HDL Drugs: What Now?

The phone call began ominously. "We've got some very bad news." It was a top official at Pfizer calling for Dr. Steven Nissen, chair of cardiovascular medicine at the Cleveland Clinic and president of the American College of Cardiology, one Saturday evening last December. The official got right to the point. The company was immediately shutting down clinical trials of torcetrapib—the experimental drug that was supposed to slash heart disease by dramatically raising HDL, or "good," cholesterol. In the largest of the four trials, the pill not only failed to reduce deaths, but actually increased mortality by 60 percent. The finding stunned Nissen. "Torcetrapib was expected to be a blockbuster," he says. "People thought the morbidity-and-mortality trial would be stopped early because the benefits were so clear, not because the drug posed hazards."

Cardiologists have long hoped for a drug to boost HDL as efficiently and with as few side effects as the statin drugs reduce LDL ("bad" cholesterol). Together, the two approaches could provide a potent, double-barreled weapon against heart disease. While excess LDL causes formation of arterial plaques, leading to heart attacks and strokes, HDL actually clears cholesterol out of the plaques, reducing risk. "Increasing HDL is like sending out more garbage trucks to get rid of junk in the arteries," says Dr. Ronald Krauss, a cholesterol researcher at Children's Hospital Oakland Research Center. "If we had the right new drug to raise it, millions of people might benefit." Torcetrapib raised HDL by 50 percent. So how did it go wrong? And is the problem specific to this drug or common to all similar medicines in development?

For the moment, pharmaceutical companies are still pursuing other drugs in the same class as torcetrapib. These pills all target a protein known as CETP, which is involved in the recycling of cholesterol. Researchers began focusing on it as early as 1990, when a study in The New England Journal of Medicine noted that Japanese subjects with naturally low levels of CETP had stunningly high HDL—often exceeding 100 milligrams per deciliter. (Normal levels are 40 or above in a man and 50 or more in a woman.)

Whether the other CETP inhibitors have a future will become clearer this weekend at the annual meeting of the American College of Cardiology. It's common knowledge among researchers that torcetrapib raised blood pressure in early tests. Scientists will reveal just how big the increase was—and, by implication, whether that was the drug's fatal flaw. (Roche and Merck are both working on CETP inhibitors that do not appear to raise blood pressure.)

But what if the problem with torcetrapib was more fundamental, such as an adverse effect on HDL's basic function? Presentations at ACC could shed light on that, too. In three separate trials, Nissen and other investigators scanned thousands of patients' blood vessels before they began taking torcetrapib, and again months later. If HDL functioned well, the trials should show that arterial plaques shrank. No matter what the results, it will take years to bring a drug like this to market.

In the meantime, what's a person who wants to boost HDL to do? The drug Niaspan—a version of the B-vitamin niacin—raises it as much as 25 percent, although it can cause flushing that resembles menopausal hot flashes. (The "no-flush niacin" in health-food stores doesn't raise HDL, so save your money.) You can also nudge up HDL through lifestyle changes. Exercise lifts levels by about 5 percent—or more, if you work out an hour a day. Weight loss helps, too, especially shedding abdominal fat. So does a healthy diet that's low in trans fats and processed sugar, but high in fish, whole grains, fruits, vegetables and legumes. Quitting smoking gives you another boost. And for your reward after all that hard work, moderate alcohol intake—defined as one glass a day for women and two for men—also elevates HDL a little. True, the collective impact does not rival the 50 percent boost from torcetrapib. On the other hand, these measures help in other ways that simply raising HDL alone does not. "If heart disease is the product of the wrong diet, obesity and smoking cigarettes, it's hard for me to believe the answer is for everyone to take medications," says Dr. Sidney Smith of the University of North Carolina, Chapel Hill, past president of the American Heart Association. It's a message we should all take to heart.

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