Bad Cholesterol or Bad Science?

The Washington Post reports that “A divided cardiology community is trying once again to make sense of a trial showing that a drug can lower levels of "bad" LDL cholesterol and yet give no apparent benefit to people at high risk of heart attack and other cardiovascular problems”

Here’s a recap of the situation (first a quick summary of the medical aspect, and then a quick look at the TV-commercial aspect of drug sales in America):

Statins are really effective drugs that offer protection against cardiovascular disease. They can slow down the build-up of fatty plaque in arteries, and they also lower LDL cholesterol levels in the blood (by interfering with cholesterol production in the liver). It has long been assumed that lowering the levels of LDL cholesterol should be protective against cardiovascular disease.

Enter the drug ezetimibe. Ezetimibe has also been shown to reduce LDL cholesterol levels, albeit by a different mechanism than statins--- ezetimibe acts by preventing the absorption of cholesterol in the intestines. As I understand it, ezetimibe was approved by the FDA solely on the basis of the fact that it could lower LDL cholesterol---there had been no study to investigate whether ezetimibe could actually slow down the accumulation of fatty plaque in arteries or whether it could reduce the incidence of heart attacks or stroke.

A few years ago, Merck (which makes Zocor---a statin) and Schering-Plough (which makes Zetia—an ezetimibe) came out with a drug called Vytorin which combined the two drugs. As most of you have doubtless seen at some point from the TV commercial blitz for this drug, the idea was that this could attack the cholesterol problem from two angles---that which results from genetics and that which results from diet.

Anyway, there was a two-year study (called the ENHANCE trial) conducted to investigate whether Vytorin (simvastatin+ezetimibe) could reduce arterial plaque build-up better than Zocor (simvastatin). Back in January, some of the results of this study were released and it appeared that while Vytorin could reduce LDL cholesterol levels better than Zocor, it was no better than Zocor at reducing arterial plaque build-up; by inference, ezetimibe didn’t necessarily contribute to better cardiovascular health.

Over the weekend, the full results of the ENHANCE study were presented at the American College of Cardiology annual meeting in Chicago, and well, nothing changed; there is still no evidence that ezetimibe can reduce arterial plaque build-up.

So what are the possibilities here?

1) That the ENHANCE trial was flawed, either due to the small sample size (~750 patients) or the nature of the patients in the study. A larger study would be needed to clarify this issue---indeed Merck says that a study with 18000 patients is currently underway and the results should be out in 2012;

2) Either that the method of measuring arterial deposits (ultrasound) is unreliable ---this is unlikely---or that the thickness of arterial plaque is a poor predictor of cardiovascular disease --- this is even more unlikely;

3) That lowering of LDL-cholesterol has nothing to do with arterial plaque build-up and cardiovascular disease (this is blasphemous to much of the medical community). This would also mean that statins primarily work not via lowering LDL-cholesterol but via an as yet unidentified or unrecognized mechanism.

This would also be mightily embarrassing to the FDA, as it approved ezetimibe based on LDL-lowering data, not on studies relating to occurrence of heart-attacks or strokes.

4) That lowering of LDL-cholesterol is beneficial, but that ezetimibe also has other (as yet unidentified) effects on the body that negate its beneficial action, resulting in arterial plaque build-up despite the lowered LDL-cholesterol.

Any which way you look at it, from what we know and have known, there has never been any direct evidence to suggest that ezetimibe can reduce the incidence of cardiovascular disease.

Which brings us to this: The New England Journal of Medicine, which has published the results of the ENHANCE study, has issued two editorials (here and here) stating essentially that Vytorin and Zetia should only be used as a last resort. But I thought that had been the recommendation to the medical community right from the beginning!

In any case, what happened? How and why did Vytorin become so popularly prescribed in the absence of any substantial data showing that it is beneficial?

From an International Herald Tribune article on this matter, “The New England Journal also published a report showing that Vytorin and Zetia's use soared in the United States amid a $200 million…advertising blitz. In Canada, where marketing drugs directly to consumers is not allowed, sales were four times lower.” (emphasis mine)

From the Washington Post article:

“Dr. Harlan M. Krumholz, a professor of medicine at Yale University School of Medicine and co-author of another of the journal papers…(which)… compared use of Vytorin in the United States and Canada. The proportion of cholesterol-lowering drug prescriptions represented by Vytorin rose from 0.2 percent to 3.4 percent in Canada from 2002 to 2006. In the United States, the increase was from 0.1 percent to 15.2 percent of all such prescriptions.

"That is a pretty remarkable difference," Krumholz said. "If we had adopted the drug at the same speed as in Canada, we would have saved $1.5 to $2 billion in health-care costs. What did we get for that? Did it produce benefits for patients? We can't say we're sure of that."

It's also possible that the new cholesterol-lowering agent might turn out to be harmful, Krumholz said. He recalled the history of torcetrapib, a drug developed by Pfizer that increased blood levels of HDL cholesterol, the "good" kind that prevents plaque formation. Pfizer stopped tests of the drug in 2006 because of a trial showing higher mortality among those taking it.

"It was a new drug, the first in its class," Krumholz said. "The laboratory results looked great, and it ended up hurting people."

It's not clear whether the same will be true of Vytorin, he said. "The evidence we have on hand makes a benefit less likely," Krumholz said. "We have a $5-billion-a-year market without outcomes data." (all emphasis mine)

Anyway, maybe someone with more Med Cred (Abel Pharmboy, or DrugMonkey or PhysioProf ) care to comment on/do a more scientific work-up on this matter?

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