What That Cholesterol Trial Didn’t Show
The cholesterol drug Vytorin became known for its commercials showing people who look oddly similar to foods like tacos and banana cream pie. But now Vytorin is getting attention that is anything but funny.
The medicine combines Zocor, a cholesterol-lowering statin, with Zetia, a drug that limits cholesterol’s absorption into the body, and the hope was that the combination would make it more effective than either drug standing alone. But last week Vytorin’s makers, Merck and Schering-Plough, announced that in a small study it had done no better than Zocor alone in slowing the growth of arterial plaque, which can lead to heart attacks. There’s nothing particularly alarming about the findings (unless you’re a shareholder, perhaps).
But the news set off a panic among patients using cholesterol drugs. One doctor said he assigned a nurse full time to take the calls “and convince patients not to stop their medicine.” Another patient argued with his doctor, claiming the study showed that the drug doubled heart attack risk. (It didn’t; the study wasn’t designed to measure heart attacks.)
“I think this study is being interpreted wrong,” said Dr. Paul D. Thompson, director of cardiology at Hartford Hospital, who personally uses Zetia and (like most of the doctors quoted in this article) has consulted with makers of cholesterol drugs.
He pointed out that Vytorin users did experience a larger drop in cholesterol than the Zocor users. The disappointment was that the decline didn’t translate into a bigger benefit in arterial health. “It didn’t show harm,” Dr. Thompson said. “There were no more cardiac events, no more side effects. There was just no change.”
The fallout from the study was not limited to Vytorin. It has led to a whole new set of questions for scientists about cholesterol drugs. Is lowering LDL, the “bad” cholesterol, all that counts? Or must a drug also raise HDL, the “good” cholesterol, and fight inflammation?
Adding to the confusion, the Vytorin makers dragged their feet on releasing the results, issued the findings in a press release rather than a medical journal and made a lot of people mad.
“Failed trials are important,” said Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. “The reason the medical community is upset about the delay in reporting this is that we learn as much from a study that fails as we do from a study that succeeds. People are not happy that we didn’t learn about this sooner.”
Dr. Nissen, who says he donates his drug-consulting fees to charity and doesn’t take a tax deduction, added that the study raised interesting scientific questions about the differences in cholesterol drugs.
The most popular — the statins, including Lipitor and Zocor — reduce the amount of cholesterol produced by the liver. In some studies, statins have lowered heart attack risk by 30 percent or more in high-risk patients. Statins also raise HDL levels and have an anti-inflammatory effect. The problem is that statins, particularly at high doses, can have a number of side effects, including muscle pain.
Zetia has a smaller anti-LDL effect than statins, and little effect on HDL or inflammation. On the plus side, because it works primarily in the digestive tract, it potentially has fewer side effects.
Vytorin, by combining Zocor and Zetia, produces a bigger drop in cholesterol than either drug could do alone, and without a marked increase in side effects. The problem is that there are no long-term studies showing that using the drug translates into fewer heart attacks or strokes.
The latest study was a step in that direction. It didn’t set out to measure heart attacks or strokes, but it did look at whether Vytorin slowed plaque buildup on artery walls more than a statin alone.
It didn’t. While it’s been reported that the Vytorin users had more plaque than the Zocor users, that’s not a scientifically correct reading of the data: the difference between the two groups was not statistically significant.
Most important, perhaps, nothing about the trial undermines the settled wisdom about cholesterol and heart disease. The science still shows that lower cholesterol is better, however you achieve it.
“Every way in which we have lowered LDL in the past” has been shown to reduce heart attacks and strokes, said Peter Libby, chief of cardiovascular medicine at Brigham and Women’s Hospital in Boston, who has consulted with drug companies. “All of these different routes to lowering bad cholesterol are correlated with a clinical benefit.”
To be sure, not everyone agrees that drugs are the best way to achieve lower cholesterol. But the Vytorin disappointment doesn’t “mean the whole concept is wrong,” said Dr. Daniel J. Rader, director of the preventive cardiology and lipid clinic at the University of Pennsylvania School of Medicine, who has also consulted with drug companies. “I firmly believe lowering cholesterol is the most validated, most important way we can reduce our risk of heart disease and stroke. Get your LDL down, and the lower the better.”
In fact, the real lesson of the Vytorin confusion may be exactly what its makers have promoted.
“It actually does get back to what the Vytorin commercials show,” said Dr. Nieca Goldberg, medical director of the women’s heart program at New York University, who does not consult for cholesterol drug companies. “Cholesterol comes from what you eat and your family history. I always put in a plug for modifying your diet and exercise. It may not bring about as big of a reduction as medication does, but it helps.”