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The Medical Treatment of Lipid Disorders

Course Authors

Ernst John Schaefer, M.D., and Robert M. Russell, M.D.

Release Date: 06/30/1998

 
Learning Objectives

Upon completion of this Cyberounds®, you should be able to:

  • Classify lipid disorders by the use of individual laboratory values for LDL cholesterol, HDL cholesterol and triglyceride

  • Identify which drugs are used for which lipid disorders

  • Identify the secondary causes of hypercholesterolemia.

 

Russell

Previously on Cyberounds I spoke with Dr. Alice Lichtenstein on dietary management of lipid disorders. In this Cyberounds®, Dr. Ernst Schaefer and I will discuss the medical treatment of lipid disorders and which drugs to use and when. Before we begin on the medical treatment, I would like to ask you, Ernie, how has the classification of lipid disorders changed from the old electrophoresis classification?

Schaefer

The old classification system was based on lipoprotein electrophoresis, where you could visually see the different lipoprotein bands. The difficulty with that method was that it was not very quantitative. Beginning in the 1970s, cholesterol, triglyceride, and HDL cholesterol measurements became standardized, so now we have very accurate automated measurements for these constituents.

Current recommendations for screening patients over the age of 20 are outlined on Table 1.

Table 1. Screening for Lipid Abnormalities*.

Step 1

Measure serum total cholesterol and HDL cholesterol fasting or non-fasting.

Step 2

Do fasting (12 hours) serum lipid profile (cholesterol, triglyceride, HDL cholesterol) if:

  1. Total cholesterol > 240 mg/dl (6.2 mmol/L);
  2. HDL cholesterol < 35 mg/dl (0.9 mmol/L);
  3. Total cholesterol > 200 mg/dl (5.2 mmol/L) and the
  4. patient has 2 or more CHD risk factors; Patient has CHD.

Step 3

Calculate LDL cholesterol as below:

LDL C = Total cholesterol - (HDL C + TG/5) provided patient is fasting and TG < 400 mg/dl.

* Alternative is non-fasting or fasting direct LDL C, HDL C, and TG

The first step is to measure serum total cholesterol and HDL cholesterol, either fasting or non-fasting.(1),(2)

In the second step you should do a fasting serum lipid profile (overnight fast of 12 hours). The fasting lipid profile consists of measuring cholesterol, triglyceride, and HDL cholesterol. This fasting lipid profile should be carried out if based on the screening tests the total cholesterol is > 240 mg/dl, or the HDL cholesterol is <35 mg/dl, or the total cholesterol is > 200 mg/dl and the patient has two or more heart disease risk factors, or if the patient has established heart disease.

The third step, then, is to calculate the LDL cholesterol by subtracting the sum of HDL cholesterol and triglycerides divided by 5 from total cholesterol. This calculation can only be carried out if the patient is fasting and the triglycerides are <400 mg/dl. It should be noted that there is an alternative to this approach, which is to measure direct LDL cholesterol, HDL cholesterol, and triglycerides in the fasting or the non-fasting state. The direct measurements provide greater accuracy and precision, and do not require fasting.(3),(4) The classification, then, is based upon LDL cholesterol, HDL cholesterol and triglyceride (see Table 2).

Table 2. Classification of Lipid Values.

< 200 mg/dl
Optimal Borderline High Risk
Total Cholesterol 200-239 mg/dl > 240 mg/dl
LDL Cholesterol < 130 mg/dl 130-159 mg/dl > 160 mg/dl
HDL Cholesterol > 60 mg/dl 35-59 mg/dl < 35 mg/dl
Triglyceride < 200 mg/dl 200-399 mg/dl > 400 mg/dl

Information to consider with regard to heart disease risk factors is shown on Table 3; these include being a male > 45 years of age, a female > 55 years of age, having a family history of premature heart disease, having an HDL cholesterol <35 mg/dl, smoking, and diabetes.

Table 3. NCEP CHD RIsk Factors*.

Positive Negative

Male > 45 years

Female > 55 years

Family History of Premature CHD

HDL C < 35 mg/dl

Smoking

Diabetes

 HDL C > 60 mg/dl

* Subtract a risk factor if the HDL C > 60 mg/dl, family history of premature CHD has been defined as the presence of CHD in a male first-degree relative prior to age 55 and prior to age 65 in a female first-degree relative.

