Solving the HDL Mystery
There was big news on the heart front last week. A hot new pharmaceutical with the tongue-twister name of torcetrapib failed miserably, despite the 15 years of research and $800 million that Pfizer devoted to it. The finding left in its wake stunned investigators and a passel of cardiologists scratching their heads over the loss of a dream drug, one they've been waiting for ever since it became clear there was such a thing as a good cholesterol. There's no doubt that torcetrapib raises HDL, the good cholesterol, just as well-known statin drugs like Lipitor lower the bad LDL cholesterol. Using both agents together seemed to offer a promising new way to fight off heart attacks and strokes.
But the complexity of the human body dashed this grand hope when an independent monitoring group-the only individuals privy to the results-advised Pfizer to halt its major research trial involving 15,000 patients. Among patients taking torcetrapib plus Lipitor, there were 82 deaths; that's compared with 51 in the group on Lipitor alone. And reportedly there was also an increase in nonfatal cardiac events including angina, heart failure, and the need for angioplasty. For the HDL-raising drug to show little added benefit is one thing. For it to increase heart problems is a real shocker.
After all, HDL acts like Drano on an artery clogged with atherosclerotic plaque. It infiltrates plaque, sucks up bad LDL, and carries it off to the liver for discard. A low HDL (less than 40 mg/dl) is a well-known cardiovascular risk factor, and each 1 mg/dl rise in HDL is estimated to reduce that risk by 2 percent. But anyone who has low HDL (mainly men) knows how hard it is to move that number. Exercise, a glass of wine, maybe a little fish oil, even the statins can bump it up a few points, but that's about it. The B vitamin niacin raises good cholesterol by up to 25 percent, but it comes with the troublesome side effect of flushing of the head and neck. That's why torcetrapib, which raises HDL by about 50 percent with few side effects except for a minor increase in blood pressure, was a long-awaited breakthrough.
By all accounts, torcetrapib seemed to be a sure bet. Its novel design inhibits a particular protein, called CTEP, that regulates cholesterol, with a net effect of making the good cholesterol rise and the bad fall. Research in animals with atherosclerosis found that plaque shrank considerably with the new drug. Indeed, the buzz at last month's annual American Heart Association meeting in Chicago was that torcetrapib was mighty close to its victory lap. Pfizer even predicted approval by the Food and Drug Administration in 2007. There were no signs to the contrary. However, in the final analysis of its heart effects in humans, it missed the mark.
Quality matters. What may explain this, plain and simple, is that all HDL is not created equal. In fact, some forms are downright dysfunctional, unable to remove the bad cholesterol from the arteries, and worse, are so chemically altered that the HDL actually stimulates inflammation and blood clots. Those are the very factors that can make atherosclerotic plaque in an artery swell up, rupture, and clot, triggering a heart attack or a stroke.