If it works as hoped, it could be the next blockbuster drug: one that shrinks artery-clogging atherosclerotic plaque, the leading cause of the heart attacks that kill some half a million people annually in the United States.
Daniel Rader, a cardiologist at the University of Pennsylvania School of Medicine, is studying several compounds that researchers say might be successful. Rader is a "key scientist" in this field, and the "prototype of a translational researcher - he goes between patients and the lab," says Glenn Gaulton, executive vice dean and chief scientific officer at Penn. While there are medicines to prevent buildup of cholesterol, a key component of plaque, there aren't any to clear it from the bloodstream, he says.
Rader argues that plaque-fighting drugs, sometimes called "Drano for the arteries," have great promise despite setbacks including a high-profile clinical trial failure for one such compound, Pfizer's torcetrapib. This drug, like the others, was supposed to work by boosting the activity of high-density lipoprotein (HDL), the "good" cholesterol that hauls the "bad" type out of the bloodstream and to the liver for disposal.
Rader says the fiasco, in which torcetrapib was linked to an increased risk of death, provided researchers with a valuable lesson: enhancing HDL's effects isn't always a matter of raising its level in the blood, as was once assumed. Instead, the lipoprotein's effectiveness seems more tied to its ability to efficiently transport cholesterol out of the blood. Increasing HDL blood levels, depending on how you do it, might just indicate that you're keeping it from escaping the circulation, Rader says; that is, "you're constipating it."
The process by which the body removes cholesterol from the bloodstream, usually by means of HDL, is called reverse cholesterol transport. Rader speaks of several promising compounds aimed at enhancing this process.
One group of compounds consists of inhibitors of the enzyme endothelial lipase (EL). In human and animal studies, Rader and colleagues have found an association between EL and atherosclerosis. In this case, the caution about higher HDL blood levels being possibly harmful - as the torcetrapib fiasco suggested - seems not to apply, Rader says, because lower EL levels correlate with higher HDL levels and with lower heart disease rates. "There are quite a few companies interested" in EL inhibitors, he says, but declines to give details.
Another experimental drug is D-4F, a peptide made by Bruin Pharmaceuticals of Los Angeles. It's a synthetic form of a mutant version of HDL's biggest protein, found in an Italian family with unusually clean arteries. The compound is under development by Basel, Switzerland-based Novartis, after Phase I human trials were done at Penn.
Yet a third category of compounds is Liver X Receptor (LXR) agonists. The LXR is a nuclear hormone receptor implicated in various cardiovascular and metabolic disorders. In a study published in the Jan. 3, 2006, issue of Circulation, Rader and colleagues found that LXR agonists boosted reverse cholesterol transport in mice without raising HDL levels, "really demonstrating for the first time that this approach has merit," he says.