FOR the last 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 bestselling drugs of all time.
But 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 LDL twin (low-density lipoprotein). But now it may be poised to receive the respect it deserves.
Recent research suggests that HDL may actually be the more important player of the two in raising or lowering heart disease risk. And as the 20th anniversary of the first cholesterol-lowering statin draws close, 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 radically new era in the battle against the No. 1 killer of Americans, responsible for 37% of adult deaths in the United States every year.
In fact, by simultaneously tinkering with good and bad -- giving medications in tandem to alter both HDL and LDL -- doctors may finally have the potent one-two punch against heart disease they have long been searching for.
“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. “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 build-up of plaque in artery walls and appears to be a significant cardiovascular risk factor independent of whether LDL is high or low.
But doctors have long known that LDL cannot be the whole story. Statins, for example, lower LDL cholesterol 30% to 40% 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.
“Even with 30% to 40% reduction, we have not eliminated cardiovascular disease,” says Dr. William Averill, a cardiologist and past president of the Los Angeles division of the American Heart Assn.
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 also, 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.
In this case, however, market forces and the quest for better heart health may happily align.
When arteries clog
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.”
But evidence for HDL’s benefits has been accumulating in recent years and can no longer be ignored. 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 their buck. Studies suggest that reducing LDL by 1 milligram per deciliter cuts cardiovascular risk by 1% -- but raising HDL by 1 mg/dl reduces risk by 2% to 3%.
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% 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% 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.
Low HDL is more common in non-hispanic white and Mexican American men than in women or other ethnic groups. But as obesity rates and the incidence of diabetes have risen, HDL levels appear to be declining throughout the population.
Renewed interest in niacin
There are a number of measures that people or doctors can take 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 (see sidebar). 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% of people can take it because of the major side effects,” Shah says.
Now, however, Merck & Co. is in the late stages of testing a pill that combines extended-release niacin with a drug called a prostaglandin D2 blocker that prevents flushing. Early studies suggest the drug may raise HDL 20% to 30%, says Dr. Yale Mitchel, executive director for clinical research at Merck.
The company plans to seek permission from the Food and Drug Administration to market the pill, called MK-0524A, next year, Mitchel says.
“I think if [Merck’s] strategy proves to be true and effective that would revive interest in niacin,” Shah says.
The company is also testing the niacin and prostaglandin D2 blocker in combination with a statin. And it is conducting an international study of 20,000 people to see if MK-0524A reduces cardiovascular events in high-risk people who have already lowered their LDL cholesterol with a statin. This study may be the first to show if raising HDL can truly reduce heart attacks, strokes and deaths even after LDL has been controlled.
“We think this study is critical,” Mitchel says. That’s because so far, the belief that raising HDL can slash heart disease risk is based on observational studies, ones in which populations of people have simply been observed.
To truly test the idea, a clinical trial is needed in which HDL is raised with drugs (after LDL has already been lowered) and the effect on heart disease is carefully monitored.
That gold-standard clinical trial hasn’t been possible before now, Mitchel says, for one principal reason. “We haven’t had drugs to raise HDL and test the hypothesis.”
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 and would thus raise HDL in patients. 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%. It boosted them higher, by 61%, 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 for certain.
“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 says.
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 bestselling statin drug, next year or in 2008.
The company recently bowed to public pressure and announced it would also 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 special 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 Assn. in 2003 that found that five weekly infusions of synthetic ApoA-1 Milano produced a 4.2% decrease in atherosclerotic plaque in people with heart disease.
Several drug companies are working on products based on ApoA-1 Milano. But 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 says.
The discovery of ApoA-1 Milano raises an intriguing question about HDL cholesterol, however. 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 says -- work that may uncover new exceptions to any simple test that just measures HDL levels. But for most of us for now, Shah adds, one thing about HDL seems clear: “The more you have, the better off you are.”
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WHO HAS TOO-LOW HDL?
(defined as less than 40 milligrams per deciliter)
Here are the numbers, as described by the American Heart Assn.
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Boost your levels
It’s more difficult to raise HDL cholesterol than it is to lower LDL. After all, statin drugs alone routinely lower LDL by 30% to 40%. But there are still ways to improve your HDL.
* Exercise: Aerobic exercise for 30 minutes several times a week can raise HDL by 3% to 9% in sedentary, healthy people. But you’ll have to get your heart rate up. There is little evidence that walking increases HDL.
* Quitting smoking: Average increase of 4 milligrams per deciliter.
* Weight control: Every 1 kilogram (2.2 pounds) of weight lost raises HDL by average of 0.35 mg/dl.
* Alcohol consumption: Mild to moderate drinking (one to two drinks a day) can raise HDL by an average of 4 mg/dl.
* Diet: A diet low in trans fatty acids and high in monounsaturated and polyunsaturated fatty acids can raise HDL. Choose oils such as olive, flaxseed and canola; nuts; cold-water fish; and shellfish. Limit high glycemic load foods such as pasta and bread made with refined flour, which can lower HDL.
* Niacin therapy: Increases of 20% to 35%.
* Fibrate therapy: Increases of 10% to 25%.
* Statins: Increases of 2% to 15%.
-- Shari Roan
Sources: American Heart Assn.; Dr. William Averill; New England Journal of Medicine