Healthy Skepticism Library item: 12616

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Publication type: news

Moss RW.
Zetia Fails Clinical Trial...Why Was it Ever Approved?
Cancer Decisions 2008 Jan 27
www.cancerdecisions.com/012708.html

Full text:

This month, scientists announced the result of the long-awaited ENHANCE study of the cholesterol-lowering drug Zetia (ezetimibe). This drug alone, or in combination with the popular statin drug, Zocor (simvastatin) conveyed no medical benefit to patients. In fact, the company-sponsored study found that the pace at which artery-clogging plaque formed within blood vessels actually doubled in patients taking the two-drug combination.

In one sense both Zetia and Zocor did what was asked of them. On average, patients in the two-year clinical trial who took Zocor alone reduced their LDL cholesterol by 41 percent, while patients who took Vytorin reduced their cholesterol by a whopping 58 percent. Yet, despite the greater reduction in cholesterol, patients taking Vytorin actually had more growth of fatty plaque in their carotid arteries than those who were on Zocor alone.

In 2006, Merck’s patent on Zocor ran out and it has been a relatively inexpensive generic drug since then. In an attempt to recapture their share of the profitable statin market the company teamed up with Schering-Plough to market Vytorin, which is in fact nothing more than a combination of Zocor and Zetia. It thus cleverly rescued Zocor from the generic drug wilderness by repackaging it as a superior two-drug combination, thereby giving Zocor new life as a high-end and patented product. In case you have not been watching much television lately, Vytorin is the subject of a barrage of TV ads about how cholesterol comes from two sources, food and family. In 2005, the advertising budget for Vytorin alone was $161.5 million, third highest for any drug on the market.

“This drug doesn’t work. Period. It just doesn’t work,” said Dr. Steven E. Nissen, the chairman of cardiology at the Cleveland Clinic. “This is as bad a result for the drug as anybody could have feared. Millions of patients may be taking a drug that does not benefit them, raising their risk of heart attacks and exposing them to potential side effects.” (Nissen, readers may recall, recently played a central role in exposing the dangers of Avandia, a drug widely used in the treatment of type 2 diabetes.)

Worldwide, one million prescriptions for Zetia and Vytorin are written each week, and about five million people are taking the drugs. Almost one million of these patients are Americans, and of these, 60 percent get Zetia as part of the Vytorin combination. Sales of Zetia and Vytorin totaled more than $5 billion last year, up 33 percent from the year before. (Advertising pays!) About 70 percent of Schering-Plough’s earnings depend on the drugs, according to the New York Times, and Merck (the company which, incidentally, manufactured the catastrophic anti-arthritis drug Vioxx) is also quite dependent on its earnings from these statins. Schering-Plough’s stock fell 8 percent with the bad news about the ENHANCE trial.

“This wraps it up,” said Dr. Nissen. “That’s all there is. There just isn’t any evidence that adding ezetimibe [Zetia, ed.] to simvastatin [Zocor, ed.] produces any advantage.” But wrapped up or not, questions remain about the actual effect of this combination on millions of patients and the manner in which it was approved and marketed.

The ENHANCE trial involved 720 patients, all of whom had a genetic condition that caused abnormally high levels of blood cholesterol. As in previous trials, Zetia was found to be successful in lowering levels of LDL or “bad” cholesterol by 15 to 20 percent. Statin drugs like Zocor and Lipitor also lower LDL cholesterol in the majority of patients. Most cardiologists believe that by lowering LDL levels, statins reduce the risk of fatal heart attacks and strokes. However, Zetia, which works by a different mechanism to reduce LDL cholesterol, has never actually been shown to reduce heart attacks or save lives.

Thus, while statins may provide benefit by some less obvious mechanism, the ENHANCE study casts doubt on the notion that lowering LDL by itself – at least in this patient population – is the key to heart health. Yet Dr. Howard Weintraub, MD of New York University Medical Center, New York City, said in reaction to the study: “These results are very important considerations on how we treat patients with elevated cholesterol and will very likely impact the way we choose drugs to lower cholesterol and eliminate plaque.”

“ENHANCE found that plaque got slightly worse when the drug combination was used,” Dr. Weintraub conceded. Then he added the following eye-opener. “But, the real take-home message here is that getting LDL down is important, and that’s not something that should be lost as a consequence of this study.”

I find this odd. It is by no means clear that manipulating risk factors for a disease is always beneficial in terms of outcome. How does this study support the notion that lowering LDL in and of itself is so important, if those who had additional lowering showed no added benefit? Doesn’t it in fact call into question the whole idea that merely lowering LDL necessarily results in significant patient benefit? As the New York Times said, the findings “raise doubts about the current belief that lowering cholesterol is the key to cardiovascular health” (Jan. 16, 2008).

Growing Anger
There is a lot of anger over the fact that so many people have been prescribed these expensive drugs (Vytorin and Zetia) as opposed to the relatively cheap generic statin Zocor. “If there is no apparent clinical benefit, why take a drug that costs three or four times more?” asked Steven Findlay of Consumer Union, published of Consumer Reports. “Most people do not need that magnitude of cholesterol reduction anyway.”

There is also anger over the fact that these results had been known for many months, but the companies apparently sat on the data. The study was completed in April 2006 but the results were only released last week after a 21-month delay. According to a report in the Washington Post, Merck and Schering-Plough had planned to release the data in March 2007, but then continually missed self-imposed deadlines, blaming the delay on “the complexities of necessary data analysis.” The New York Times reports that it took pressure from the House Energy and Commerce Committee to get the companies to finally release the results.

“In light of today’s results, which were released nearly two years after the ENHANCE trial ended, it is easy to conclude that Merck and Schering-Plough intentionally sought to delay the release of this data,” Representative Bart Stupak, Democrat of Michigan, said in a statement. Mr. Stupak is chairman of the committee’s Subcommittee on Oversight and Investigations. In fact, the ENHANCE results will not be officially released until a cardiology conference in March 2008.

While granting that the clinical trial was relatively small, and that the patients were not typical of most potential users, The New York Times concluded: “The two companies that reap billions from the drug had been cynically sitting on the results for more than a year” (Jan. 16, 2008).

Amazingly, people on Wall Street who follow pharmaceutical stocks seemed unfazed by the latest study. Goldman Sachs analyst James Kelly reaffirmed his “Buy” rating for Schering-Plough, calling the ENHANCE results a “non-event” that does not represent Vytorin’s commercial prospects. He said the results reaffirmed the drug’s safety, which had been the key concern of the financial community. How one extracts a reaffirmation of Vytorin’s safety from the above data is anybody’s guess. Wall Street seems to be counting on the public’s short memory, and of force of habit among cardiologists to keep them prescribing these dubious drugs.

Congressional investigators should closely look at the circumstances surrounding the approval of Vytorin in July 2004. Once again we see the Food and Drug Administration (FDA) basing its decision to approve a drug on presumed benefit as measured by changes in so-called ‘surrogate markers’ rather than on direct evidence of lives saved. In this case, the surrogate marker was the fact that Vytorin lowered LDL more effectively than did Zocor alone. But lowering a risk factor in this way emphatically did NOT mean that the combination actually prevented any disease, much less lowered the heart attack or death rates. As we now see, the use of Zetia, alone or in combination with Zocor, may have actually led to a harmful result for some patients.

Approval based on surrogate markers has become the rule rather than the exception. One can only hope that the next president, whoever he or she may turn out to be, will take a fresh look at the FDA and its disturbingly close relationship with those whom it is supposed to regulate.