Good News for Ezetimibe? Not!

December 5, 2008

The headlines sounded impressive: “Study Says Zetia May Help Fight Heart Disease” (Wall Street Journal), “Statins, Zetia reverse atherosclerosis in study” (Reuters).

Zetia is ezetimibe, a component of Vytorin and the subject of the ENHANCE and SEAS trials, covered on GoozNews here, here, and here. In the ENHANCE trial, ezetimibe had no effect on atherosclerosis, leading a panel at the American College of Cardiology conference in March 2008 to recommend that it be used only as a last resort. To make matters worse, the SEAS trial found a troubling increase in cancer in the patients who received ezetimibe, leading to uncertainty as to ezetimibe’s safety.

Unfortunately, the new study, published December 3 in the Journal of the American College of Cardiology adds nothing to our knowledge about ezetimibe’s safety and efficacy. The study was an analysis of data from the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial, in which the effects of aggressive goals for cholesterol and blood pressure lowering were compared to standard goals in 500 patients with type 2 diabetes. The results of the study were originally published last April in the Journal of the American Medical Association and showed that lower cholesterol and blood pressure resulted in less atherosclerosis. The new study is a post-hoc analysis, a term which refers to testing data for patterns that you had not planned to look for when the study was designed. Sometimes called “data dredging,” this technique has been compared to shooting an arrow into a target and then drawing a bull’s-eye around it.

In this case, the researchers compared patients who achieved low cholesterol levels with a combination of a statin and ezetimibe with patients who achieved similar levels with a statin alone, and found no difference in the effect on atherosclerosis. However, only 69 patients received ezetimibe and the two groups were not determined through randomization. Thus, the groups could have differed for any number of reasons. The researchers’ conclusion that their study shows that achieving low cholesterol targets by adding ezetimibe to a statin is just as effective as reaching the target with a statin just is not at all convincing.

Although SANDS was funded by the National Institutes of Health, several of the researchers have close ties to Merck and Schering-Plough, the manufacturers of ezetimibe, having received research support from and served on the scientific advisory boards and/or speaker’s bureaus of those companies. Inexplicably, Evan Stein, a well-known proponent of ezetimibe, was chosen to write an editorial, which reaches similar unwarranted conclusions. Stein was one of the ENHANCE investigators and has received consulting fees from Merck and Schering-Plough.

– Marilyn Mann

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