It should be noted that a risk factor is subtracted if the HDL cholesterol is > 60 mg/dl.

Russell

Does diabetes as a risk factor include non-insulin-dependent diabetes or just insulin-dependent diabetes?

Schaefer

It includes all diabetics.

Russell

Can I get back to the classification issue for a minute? The clinical classifications that are used are hypercholesterolemia, hypertriglyceridemia, hyperchylomicronemia, low HDL, and dysbetalipoproteinemia. How does this classification help the physician? Does it give the physician an automatic approach of what diet and drugs to use, for example?

Schaefer

Actually, the classification system is based on the individual values, as shown in Table 2. A total cholesterol of > 240 mg/dl is considered elevated and a high-risk value but, in order to evaluate lipids, one needs to know the LDL cholesterol, HDL cholesterol and triglyceride values. An LDL cholesterol of > 160 mg/dl is considered a high-risk value; and triglycerides of > 400 mg/dl are considered elevated, while an HDL cholesterol <35 mg/dl is considered decreased and is also a high-risk value (see Table 2). Therefore, patients may also have a combination of these abnormalities, such as combined hyperlipidemia (elevations of LDL cholesterol and triglyceride), or dyslipidemia (elevated triglycerides and decreased HDL cholesterol).

Russell

Let's talk about that classification first. What should be the approach of the physician for someone who falls into the classification of hypercholesterolemia, due to elevated LDL cholesterol? When is diet instituted, and when do drugs get immediately instituted, even before diet is tried? What should be the approach that you would advise practicing physicians to take?

Schaefer

The current National Cholesterol Education Program guidelines are primarily based on LDL cholesterol. This is because elevated LDL cholesterol levels have clearly been shown to be a significant risk factor for coronary heart disease (CHD) and lowering LDL cholesterol has been associated with significant reduction in risk. The National Cholesterol Education Program Adult Treatment Panel guidelines for the treatments with patients with elevated LDL cholesterol levels are shown in Table 4.

Table 4. Treatment Guidelines for Patients with Elevated LDL Cholesterol.

Initiate Diet Therapy After Diet Therapy Initiate Drug Therapy Goal of Therapy
< 2 CHD risk factors > 160 mg/dl (4.1 mmol/L) > 190 mg/dl (4.9 mmol/L) < 160 mg/dl (4.1 mmol/L)
2 or more CHD risk factors > 130 mg/dl (3.4 mmol/L) > 160 mg/dl (4.1 mmol/L) < 130 mg/dl (3.4 mmol/L)
CHD > 100 mg/dl (2.6 mmol/L) > 130 mg/dl (3.4 mmol/L) < 100 mg/dl (2.6 mmol/L)

LDL, low density lipoprotein; CHD, coronary heart disease.

If the patient has less than two heart disease risk factors (see Table 3), diet is initiated if the LDL cholesterol is > 160 mg/dl, and then drug therapy after diet therapy is initiated if the LDL cholesterol is > 190 mg/dl. The goal of therapy in this group is to get the LDL cholesterol to <160 mg/dl. In patients with two or more heart disease risk factors, diet and drug therapy are initiated 30 mg/dl lower than in the previous group and the goal of therapy is to get patients to LDL cholesterol values <130 mg/dl. In patients with established heart disease we are even more aggressive -- we initiate diet if the LDL cholesterol is > 100 mg/dl; we initiate drug therapy after diet if the LDL cholesterol is > 130 mg/dl. The goal of therapy is to get the LDL cholesterol to <100 mg/dl.

Before placing the patient on diet therapy, it is important to rule out secondary causes of hypercholesterolemia (see Table 5).

Table 5. Secondary Cause of Hypercholesterolemia.

  • Hypothyroidism
  • Obstructive Liver Disease
  • Nephrotic Syndrome
  • Diabetes Mellitus
  • Progestins
  • Anabolic Steroids

The ideal approach is to refer the patient to a dietitian who can work with the patient and his/her spouse, either individually or in a group setting. There are some patients whom we place on drug therapy immediately, especially those with established heart disease who are unlikely to achieve goal with diet alone. However, all such patients are also referred for diet counseling.

With regard to the diets that are recommended, they are shown in Table 6.

Table 6. National Cholesterol Education Program Guidelines on Dietary Therapy*.

