Ernst John Schaefer is professor of medicine at Tufts University School of Medicine, Director of the Heart Disease Prevention Program at New England Medical Center, and senior scientist and Chief, Lipid Metabolism Laboratory of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. He graduated from Harvard College, Dartmouth Medical School and Mt. Sinai School of Medicine, trained in internal medicine at Mt. Sinai and in endocrinology and lipoprotein research at the National Institutes of Health. Dr. Schaefer served on the first and second Adult Treatment Panels of the National Cholesterol Education Program which generated U.S. guidelines for cholesterol management. He is the U.S. editor of the journal Atherosclerosis. His research focuses on the nutritional and genetic regulation of plasma lipoproteins.
What's the right treatment for a person who has too much of the bad kind of cholesterol — LDL (low density lipoprotein)? Should he or she diet first or is it better to begin using drugs right away, even before diet is tried?
Elevated LDL cholesterol, levels over 160 mg/dl, have clearly been shown to be a significant risk factor for coronary heart disease (CHD). Lowering LDL cholesterol has been associated with significant reduction in risk (see Table 1 below).
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)
||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
You have less than two heart disease risk factors (see Table 2 below), diet is initiated if the LDL cholesterol is greater than 160 mg/dl. For those with LDL cholesterol higher than 190 mg/dl, the doctor will also add drug therapy. The goal of therapy in this higher group is to bring the LDL level below 160 mg/dl as soon as possible
NCEP CHD Risk Factors*
*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
- Male > 45 years
- Female > 55 years
- Family History of Premature CHD
- HDL C < 35 mg/dl
In people with two or more heart disease risk factors, for example if you smoke and have a family history of heart disease, diet and drug therapies are initiated at a 30 mg/dl lower level. Here, the goal is to lower LDL cholesterol values below 130 mg/dl. In patients with established heart disease, we are even more aggressive — we initiate diet if the LDL cholesterol is more than 100 mg/dl; we initiate drug therapy after diet if the LDL cholesterol is more than 130 mg/dl. The goal of therapy is to get the LDL cholesterol to less than 100 mg/dl.
Before placing someone on diet therapy, it is important to make sure they don't have other secondary causes of hypercholesterolemia, as follows:
- Obstructive Liver Disease
- Nephrotic Syndrome
- Diabetes Mellitus
- Anabolic Steroids
The ideal approach is to refer the person to a dietitian who can work with the patient and his/her spouse, either individually or in a group setting. There are some people 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 3 below. 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. The Step II diet, which is recommended for patients who have high blood levels of cholesterol, is generally more difficult 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.
National Cholesterol Education Program Guidelines on Dietary Therapy*
||Average U.S. Diet**
||Step 1 Diet
||Step 2 Diet
|Saturated Fat 1
|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.
Obviously, it is also important to recommend daily exercise, 30 minutes per day. For elderly patients, especially those with established heart disease, often walking is the only thing they 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 below.
- 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.
- 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.
- 2-4 servings of fruit
- 1 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.
- 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.
- 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.
- Use fats, oils, and sugars (including syrup) sparingly.
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%. This is mainly due to decreased compliance. It should be noted, however, that there is a great deal of variability in response. When followed strictly, the Pyramid Diet will also promote weight loss, which is another benefit.
So you often begin with diet therapy. When, if ever, do you skip the diet approach and start drugs right away?
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 less than 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 make sure there are no secondary causes of high LDL levels prior to going to drug therapy. These other causes are shown in Table 3.
Of these secondary causes, the one that is often missed is hypothyroidism, an underactive thyroid gland. The condition should be corrected before placing the patient on a cholesterol-lowering drug.
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.
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?
HMG CoA reductase inhibitors are now the most widely used and most effective LDL cholesterol-lowering drugs. These first-line agents include lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and cerevastatin. Of these, only pravastatin and lovastatin have been tested in primary prevention studies.
In all these studies, the drugs did not appear to cause cancer or other diseases, indicating that these drugs do appear to be safe, at least over the five-year course of the studies.
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. 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.
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 for patients who have very high blood levels, more than 1000 mg/dl, of triglycerides, where it is important to reduce their triglycerides and cut down their risk of pancreatitis (inflammation of the pancreas).
With statin treatment, it's not usually necessary to add another medicine, but if we must because a patient 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. The anion exchange resins do decrease LDL cholesterol quite well, but they are very difficult because they produce bloating and constipation. In the past, we've also prescribed niacin, but it has a lot of side effects, such as flushing, elevation of liver enzymes, elevation of blood sugar, elevation of uric acid and gastritis. For these reasons, both niacin and cholestyramine or colestipol are generally now second-line agents.
Do vegetarians and people on macrobiotic diets get into problems with protein malnutrition?
There are two types of vegetarians. Lacto-ovo vegetarians and strict vegetarians or "vegans". Lacto vegetarians eat animal protein of high biological value, eggs and dairy products. Vegans, however, eat a more limited diet and often must take amino acids supplements to make up for their not-so-high biological protein diet. If vegans eat a variety of plant foods — cereals, nuts, seeds, grains and legumes — they'll be fine. They don't have to eat all these food items at a given meal. However, they should consume most or all of them during the course of the day to insure a well balanced protein diet of high biological value.
Do you have a favorite among these new drugs?
As I said before, pravastatin and lovastatin have 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.
Are the resin and niacin drugs, then, more or less obsolete at this point?
Right now we use resins when we need more LDL lowering in the patient who has pure hypercholesterolemia (high blood levels of cholesterol). 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. Niacin does have a special place, especially since there is now a long-acting formulation, called sustained release niacin, available. Niacin not only lowers LDL cholesterol and triglyceride, but it also increases HDL cholesterol (the good 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.
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?
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. One adult aspirin per day sometimes relieves the flushing.
While we are still talking about drugs, in post-menopausal women, are estrogens ever utilized to reduce cardiac risk from high LDL cholesterol?
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. 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. We use these agents in a continuous fashion. Some women will occasionally have break-through bleeding and then we have to alter their dosage schedule.
What do you for patients with low HDL cholesterol, the good cholesterol? As I understand it, this condition is difficult to treat with drugs?
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.
It certainly sounds like we have made a lot of progress in managing lipid disorders. Where do you think the new frontiers are going to be, over the next five years? 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?
In my view, another area of interest is an elevated level of Lp(a), a lipoprotein. 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. So, hopefully, we'll have some additional information in the future, in this regard.
Another interesting risk factor in the future is homocysteine. Though not a lipid, most medical experts believe this amino acid is an important heart disease risk factor and its blood level can be reduced by folate. 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 multi-vitamin that has 400 mcg of folate would be a good idea.
In the next century, gene therapy will become increasingly important.
Remember, however, that lipid abnormalities are not the only causes of premature hardening of the arteries. Don't expect that aggressive lipid management will eradicate heart disease. Smoking, hypertension and diabetes are also very important in this story and must be aggressively managed.
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.