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An Approach to Hyperlipidemia

Thomas Higgins, MD, MSPH
Nanci Grayson, MS, RD
6/25/01

SCREENING GUIDELINES:

We have summarized below the current national recommendations. These recommendations need to be modified for individual patients.

The rationale for screening for cholesterol problems rests on the observations that there is a direct relationship between cholesterol level and the risk of heart attacks and that lowering levels (at least in high-risk patients) leads to a reduction in heart attacks. More recently, other problems related to arteriosclerosis such as stroke have also shown to be correlated with cholesterol levels. As a result, screening should be done at least once every five years for all persons age 20 and over. 

On May 15, 2001 the National Cholesterol Education Program issued their Adult Treatment Panel (ATP) III guidelines which significantly modified older treatment recommendations. For example, no longer is it adequate to screen solely with the use of a total and HDL cholesterol on non fasting samples. The current recommendation is to do a complete lipid profile. The total lipid panel contains a measurement of total cholesterol, HDL cholesterol, triglycerides and a calculation of LDL cholesterol & is done after a 9 to 12 hour fast. Normal values for Total Cholesterol are no longer given by the ATP III guidelines but are included below based on older recommendations. 

Total Cholesterol: stratified according the following criteria:

  • Desirable — below 200 mg/dL
  • Borderline high — 200 to 239 mg/dL
  • High — above 240 mg/dL

HDL Cholesterol: "Good Cholesterol"; it is a negative risk factor for heart attack and is stratified according the following criteria:

  • Very High — above 75 mg/dL (associated with the "longevity syndrome")
  • High — above 60 mg/dL (allows the subtraction of one other risk factor)
  • Normal — 40 to 60 mg/dl in men & women
  • Low — less than 40 mg/dl

Triglycerides: "Blood fats"; they are not directly associated with vascular disease but higher levels are associated with lower HDL values & are often associated with glucose intolerance. They are stratified according the following criteria:

  • Normal — below 150 mg/dL
  • Borderline high — 150 to 199 mg/dL
  • High — 200 to 499 mg/dL
  • Very High — above 500 mg/dL

LDL Cholesterol: "Bad cholesterol" and is stratified according to the following criteria:

  • Optimal - below 100 mg/dl
  • Near Optimal - 100 to 129 mg/dl
  • Borderline High - 130 to 159 mg/dl
  • High - 160 to 189 mg/dl
  • Very High - greater than 190 mg/dl

TREATMENT GUIDELINES:

LDL Cholesterol

Older recommendations were based on Primary & Secondary prevention of coronary artery disease and separated people into those with (secondary prevention) & without (primary prevention) a previous heart attack. The ATP III recommendations are based on the calculation of a 10 year risk of having a heart attack. The treatment groups are divided into those persons at very high risk (10 year risk of > 20%), persons with moderate risk (10 year risk of < 20%) and persons with low risk.

1) High Risk Group. These persons are defined as having had a prior heart attack or as having a heart attack equivalent condition. Heart attack equivalent conditions include diabetes, symptomatic cerebrovascular, peripheral vascular disease, an abdominal aortic aneurysm or a 10 year risk > than 20% as calculated by the Framingham Risk Tables. The LDL goal in this group is less than 100, Life style modification is begun over 100 & drugs are recommended above 130.

2) Moderate Risk Group: These persons have 2 or more major additional risk factors. The major additional risk factor list includes:

  • Male above 45 years of age or female above 55 years of age.
  • Family history of premature CHD as defined by definite heart attack or sudden death before age 55 in father or other first-degree male relative or before age 65 in mother or other first-degree female relative.
  • Current cigarette smoking.
  • Hypertension, as manifested by blood pressure above 140/90 or treatment with blood pressure medications.
  • Low HDL (< 40 mg/DL)

These persons are further divided by the Framingham Risk Tables into those having a 10 year risk of from 10 to 20% & into those having a 10 year risk under 10%. The LDL goal in the patients having a 10 to 20% risk is less than 130, lifestyle modification is begun over 130 & drug therapy is recommended above 130 to 160. In the group with a 10 year risk under 10%, the recommendations are the same except the threshold for drug therapy is increased to 160.

