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Health |​​From the New York Times                                   

Study Finds Alternative to Anti-Cholesterol Drug

By GINA KOLATANOV. 17, 2014

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Dr. Robert Califf, a Duke cardiologist, led a six-year study of a new cholesterol-lowering drug.      

Jeremy M. Lange for The New York Times          

For the first time since statins have been regularly used, a large study has found that another type of cholesterol-lowering drug can protect people from heart attacks and strokes.

 

The finding can help millions at high risk of heart attacks who cannot tolerate statins or do not respond to them sufficiently. And it helps clarify the role of LDL cholesterol, the dangerous form. Some had argued that statins reduced heart attack risk not just by lowering LDL levels but also by reducing inflammation. The new study indicates that the crucial factor is LDL, and the lower, the better.

 

The six-year study, reported Monday at the annual meeting of the American Heart Association, involved 18,000 people who had had heart attacks or episodes of chest pain so severe they went to a hospital. They were randomly assigned to take a statin or a combination of a statin and the alternative drug to further reduce LDL levels.             

                       

Both groups ended up with very low LDL levels — those taking the statin, simvastatin, had an average LDL of 69, and those taking simvastatin and the other drug, ezetimibe, or Zetia, in a combination pill sold as Vytorin, had an average LDL of 54. No clinical trial had ever asked what happened when LDL levels get below 70 because, said Dr. Robert Califf, a Duke cardiologist and the study chairman, “many people were nervous about going this low and imagined a lot of possible toxicities.”

 

Statins lower LDL by preventing it from being made. Ezetimibe lowers LDL by preventing cholesterol from being absorbed in the gut.

 

The drugs were so effective that there were few cardiac events among the participants but eventually a difference emerged. There were 6.4 percent fewer cardiac events — heart disease deaths, heart attacks, strokes, bypass surgeries, stent insertions and hospitalizations for severe chest pain — in those assigned to take Vytorin. The amount corresponded to what was predicted from the extra degree of cholesterol lowering with the combination drug.

 

Those results translate into 2,742 events in those taking simvastatin and 2,572 in those taking the combination drug. That means, said Dr. Christopher Cannon, a principal investigator and cardiologist at Brigham and Women’s Hospital, that two out of every 100 people who would have had a heart attack or stroke by taking the statin avoided those outcomes by taking the combination drug.

 

And, adds Dr. Califf, the study found no side effects from ezetimibe — no excess cancer, no muscle aches no headaches. “It looks like placebo,” he said.

The study was sponsored by Merck, the maker of Vytorin, but the investigators had the right to publish what they wanted, with final say over what they wrote.

“Fantastic,” said Dr. Sekar Kathiresan of the Broad Institute and Massachusetts General Hospital who studies the genetics of heart disease but had no part in the study. “A truly spectacular result for patients.”

Dr. Harlan M. Krumholz, a Yale cardiologist not associated with the study, said he wished there was a peer-reviewed journal article instead of a presentation of the results at a meeting — the data analysis was completed just last week — but, assuming the result holds up, “this is the result we were hoping for.”

 

At the same time, and by sheer coincidence, two other groups of researchers reported genetic studies that supported the trial’s conclusions. One, led by Dr. Brian A. Ference of Wayne State University School of Medicine found that gene mutations mimicking the effect of ezetimibe and ones mimicking the effect of statins had the same effect on heart disease risk for a given reduction in cholesterol. The implication, he said, is that “lowering cholesterol with ezetimibe, or a statin, or both, should each lower the risk of heart disease by about the same amount.”

 

The other, led by Dr. Kathiresan, examined mutations that disabled one copy of the cholesterol absorption gene, producing the same effect as ezetimibe. The result was a 50 percent reduction in cholesterol absorption — the same as produced by ezetimibe — and an LDL reduction of 12 milligrams per deciliter of blood, also the same amount as produced by ezetimibe. The mutation, which gave people the equivalent of a lifelong exposure to ezetimibe, reduced the heart attack rate by 50 percent.

 

The study’s results are making many wonder about the latest cholesterol guidelines, which did not mention any drug other than a statin. And instead of providing goals for cholesterol levels, they simply advised those at high risk to take a statin.

“The guidelines didn’t say they didn’t believe in cholesterol, but they made it clear that the evidence is for a statin, not for any agent that lowers cholesterol,” said Dr. Eugene Braunwald, a study chairman who is a cardiologist at Brigham and Women’s and a longtime leader in the field.

 

Dr. Neil Stone, the head of the guidelines committee and a cardiologist at Northwestern University, has a more nuanced view of what the guidelines say, but adds that the study result “gives doctors another option if they have a patient who can’t tolerate a high-intensity statin.”

 

The new data are in sharp contrast to what happened in 2006, when ezetimibe seemed useless. The study was small, with just 750 participants, all of whom had very high cholesterol levels. Instead of looking at heart attacks or strokes, the researchers looked at a surrogate, the buildup of plaque in the carotid artery of the neck. That made the study quicker and easier than waiting for people to have heart attacks. But it was not clear whether those carotid plaque measurements really reflected heart attack risk.

But ezetimibe had been approved purely on the basis of its ability to lower LDL. With that stunning negative result, the question about LDL’s lowering could not be avoided. Perhaps statins, the exemplar for the benefits of lowering LDL levels, were effective for more than just their effects on LDL.

“This is as bad a result for the drug as anybody could have feared,” said Dr. Steven Nissen, the chairman of cardiovascular medicine at the Cleveland Clinic, when the 2006 ezetimibe results came out. The results, he said, were “shocking.”

The drug, Dr. Nissen noted in a telephone call Friday, had reached 17 percent of market share for cholesterol-lowering drugs with no evidence of benefit.

“Now we have the result,” Dr. Nissen said. “They were successful, and that’s great. But at this point, it really doesn’t matter. They made their $30 billion.” The drug will be available as a generic in 2016, Merck says.

That the drug was promoted and sold for so many years without evidence that it helped was inexcusable, Dr. Krumholz said.

“The fact that the trial exists says there was uncertainty,” he said. “The company and the investigators and the scientific community were uncertain about it. This is a cautionary tale.”

“The results could easily have gone the other way,” he added.

For Dr. Cannon, the study has a broader lesson. “It reminds us that lowering LDL prevents heart disease,” he said.

Now, Dr. Braunwald said, the arguments over cholesterol lowering should be settled.

“People can stop yapping.”

 

Correction: November 17, 2014
An earlier version of this article misspelled the name of a drug in the trial. It is Vytorin, not Vitorin. It also misspelled, in two instances, the name of another drug. As the article correctly noted elsewhere, it is ezetimibe, not ezetimide or ezitimibe. And it mispelled the surname of a doctor not involved in the trial. He is Dr. Harlan Krumholz, not Krunholtz or Krumholtz.