Vytorin trial shows little or no benefit against heart disease

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For the second time in as many years, a large clinical trial has found that the key ingredient in the heavily advertised drug Vytorin provides little or no benefit in preventing heart disease compared to a competing product. The ingredient is ezetemibe, which blocks the absorption of cholesterol in the intestines. It is sold alone under the brand name Zetia or in combination with the cholesterol-lowering drug simvastatin under the brand name Vytorin. The combination of drugs has been shown to reduce cholesterol more than simvastatin alone, but that apparently does not translate into a lower risk of heart disease.

In the original trial, reported last year in January, Vytorin was compared with generic simvastatin in a group of 720 patients with a genetic disorder called heterozygous familial hypercholesterolemia, in which unusually high levels of low-density lipoproteins, commonly known as LDL or ‘bad’ cholesterol, accumulate in the blood, increasing the risk of cardiovascular disease. Vytorin reduced the level of LDL in the blood of the patients by 58%, compared with a 41% reduction produced by simvastatin, which blocks production of cholesterol in the liver. But to determine how the drugs affected the risk of heart disease, researchers looked at the thickness of plaque in the carotid and other arteries. Thicker plaque increases the risk of plaque breaking off and producing clots that lead to heart attacks. The researchers found that plaque actually grew slightly more in the patients taking Vytorin than it did in those taking only simvastatin. Since then, prescriptions for Zetia have fallen from nearly 16.5 million in 2007 to less than 13 million in 2008, while those for Vytorin fell from 22 million to 16.5 million. The new results could lead to further declines.

A new study to be reported Monday at the American Heart Assn. meeting in Orlando, Fla., and published online in the New England Journal of Medicine compared ezetemibe to Niaspan, a controlled-release version of the B vitamin niacin. Niacin is known to raise levels of high-density lipoprotein, commonly known as HDL or ‘good’ cholesterol. Many people have problems taking niacin, however, because it causes flushing. It is thought that Niaspan, because of its slow release, is less likely to produce this side effect.

Dr. Allen Taylor, who was at the Walter Reed Army Medical Center in Bethesda, Md., when the study began, and his colleagues enrolled 363 people with heart disease or at a high risk of developing it and who had been taking statins for an average of six years. About half were given Zetia in addition to their statins and the rest Niaspan. The study was terminated early in July, about four months early, when investigators concluded there was a clear difference between the two groups -- although they did not say which was better at the time.

Taylor reported at a news conference Sunday that Niaspan shrank plaque in carotid arteries by about 2%, while Ezetemibe had no effect, even though it reduced cholesterol. There were two heart attacks or heart-related deaths in the 160 people given Niaspan, but nine among the 165 given Zetia. About a third of those who received Niaspan did suffer flushing, however.

Zetia ‘should be better for the arteries and it wasn’t,’ Taylor said at the news conference. ‘The drug wasn’t operating as you would otherwise expect it to.’

But Peter Kim, director of research at Merck & Co., which markets Vytorin along with Schering-Plough Corp., said the study was too small to draw any firm conclusions from it. He said the drug is now in other trials involving about 25,000 people and that physicians should wait for results from them before deciding not to prescribe the drug.

In an editorial accompanying the paper in the New England Journal, researchers from Johns Hopkins University agreed with him. ‘Although the study results are provocative, I am not convinced,’ said Dr. Roger S. Blumenthal, a cardiologist, who argued that the study was too small and too short. ‘These early results offer no conclusive evidence that niacin along with a statin will actually lower the number of deaths and incidents of heart attack from coronary artery disease down the road.’

Until those results are available, however, consumers might find that a combination of a generic statin and over-the-counter niacin might be more cost effective. While Vytorin and Niaspan each cost about $3 to $4 per day, niacin can be had for a few pennies and generic simvastatin costs less than 40% of the price of Vytorin.

— Thomas H. Maugh II

[Updated, 7:30 p.m.: According to Merck, Zetia costs $3.23 a day, and the amount of Niaspan used in the study costs $7.48 a day.]