Nutrient Average U.S. Diet ¸ Step 1 Diet Step 2 Diet
Total Fat 34% < 30% < 30%
Saturated Fat 1 2% < 10% < 7%
Monounsaturated Fat 13% < 15% < 15%
Polyunsaturated Fat 7% < 10% < 10%
Total Energy Calories To achieve and maintain desirable body weight

* Percent of total energy calories.
¸ Total population data from National Health and Nutrition Examination Survey (NHANES) III, excluding children under 2 years of age.

Since the Step I diet is recommended for the entire U.S. population, we tend to go to the Step 2 diet when we refer the patient to the dietitian. On the other hand, one can try to use a pamphlet approach, and physician counseling to get the patient to follow a Step I diet. The Step II diet, which is recommended for hypercholesterolemic patients, is generally more difficult for patients to follow and requires the input of a registered dietitian or nutrition counselor who can spend substantial amounts of time with the patient to achieve these goals.

Obviously, it is also important to recommend daily exercise, 30 minutes per day. Often walking is the only thing that elderly patients, especially those with established heart disease, can achieve.

We tend to use the Pyramid Diet approach which is recommended by the U.S. Department of Agriculture. We think this is an excellent diet. A brief outline of the diet is shown in Table 7.

Table 7. Daily Food Intake Recommendations.

  1. 6-11 servings of bread, cereal, rice, or pasta
    • 1 serving is 1 slice of bread, 1 ounce of ready-to-eat cereal, or a 1/2 cup of cereal, rice, or pasta.
    • Emphasis should be placed on whole grain foods prepared with little or no fats or sugars.
  2. 3-5 servings of vegetables
    • 1 serving is 1 cup of leafy vegetables, a 1/2 cup of other vegetables (cooked or chopped raw), or 3/4 cup of vegetable juice.
  3. 2-4 servings of fruit
    • serving is 1 apple, banana, or orange, a 1/2 cup of chopped, cooked, or canned fruit, or 3/4 cup of fruit juice.
    • Use items with little or no added sugar.
  4. 2-3 servings of milk, yogurt, or cheese
    • 1 serving is 1 cup of milk or yogurt, 1 1/2 ounces of natural cheese, or 2 ounces of processed cheese.
    • Use non-fat or low fat items such as skimmed or low fat milk, or cheeses made from these products.
  5. 2-3 servings of meat, poultry, fish, dried beans, or nuts
    • 1 serving is 2-3 ounces of lean meat, poultry (white meat without skin), or fish, or 1 cup of beans or nuts.
  6. Use fats, oils, and sugars (including syrup) sparingly.

NOTE: Eggs have been deleted because of their high cholesterol content (210 mg per egg); however, egg whites are an excellent source of dietary protein.

In our experience, when we put patients on such a diet under controlled circumstances, reductions in LDL cholesterol of 15-20% have been achieved but in the out-patient setting this reduction is generally approximately 5%.(5),(6),(7) This is mainly due to decreased compliance. It should be noted, however, that there is a great deal of variability in response. It should be noted that the Pyramid Diet under ad libitum circumstances promotes weight loss.(8)

Russell

So you must always begin with diet therapy. I now have two questions: Do you ever make the decision to go directly to drugs without going to diet? In other words, do you ever short-cut diet if the LDL cholesterol is too high? Secondly, what is your approach with drugs? What is the first-line drug you use for high LDL cholesterol and what kind of response do you look for in these drugs before changing to other drugs or adding another drug as a combination?

Schaefer

We only go directly to drug therapy without first testing the diet response if the patient has established heart disease with fairly elevated levels of LDL cholesterol and is unlikely to achieve the LDL cholesterol goal of <100 mg/dl with diet alone. In patients without established heart disease, we usually give diet therapy alone at least six months to work, usually with the help of a dietitian. With regard to drug therapy, it is very important to rule out secondary causes of hypercholesterolemia prior to going to drug therapy and these are shown in Table 5.

Of these secondary causes, the one that is not uncommonly missed is hypothyroidism and clearly it is very important to correct the hypothyroidism before placing the patient on a drug specifically for cholesterol lowering. The screening tests we use to rule out secondary causes of hypercholesterolemia are TSH, liver enzymes, glycosylated hemoglobin, a serum albumin level and urinalysis. We also get baseline creatine phosphokinase levels and question the patient about use of medications that might affect cholesterol levels, such as progestins and anabolic steroids.

