September 3, 2008

Don’t ‘Just Brush Aside’ Vytorin Risk

By Steve Sternberg

The editors of a leading medical journal cautioned Tuesday that, without more data, it's impossible to rule out a link between the cholesterol-lowering drug Vytorin and cancer.

The cancer link surfaced unexpectedly in July in three studies designed to show whether the drug prevents deaths from heart attacks and strokes. Researchers found evidence that patients who took Vytorin appear to have at least a 40% greater risk of dying from cancer than those who took a placebo. A separate statistical analysis of the data, however, concluded that the link wasn't credible.

"You should not just brush this aside," says Jeffrey Drazen, editor of The New England Journal of Medicine, who wrote the editorial along with four other editors, two of whom are statisticians.

Vytorin is the combination of two drugs, ezetimibe and simvastatin. Together they've been heavily promoted for their power to combat cholesterol from "food and family." Partly on the strength of those ads, ezetimibe, which is also sold separately in Zetia, has become one of the world's top selling drugs, with combined sales of $5.2 billion last year.

But no studies have shown that ezetimibe can prevent heart attacks or deaths. In January, another trial called ENHANCE failed to show the drug offered a benefit, prompting a panel of leading cardiologists to recommend using Vytorin and Zetia only in patients who can't use other cholesterol-lowering drugs.

The latest controversy began in July when Terje Pedersen of Ulleval University Hospital in Oslo reported the results of a 2,000-patient SEAS study, which was designed to find out whether Vytorin could prevent the progression of heart-valve disease. It did not. But Pedersen did report a "disturbing" increase in the risk of dying from cancer.

To tease out whether the finding was real, Sir Richard Peto and his team at Oxford examined data from SEAS and two ongoing ezetimibe studies, SHARP and IMPROVE-IT, that together involve more than 10,000 patients. Peto says that patients weren't taking the drug long enough to get cancer and that there's no biological explanation for why Vytorin would cause cancer.

Pedersen and Peto reported their findings today at a meeting of the European Society for Cardiology. Pedersen says that, based on Peto's analysis, he's convinced that the finding was a fluke. "It's very difficult to produce cancer in three years," he says.

But the journal editors say the odds could be as low as seven in 1,000 that the cancer deaths occurred by chance. "We want to say, as editors, that this may not simply be the play of chance," Drazen says.

The question is likely to remain unanswered until 2012, when researchers at Duke and Harvard universities wrap up the 12,000-patient IMPROVE-IT trial, designed to explore ezetimibe's risks and benefits. (c) Copyright 2008 USA TODAY, a division of Gannett Co. Inc. <>