Ezetimibe at SEAS

September 2, 2008

Let’s not mince words. The New England Journal of Medicine dealt a major blow today to ezetimibe (Vytorin, Zetia) in a hard-hitting editorial on the apparent link between cancer and ezetimibe. The editorial accompanied the publication of the SEAS trial and a statistical analysis of cancer incidence and deaths in SEAS and two other ezetimibe trials conducted by Richard Peto and the Clinical Trials Service Unit of Oxford University (see these Gooznews posts here, here, here, and here for the backstory).

To recap, the SEAS trial found an increase in cancer cases and deaths in the group that received ezetimibe. The Peto analysis of two ongoing ezetimibe trials found no increase in cancer cases, but did find more cancer deaths (97 vs. 72 in the control group), although the increase in cancer deaths did not reach statistical significance (p = .07). When all three trials (SEAS, IMPROVE-IT and SHARP) were combined, there was a significant excess of cancer deaths among the patients assigned to ezetimibe (134 vs. 92; risk ratio, 1.45; p = 0.007). The Oxford group believes this is a statistical fluke, noting that there was no trend in the relative risk of death from cancer over time in SHARP and IMPROVE-IT alone or in all three trials combined.

In a recent post-hoc analysis of ezetimibe and ezetimibe/statin trials (subscription required), investigators funded by Merck/Schering-Plough found that ezetimibe by itself significantly lowered blood levels of both sitosterol and campesterol (-54 percent and -58 percent, respectively) over a period of 12 weeks. Similar results were found when ezetimibe was combined with a statin.

Sitosterol and campesterol are both plant sterols that come exclusively from dietary sources (unlike cholesterol, our bodies cannot manufacture plant sterols). It seems likely, therefore, that the plant sterol levels in the blood of patients on long-term ezetimibe therapy are even lower than those found in this analysis of short-term trials. In addition to ezetimibe’s effect on plant sterols, there are test-tube studies suggesting that it may interfere with the absorption of carotenoids and alpha-tocopherol or vitamin E (see the studies here, here, here and here.

As previously discussed on GoozNews, several lines of evidence suggest that plant sterols may have anti-cancer effects. The New York Times in this story interviewed Peter Bradford, a pharmacologist at SUNY Buffalo who has extensively studied plant sterols. Bradford explained that in laboratory tests plant sterols promote cell death in a way that could make them valuable anti-cancer agents as weapons against tumors. By blocking plant sterol absorption, ezetimibe could be promoting cancer, he said. “One might envision that link,” he said. “This is a very large question.” See these links for some recent studies by Bradford and other plant sterol researchers: here, here and here.

More data is urgently needed before patients can again feel comfortable taking ezetimibe. It would be useful for the SEAS investigators to test the levels of plant sterols and carotenoids in blood samples from participants in the SEAS trial. Until more information is available, ezetimibe use should be limited to patients in clinical trials.

– PM

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