With regard to documented benefits from diet and drug therapy in prospective intervention studies, the benefits of dietary intervention occur largely by reducing saturated fat and cholesterol in the diet and in many cases increasing the polyunsaturated fats. Information about these studies is shown in Table 8.(9)(16)

With regard to benefit from pharmacological intervention, the studies are shown in Table 9.(17)(28)

More recently, we have obtained information about HMG CoA reductase inhibitors which are now the most widely used and most effective LDL cholesterol-lowering drugs that we have available to us and these are generally the first-line agents that we use in patients with elevated LDL cholesterol levels.(24),(25),(26),(27)(28)

These agents include lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and cerevastatin. Of these, only pravastatin and lovastatin have been tested in primary prevention studies (see Table 9). In the large West of Scotland Study and the APSCAPS/TEXCAPS Study, both these agents reduced heart disease risk by about one-third, and lowered total cholesterol levels about 20 and 22% respectively, and LDL cholesterol levels 25 and 26% respectively.(24),(26) The dose of pravastatin that was used was 40 mg per day and the dose of lovastatin that was used varied between 20 and 40 mg per day in these studies.

In large-scale secondary prevention studies with the statins, simvastatin and pravastatin have been tested. In the large Scandinavian Simvastin Survival Study (4S) of patients with established heart disease, there was a 34% reduction in heart disease risk and a 30% reduction in total mortality.(23) In the Cholesterol and Recurrent Events Trial (CARE) study in patients with established heart disease and lower LDL cholesterol levels, with a mean of 137 mg/dl at baseline, there was a 24% reduction in heart disease risk and, also, in both (4S and CARE), a reduction in stroke.(25) In the most recent study, LIPID, which was also secondary prevention, there was a 23% reduction in total mortality, a 24% reduction in heart disease mortality and a 20% reduction in stroke mortality.(28)

In all these studies, there was no excess incidence of cancer or other diseases observed, indicating that these drugs do appear to be safe, at least over the five-year course of the studies, when tested in a randomized, placebo-controlled, double-blinded fashion.

With regard to the newer statins, fluvastatin has the benefit of being less costly, while atorvastatin has the benefit of lowering LDL cholesterol by as much as 60% and also being quite effective in lowering triglyceride levels.(29),(30) The starting dose of all of these agents is either 10 or 20 mg per day, and the maximal doses are either 40 or 80 mg per day. Incidence of liver enzyme elevation is minimal, at 1-2%, but liver enzymes need to be monitored. A baseline CPK should be obtained and if patients complain of muscle aches or pains, the test repeated at that point in time.

Because of their efficacy in LDL cholesterol lowering as well as heart disease risk reduction, the HMG CoA reductase inhibitors are now the drugs of choice for LDL cholesterol lowering.

The other agents that we use that are well tolerated are the fibric acid derivatives, especially gemfibrozil at a dose of 600 mg twice a day. This is mainly now used in patients with hypertriglyceridemia, especially in those with values >1000 mg/dl where it is important to reduce their triglycerides to reduce the risk of pancreatitis. In this setting it is obviously also important to control the blood glucose levels, since many of these patients are diabetic.

With regard to combination therapy, if one needs additional LDL lowering after going to a maximal dose of a statin, then we would add low doses of an anion exchange resin such as cholestyramine or colestipol, but now that atorvastatin is part of our armamentarium, usually we don't need to go to that combination. The anion exchange resins do decrease LDL cholesterol quite well, but they are very difficult for patients to tolerate because of bloating and constipation. Another agent that has been used in the past is niacin, but niacin has a lot of side effects, such as flushing, elevation of liver enzymes, elevation of glucose, elevation of uric acid and also gastritis. For these reasons, both niacin and anion exchange resins such as cholestyramine or colestipol are generally now second-line agents.

It should be noted that in the CARE study, patients with baseline LDL cholesterols of 125 mg/dl or less (even though they had established heart disease) did not get significant benefit from LDL cholesterol lowering, and these data would suggest that, in patients with established heart disease and an LDL level below 125 mg/dl, one might consider other agents. For example, many of these patients may have increased triglyceride levels and decreased HDL cholesterol and gemfibrozil should be considered in these patients, or niacin. Gemfibrozil was tested in a large Helsinki Heart Study and was shown to reduce heart disease risk by 34%.(20),(21),(22) In the recent Veterans Administration High Density Lipoprotein Intevention Trial (HIT) in men with CHD, HDL cholesterol < 40 mg/dl, triglycerides < 300 mg/dl and LDL cholesterol < 140 mg/dl, gemfibrozil reduced CHD risk 22% versus placebo over five years.(31) Niacin was tested in the Coronary Drug Project in patients with established heart disease and reduced heart disease risk 20%.(23)

Russell

What drugs do you start with, for an elevated LDL cholesterol, and how tolerable are these drugs?

