Lipoprotein Disorders

The most common lipoprotein disorders are hypercholesterolemia (type II hyperlipoproteinemia); hypertriglyceridemia (primarily types IV and V hyperlipoproteinemia); hypoalphalipoproteinemia; and high lipoprotein(a) (Lp[a]) levels. However, hypercholesterolemia and hypoalphalipoproteinemia may not be as prevalent among the elderly as among the general population because mortality risk is so high that patients with these disorders do not survive to old age.

The association between high serum cholesterol levels and coronary artery disease (CAD), whose prevalence and mortality rate increase with age, is well established. High levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a) and a low level (< 35 mg/dL [< 0.91 mmol/L]) of high-density lipoprotein cholesterol (HDL-C) are significant independent positive risk factors for CAD and carotid artery atherosclerosis. A high level (>= 60 mg/dL [>= 1.55 mmol/L]) of HDL-C is a significant independent negative risk factor. However, the total cholesterol (TC)/HDL-C ratio is a more valuable measure of CAD risk than TC or LDL-C levels alone; the risk is higher in men when the ratio is > 6.4 and in women when the ratio is > 5.6.

For the elderly, the predictive value of high cholesterol levels in determining the risk of CAD is unclear, and the value of lowering high cholesterol levels--in terms of quality of life, morbidity, and mortality--is disputed. Some studies suggest that high cholesterol levels are an important risk factor for CAD in the elderly, others suggest that the risk decreases with age, and still others suggest a U-shaped relationship in which both high and low cholesterol levels are associated with an increased risk of morbidity and mortality. Some studies suggest sex differences: the mortality rate was lowest at a TC level of 215 mg/dL (5.55 mmol/L) for elderly men and 270 to 280 mg/dL (7.00 to 7.25 mmol/L) for elderly women.

There may also be a U-shaped relationship between cholesterol levels and death due to stroke. High cholesterol levels have been associated with increased risk of death due to nonhemorrhagic stroke, whereas low cholesterol levels have been associated with increased risk of death due to hemorrhagic stroke.

Studies of lipid-lowering treatments in the elderly, particularly primary prevention studies, have not consistently shown a significant reduction in the overall mortality rate. However, most studies have shown that for patients who have had a myocardial infarction (MI) or who have hemodynamically significant CAD, lowering lipid levels can stop or reverse disease progression and reduce the incidence of CAD events, CAD mortality, and all-cause mortality.

Classification and Etiology

Lipoprotein disorders may be primary (usually familial and usually classified based on lipoprotein elevation patterns--see Table 63-1) or secondary. However, genetic and secondary factors, such as various disorders and drugs (see Table 63-2), diet, obesity, physical activity, alcohol use, and cigarette smoking, are often interrelated.

The most common cause of secondary hypercholesterolemia is probably a diet high in saturated fat or cholesterol, whether or not a polygenic tendency for hypercholesterolemia exists. Covert hypothyroidism (with normal thyroxine and high thyroid-stimulating hormone levels) is a relatively common cause of high TC and LDL-C levels and is associated with an increased risk of premature MI.

The most common causes of secondary hypertriglyceridemia among the elderly are excessive alcohol intake, exogenous estrogen supplementation, poorly controlled diabetes, uremia, corticosteroid use, and -blocker use. Isolated low HDL-C levels with normal triglyceride (TG) levels may result from smoking, androgenic steroid use, severe restriction of physical activity, or morbid obesity.

Generalized obesity may cause an increase in TG levels but not in cholesterol levels and, in persons > 60, may not contribute to risk of CAD. However, abdominal/upper body (male-pattern) obesity appears to be correlated with increased risk.

Age and sex have a major influence on lipid levels. For persons living in most industrialized countries, cholesterol and TG levels increase through middle age. In men, mean levels of TC increase until about age 50, then plateau, and then decrease starting at about age 70. In women, they increase more gradually up to age 65 to 69, then decrease. Starting at about age 55 to 60, women have higher TC levels than men. The age-related increase in TC, particularly in women, results primarily from an increase in LDL-C levels and much less from a small increase in very-low-density lipoprotein cholesterol (VLDL-C) levels.

TG levels progressively increase from birth through adulthood. The rate of increase is greater in men than in women. TG levels increase until age 55 in men and until about age 70 in women, then decrease, gradually in men.

