New York, NY - Merck and Schering-Plough, which produced the combination drug Vytorin (ezetimibe and simvastatin) have been sitting on studies that contain important information on hepatic side effects and may never publicly release these results, the New York Times reports [1]. According to Times reporter Alex Berenson, the studies pertain primarily to ezetimibe and its liver risks when used with any statin or in the combination drug. The FDA has seen these data, and Schering chief medical officer Dr Robert J Spiegel "confirmed their existence" but said the findings were not "scientifically important enough" to publish, although some eventually may be, the Times reports.

As reported by heartwire, the news comes as Merck and Schering-Plough are on their heels explaining why results from their 800-patient ezetimibe trial, ENHANCE, are so slow in coming, despite concluding in April 2006. In fact, the Times article cites a Schering spokesperson who acknowledged that some study participants had dropped out of ENHANCE due to elevated liver-enzyme tests, although it was not known whether these patients were in fact taking the combination drug or simvastatin alone. Those dropouts are unrelated to the trial's delay, however.

In the Times article, Berenson quotes Dr Bruce Psaty (University of Washington, Seattle), who points out that the delay in releasing the ENHANCE data smacks of a problem. "When there have been adverse effects, when the benefits don't look impressive, those are the trials that historically don't make it to press."

And Dr Harlan Krumholz (Yale University, New Haven, CT), when told of the unpublished studies, commented to the Times: "We keep telling people we want to practice evidence-based medicine, and what we keep finding out is that much of the evidence is obscured. . . . There is important evidence, but it's not in public view. It's hidden from investigators."

Berenson notes that most doctors believe the drug is safe, but concerns about liver toxicity are not new.

During the FDA review of the drug in 2002, one reviewer voiced concerns about liver damage in animal studies. In the interim, case reports have also described liver damage in patients taking ezetimibe in combination with statins, including case reports published by Dutch gastroenterologist Dr Mark Stolk in 2006 that described two patients who developed hepatitis, one of whom has since died [2]. "I think other cases will emerge," Stolk is quoted in the Times.

Also interviewed for the story, Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA) is quoted saying that he suggested to Merck and Schering-Plough more than four years ago that they conduct an adequately powered, long-term safety trial, but the companies "looked at me like I was an alien," Topol told Berenson.

While countries such as Canada and Australia have issued a series of warnings about the risks of ezetimibe, including its potential to cause hepatitis, the US labeling contains "only mild warnings," Berenson notes.

On the company's side, Spiegel downplayed any safety concerns, telling the Times, "We're pretty comfortable that people don't have trouble tolerating Zetia."

Safety questions aside, an overarching issue is whether the combination drug is even any better than a high-dose statin alone, not just at lowering cholesterol but preventing cardiovascular events, Berenson asks. That question will not be answered until other trial results are in, in 2011 at the earliest.