Note: A 10 year risk calculator provided by the National Cholesterol Education Program is available for use on line.

3) Low Risk Group: These persons have 0 to 1 major additional risk factor. The major additional risk factor list includes:

  • Male above 45 years of age or female above 55 years of age.
  • Family history of premature CHD as defined by definite heart attack or sudden death before age 55 in father or other first-degree male relative or before age 65 in mother or other first-degree female relative.
  • Current cigarette smoking.
  • Hypertension, as manifested by blood pressure above 140/90 or treatment with blood pressure medications.
  • Low HDL (< 40 mg/DL)

Almost all persons in this group have a 10 year risk well under 10%. The LDL goal in this group is less than 160, lifestyle modification is begun over 160 & the threshold for drug therapy is 190.

Triglycerides 

The Friedewald formula used to calculate LDL in the lipid profile is only valid if the triglyceride concentration is less than 400 mg/dl. Because the LDL can't accurately determined in the presence of high triglycerides, the ATP III criteria have defined a new "Non-HDL Cholesterol" Goal for those situations when the LDL can not be calculated. The Non-HDL Cholesterol is defined as total cholesterol - HDL cholesterol. In all of the categories listed above, the Non-HDL cholesterol goal is 30 mg% higher than the LDL goal. For example, in persons with a risk of greater than 20% where the LDL goal is < 100, the Non-HDL cholesterol goal is 130.

If the triglycerides are 200 to 499 after the LDL or Non-HDL cholesterol goal has been reached, drug therapy for the triglycerides should be considered.

If the triglycerides are over 500, it is recommended to treat them prior to treating the LDL or Non-HDL levels.

HDL

The LDL or Non-HDL cholesterol levels & triglyceride levels need to be addressed. Weight loss & physical activity are important. Additional drug treatment should be considered in persons with a persistent HDL of less than 40 & a 10 year risk of greater than 20% after other treatment recommendations have been implemented. 

TREATMENT:

Therapeutic Lifestyle Changes

Initial therapy for lowering LDL begins with lifestyle modifications such as reductions in dietary saturated fat to less than 7 percent of caloric intake, reduction of dietary cholesterol to less than 200 mg/day, weight loss in overweight patients, stress management and aerobic exercise.

The addition of soluble fiber (10 to 25 g/day) and plant stanols/sterols (2 gm/day) should also be considered. Good sources of fiber include legumes, cereal grains, beans & many fruits and vegetables. Plant stanols/sterols are found in certain margarine & salad dressings.

Restrictions on total dietary fat have been relaxed with allowances of up to 35% of the daily calories being from fat provided the saturated fat is kept to the 7% limit.

Drug Treatment

Bile Acid Sequestrants

Effective in patients with mild to moderate elevations of LDL cholesterol.

Side effects — The major adverse reactions include nausea, bloating, cramping and an increase in liver function tests. Bile acid sequestrants can also bind to and impair the absorption of other drugs. This effect can be minimized by administering the other drugs one hour before or four hours after the bile acid sequestrants. Patients with preexisting elevated triglycerides may have a increase in their triglycerides on these agents.

Nicotinic Acid

Effective in patients with hypercholesterolemia, hypertriglyceridemia and in patients with low levels of HDL. The HDL raising properties of nicotinic acid occur with dosages as low as 1 to 1.5 g/day. In contrast, the cholesterol and triglyceride lowering effects are typically seen with higher doses (3 g/day).

Side effects — The use of nicotinic acid is often limited by side effects. At standard doses (1.5 to 4.5 g/day), flushing occurs in 80 percent of cases while itching and nausea occur in about 20 percent. Flushing can be decreased by starting at low doses and gradually building up the dose over several weeks. Taking aspirin before each dose can also help. Elevations of liver function tests are common and may lead to severe liver toxicity. Other potential problems include high blood sugar, gout and increased homocysteine levels. Crystalline niacin is preferred to sustained-release preparations since the former is associated with a greater therapeutic effect and seemingly less liver toxicity. The dose recommendations for sustained release niacin are about 1/2 of those for crystalline niacin given above.

