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.
About 30 percent of American adults who have heart disease have sub-optimal HDL as their "dominant abnormality," says Shah - in other words, low HDL is their most glaring risk factor for heart trouble.
There are a number of things people or doctors can do to ramp up HDL levels. Lifestyle changes, such as a healthful diet and exercise, can boost HDL slightly - and even small changes can lower heart-disease risk. So can statins and drugs called fibrates.
Niacin, also known as vitamin B3, can raise HDL substantially. But there has been a significant problem with this remedy: It can cause intense itching and facial and upper-body flushing.
"Niacin is the most effective HDL drug available. But the problem is that only about 70 percent of people can take it, because of the major side effects," Shah said.
Merck & Co. is in the late stages of testing a pill that combines extended-release niacin with a drug called a prostaglandin D2 blocker, which prevents flushing. Early studies suggest the drug may raise HDL 20 percent to 30 percent, says Dr. Yale Mitchel, executive director for clinical research at Merck.
Other researchers are focusing on new drugs to improve levels of HDL. One approach evolved after a discovery about 15 years ago of a group of people in Japan who have a genetic mutation that causes high levels of HDL. The people, who have a low incidence of heart disease, lack an enzyme called CETP (cholesteryl ester transfer protein) that is responsible for transferring cholesterol from HDL particles to LDL particles.
Several drug companies are working on oral drugs that block CETP. Torcetrapib, under development at Pfizer Inc., is furthest along. In a small 2004 study of 19 patients with low HDL, torcetrapib raised HDL levels by 46 percent. It boosted them higher, by 61 percent, in people receiving torcetrapib plus the statin atorvastatin (Lipitor).
Questions remain about the drug. It may, for one thing, increase blood pressure, Shah says, undermining its benefit to the heart. And even if it raises HDL, that doesn't necessarily mean it will reduce heart disease.
"It may lead to a form of HDL that is dysfunctional. You may get a lot of HDL but it doesn't do anything. That is a concern that has been raised," Shah said.
Heart-disease experts are anticipating the results of the company's Phase 3 clinical trials, expected early next year. These will gauge the medicine's effects on heart disease, measuring whether atherosclerotic plaque is reduced.
If the findings are promising, Pfizer could seek approval to sell torcetrapib in combination with Lipitor, its best-selling statin drug, in the next couple years.
The company recently bowed to public pressure and announced it would sell torcetrapib alone, so that people who don't need a statin (or use statins other than Pfizer's) could benefit from the medication.
Another novel approach to raise HDL - this one advanced by Shah's studies in animals - uses high doses of a synthetic type of HDL to diminish plaque buildup. Again, the research stems from observing unusual human beings.
In the 1980s, doctors discovered a small group of people in a picturesque Italian village near Milan who had extraordinarily low levels of HDL but no heart disease. The scientists determined that these people carried a genetic mutation, named ApoA-1 Milano, that gave them a kind of super-charged HDL that is more protective than regular HDL. The gene variant prevents the accumulation of plaque in spite of low HDL levels.
Shah showed that this HDL could shrink plaque in the arteries of lab animals. That finding was followed by a landmark study published in the Journal of the American Medical Association in 2003 that found that five weekly infusions of synthetic ApoA-1 Milano produced a 4.2 percent decrease in atherosclerotic plaque in people with heart disease.
Several drug companies are working on products based on ApoA-1 Milano. Because it has to be infused into the blood, such a treatment would probably be reserved for people with acute heart disease. "It's not ideally suited for repeat therapy over many years," Shah said.
The discovery of ApoA-1 Milano raised an intriguing question about HDL cholesterol. It could be that the quality of HDL is just as important as the quantity, affected by genes or environmental factors that subtly alter its structure and properties. It could be that scientists have just begun to explore the complexities of the good fat that flows through our bloodstreams.
"There is a lot of work going on," Shah said - work that may uncover new exceptions to any simple test that just measures HDL levels.
But for most of us for now, Shah says, one thing about HDL seems clear: "The more you have, the better off you are."
Shari Roan writes for the Los Angeles Times.