As reported earlier this week, the latest trial involving cholesterol-lowering drugs found a troubling increase in cancer cases and cancer deaths in the group that received Vytorin, a combination of ezetimibe (Zetia) and simvastatin (Zocor, a statin). Ezetimibe is a cholesterol absorption inhibitor, a first-in-class drug that operates by a different mechanism than statin drugs.
As previously reported on GoozNews, ezetimibe was approved in 2002 solely on the basis of its ability to lower LDL (“bad”) cholesterol, a surrogate endpoint. The FDA did not require Merck Schering Plough (MSP) to conduct clinical trials evaluating ezetimibe’s effect on clinical endpoints (heart attacks, strokes, death, etc.), an unfortunate decision that we are still paying for today as millions of people continue to take a drug that may not be benefiting them.
Eventually, under pressure from the medical community, MSP sponsored a trial testing ezetimibe’s effect on atherosclerosis — the ENHANCE trial — and started three trials testing ezetimibe’s effect on clinical endpoints. ENHANCE tested the effect of adding ezetimibe to a statin (as compared with the statin alone) and showed no effect on atherosclerosis from ezetimibe, despite substantially lower LDL levels in the ezetimibe group.
The latest trial, known as SEAS, is the first Vytorin trial since ENHANCE to be completed. Unfortunately, SEAS tested Vytorin versus a placebo, so we have no way of separating out the effect of ezetimibe from the effect of the statin. Vytorin was no better than placebo in reducing the primary combined endpoint of aortic valve and ischemic cardiovascular events and a secondary endpoint of aortic valve events. However, Vytorin achieved a 22 percent reduction in the risk of ischemic cardiovascular events. This positive result was expected, given that Vytorin contains a statin that has reduced such events in other trials. The result, however, is somewhat underwhelming given that the Vytorin group’s LDL went down a whopping 61 percent.
No two clinical trials are directly comparable, but as Allen Taylor (head of cardiology at Walter Reed Army Medical Center) pointed out in an interview with heartwire, the 22 percent risk reduction in a high risk population is less than was achieved in two other trials that tested simvastatin versus placebo. “That’s actually less relative risk protection than was seen in 4S and the Heart Protection Study, studies using similar doses of simvastatin but with less LDL reduction,” said Taylor, “It falls beneath one’s expectations.”
How ezetimibe works to lower cholesterol and whether it might have off-target effects is a matter of dispute, as discussed in a recent editorial by Allen Taylor that appeared in the Cleveland Clinic Journal of Medicine. That leaves many doctors reluctant to discount the cancer risk. “Obviously, if you see it in one study, even if it’s not statistically significant, you’ve got to be worried,” oncologist Ezekiel Emanuel of the National Institutes of Health said in an interview with USA Today. “Maybe this has a biological mechanism we don’t know anything about.”
“Your first reaction is, ‘Is it just a chance finding?’ Then you see it in a second trial, and say, ‘Whoa, can this be true? What’s the science here?’” Taylor told USA Today.
Asked about the results and how they fit into the context of existing Vytorin data, Harlan Krumholz of Yale University School of Medicine told heartwire that SEAS reinforces the message from March when the ENHANCE trial was presented at an American College of Cardiology conference. “This drug does not have sufficient evidence for it to be used as a front-line agent,” he said. “Statins are the drugs of choice. The evidence is not even strong enough to say that people who cannot tolerate statins should go on it. It is an option. Right now using it is based on an assumption that you know what IMPROVE-IT will find.” IMPROVE-IT is a large clinical trial testing Vytorin versus simvastatin alone, but the results will not be available until 2012, ten years after ezetimibe was approved.