In men, mean levels of HDL-C decrease at puberty, increase at about age 45, and then level off at age 50 to 59. These changes may be an effect of testosterone; generally, levels of plasma testosterone and HDL-C are positively correlated in adult men. After puberty, women have higher HDL-C levels than men despite a decrease after age 65.

Premenopausal women have lower LDL-C and higher HDL-C levels than men, partly because of endogenous estrogens. This difference may contribute to the lower CAD rates in premenopausal women. At menopause (whether natural or surgical), women lose this protection against CAD: LDL-C and Lp(a) levels increase and HDL-C levels decrease.

Diagnosis

Patients who have had an MI, a stroke, or other manifestations of significant atherosclerosis (eg, peripheral arterial disease, carotid artery stenosis) before age 60 should be screened for familial lipoprotein abnormalities. The Lp(a) level should be measured in patients who have had an MI or a stroke or who have CAD and in patients who have other major CAD risk factors, because a high Lp(a) level probably acts synergistically with other risk factors. If a lipoprotein abnormality is detected, the physician should try to determine whether the lipoprotein disorder is primary or secondary and assess the patient for other CAD risk factors (eg, smoking, hypertension, a high-fat diet, physical inactivity). If secondary causes can be ruled out, the disorder is usually one of the common familial hyperlipoproteinemias.

Screening and identification criteria for hypercholesterolemia are controversial. The National Cholesterol Education Program (NCEP) provides guidelines for identifying high TC and LDL-C levels (see Table 63-3) and low and high HDL-C levels.

According to NCEP guidelines, no single cholesterol value should be used to classify a patient clinically, because values may vary from day to day. If the first screening test detects an abnormality, two subsequent tests are recommended. The NCEP does not give guidelines by age group; its guidelines are based on data from middle-aged persons and do not consider the increase in serum lipids that occurs with age. (As a result, 60% of persons > 65 would be classified as candidates for treatment.)

In contrast, the American College of Physicians guidelines recommend a single measurement of TC alone to identify patients who would benefit from lipid-lowering therapy. These guidelines note that evidence is insufficient to recommend or discourage the screening of men and women aged 65 to 75 for primary prevention, and screening is not recommended for persons > 75.

If elderly persons are screened, a full lipid profile should be obtained. For many elderly persons, the predominant reason for a high TC level is a high HDL-C level, not a high LDL-C level; therefore, their risk of CAD is decreased, not increased. Some persons have normal TC and TG levels but an HDL-C level below the 10th percentile and thus have a very high risk of CAD.

TG levels can be accurately measured only after a fast. If the TG level is < 400 mg/dL (< 4.52 mmol/L), the LDL-C component of the lipid profile can be estimated using the Friedewald equation: LDL-C = TC - [HDL-C + (TG/5)].

Basal lipoprotein measurements usually cannot be determined in the following situations: during a fever or major infection; within 4 weeks of an acute MI, a stroke, or major surgery; immediately after acute excessive alcohol intake; in diabetes mellitus that is severely out of control (fasting blood glucose level > 250 mg/dL (> 13.9 mmol/L), glycosylated hemoglobin > 9%); or during rapid weight loss.

Certain characteristic findings (eg, tendinous, tuberous, or palmar-planar xanthomas; arcus juvenilis corneae) are diagnostically useful (see Table 63-1). Obesity (with or without essential hypertension), glucose intolerance, and hyperuricemia may indicate primary hypertriglyceridemia or hypoalphalipoproteinemia.

Secondary lipoprotein disorders are common, even among patients with a well-defined primary lipoprotein disorder, and may exacerbate the expression of the primary disorder, particularly severe hypertriglyceridemia. Thus, when a primary lipoprotein disorder is first diagnosed, a physical examination should be performed, and a drug, occupational, family, dietary, and alcohol-intake history should be obtained. Levels of thyroxine, thyroid-stimulating hormone, blood urea nitrogen or creatinine, and fasting blood glucose should be measured, and urinalysis and liver function tests should be performed.

