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David Baxter

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Cholesterol: No Easy Answers
February 12, 2008
New York Times

Once, it all seemed so simple.

When it came to cholesterol, there were good guys (HDL) and bad guys (LDL).

And for decades, we were told only the bad guys really mattered.

So, tens of millions of Americans started taking drugs called statins that promise to lower LDL and, by extension, reduce heart attacks and other life-threatening cardiac conditions.

But, it turns out, that's not enough.

"There's a huge number of people who are still having heart attacks while on these drugs," said Dr. H. Robert Superko, a veteran cholesterol researcher.

It is the cholesterol conundrum, touching on the realms of medicine, economics, and human expectation: What else can be done to stop the nation's number one killer? And how big a role should the "good guy" play in the solution?

Those questions rang anew last month. First, came the news that a powerful LDL-lowering drug did not have the expected medical benefits, failing to reduce dangerous plaque build-ups any better than a less aggressive medication. Then, specialists sparred over the merits of LDL lowering in the prestigious journal Circulation.

More than anything, those recent events combined to illustrate the complexity of treating heart disease, a condition responsible for more than 600,000 deaths annually in the United States.

"The American public's appetite for a magic bullet solution to problems is always there," said Dr. James Cleeman, coordinator of the government's National Cholesterol Education Program. "But with cholesterol, it isn't just one thing you need to do. You need to be paying attention to your eating habits, your physical activity, weight control -- all of those things are important to keeping your cholesterol down."

Specialists increasingly believe that means boosting the reservoir of HDL cholesterol as well as diminishing the dangerous form of the fat-like substance.

There's even some evidence that raising HDL has a more potent effect than lowering LDL. "It's quite a powerful relationship," said Dr.

Jorge Plutzky, director of the Vascular Disease Prevention Program at Brigham and Women's Hospital.

High levels of LDL contribute to the accumulation of dangerous plaque in blood vessels that, in turn, can spawn heart attacks and strokes.

HDL acts like a roving garbage truck, picking up cholesterol and ferrying it back to the liver for proper disposal. So, in theory, raising HDL should lower the threat from plaque.

There's even a low-cost drug, niacin, that raises HDL levels.

"So why isn't it popular?" asked Dr. B. Greg Brown, a prominent cholesterol researcher at the University of Washington in Seattle.

One answer is that niacin can cause facial flushing, leaving some patients reluctant to take it.

Another answer reflects the realities of pharmaceutical economics. The standard form of niacin has been around so long that it's well beyond the point where it can be patented. And that translates into little profit incentive for drug companies, meaning there's no global marketing force pounding on the doors of doctors' offices trumpeting the benefits of niacin.

Champions of HDL-boosting argue that the profit motive has long driven the intense interest in LDL-lowering drugs. In 2006, a single statin, Pfizer Inc.'s Lipitor, fueled $8.6 billion in sales, according to data from IMS Health, a healthcare information company.

"The overriding drive to sell statin drugs has misled people into this false sense of security if their LDL cholesterol is normal," Superko said.

Studies have shown that patients with significant risk factors for cardiovascular disease - including high blood pressure, smoking or previous heart attack - benefit from taking statins, with their chance of suffering a life-threatening condition reduced roughly 25 to 30 percent compared with patients not on the medication. There's less scientific support for the use of statins in patients whose risk of cardiac problems is lower.

Dr. Om Ganda, director of the lipid clinic at the Joslin Diabetes Center, said that by the time patients begin taking statins, a cascade of damage may have been underway for decades.

So part of the reason that the drugs aren't more successful, he said, "could be that we're trying to quench the fire after it's been burning for so long."

Still, a Pfizer executive and the federal government's Cleeman argued that the benefits of statins are too substantial to ignore.

"If we can reduce risk 25 to 30 percent," said Halit Bander, global medical team leader for Lipitor at Pfizer, "it's an important message for a physician and a patient."

Driven both by expiring patents on statins and a desire to develop better drugs to tame cholesterol, pharmaceutical companies are now trying to figure out ways to combine agents that lower LDL with those that boost HDL.

In some cases, that means coming up with forms of niacin that diminish the flushing side effect.

One medication on the market combines an early generation statin with a slower-release form of niacin; another one is on the way from Abbott Laboratories, pending approval from drug regulators.

Brown is directing a nationwide study involving 3,300 patients that hopes to definitively answer whether combining niacin with a statin produces more benefit than a statin alone.

Drug companies are also testing other HDL-raising compounds, notwithstanding Pfizer's disastrous experience with an experimental HDL-raising drug called torcetrapib. After spending $1 billion developing the medication, the company in 2006 pulled the plug on trials after more people died than expected.

The search for cholesterol treatments beyond statins is imperative, said Dr. Richard Karas of Tufts-New England Medical Center, because "they're good, but they're not enough."
 

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