In December 2007, the New York Times published an article entitled “Data about Zetia risk was not fully revealed.” The article claimed that Merck and Schering-Plough, the manufacturers of Zetia (aka ezetimibe), have information pertaining to the risk of liver damage when taking this cholesterol lowering medication in combination with statin drugs but that the companies have not released them to the public. The 2 companies confirm that this information exists yet justify not publishing them since they deemed them to be “not scientifically significant.” To make the medical community and the public lose even more confidence in Zetia, the companies have also not released the results from a large study called ENHANCE which was designed to evaluate the effectiveness of Zetia with and without Zocor (a type of statin drug) in the prevention of carotid artery thickening. Carotid artery thickening is often used as surrogate for the development of heart artery disease. That study was completed in April 2006. The US Congress had even asked Merck and Schering-Plough to explain the delay. The companies responded by saying that there was confounding data that needed to be sorted out in order to confirm the final results. Skeptics wonder if liver damage is involved in that “confounding” data.
The FDA reviewed all the available published and unpublished data concerning Zetia and approved it in 2002. People can take this medication alone or in combination with a statin to further reduce LDL cholesterol. In fact, the medicine Vytorin is a combination of Zetia and Zocor in one pill. Zetia works differently than statins in treating high cholesterol. It decreases the absorption of dietary cholesterol in the gut. Statins work at the level of the liver to reduce cholesterol. Zetia alone can reduce LDL cholesterol ~15-20%. More LDL reduction can be seen when Zetia is added in addition to a statin. Earlier studies from 2002 demonstrated that Zetia alone is quite safe. In fact, there was no difference in muscle or liver damage when Zetia was compared to placebo. When added to a statin, the risk of liver injury was only minimally increased compared to when taking only a statin alone. The problem with these earlier studies was that the duration of treatment was relatively short i.e. 12 weeks. When someone gets prescribed Zetia these days, it’s usually indefinite i.e. years to lifetime. The other problem with Zetia is that as of today, there are no studies that show it reduces heart attacks, strokes, and death as opposed to the numerous studies which exist showing the overall clinical benefits of statins. A study is underway to address this potential benefit of Zetia but results won’t be available till 2011.
Given the above information, who should be taking Zetia? If LDL reduction is indicated i.e. history of heart attack or high LDL with other heart disease risk factors, then first line drug treatment should be a statin given the abundant evidence of benefit. If a statin cannot be tolerated for whatever reason, then Zetia can be considered an alternative. If a statin alone at maximum dose does not lower LDL to target goal, then Zetia can also be considered for add on treatment. Some advocate using Zetia in order to avoid prescribing high doses of statin. My take is to first try to maximize the statin to reach your LDL goal since statins have proven benefit. I would only add Zetia to avoid high dose statins if the high dose statin was causing side effects such as muscle discomfort. Not surprisingly, everyone should have liver function tests checked before starting Zetia and a statin. The liver function test should be repeated when the dose is increased. Most recommend checking liver function tests at least every 6 months.
Merck and Schering-Plough should come forth with any information that may have relevance to Zetia especially if it pertains to long term safety. Although they may not think it’s scientifically significant, people who are taking and prescribing this medicine want to be reassured that this drug is at least safe while we wait for the heart protective benefits to be proven in the future.