherited disorder that can push total cholesterol levels far above 300. Half took high-dose Vytorin (10 mg of Zetia plus 80 mg of Zocor) for two years and half took high-dose Zocor (80 mg) alone.

At the study’s end, LDL levels were substantially lower in the Vytorin group. But that didn’t translate into less cholesterol-laden plaque in the carotid arteries (see “ENHANCE results”). In fact, there was slightly more plaque with Vytorin. This could have been due to differences between Vytorin and Zocor. It could also be a chance finding.

The ENHANCE results can be interpreted in any of three ways:

1. Vytorin doesn’t work any better than Zocor alone.

2. Vytorin is worse than Zocor alone.

3. For people with garden-variety high cholesterol who haven’t been taking a statin for a long time, Vytorin might be better, or worse, than a statin alone.

We probably won’t know which of these is correct until results are in from the IMPROVE-IT study in 2011. It is comparing Vytorin against a statin among 12,500 men and women who survived a heart attack or episode of unstable angina. Two smaller outcomes studies should also clarify the picture.

One ray of sunshine from ENHANCE is that we won’t be bombarded by those irritating ads featuring eccentric “relatives” dressed up to look like cholesterol-boosting foods. They were pulled after the trial’s results were made public.

Don’t panic

The most immediate question spawned by the ENHANCE trial is “Should I keep taking Zetia or Vytorin?” It depends on why you are taking it in the first place. If Zetia or Vytorin is the first medication you have tried for lowering your cholesterol, talk to your doctor about switching to a statin. These drugs not only lower LDL but have also been shown to prevent heart attacks and premature deaths from heart disease. If you are taking Zetia, either alone or as part of Vytorin, because you can’t tolerate a statin or because your LDL hovers well above the target your doctor has set even with a statin, then it isn’t unreasonable to stick with it.

If the ENHANCE results have spooked you, alternatives include combining a statin with niacin, plant sterols, another cholesterol-blocker called WelChol, or a cholesterol-lowering diet.

Zetia is an interesting drug, but not an essential one. It lowers cholesterol, but its effect on heart attack, stroke, and longevity is unknown. Although it is generally regarded as safe, an investigation by The New York Times raised some questions about the risk of liver damage from Zetia. Reporters uncovered the results of unpublished studies showing that long-term use of Zetia plus a statin was more likely to cause health problems, most of them liver-related, than a statin alone.

In short, until we know more about the long-term effects of Zetia and Vytorin, they should be used as second-string backups for people who can’t take a statin or who need a bigger cholesterol-lowering push.