HMG CoA Reductase Inhibitors

Currently available HMG CoA reductase inhibitors include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor) and cerivastatin (Baycol). Reductase inhibitors are the most potent drugs for lowering LDL cholesterol, with reductions in the range of 20 to 60 percent. They also have modest HDL raising properties (about five percent) and triglyceride concentrations fall by an average of 20 percent.

Side effects — Adverse reactions occur less frequently with the HMG CoA reductase inhibitors than with the other classes of lipid-lowering agents. One concern has been the development of muscle toxicity. Enhanced susceptibility muscle toxicity occurs in patients with chronic renal failure, obstructive liver diseases, and in patients receiving concurrent therapy with cyclosporine, gemfibrozil, nicotinic acid, or macrolide antibiotics (e.g., erythromycin) all of which increase the blood level of the reductase inhibitor. Pravastatin may be less toxic in the above situations.

Fibrates

Gemfibrozil (Lopid), clofibrate (Atromid-S) and fenofibrate (Tricor) lower triglycerides (35 to 50 percent) and raises HDL levels (15 to 25 percent). Side effects are minimal.

Estrogen Replacement Therapy

Reduces LDL (15 percent) and Lp(a) (20 percent) and elevates HDL (10 to 15 percent) and triglycerides (24 percent). Effects are somewhat mitigated by concomitant progesterone therapy. The significance of progesterone is uncertain, since it may not reduce the cardio protective effect of estrogen therapy. Transdermal estrogen does not affect lipid levels, perhaps due to lack of first-pass effect on the liver.

SERM’s — Tamoxifen and more recently raloxifen appear to have a somewhat similar but less effect on lipid levels.

The cardio-protective effect of postmenopausal estrogen replacement is now being questioned and there may actually be an increase in cardiovascular risk early after the initiation of estrogen in women with established coronary disease. It is now recommended not to start estrogen replacement in women with established coronary disease & not to use estrogen in the place of other more definitive treatment for hyperlipidemia. It is not necessary to stop estrogen replacement in patients with hyperlipidemia. 

Fish Oil

High doses (>6 g/day) can reduce levels of triglycerides but there may be an increase in LDL cholesterol especially in higher doses (15 g/day). Fish oil administration can also cause a fall in circulating levels of vitamin E and cause gastrointestinal side effects.

OTHER ISSUES:

Lp(a):

Studies have been consistent in establishing a role for Lp(a) excess in predicting heart attacks and strokes in patients with concomitant high cholesterol. Reductase inhibitors and bile acid sequestrants do not lower Lp(a) levels appreciably. Therefore Lp(a) should be suspected in patients unresponsive to standard LDL treatment. Screening for Lp(a) should also be considered in patients with known CAD but no obvious risk factors.

TREATMENT — To date, no clinical trials have evaluated the effects of specific Lp(a) lowering therapy. If the LDL concentration cannot be reduced to less than 130 mg/dL, Lp(a) measurement and specific Lp(a) lowering therapy may be indicated. One possible goal is to lower Lp(a) levels to less than 30 mg/dL. Nicotinic acid (3 to 4 g/day) and/or neomycin (2 to 3 g/day) are effective. Estrogens are the treatment of choice in postmenopausal women and can reduce Lp(a) levels by up to 50 percent.

Low HDL Levels:

HDL, in contrast to LDL, has antiatherogenic properties. Exercise, weight loss (in overweight subjects), substitution of monounsaturated for saturated fatty acids, and smoking cessation can all raise HDL cholesterol. In addition, medications that lower HDL-cholesterol (B blockers, benzodiazepines, and androgens) should be discontinued, if possible. Nicotinic acid, gemfibrozil, and estrogen therapy can all increase HDL levels.

