Cholesterol146;s Better Half

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. By simultaneously tinkering with good and bad 8212; giving medications in tandem to alter both HDL and LDL 8212; doctors may finally have the potent one-two punch against heart disease they have long been searching for.

If approved, it could usher in a new era in the battle against the No. 1 killer, responsible for 37 per cent of adult deaths in the US every year.

8220;We8217;ve taken LDL management as far as we can go,8221; says Dr. Prediman K. Shah, director of the division of cardiology and the Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles. 8220;Everyone is on the bandwagon that HDL is the next frontier for atherosclerosis management.8221;

Interest in raising HDL cholesterol has been growing 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 per cent to 40 per cent and reduce heart attack and stroke rates by about the same amount 8212; but most doctors can remember patients who dutifully lowered their LDL and still suffered heart attacks.

Doctors also know people who have too-high LDL but never succumb to cardiac trouble 8212; 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 they8217;re searching for ways to reignite the market for treating cardiovascular disease.

Cholesterol is a type of lipid that helps many types of body cells function. The liver manufactures most, 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 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.

8220;We8217;ve had a blind spot about HDL,8221; says Dr. William Tierney, chancellor8217;s professor of medicine at Indiana University School of Medicine and author of a recent study highlighting the importance of HDL levels. Evidence of HDL8217;s benefits can no longer be ignored.

Studies suggest that reducing LDL by 1 mg per deciliter cuts cardiovascular risk by 1 per cent 8212; but raising HDL by 1 mg/dl reduces risk by 2 per cent to 3 per cent. Tierney8217;s study, published 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 per cent decrease in heart attacks and other so-called acute coronary events.

Based on the science so far, the US National Cholesterol Education Programme 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.

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 8212; 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 is a significant problem: It can cause intense itching and facial and upper-body flushing. 8220;Niacin is the most effective HDL drug available. But only about 70 per cent of people can take it because of the major side effects,8221; Shah said. 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 to LDL particles. Several drug companies are working on oral drugs that block CETP. Torcetrapib, under development at Pfizer Inc., is furthest along. But the drug may, for one thing, increase blood pressure, Shah says, undermining its benefit to the heart.

Another novel approach to raise HDL 8212; this one advanced by Shah8217;s studies in animals 8212; uses high doses of a synthetic type of HDL .In the 1980s, doctors discovered a group of people in an Italian village near Milan who had extraordinarily low levels of HDL but no heart disease. They carried a genetic mutation, ApoA-1 Milano, that gave them a kind of super-charged HDL more protective than regular HDL. The gene variant prevents the accumulation of plaque in spite of low HDL levels.

Based on that, another study found that five weekly infusions of synthetic ApoA-1 Milano produced a 4.2 per cent decrease in plaque. Several drug companies are working on products based on ApoA-1 Milano. The discovery of ApoA-1 Milano raised an intriguing question. 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 blood streams.

8211;Shari Roan

Boosting HDL Levels

It8217;s more difficult to raise HDL cholesterol than it is to lower LDL. Statin drugs routinely lower LDL by 30 per cent to 40 per cent. Here are ways to improve HDL:

Exercise: Aerobic exercise for 30 minutes several times a week can raise HDL by 3 per cent to 9 per cent in sedentary, healthy people. But you8217;ll have to get your heart rate up. There is little evidence that walking increases HDL.

8226; Quitting smoking: Average increase of 4 milligrams per deciliter.

8226; Weight control: Every 1 kilogram 2.2 pounds of weight lost raises HDL by an average of 0.35 mg/dl.

8226; Alcohol consumption: Mild to moderate drinking one to two drinks a day can raise HDL by an average of 4 mg/dl.

8226; 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 8211; glycemic-load foods such as pasta and and bread made with refined flour, which can lower HDL

8226; Niacin therapy: Increases of 20 per cent to 35 per cent

8226; Fibrate therapy:Increases of 10 per cent to 25 per cent.Statins: Increases of 2 per cent to 15 per cent.