After nearly two years of waiting, the results came out on Monday on the long-awaited heart drug Vytorin and the news wasn't good. Vytorin's manufacturers, Merck and Schering-Plough, announced that while the drug reduced levels of LDL, or bad cholesterol, in a group of 750 patients, the medication, which has been on the market since 2004, had little effect on the buildup of plaque in the arteries, a harbinger of heart attack and stroke.
To many experts, the results were both a surprise and a warning. "The fact that the trial showed a huge LDL reduction, and that things were still going the wrong way [in terms of plaque buildup] is stunning," says Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic and an outspoken critic of the delay in the release of the study results. "This study shows that it matters how you lower cholesterol, not just how much you lower cholesterol."
It's becoming clear, for example, that statins, an $18 billion market in the U.S., may lower the risk of heart disease by doing more than just lowering cholesterol studies have shown that statins can also lower inflammatory factors that can aggravate plaques, causing them to burst and block heart arteries, as well as reduce amounts of triglycerides, a particularly dangerous form of fat for the heart. "The bottom line is that we just don't know what Vytorin does, because we don't have the clinical trials," he says. "We know Vytorin blocks absorption of cholesterol. But what else does it block something else in the diet that could be beneficial? We just don't understand fully how it works."
As for the extended delay in reporting the results of the Vytorin study called ENHANCE Schering-Plough spokesperson Lee Davies told TIME that it was due to the time involved in reading and interpreting the tens of thousands of images of the carotid arteries that the study generated data that had been available since April 2006. The company's procrastination prompted much discussion among heart doctors and on Capitol Hill: At the end of 2007, the House Energy and Commerce Committee sent a letter to the two manufacturers asking for the findings and noting that the end point of the study specified in the companies' original study design differed suspiciously from that submitted to the government's clinical trials database in October 2007. "We are concerned ... with the apparent manipulation of trial data," the letter read.
"ENHANCE was never designed to provide outcomes, meaning the prevention of major adverse cardiovascular events such as heart attack or stroke," says Davies. "This was an interesting scientific exercise to look at the impact of the drug on plaque, which is itself a surrogate end point for these events."
But even there, Vytorin failed to show much effect. Vytorin is actually the combination of two drugs one of the early statin medications, simvastatin (also known as Zocor), made by Merck, and ezetimibe, or Zetia, made by Schering-Plough. Ezetimibe is the first cholesterol-lowering medication that works by blocking absorption of cholesterol in the gut, rather than regulating the fat's production in the liver, like other statins do. ENHANCE compared the effect of Vytorin to simvastatin alone, and showed little difference between the two medications when it came to plaque size in the arteries. Simvastatin came off patent in 2006, and these results suggest that the generic form of simvastatin may be as effective as the more expensive Vytorin.
ENHANCE may only be the opening salvo against Vytorin three larger trials are currently under way to measure the drug's effect on heart attack and stroke and many physicians are not optimistic. "Given these results, it's highly unlikely that those outcomes studies will show dramatic benefit for Vytorin," notes Dr. Raymond Gibbons of the Mayo Clinic, and past president of the American Heart Association.
So how could such a drug be approved in the first place? The Food and Drug Administration would only say that it is "evaluating the available data related to the ENHANCE study." That would include the "food and family" advertisements for Vytorin, which claim that the drugs attack high cholesterol levels, whether they come from your diet or from your genes, or some combination of both. Davies says the company has made "no determination at this time" on the fate of that campaign. But it should give the FDA good reason to evaluate how it approves future medications in this class. "I suspect that in the future, FDA will require that drugs that lower cholesterol in novel ways show good clinical endpoints before getting approved," says Dr. Roger Blumenthal, director of preventive cardiology at Johns Hopkins Hospital."
In the meantime, doctors are likely to dial back on their use of Vytorin. "If they aren't getting to the target goal [cholesterol level] with generic simvastatin, then because this study is raising questions I think a lot of physicians will think about switching to higher doses of drugs like Lipitor or Crestor before going to Vytorin," says Blumenthal. At least the commercials got one thing right your risk of heart disease does depend on the food you eat and the genes you inherit. It's just that Vytorin may not be best way to fight those factors when it comes to keeping your heart healthy.