Cholesterol Drug Has No Benefit in Trial, Makers Say

Published: January 14, 2008   in the New York Times
A clinical trial of Zetia, a cholesterol-lowering drug prescribed to about 1 million people a week, failed to show that the drug has any medical benefits, Merck and Schering-Plough said on Monday.

The results will add to the growing concern over Zetia and Vytorin, a drug that combines Zetia with another cholesterol medicine in a single pill. About 60 percent of patients who take Zetia do so in the form of Vytorin, which combines Zetia with the cholesterol drug Zocor.

While Zetia lowers cholesterol by 15 percent to 20 percent in most patients, no trial has ever shown that it can reduce heart attacks and strokes ”” or even that it reduces the growth of the fatty plaques in arteries that can cause heart problems.

This trial was designed to show that Zetia could reduce the growth of those plaques. Instead, the plaques actually grew almost twice as fast in patients taking Zetia along with Zocor than in those taking Zocor alone.

Patients in the trial who took the combination of Zetia and Zocor were receiving it in the form of Vytorin pills. The trial, called Enhance, lasted two years and covered about 720 patients with extremely high cholesterol, mostly in the Netherlands.

Dr. Steven Nissen, the chairman of cardiology at the Cleveland Clinic, said the results were “shocking.” Patients should not be prescribed Zetia unless all other cholesterol drugs have failed, he said.

“This is as bad a result for the drug as anybody could have feared,” Dr. Nissen said. Millions of patients may be taking a drug that has no benefits for them, raising their risk of heart attacks and exposing them to potential side effects, he said.

Still, patients who are taking Vytorin or Zetia should talk to their doctors if they are concerned and not discontinue taking the medicines on their own, Dr. Nissen said.

Dr. Howard Hodis, a cardiologist at the University of Southern California, also said he was concerned by the trial’s results. Growth in fatty plaques ”” called atherosclerosis ”” is highly correlated with heart attacks and strokes, Dr. Hodis said.

“Clearly, progression of atherosclerosis is the only way you get events,” Dr. Hodis said. “If you don’t treat progression, then you get events.”

The results of the trial “necessitate further investigation ”” that just can’t be ignored,” Dr. Hodis said.

Both companies’ stocks were down in mid-day trading in New York on Monday, with Merck’s share price off by 2.4 percent and Schering-Plough’s down nearly 6 percent.

The results will also add to the controversy surrounding a long delay in releasing the results of the trial. Merck and Schering-Plough completed the trial in April 2006 and had initially planned to release the findings no later than March 2007. But the companies then missed several self-imposed deadlines, citing the complexity of the data analysis from the study and saying they did not know when or if the data would be ready for publication.

Last month, after several news articles highlighted the delay, they finally agreed to release the results soon.

For Merck and Schering-Plough, which jointly market Zetia and Vytorin and share profits from the drugs, the trial’s results are a serious setback. Zetia and Vytorin are important contributors to both companies’ profits, especially to Schering, which is smaller and less profitable than Merck.

Analysts estimate that about 70 percent of Schering’s earnings depend on the drugs. The controversy over the trial is also a problem for Merck, which is trying to repair its reputation after withdrawing the painkiller Vioxx from the market in September 2004.

In the United States, Zetia and Vytorin combined account for about 20 percent of the overall cholesterol-lowering market. More than 100 million prescriptions have been filled in the United States for Zetia and Vytorin since the Food and Drug Administration approved them in November 2002 and August 2004 respectively. Both drugs cost about $3 a day.

Because Zetia reduces cholesterol differently from statins like Lipitor and Zocor, doctors often prescribed it as an additional therapy for patients whose cholesterol remains high even after they are already taking statins. But even before Zetia was introduced in 2002, some cardiologists argued that statins had positive cardiovascular effects that go beyond their ability to reduce cholesterol, and that Zetia lacks those effects.

The Enhance trial covered patients with a gene that causes them to produce very high levels of low-density lipoprotein cholesterol, commonly called L.D.L., or bad cholesterol. Patients in the trial had L.D.L. levels of about 320 milligrams per deciliter at the beginning of the trial, about three times the level cardiologists recommend.

Over the two years of the trial, patients who took Zocor alone reduced their L.D.L. by 41 percent on average, while patients who took Vytorin reduced their cholesterol by 58 percent. Yet despite the larger cholesterol reduction, patients taking Vytorin actually had more growth in fatty plaques in their carotid arteries than those on Zocor. The carotid artery runs through the neck and delivers oxygenated blood to the brain.

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