For the past two decades, a fear of bad cholesterol has gripped Americans. We've measured it, compared it, worried about it and doused it with statins, now among the best-selling drugs of all time.
Hovering on the sidelines has been another type of cholesterol - HDL, the good kind, also known as high-density lipoprotein. HDL cholesterol doesn't get anywhere near the attention of its bad twin, LDL (low-density lipoprotein). Now it may be poised to receive the respect it deserves.
Recent research suggests that HDL may be the more important player of the two in raising or lowering heart-disease risk.
As the 20th anniversary of the first cholesterol-lowering statin draws near, a new heart-disease deterrent is ready to leap onto the stage: the first drug to substantially raise good cholesterol.
If approved, it could usher in a new era in the battle against the No. 1 killer of Americans, responsible for 37 percent of adult deaths in the United States every year.
By simultaneously tinkering with good and bad - giving medications in tandem to alter HDL and LDL - doctors may finally have the potent one-two punch against heart disease for which they have long been searching.
"We've taken LDL management as far as we can go," says Dr. Prediman K. Shah, director of the division of cardiology and the Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles. "Everyone is on the bandwagon that HDL is the next frontier for atherosclerosis management."
Interest in raising HDL cholesterol has been growing in recent years for several reasons. Chiefly, researchers have discovered that HDL prevents or reduces the buildup of plaque in artery walls and appears to be a significant cardiovascular risk factor independent of whether LDL is high or low.
Doctors have long known that LDL cannot be the whole story. Statins, for example, lower LDL cholesterol 30 percent to 40 percent and reduce heart attack and stroke rates by about the same amount - but most doctors can remember patients who dutifully lowered their LDL and still suffered heart attacks or strokes.
Doctors also know people who have too-high LDL but never succumb to cardiac trouble - perhaps, in some cases, because their high HDL is protecting them.
The interest in HDL cholesterol is to some extent market-driven. Many drug companies have blockbuster statin drugs with patents that are expiring, and they're searching for ways to reignite the market for treating cardiovascular disease.
Cholesterol is a type of fat known as a lipid that helps many types of body cells function. The liver manufactures most of what the body needs; the rest is obtained through diet.
The lipid uses a two-way street to travel through the bloodstream: LDL particles are carried from the liver to body cells; HDL particles move in reverse, returning extra cholesterol to the liver for disposal.
When too much LDL is in the blood, it can accumulate along the artery walls, forming the hard plaque deposits that lead to heart attacks. Statins help fight this traffic pileup.
Until the last decade or so, the role of HDL cholesterol in this process was largely overlooked.
"We've had a blind spot about HDL," says Dr. William Tierney, chancellor's professor of medicine at Indiana University School of Medicine and author of a recent study highlighting the importance of HDL levels. "I think that's because we're used to focusing on the bad risk factors. As physicians we think, what can we fix? We fix something that is broken."
Evidence for HDL's benefits has been accumulating in recent years. Animal studies and lab research on cells show that HDL has properties that reduce tissue inflammation and blood clotting and improve blood vessel function.
Additional research has found that the risk of heart disease is lower in people with higher levels of HDL and that tinkering with HDL may give patients more bang for the buck. Studies suggest that reducing LDL by 1 milligram per deciliter cuts cardiovascular risk by 1 percent - but raising HDL by 1 mg/dl reduces risk by 2 percent to 3 percent.
Tierney's study, published in March in the American Heart Journal, examined 7,000 individuals who had two or more cholesterol measurements between 1985 and 1997. The scientists found that for every 10 mg/dl increase in the HDL level, there was an 11 percent decrease in heart attacks and other so-called acute coronary events.
In contrast, changes in the subjects' blood LDL levels or in levels of lipids known as triglycerides (also heart-disease risk factors) did not decrease the risk of heart attack or stroke.
"If you believe our research, HDL turns out to be the more important of the two," Tierney says.
Based on the science so far, the National Cholesterol Education Program (a federally funded group that issues guidelines) categorizes people as being at high risk for heart disease if their HDL is less than 40 mg/dl in men and less than 50 mg/dl in women. A level of 60 or higher is considered protective.