Schaefer

The drugs that we start with now are the HMG CoA reductase inhibitors, because of the large prospective studies, and these are very well tolerated agents.

Russell

It looks like one has a lot of choice in that class of drugs, and maybe you should briefly elaborate on how you should decide on which one to pick but the other question that comes up is, What is the role of fibric acid derivatives and probucol? Are there specific dyslipidemias where these are more effective drugs to try as a first-line or are they always second-line drugs?

Schaefer

We don't use probucol because it lowers LDL cholesterol only about 10% and lowers HDL cholesterol by about 25%.(32) It also has not been shown to be beneficial in reducing atherosclerosis in one angiographic study.(30) It has recently been reported, though, to decrease restenosis after angioplasty, so it might be considered in these patients at a dose of 500 mg twice a day.(33) Gemfibrozil is the drug of choice in the treatment of patients with significant hypertriglyceridemia, while the HMG CoA reductase inhibitors are the drugs of choice for significant elevations of LDL cholesterol. With regard to the HMG CoA reductase inhibitors, one could start with one of the agents that has been tested in large primary or secondary prevention studies but if one needs more LDL cholesterol lowering, generally, the drug of choice would be atorvastatin.

Russell

Are the resin and niacin drugs, then, more or less obsolete at this point?

Schaefer

Right now we tend to use resins when we need more LDL lowering in the patient who has pure hypercholesterolemia. Resin therapy has also improved to some extent; we now have colestipol tablets which are one-gram tablets that many patients prefer to the powder. The side effects of bloating and constipation are not uncommon with these drugs. I tend to give them twice a day and go up to as many as four one-gram tablets twice daily. If we go to higher doses, such as 16 grams per day of resin, then we would tend to use the packets or the scoops. I agree with your statement that these have become second-line agents. Niacin does have a special place, especially since there is now a long-acting formulation called sustained release niacin available, where we start patients at 375 mg per day and then weekly increase to 500 mg per day, then 750 mg per day, then one gram per day and then go up to as much as two to three grams per day. The benefits of niacin are that it not only lowers LDL cholesterol and triglyceride, but it also increases HDL cholesterol and even lowers an independent risk factor known as Lp(a). Therefore, niacin, especially sustained release niacin, should, in our view, be considered a first-line agent in patients with established heart disease.

Russell:

Flushing can be a bothersome symptom for patients taking niacin. Is it usually just a minor irritant that goes away with time? What percentage of patients, at one gram per day, are able to tolerate and keep on it?

Schaefer

Most patients who are on niacin will get flushing but there is less flushing over time, and they tend to get used to the agent. Usually, you have to use two to three grams of niacin to get a significant efficacy in terms of lipid lowering; you can use one adult aspirin per day that sometimes decreases the flushing but, in general, niacin is not a first-line agent. In most patients, we would use HMG CoA reductase inhibitors.

Russell

While we are still talking about drugs, how important is it to decrease beta adrenergic blockers and thiazide diuretics? Also, in post-menopausal women, are estrogens ever utilized to reduce cardiac risk from high LDL cholesterol?

Schaefer

Those are excellent questions. Let me take the post-menopausal estrogen question first. It turns out that observational data clearly indicate that post-menopausal women on estrogens have a significant reduction in all-cause mortality and heart disease mortality, which appears in part to relate to the fact that estrogens will lower LDL cholesterol and raise HDL cholesterol.(34),(35),(36) However, estrogens can raise triglycerides, as well, so they should not be given to a woman who has triglycerides of over 400 mg/dl. If one needs to give such a woman estrogens, one should use the estrogen patch, which has a minimal effect on lipids. Generally, for oral estrogen we use conjugated equine estrogen at a dose of 0.625 mg per day. If breast tenderness becomes a significant issue we might reduce that dose to 0.3 mg per day. In patients with an intact uterus we then would give progesterone, at a dose of 2.5 mg per day. We use these agents in a continuous fashion. Some women will occasionally have break-through bleeding and then we have to alter this dosage schedule. Estrogens, like niacin, lower Lp(a) levels.(37),(38) Hormonal replacement therapy (combined estrogen/progesterone) did not reduce CHD risk in a recent secondary prevention study in women.(39)