Treatment

The NCEP guidelines recommend treatment of persons in the top quintile for TC levels (although in the elderly, use of TC levels alone can be misleading) and of persons with an LDL-C level >= 160 mg/dL (>= 4.14 mmol/L) or lower depending on the number of CAD risk factors and the presence of CAD or other atheromatous disease. Patients are considered at high risk if they have two or more CAD risk factors (age > 45 for men or > 55 for women, premature menopause without estrogen replacement therapy, a family history of CAD, current cigarette smoking, hypertension, low HDL-C levels, and diabetes). One risk factor is subtracted if HDL-C levels are >= 60 mg/dL (>= 1.55 mmol/L).

Therefore, NCEP recommendations for initiation of dietary or drug treatment are based on LDL-C levels (see Table 63-3). The goals of treatment are to lower TC and LDL-C levels to the recommended levels, to lower TG levels to < 500 mg/dL (< 5.65 mmol/L) and thus avoid pancreatitis, and to increase HDL-C levels to > 35 mg/dL (> 0.91 mmol/L), preferably to >= 40 mg/dL (>= 1.03 mmol/L). For postmenopausal women, a high TG level is an important independent risk factor for CAD; thus, lowering the level to < 250 mg/dL (< 2.82 mmol/L) is probably valuable.

Because the NCEP guidelines are not based on data from nor designed specifically for the elderly, several factors should be considered when deciding whether elderly patients with a lipoprotein abnormality should be treated:

• Decisions should not be based primarily on the patient's age. Many elderly patients are physiologically and mentally much younger than their chronologic age.
• Some benefits of treatment may be realized almost immediately: Significant lowering of LDL-C levels can lead to increased endothelial cell production of nitrous oxide (a potent vasodilator) and can reduce platelet aggregation; significant lowering of TG levels sharply decreases plasminogen activator inhibitor activity and increases fibrinolysis. Often, treatment stops progression of atherosclerotic lesions or induces regression within 1 to 2 years.
• If patients have other life-limiting conditions, aggressive lipid-lowering treatment may be inappropriate or less useful.
• Elderly patients who take many drugs may be less likely to comply with drug regimens, and their risk of drug-drug interactions is increased. Although lipid-lowering treatment can reduce long-term costs for some patients, elderly patients with a fixed income may have difficulty affording the better tolerated and more effective drugs.
• Strict lipid-lowering diets may be effective in the elderly but may lead to or exacerbate malnutrition, as may voluntary dietary restriction. Unappetizing low-fat diets can cause anorexia and eventually lead to nutritional deficiencies. The potential morbidity of protein-energy malnutrition probably outweighs that of moderate hypercholesterolemia.

Dietary treatment: Because the elderly have difficulty maintaining adequate caloric and protein intake and are at risk of malnutrition, a moderate approach to diet is generally recommended (see Table 63-4). Patients can be advised to trim fat from meat; to increase intake of fish, soybean products, and beans; to avoid fried foods; and to use monounsaturated fats (eg, olive oil). Consumption of foods rich in soluble fiber (eg, oat bran) may also lower lipid levels. Phytosterols, present in soybean products, and stanol esters, available as a margarine product, decrease cholesterol absorption.

A strict diet may be preferred for some patients. Aerobic exercise should be included as part of treatment because the benefits of diet without exercise may be limited. A low-saturated-fat, low-cholesterol diet should be tried for 6 months before drug therapy is instituted.

For patients with a high LDL-C level, the American Heart Association and NCEP recommend a two-step diet (see Table 63-5). High-risk patients should start with the step 1 diet. Patients who are already following the equivalent of a step 1 diet should start with the step 2 diet. Elderly persons may have difficulty consuming adequate calories and protein, so the diet must be modified cautiously. However, the step 1 and 2 dietary guidelines and the practical approach shown in Table 63-4 should be safe for most elderly persons. The full effects of dietary treatment at either step may not be achieved for 8 to 12 weeks; therefore, patients should advance to step 2 only if the therapeutic goal is not reached in 8 to 12 weeks. Weight loss helps lower TC, LDL-C, and TG levels but is at least as difficult for the elderly as for younger persons.

For patients with hypertriglyceridemia, a low HDL-C level, and an increased risk of CAD, dietary interventions are important. The major goal is to increase the HDL-C level, although lowering the TG level alone may be valuable for women > 50. When the TG level is > 1000 mg/dL (> 11.29 mmol/L), a sharp reduction in total fat intake (to < 30 g/day) helps prevent TG-induced pancreatitis. Other goals are to lose weight, because modest weight loss can markedly lower TG levels; to reduce alcohol intake to <= 3 drinks per week or, if TG levels are >= 500 mg/dL (>= 5.65 mmol/L), to discontinue alcohol; and to reduce the intake of total fat, saturated fat, and cholesterol using the step 2 diet.

