Vytorin: Using medical reports for media hype and political attention

Armen Hareyan's picture
Advertisement

If you are a reader of this blog, you will know that I am no fan of Vytorin. Despite their massive marketing campaign, Merk-Schering has failed to prove why treating the "two sources of cholesterol" has any benefit to just treating patients with a statin. Both the ENHANCE study and SEAS studies (the only outcomes studies thusfar) failed to show any benefit of Vytorin , and thus there is really no need to use it.

However, the Vytorin saga seems to have struck and chord with the public, and so folks are piling on.

It was not surprising that many of the media outlets like Forbes, MSNBC, ABC news and others reported on the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial. As I have mentioned in a previous post, SEAS compared Vytorin to placebo in about 1800 patients with aortic stenosis, and showed no difference in the primary endpoint of both aortic valve events combined ischemic events (nonfatal MI, coronary, CABG, etc.). It was also not surprising to see that the media reported on an unexpected finding in the study, double the risk of cancer for those patients taking Vytorin.

Advertisement

However, apparently congress is now asking for a cancer investigation. According to the Wall Street Journal:

In a letter to the FDA, Rep. John Dingell (D., Mich.) said that based on the study's finding, "Vytorin may not be safe. Its potential for cancer and cancer deaths may be a significant cause for concern among physicians and patients."

And of course, this brings more media attention to the issue. The problem is that this is a non-issue. The SEAS study was not a Merk-Schering study. Cancer rates in the SEAS study were doubled, (106 in the Vytroin group versus 67 in the controls) but absolute difference was about 7% and did not reach (though it came close) statistical significance. Moreover, there is really no biologically plausible reason for Vytorin to cause cancer . In addition, as a result of these findings, analysis of large ongoing Vytorin studies (IMPROVE-IT and SHARP) showed fever cancers in the Vytorin group (313) then in patients not taking Vytorin. In other words, Vytorin very likely does not cause cancer.

On the one hand, I am in favor of further reasons for physicians not to prescribe/patients not to take Vytorin. On the other hand, I am annoyed that congressmen are using media-hyped anti-pharma fear to try to earn political clout. I would be the first to say that further scientific investigation on the issue of Vytorin and cancer is probably warranted. However, let's leave this to the scientists and the FDA. Why does congress need to get involved? Aren't there better things for them to worry about, like say 47 million Americans without health insurance?

Advertisement

Comments

Very well written; thanks for the summary. Agree: Doctors should not award Vytorin, period. My best friend died from the use of this dangerous drug; hidden trial results on the very day he died, the manufacturers diluted the issue of "safety" with an allied pill study cluttered with the word cancer when the issue of vytorin's effect on MUSCLE DETERIORATION especially of the heart (a very true muscle). Its just too ugly a scene.
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. Gregory D. Pawelski
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. Gregory D. Pawelski