High Triglycerides:

High triglycerides are not directly associated with arteriosclerosis but do cause a lowering of HDL levels and the production of small dense LDL as well as other remnant particles which are associated with arteriosclerosis. Patients with very high triglyceride levels (>1000 mg/dL) can develop the "chylomicronemia syndrome". This disorder can develop quickly and is potentially fatal because of the potential for pancreatitis which is an inflammation of the pancreas. Diet and exercise are important in reducing triglycerides and appear to be most effective in men. The most effective triglyceride lowering drugs are gemfibrozil and nicotinic acid. Refractory cases may benefit from fish oil supplements. Bile acid sequestrants can increase the high triglycerides especially if used before the triglycerides are controlled. 

As mentioned previously, the ATP III recommendations have coined a new term called Non-HDL Cholesterol. Non-HDL Cholesterol = Total Cholesterol - HDL Cholesterol. The Non-HDL Cholesterol is a useful concept in situations where the LDL cholesterol can not be calculated in the fasting lipid profile because the triglyceride levels are too high. In these situations, the Non-HDL Cholesterol can be substituted for the LDL cholesterol in the recommendations for treatment. Goal levels for the Non-HDL Cholesterol are all 30 mg/dl higher than the corresponding LDL cholesterol

High Homocysteine Levels:

It is recommended that screening be done for high homocysteine levels in patients with premature atherosclerotic disease and a paucity of more conventional risk factors. Treatment involves vitamin supplementation with folic acid, pyridoxine, and vitamin B12. The minimal doses are uncertain but current recommendations are to treat homocysteinemic patients who have premature coronary disease with folic acid (1 mg/day) pyridoxine (10 mg/day), and vitamin B12 (0.4 mg/day). Normalization of the plasma homocysteine concentration has been reported within two weeks, but further lowering of homocysteine levels can occur by six weeks.

Arteriosclerosis as a possible  infectious disease:

Recently there has been an association of atherosclerotic lesions and Cytomegalovirus and Chlamydia pneumoniae. Studies are now underway using antibiotics after heart attacks.

C-Reactive Protein: 

Elevation of the C-Reactive Protein for the purposes of risk assessment is in the upper 1/2 of the normal range in the absence of other causes of inflammation. C-Reactive Protein is a non specific marker for inflammation and is felt to indicate inflammatory (more active) atherosclerotic plaques.

Metabolic Syndrome:

This is essentially a manifestation of insulin resistance. Many patients with insulin resistance have smaller, denser & more atherogenic LDL particles. Of interest is that the medications used to reduce insulin resistance seem to make the LDL particle less atherogenic. It is associated with a higher risk of coronary disease & is considered by the ATP III recommendations to the present if any 3 of the following are present:

  • Abdominal obesity: waist circumference > 40 in in men & 35 in in women
  • Triglycerides over 150 mg/dl
  • HDL under 40 mg/dl in men & 50 in women
  • Blood pressure over 130/85
  • Fasting glucose over 110 mg/dl

If it is present, treatment of the metabolic syndrome with diet, aerobic exercise, blood pressure control & perhaps insulin sensitizing agents is important in all persons trying to lower their ateriosclerotic risk.

Cholesterol in the Elderly:

The prevention of heart attacks in the elderly has been hindered by the perception that LDL lowering therapy requires many years before the course of arteriosclerosis can be altered. This concept has been challenged by several recent clinical trials that demonstrate clinical benefits as early as 6 months to 2 years.

The decision to treat hypercholesterolemia in an elderly individual needs to be highly individualized, being based upon both chronological and physiologic age. As an example, a patient with a limited life span from a concomitant illness is probably not a candidate for drug therapy. On the other hand, an otherwise healthy elderly individual should not be denied drug therapy simply on the basis of age alone.

SUMMARY:

Hyperlipidemia is a serious but modifiable health risk. The increasing weight & associated epidemic of insulin resistance & diabetes in our population is aggravating the problem. 

The ATP III recommendations are expected to substantially increase the number of Americans being treated for high cholesterol. Estimates suggest that the number of persons on dietary treatment will increase from 52 to 65 million & the number on lipid lowering medications is expected to rise from 13 to 36 million people.

It is our opinion that aggressive life style modification should be the main focus of therapy. The decision to embark on medical therapy and the aggressiveness of that therapy can not solely be based on recommendations from the National Cholesterol Education Program but rather needs to individualized to fit each person's situation. 

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