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FAQ: Why Congress and the FDA Are Investigating Vytorin
By Daniel J. DeNoon
Reviewed By Louise Chang, MD
Some experts don't think so. Other experts do. Congressional and FDA investigations are under way.
What's going on? This WebMD FAQ provides a guide to the ongoing story.
What is Vytorin?
Vytorin is a combination of two cholesterol-lowering drugs, the statin drug Zocor (from Merck) and Zetia (from Merck and Schering-Plough). Like other statins, Zocor blocks an enzyme needed for cholesterol production. Zetia works differently: It prevents the gut from absorbing cholesterol.
Does Vytorin work better than a statin drug taken alone?
That's what ongoing clinical trials are trying to find out. Controversy surrounds the first of these trials — it was finished in 2006, but results came out only this year.
Those results suggested that while Vytorin cuts cholesterol, it does not reduce heart disease any more than a statin alone.
Recently, researchers reported results from a study of Vytorin vs. Zocor alone in patients with narrowing of a major heart valve: the SEAS study, sponsored by Merck.
This report, too, is controversial. Instead of reporting the findings at a major medical meeting, the investigators held a press conference. And instead of publishing the results in a peer-reviewed medical journal, the investigators issued a press release.
The results were not impressive. They suggest that Vytorin did not reduce heart "events" better than placebo, although it did cut cholesterol and also reduced clot-related strokes by 22%.
Does Vytorin cause or promote cancer?
There is no proof that Vytorin causes or promotes cancer.
But in the 2,000-patient SEAS study, patients taking Vytorin died of cancer twice as often as did patients taking an inactive placebo.
The numbers aren't big — 39 cancer deaths in the Vytorin group (4.1% of patients) vs. 23 cancer deaths in the placebo group (2.5% of patients). But they seem scary. So study leader Terje R. Pedersen, MD, of Ulleval University Hospital in Oslo, Norway, asked for help.
He and his colleagues turned to Richard Peto, FRCP, professor of medical statistics and epidemiology at Oxford University in England. Peto was leading the SHARP study, one of two large ongoing trials of Vytorin (which, like the other trial, IMPROVE-IT, is sponsored by Merck and Schering-Plough).
Peto, a world-renowned expert in cancer epidemiology, took an unusual step. He got permission to take a look at the unblinded data from the two ongoing studies.
The result: Among the 20,000 patients in the two ongoing trials, there were 97 cancer deaths among patients taking Vytorin and 72 cancer deaths among control patients taking Zocor. However, there were about the same number of cancers in each group: 313 cancers in the Vytorin group and 326 cancers in the control group.
Peto dismissed the cancer-death disparity and focused on the number of cancers and when they occurred. If Vytorin was causing cancer, he said, the number of cases should have increased as patients stayed on the drug longer and longer. But this trend was not seen. Moreover, there was no increase in any particular kind of cancer — just an overall increase in cancer deaths.
"Because these [trials] do not show excess cancer, because there is no time trend effect, these trials together do not provide any credible evidence of any effect [of Vytorin] on cancer," Peto said at the July 21 press conference announcing the SEAS findings. "The SHARP and IMPROVE-IT trials will have to run for some more years until they answer their main questions, but I think we should not be diverted by fears of cancer.
Richard H. Karas, MD, PhD, director of preventive cardiology at Tufts Medical Center, Boston, is convinced by the Peto analysis.
"In my opinion, looking at all of the information we have taken together, there is unlikely to be an increase in cancer with Vytorin," Karas tells WebMD. "The Peto analysis is well done and convincing. I think it is appropriate for the FDA to look at the data independently, but in the end, I think this is going to prove to be a non-issue."
But Steven Nissen, MD, head of cardiovascular medicine at the Cleveland Clinic and past president of the American College of Cardiology, feels very differently.
He says the Peto analysis is flawed because it looks at patients who have not been taking the study drug long enough to show a true difference. Indeed, the IMPROVE-IT trial is still recruiting patients. And Nissen strongly objects to "releasing clinical data at company-sponsored press conferences rather than via the scientific literature." (Merck tells WebMD the SEAS results were presented by the investigators and not by the company).
Why Is the FDA Investigating?
It's the FDA's job to ensure drug safety. And it probably didn't hurt that a U.S. congressional committee led by Rep. John Dingell (D-Mich.) demanded a look at the data just hours before the FDA said it would investigate.
Merck and Schering-Plough tell WebMD that they are cooperating fully with both the FDA and Congress.
But doubts remain. Still unexplained are the extra cancer deaths in patients taking Vytorin, says Nissen.
In a statement, Merck says the data show "a non-significant increase in deaths from cancer in patients in the group who took Vytorin compared to those who took placebo."
Nissen disagrees. He says the difference is highly significant and very unlikely to have occurred by chance, as Peto asserts.
"The SEAS, SHARP, and IMPROVE-IT trials, taken together, show an excess of cancer mortality associated with the Zetia-containing product Vytorin: 136 cancer deaths in treated patients vs. 95 cancer deaths in the control arms," Nissen tells WebMD.
Nissen is quick to add that the studies do not prove Vytorin causes cancer.
"The jury is still out on whether Vytorin or Zetia is associated with an increased risk of cancer," he says. "Therefore, we need careful evaluation of all the data by independent physician scientists and the FDA. And we need to be cautious about prescribing this drug until we have more data."
The FDA and the American Heart Association have warned patients not to stop taking any cholesterol-lowering drug without talking with their doctors.
How Might Vytorin Up Cancer Risk?
Vytorin contains Zocor, a statin drug — and statin drugs do not cause cancer.
Pointing to this data, Peto says there's absolutely no reason to suspect that Vytorin can cause cancer.
"This isn't the sort of drug that is expected to have any material effect on cancer," he said at the July 21 press conference.
But Vytorin also contains Zetia. Zetia blocks absorption of cholesterol in the gut. It also blocks uptake of plant sterols, one of the healthful byproducts of eating vegetables.
In animal studies, plant sterols have an anti-cancer effect. One study shows they keep tumors from spreading.
This slim body of circumstantial evidence does not convict Zetia or Vytorin of causing cancer. Currently, neither Zetia nor Vytorin is known to cause or promote cancer or to increase cancer risk.
What is known is that Zetia and Vytorin lower cholesterol. The benefits of these drugs may outweigh any potential risks for individual patients at risk of heart disease.
WebMD writer Miranda Hitti contributed to this article.
SOURCES: News conference, "Update on SEAS Study," with Terje R. Pedersen, MD, head of the Center for Preventive Medicine, Ulleval University Hospital, Oslo, Norway; and Richard Peto, FRCP, University of Oxford Clinical Trial Service Unit and Epidemiological Studies, July 21, 2008 (transcript downloaded Aug. 21, 2008). News release, University of Oxford Clinical Trial Service Unite and Epidemiological Studies Unit. News release, SEAS Study Investigators. News release, American Heart Association. Statement and email, Merck. Email, Schering-Plough. Steven Nissen, MD, head of cardiovascular medicine, Cleveland Clinic. Richard H. Karas, MD, PhD, director of preventive cardiology, Tufts Medical Center, Boston. Salen, G. Circulation, March 2, 2004; vol 109: pp 966-971. Imanaka, H. Biological & Pharmaceutical Bulletin, March 2008; vol 38: 400-404. WebMD Health News: "Study Casts Doubt on Vytorin, Zetia." WebMD Health News: "Vytorin Study to Get FDA Review." WebMD Health News: "Vytorin Study: Disappointing Results." WebMD Health News: "Statins: No Cancer Risk."
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