The Helsinki Heart Study had good news last week: yet another cholesterol-lowering drug was found to be safe and effective in reducing the risk of having a heart attack.
The endorsement of the drug gemfibrozil results from the latest in a series of large, long-term scientific studies around the world designed to prove the value of lowering cholesterol levels to prevent heart disease and to test the ability of various drugs to clean up the blood.
Basic research has begun to pay off. The way the body processes cholesterol is now so well understood that scientists have been able to create drugs that, used alone or in combination, selectively block cholesterol at several different points in its cycle. If cholesterol levels are lowered, doctors say, then placques are less likely to form on arteries feeding the heart, and heart attacks may be prevented.
"Using the drugs in patients, alone or with diet, we can effectively control the cholesterol level in virtually everybody," Dr. Donald B. Hunninghake of the Heart Disease Prevention Clinic at the University of Minnesota in Minneapolis, said yesterday at the American Heart Association's 60th scientific conference in Anaheim, Calif.
"This is an exciting time," said Dr. Bryan Brewer, chief of the National Heart, Lung and Blood Institute's molecular disease branch. "A lot of the drugs have been around for years. What is happening is that many studies initiated with these drugs are coming due. You see so many studies saying, 'O.K., this drug works and that drug works.' "
The studies, however, do not mean that Americans should automatically turn to drugs to solve their cholesterol problems.
"There is a tendency to want to take the easy way out, a pill instead of a diet," Brewer said. "It is important for people to understand that if they do not go on a diet, the pill may not work."
The National Cholesterol Education Program urges diet as the first line of defense against high cholesterol. The recommended diet alone should succeed in reducing an individual's cholesterol by 10 to 15 percent. And that reduces the risk of heart disease by 20 to 30 percent, a significant amount, said Dr. James Cleeson, program coordinator.
"Most people with high cholesterol will be satisfactorily controlled by diet," said Dr. Scott M. Grundy of the University of Texas Health Science Center in Dallas.
"If after six months of intensive therapy, the diet is not working, then consideration can be given to drugs," Cleeson said of the program guidelines. And at that, the drugs are added to the diet, not used instead of it. "You keep the diet going to try to make the dose as low as possible."
Physicians worry that patients will demand pills instead of struggling with a fat-lowering diet, Grundy said. But most drugs have side effects. "Cost is also a problem, but mainly side effects," he said. "You do not want to take a drug if it is going to have a bad effect later on, and one that is even more serious than having high cholesterol."
But the current bunch of drugs reportedly have a pretty good safety record, at least in the short run of a few years. "They are pretty safe," Grundy admitted, "but people have not taken them for many, many years, 20 to 25 years, to know whether there might be some problems with them."
Such concerns arose when drugs were introduced to control another circulatory problem, high blood pressure. Initially, the drugs seemed benign, but after decades of use among hundreds of thousands of people, "various side effects began to arise. Now, the whole business of treating high blood pressure with drugs is more complicated and controversial than it used to be," Grundy said.
That's why diet is preferred to drugs in controlling cholesterol, Cleeson said. "Using the diet is all benefit and no risk."
For individuals with uncontrollable high cholesterol, NHLBI released specific drug treatment guidelines a few weeks ago. The committee recommends first using the drugs cholestyramine, colestipol and nicotinic acid. All three have been proven safe and effective and are drugs physicians have had years of experience using.
The newer drugs, including the recently approved lovastatin, and the other drugs including gemfibrozil and probucol, also were recommended for use if the first set of drugs failed to lower cholesterol sufficiently.
Here are the drugs and how they are believed to work: Cholestyramine and colestipol are closely related drugs that trap bile acids in the intestines. Bile, which the liver produces to break up fats in food, is normally reabsorbed. The drugs block that reabsorption, forcing the liver to produce more. Since cholesterol is a starting material of bile, the liver pulls cholesterol out of the blood, causing total cholesterol to drop 20 to 25 percent and low-density lipoproteins -- the so-called bad cholesterol -- to drop 30 to 35 percent.
"The drugs are fairly safe and effective," said Dr. David J. Gordon, medical officer of NHLBI's lipid metabolism-atherogenesis branch. "The drawback is that rather than being a little pill, they come as powders that have to be mixed in a slurry with juice or water, and you have to drink large volumes of it six times a day . . . The inconvenience of it and the grittiness of it is a drawback." It also can cause constipation, gas and a bloating sensation.
"The bile acid sequestrants are the drugs of first choice because they do have records of long-term safety," Cleeson said. Both drugs were used in a large national study of cholesterol lowering.Nicotinic acid, a B vitamin, has been used in high doses to lower LDL 15 to 30 percent and lower triglycerides as well. It also raises the concentration of high-density lipoprotein -- the good cholesterol.
How nicotinic acid reduces cholesterol is not well understood, Gordon said. It may block the synthesis of cholesterol by inhibiting some of the critical enzymes.
The treatment can cause a hot flushing sensation that can be disturbing, Gordon said. It also can cause problems if the individual has a predisposition to get gout because nicotinic acid tends to raise uric acid in the blood. Lovastatin, the newest anticholesterol drug, has caused a lot of excitement about drug treatments to prevent heart disease.
"Lovastatin looks like a godsend in being very effective in lowering LDL," Gordon said. It is a pill, taken in a small dose, and almost everyone tolerates it well; it can lower LDL levels by 40 percent on average.
It is the first of a number of similar drugs that block the action of an enzyme -- HMG-CoA reductase -- that is critical for the production of cholesterol in the liver. With that one enzyme blocked, cholesterol synthesis is effectively shut down. Generally, the drug is given in doses that only block cholesterol production for part of the day.
It also raises HDL slightly and seems to lower triglycerides a little, Gordon said.
"The only drawback is its newness," Gordon said. "It is more of a cautionary note . . . it is one thing to test a couple of thousand people, but it is another thing when it is prescribed widely. Some side effects can take a long time to show up."
Another drawback is price -- $1.25 per tablet, not counting pharmacy markup. A spokesman for maker Merck, Sharp and Dohme said a year's treatment could cost as little as $700, but it probably will be more for many people. Gemfibrozil is the drug used in the recently reported Helsinki Heart Study, in which more than 2,000 men received the drug and showed a shift in the types of cholesterol in the blood and a reduction in the number of heart attacks.
Gemfibrozil does not lower LDL much, maybe 10 to 15 percent, Gordon said, but it substantially increases HDL, a form of cholesterol shown to help lower the risk of heart attacks.
If the Helsinki study proves accurate, it will provide the first long-term data on gemfibrozil's safety and effectiveness, Cleeson said. The results of the study look good, but several researchers said the data will have to be examined by many scientists before it is uniformly accepted.
Gordon said it also is not yet clear which patients should get gemfibrozil since the current guidelines recommend reducing LDL with diet and drugs, but gemfibrozil only shifts the ratios of LDL to HDL.
"It is not clear that you should use a drug that does not reduce LDL levels that much," Gordon said. Probucol is an anticholesterol drug that is not well understood. It appears to lower all the cholesterol levels and its success varies in different people, Gordon said. "It is not a very potent cholesterol-lowering drug, and there is some worry about this drug because it lowers HDL in many people."
Several of the drugs can be combined to achieve a greater lowering of cholesterol than with any of the drugs alone, Gordon said, especially with Lovastatin.
And while they seem to work well either together or alone, Gordon cautioned, it is important to remember that no drug is completely safe. And the anticholesterol drugs "are not like taking an antibiotic for 10 days and then you are through. It is a life-long treatment."