Healthy Skepticism Library item: 12718

Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.

Publication type: news

Jordan GE, Todd S.
In wake of Vytorin study, some heart doctors reassess LDL factor
The Star Ledger 2008 Feb 4
http://www.nj.com/business/index.ssf/2008/02/in_wake_of_vytorin_study_heart.html

Full text:

Lower is better.

For two decades, that has been the mantra of heart doctors and their patients: Lower LDL, or “bad” cholesterol, reduces the risk of heart attack and stroke and prolongs life.

But a controversial study of the widely prescribed medicine Vytorin, coupled with negative publicity about other cholesterol drugs, has touched off an intense debate among cardiologists and researchers about the importance of controlling LDL.

Some of the world’s leading heart doctors have begun to question whether the lower-is-better theory of cholesterol management still holds.

The outcome of the debate could have important implications for the nearly 20 million Americans taking cholesterol medicines as well as for the pharmaceutical industry, which sells tens of billions of dollars’ worth of cholesterol drugs worldwide each year.

“It isn’t just what your LDL level is,” said Eric Topol, a prominent cardiologist and director of the Scripps Translational Science Institute in La Jolla, Calif., who suggests the preoccupation with bad cholesterol ignores other factors that can lead to heart attack and stroke.

“You can have low LDL but very active … LDL,” he said in a telephone interview this week. “What subspecies of LDL are you lowering — the noxious, oxidized types? That’s how it’s become oversimplified.”

But Philip Barter, a prominent Australian researcher and director of the Heart Institute in Sydney, said decades of medical research should not be dismissed so quickly.

“The available evidence strongly supports the view that lower LDL is better,” he said.

NOT A SURE THING

No one is suggesting heart doctors or patients abandon statins or other cholesterol-lowering medicines; in addition to lowering LDL, or low-density lipoprotein, statins have been shown to reduce heart-related deaths by 22 percent.

But research cardiologists such as Spencer King at Emory University School of Medicine and Robert Superko at St. Joseph’s Hospital in Atlanta are now questioning whether the pharmaceutical industry’s longtime focus on bad cholesterol is fully supported by scientific evidence. In the current issue of the journal Circulation, King and Superko argue that while LDL is clearly associated with heart disease, it’s no longer clear that simply lowering bad cholesterol will reduce heart attacks, strokes and deaths.

The “LDL hypothesis,” which was born in the 1980s with the first statin, Merck’s Mevacor, holds that lowering bad cholesterol prevents plaque buildup in the arteries. And that, in theory, reduces the risk of heart attack and stroke.

That assumption is now being shaken by a Merck and Schering-Plough study of Vytorin, a combination cholesterol medicine jointly marketed by the New Jersey drugmakers. The long-awaited results, released two weeks ago, showed that Vytorin — which combines Merck’s Zocor, a statin, and Schering-Plough’s Zetia, a new class of LDL-lowering medicine — did, in fact, reduce bad cholesterol.

But much to the disappointment of the two companies, the results also showed that plaque in the carotid arteries of patients in the study who took Vytorin thickened more than in those who took Zocor alone — apparently contradicting the “LDL hypothesis.”

Adding to the skepticism about statins was a lengthy report in a recent issue of BusinessWeek that questioned the benefit for many patients of Lipitor, the world’s top-selling cholesterol drug with $12 billion in annual sales.

LONGTIME DOUBTS

But the doubts go back even further, to studies of an experimental cholesterol drug called torcetrapib on which Pfizer, the world’s biggest drugmaker, was betting its future.

Torcetrapib represented a new class of cholesterol medicine designed not only to lower LDL cholesterol but also to boost HDL, or “good” cholesterol. But the results of two large-scale studies linked torcetrapib to deaths and showed it failed to prevent the buildup of arterial plaque. Soon after, Pfizer abandoned the project.

Drug company executives and Wall Street analysts warn the building controversy over cholesterol treatments has the potential to slow sales of the most widely prescribed medicines in the world, with annual sales of $40 billion. Already, the results of the Vytorin study have punished the two drugmakers, driving down shares of Merck 25 percent and Schering-Plough 30 percent so far this year.

Merck’s chief executive, Richard Clark, defended Vytorin this week during a conference call with industry analysts to discuss the company’s fourth-quarter results. He insisted lowering LDL remains essential for a healthy heart.

“Let’s keep this trial in perspective,” Clark said. “It was not designed to assess clinical outcomes, and one of the most overlooked results is that it lowers LDL.

“LDL lowering is key. And frankly, there are no better products at doing that than Vytorin and Zetia.”

The Vytorin study may not have attracted quite so much attention had Merck and Schering-Plough not delayed the results for 18 months, which prompted some critics to question the companies’ scientific ethics. The companies’ handling of the study now faces scrutiny from a slew of state and federal agencies, including the Food and Drug Administration, a Congressional subcommittee and the New York Attorney General’s Office.

As drug trials go, the Vytorin study was small-scale, enrolling only 720 patients. Merck and Schering-Plough have a large-scale study underway that medical researchers say will definitively measure Vytorin’s ability to prevent heart attacks, strokes and deaths. But the results will not be available until 2011.

For now, the scientific community is focused on the latest Vytorin results, with some cardiologists arguing strongly that lower-is-better should remain the standard, while others say a different approach is needed.

Some doctors argue that how cholesterol is lowered — the mechanism of the drug — may be just as important in the long run as how much it is lowered. Others theorize yet-to-be discovered subtypes of LDL may play a key role in triggering cardiovascular events.

The National Heart, Lung, and Blood Institute recommendations remain unchanged: People at high risk for heart disease should lower their LDL cholesterol to less than 100 milligrams per deciliter, with a target of 70. Under these guidelines, about 36 million Americans should be taking a cholesterol treatment such as a statin, but only about half currently take cholesterol pills.

Charles Hennekens, one of the country’s foremost public-health researchers, said every landmark cholesterol study this decade has reached the same conclusion: Heart patients should take statins to lower LDL and reduce other risk factors such as total cholesterol, triglycerides and C-reactive proteins.

Hennekens, credited with the discovery that taking an aspirin daily dramatically lowers the risk of heart attack, said in an e-mail that patients and doctors should wait for more clinical evidence before changing treatment.

“The totality of evidence favors aggressive management with statins to the U.S. federal guidelines before considering any other adjunctive therapy,” he wrote.