Zetia: How Did It Get Here?

Washington, DCThe emerging scandal surrounding Merck/Schering-Plough's Zetia and Vytorin cholesterol-lowering drugs has raised questions about some related issues. To recap: on January 14, after nearly a two-year delay, Merck/Schering released the results of its ENHANCE testing program for their combination Zetia/simvastatin (Zocor) drug called Vytorin. Those results indicated that Vytorin, and by implication Zetia, apparently was no more effective than simvastatin drugs alone in reducing or inhibiting arterial plaque in users. Arterial plaque is the prime cause of stroke and heart attack.

Doctors have been prescribing Zetia, either alone or in Vytorin, for patients at risk for heart attack or stroke based on its known ability to reduce LDL (bad) cholesterol. Unlike statin drugs, which block cholesterol production in the liver, Zetia inhibits LDL cholesterol absorption in the digestive tract. So it was no surprise that patients in the ENHANCE tests who took Vytorin showed a higher cholesterol reduction than those who received a statin drug alone.

However, the ENHANCE results proved that once again that reduced cholesterol is not the whole story when it comes to protecting against stroke and heart attack. So far, the best that can be said for Zetia in either of its forms is that is does reduce cholesterol. Whether it's any use for the desired outcome—reducing heart attack and stroke risk—remains highly questionable.

With annual Zetia sales running around $5 billion, that's disturbing news to say the least. Insurance plans, Medicare and Medicaid, and no doubt many people with no prescription drug coverage, have all spent a lot of money on an expensive drug that may well be essentially useless in protecting its users against stroke and heart attack.

Something's wrong here—and in the aftermath of the ENHANCE trials, the finger pointing is now being directed at the federal Food and Drug Administration (FDA), and specifically how it approves drugs for sale. It's about something called "surrogate markers."

Surrogate markers are sort of a stand-in for actual detailed clinical trials. They were first brought into use to speed the process of bringing desperately needed HIV/AIDS drugs to patients who would certainly die without them. Instead of running lengthy clinical trials that focused on the desired outcome—in this case, long-term survival of HIV-infected patients—the drugs were given shorter trials that measured some other medical effect.

In the case of AIDS drugs, this might be a measurable increase in immune system antibody production, for example, or a significant reduction in the HIV virus in the bloodstream. It didn't promise a cure, but it looked like it might help; for patients under a death sentence, that was pretty good.

Surrogate markers were also a nice loophole for drugs that might be less urgently needed, and Merck took advantage of them to win FDA approval for Zetia in 2002. That approval was based on Zetia's meeting a surrogate marker—in this case, a certain reduction in LDL cholesterol. What was not tested then was whether Zetia helped produce the right outcome—reduced heart attack and stroke in its users. And it was nearly six years before we learned that it might very well not.

The ENHANCE trial results have brought the FDA's policy of allowing widespread use of proxy markers in the drug approval process under fire. In the case of Zetia, that was aggravated by the FDA's failure to require detailed post-approval monitoring and further testing. John Buse, a professor at the University of North Carolina, says, "The FDA needs to have more teeth. They need to demand hard endpoint studies at the time of approval and they need to have some system for monitoring progress."

That didn't happen with Zetia. Merck/Schering marketed Zetia and Vytorin aggressively, doctors prescribed it, patients took it thinking it would help, and the companies dragged their heels on releasing the ENHANCE results. And meanwhile, the money came pouring into their coffers.

Merck/Schering are now asking doctors, patients, and the FDA to wait for the results of their current clinical tests that will actually measure stroke and heart attack rates for Zetia and Vytorin. How long? Well, 2011 or so. Do you feel lucky?