Vytorin and Cancer - is there a link?

[gpawelski]

The New England Journal of Medicine (NEJM) editorial blasted the analysis by Oxford University statistician, Richard Peto that dismissed Vytorin's possible link to cancer. The SEAS study found that Vytorin patients had higher rates of cancer and cancer deaths. The results for cancer incidence was clearly significant, as well as the results for cancer death.

The NEJM editorial on ezatimibe 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.

Vytorin is a combination of cholesterol-lowering Zetia (ezetimibe) and the statin Zocor (simvastin). As mentioned in the NEJM editorial, some have theorized that Zetia could cause cancer because it blocks chemicals called plant sterols, which may cause heart disease but could also have some anti-cancer effect.

Plant sterols (phytosterols) resemble cholesterol in structure but are found exclusively in plant-based foods like fruits, vegetables, nuts and whole grains. A number of tissue culture studies have exposed various types of human cancer cells to plant sterols and have found a slowing of the progression of cells from one stage to another, something that is abnormal in cancer cells.

In addition, plant sterols have been found to cause apoptosis and shown to inhibit changes in cells that take place when tumor cells metastasize. Also, it has been shown an increase in growth of cells that are part of the human immune system, such as natural killer cells, which could be protective against cancer.

Ezetimibe inhibits cholesterol absorption, as opposed to removing cholesterol from the blood like statins. But ezetimibe also inhibits absorpotion of dietary plant sterols and there is a plausible theory that the reduction in sterol absorption in patients in the SEAS trial may have increased risk of contracting cancer.

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.

Several lines of evidence suggest that plant sterols may have anti-cancer effects. The New York Tiimes 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. But by blocking plant sterol absorption, ezetimibe could be promoting cancer, he said.

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. Zetia should not be used in clinical medicine until the justifiable and substantial cloud of uncertainty over it is resolved.

[gpawelski]

Zetia is ezetimibe, a component of Vytorin. In the ENHANCE trial, ezetimibe had no effect on atherosclerosis, leading a panel at the American College of Carbiology conference in March 2008 to recommend that it be used only as a last resort. The SEAS trial found a troubling increase in cancer in patients who received ezetimibe, leading to uncertainty as to ezetimibe's safety.

A new study, published in the December issue of the Journal of the American College of Cardiology, added nothing to the knowledge about ezetimibe's safety and efficacy. This study was an analysis of data from the SANDS trial.

This 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.

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 these companies.

Source: GoozNews

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