How could a drug that seems to make a condition worse actually get approved for sale by the FDA? The answer lies in the term "surrogate markers", which I'll discuss below.

Zetia® (ezetimibe) is a cholesterol-lowering drug that works in a different way from statins - it blocks the absorption of cholesterol from the intestines. You've probably seen the ads claiming that a combination of a statin (Zocor®) with Zetia - called Vytorin® - offers a double-whammy approach to cholesterol control. In two, multicenter, double-blind, placebo-controlled, 12-week studies in 1700 patients with high serum cholesterol levels, Zetia significantly lowered total-, low-density-cholesterol and triglycerides, and increased high-density-cholesterol. That was adequate to allow approval of Zetia as a cholesterol-lowering drug.

Cholesterol is a surrogate marker , i.e. a measurement that substitutes for more real measures of health that can't readily be made. Examples are: uric acid in gout, CD4/CD8 cell counts in HIV/AIDS, and PSA levels in cancer of the prostate.

Clinical decisions based on surrogate marker results should be approached with caution, but in general they serve as good guides, both as risk factors and to the development of the condition. With the statins, cholesterol control has been shown to be linked to decreased mortality, heart attacks, stroke, and so on.

In the recent study of Zetia, which has caused all the trouble, the critical endpoint chosen was not the low-density-cholesterol level, but a more specific measure of arterial disease, the carotid intima-media thickness. It was expected that Zetia would slow the development of arterial plaque as shown by ultrasound, but in fact growth was slightly enhanced, though not to a significant degree.

The logical conclusion of this affair is that FDA will demand carotid intima-media thickness measurements in studies of effectiveness of drugs for cardiovascular disease, rather than relying on the less-specific surrogate - a reduced cholesterol level. But then how long will it be before a newer, even more specific measure is necessary? For instance, biopsy of a mid-sized artery?

The media has made much of the failure of Zetia to fulfill its promise. But that is all part of the progress in discovering how drugs work. Certainly the two pharmaceutical companies concerned should be faulted for delay in making the results of the study known; one cannot help but believe that financial considerations may have influenced the speed of their evaluation. The lesson for the rest of us - take care in accepting the results of surrogate markers without question.