Check Up: HDL-boosting drugs remain elusive

A low level of so-called good HDL cholesterol is a major risk factor for heart disease.

Yet experimental drugs that increase HDL have failed to reduce heart attacks in studies, to the dismay of drug companies. Their goal is to develop HDL boosters that are as beneficial as widely used statin drugs that lower "bad" LDL cholesterol.

Now, a new study shows that HDL does reduce the risk of heart disease, but only if it is greedily doing one of its jobs - grabbing fat particles from scavenger cells.

The study of almost 3,000 adults, published last week in the New England Journal of Medicine, found that the 731 participants with the greediest HDL had a 67 percent lower chance of heart attacks, stroke, and narrowed arteries compared with those with the least greedy HDL.

"A lot of drugs that have targeted HDL have come up short," said lead author Anand Rohatgi, a preventive cardiologist at the University of Texas Southwestern Medical Center in Dallas. "This [study] gets at what's happening mechanistically."

Rohatgi's co-authors include his mentor, University of Pennsylvania cardiologist Daniel R. Rader.

In 2011, Rader's team published definitive evidence that the amount of HDL is less important than its greediness.

HDL, or high-density lipoprotein, zips through the blood, collecting unused cholesterol, the waxy, fatty particles that can build up in arteries. Then HDL ferries the cholesterol to the liver to be excreted.

Equally important, HDL can force scavenger cells to expel their cholesterol load, then grab it for transport to the liver. The scavenger cells contribute to artery clogging by getting trapped with microscopic debris and cholesterol that "bad" LDL, or low-density lipoprotein, leaves on the vessel walls.

Rader's lab developed a sophisticated test to measure HDL's ability to grab from scavenger cells, called "cholesterol efflux capacity." In the 2011 study, which tested 1,000 people, HDL efflux capacity was a better predictor than HDL levels of who had narrowed arteries and heart disease.

Rohatgi's team went further, using blood samples from 3,000 people with initially healthy hearts who were followed for an average of 10 years.

During that period, 132 of them suffered heart attacks or strokes, or needed artery-widening procedures. They had much lower efflux capacity than those who did not develop heart disease.

The researchers found only a "modest" link between efflux capacity and traditional cardiac risk factors such as obesity and arterial inflammation.

Researchers still don't know exactly how HDL makes scavenger cells cough up excess cholesterol, much less how to fix HDL that is malfunctioning. Measuring the efflux process is so complex, and not yet standardized, that only research labs can do it, Rohatgi said. Roche, Merck, and Eli Lilly are developing drugs that boost HDL by blocking a protein involved in cholesterol transport. (Pfizer abandoned its version, which raised HDL yet somehow increased cardiovascular deaths.)

Although these drugs do increase efflux capacity somewhat, Rohatgi believes that the key to success is "improving the most relevant efflux pathways."