With regard to thiazides and beta blockers, the newer beta blockers are more selective and have less of an effect on raising triglycerides than was the case with propanolol; it should be noted that beta blockers have been shown to have a significant benefit in patients with established heart disease, so that we would tend not to take those patients off beta blockers but would switch them from propanolol to a newer, more selective, beta blocker. With regard to thiazide diuretics, they can be quite beneficial in lowering blood pressure,but from the point of view of lipid-neutral drugs, we prefer angiotensin converting enzyme inhibitor agents.

Russell

Two syndromes that are relatively resistant to drug therapy are an isolated low HDL cholesterol and dysbetalipoproteinemia. You mentioned that niacin can help in the situation of low HDL cholesterol. What can be done for patients with these syndromes?

Schaefer

With low HDL cholesterol there are three agents that will raise HDL cholesterol significantly. In men and women one can use either gemfibrozil 600 mg twice daily or niacin, going up to two to three grams per day, whereas in women we can also use estrogen replacement therapy, which can increase HDL cholesterol significantly. New HDL intervention trials will be presented at the American Heart Association meetings in November, 1998, as will a large estrogen trial, so we should have better information as to how to treat patients with low HDL cholesterol levels and normal LDL cholesterol levels; these studies are being done in patients with established heart disease. At the present time, all three options mentioned above, though, can be considered in patients with established heart disease and normal LDL cholesterol levels, (<130 mg/dl) and decreased HDL cholesterol (<35 mg/dl).

With regard to dysbetalipoproteinemia, this is a difficult diagnosis to make unless one measures lipoproteins directly; these patients do respond very nicely to HMG CoA reductase inhibitors. They also respond reasonably well to gemfibrozil and also to niacin. Dysbetalipoproteinemia is defined as an elevated level of VLDL cholesterol, and the ratio of VLDL cholesterol measured directly by ultracentrifugation divided by triglycideride generally exceeds 0.3, whereas in normal people it is 0.2. Most of the patients are apoE2/2 homozygotes.(40) This form of apoE has decreased binding to the chylomicron remnant receptor in the liver. However, this diagnosis is generally not made in the clinic setting unless one does specialized testing.(40) These patients are very responsive to diet as well as medications. Once we begin measuring lipoproteins directly in the clinic, then the diagnosis of Type III hyperlipoproteinemia, or dysbetalipoproteinemia, will be made more readily.(41) It should be noted that this is a rare disorder.

If the LDL cholesterol is normal in these types of patients (low HDL or dysbetalipoproteinemia) and they do not have heart disease, all we can recommend is diet and exercise at this point in time. However, in patients with established heart disease, one could consider either gemfibrozil, niacin, or estrogen replacement. We will have further information once the results of these three prospective trials are presented in November of 1998.

Russell

It certainly sounds like we have made a lot of progress in managing lipid disorders clinically. Where do you think the new frontiers are going to be, over the next five years? You mentioned that drugs to raise HDL cholesterol more effectively is one frontier; what are some of the other areas that you think are going to be investigated, over the next five to ten years?

Schaefer

In my view, another area of interest is an elevated level of Lp(a). This is a genetically-determined particle that in our view is an independent risk factor for heart disease. Drugs that will lower Lp(a) include niacin and estrogens. An elevated Lp(a) is a common genetic cause of premature heart disease and I think we should begin screening our patients for this abnormality if they have heart disease or a very strong family history of premature heart disease, especially in the absence of other risk factors.(42),(43),(44) So, hopefully, we'll have some additional information in the future, in this regard.

Another interesting risk factor in the future, of course, is homocysteine, which is not in the lipid field, but, in our view, is an important heart disease risk factor, Then the question is whether giving such patients vitamins B6, B12 and folic acid will be beneficial to reduce heart disease risk. I think certainly giving patients with heart disease a multivitamin that has 400 mcg of folate would not be unreasonable.

In the next century, gene therapy will become increasingly important. It has recently been documented that, with newer vectors that don't express viral proteins, gene therapy can have a lasting effect. This has now been documented in animal models, so that this approach could also be used for LDL lowering or for HDL raising and, in my view, will have significant benefit, especially in those patients with established heart disease who have either of these two abnormalities. I believe that the future is bright. I would caution that lipid abnormalities are not the only causes of premature atherosclerosis and one should not expect that aggressive lipid management will eradicate heart disease. Smoking, hypertension and diabetes are also very important in the pathogenesis of atherosclerosis, and these risk factors also need to be aggressively managed.

It should be noted that the importance of nutrition and exercise also need to be emphasized and, in the future, more aggressive lifestyle modification programs will, hopefully, be implemented. However, at the present time, there are still many patients who are not being adequately treated for elevated LDL cholesterol with either diet or drug therapy.

The implementation of the recommendations of the Adult Treatment Panel II of the National Cholesterol Education Program still remains a significant challenge and has by no means been achieved.
Footnotes

1The Expert Panel. Summary of the second report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). JAMA 269:3015-3023, 1993.
2The Expert Panel. Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. (Adult Treatment Panel II). Circulation 89:1329-1445;1994.
3McNamara JR, Cohn JS, Wilson PWF, Schaefer EJ: Calculated values for low density lipoprotein cholesterol in the assessment of lipid abnormalities and coronary disease risk. Clin Chem 36:36-42, 1990.
4McNamara JR, Cole TG, Contois JH, Ferguson CA, Ordovas JM, Schaefer EJ. Evaluation of an immunoseparation method for measuring LDL cholesterol directly from serum. Clin Chem 41:232-240;1995.
5Schaefer EJ, Lichtenstein AH, Lamon-Fava S, Contois JH, Li Z, Rasmussen H, McNamara JR, Ordovas JM. Efficacy of a National Cholesterol Education Program Step 2 Diet in normolipidemic and hyperlipidemic middle aged and elderly men and women. Arterioscler Thromb Vasc Biol 15:1079-1085;1995.
6Schaefer EJ, Lamon-Fava S, Ausman LM, Ordovas JM, Clevidence BA, Judd JT, Goldin BR, Woods M, Gorbach S, Lichtenstein AH. Individual variability in lipoprotein cholesterol response to National Cholesterol Education Program Step 2 diets. Am J Clin Nutr 65:823-830;1997.
7Hunninghake DB, Stein FA, Dujorne CA, Harris WS, Feldman EB, Miller VT, Tobert JA, Laskarzewski PM, Quiter E, Held J, Taylor AM, Hoffer S, Leonard SB, Brewer BR. The efficacy of intensive dietary therapy alone or combined with lovastatin in outpatients with hypercholesterolemia. New Eng J Med 1993; 328: 1213-1219.
8Schaefer EJ, Lichtenstein AH, Lamon-Fava S, McNamara JR, Schaefer MM, Rasmussen H, Ordovas JM. Body weight and low-density lipoprotein cholesterol changes after consumption of a low fat ad libitum diet. JAMA 274:1450-1455;1995.
9Turpeinen O, Miettinen M, Karvonen MJ, et al. Dietary prevention of coronary heart disease: Long-term experiment. I. Observations of male subjects. Am J Clin Nutr 21:255;1968.
1616. deLorgeril M, Salen P, Martin JL, et al. Effect of a Mediterranean type of diet on the rate of cardiovascular complications in patients with coronary artery disease. J Am Coll Cardiol 28:1103-1108;1996.
17The Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-364.
20Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Maenpaa H, Malkonen M, Mantari M, Norola S, Pasternak A, Pikkaranen J, Romo M, Sjomblom T, Nikkila EA. Helsinki Heart Study: Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 317:1237-1245, 1987.
21Manninen V, Elo O, Frick MH, Haapak, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitanceim P, Koskinen P, Maenpaa H, Malkonen M, Mantari M, Norola S, Pasternak A, Pikkaranen J, Romo V, Sjomslom T, Nikkila K. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988; 260 (5): 641-651.
22Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Martarri M, Heinonen OP, Frick MH. Joint effects of triglyceride, LDL cholesterol, and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implication for treatment. Circulation 1992; 85: 37-45.
23Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W. Fifteen-year mortality in Coronary Drug Project patients: Long-term benefit with niacin. J Am Coll Cardiol 8:1245-1255, 1986.
24Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344:1383-1389;1994.
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