For patients who have a TG level >= 1000 mg/dL (>= 11.29 mmol/L) with high levels of chylomicron and VLDL-TG or who have the much rarer primary hyperchylomicronemia, total fat intake should be restricted to 10 to 20% of total calories, primarily to prevent TG-induced pancreatitis. Also, the sharp decrease in VLDL-C levels and the increase in HDL-C levels that result may help prevent patients with high levels of chylomicron and VLDL-TG from developing severe premature CAD. Weight loss is crucial for obese patients. For patients with severe hypertriglyceridemia, estrogen is contraindicated.

For patients who have type III hyperlipoproteinemia and are overweight, the single most important strategy is weight loss. Patients should reduce intake not only of total fat, saturated fat, and cholesterol but also of dietary sugars.

For patients with hypoalphalipoproteinemia, the only consistently effective dietary strategy is weight loss, which may increase HDL-C levels. Other strategies to increase HDL-C levels include supplementation with fish oils rich in omega-3 fatty acids (4 to 12 g/day), smoking cessation (or at least reduction), and aerobic activity (three to five 30-minute periods per week). At least initially, exercise should be supervised by a physician. Intake of moderate amounts of alcohol can increase HDL-C levels, but only if hepatic synthetic function is normal.

Drug treatment: If hyperlipoproteinemia persists after secondary causes have been identified and treated when possible and after dietary treatment has been tried, drug treatment should be used (see Table 63-6). When a single drug is inadequate, two drugs may be required.

Bile acid-binding resins (eg, cholestyramine, colestipol) interrupt the normal enterohepatic circulation of bile acids and indirectly increase the liver's catabolism of LDL-C by stimulating hepatocytes to synthesize more LDL receptors. These drugs can reduce CAD risk.

Resins are effective and safe as first-line drugs to lower the LDL-C level in patients whose primary abnormality is a high LDL-C level and whose TG level is < 250 mg/dL (< 2.82 mmol/L). However, they may increase the TG level. If the TG level increases to > 300 mg/dL (> 3.38 mmol/L) during resin therapy, nicotinic acid or gemfibrozil (1200 mg/day) may be added, particularly if the patient has high LDL-C and TG levels; the resin and nicotinic acid act synergistically. Alternatively, an HMG-CoA reductase inhibitor (statin) can be used instead of the resin or resin combination therapy.

Resins should be started in small doses (8 to 10 g/day), particularly for the elderly. Many patients respond to the lowest dose, but the dose should be adjusted according to effect on LDL-C levels. Constipation, the most common adverse effect, can usually be avoided by increasing dietary fiber or by using stool softeners. Because resins are not systemically absorbed, they have essentially no systemic adverse effects (except for rare, mild, reversible changes in liver enzymes).

Resins can augment warfarin's effects; however, if a resin and warfarin are taken within a short time, the resin can also bind warfarin. Thus, resins should be used cautiously, if at all, with warfarin-like anticoagulants. Resins should not be given concurrently with exogenous thyroid hormones, sex hormones, prednisone, or digoxin, all of which may be bound in the intestine by resins. These drugs should be given at least 2 hours before the first resin dose of the day.

Resins are probably contraindicated as single-drug therapy in patients with a high LDL-C level and a TG level > 300 mg/dL and in those with severe hemorrhoids or a history of bowel resection or severe constipation; a statin may be used.

Nicotinic acid (niacin) inhibits secretion of VLDL from the liver, lowering VLDL-C and LDL-C levels. In patients with CAD, it reduces the incidence of recurrent MI and all-cause mortality. Nicotinic acid can be used as a first-line drug, but it is usually added to resin therapy if the resin does not lower LDL-C levels sufficiently. The initial dose is 100 mg bid or tid. The frequency of administration and total daily dose should be increased slowly at about weekly intervals, as necessary. Generally, an initial maintenance dosage of 1.5 to 2 g/day is required. Every 6 to 8 weeks, liver function tests and stool tests for occult blood should be performed, and blood glucose, uric acid, and LDL-C levels should be measured.

Adverse effects of nicotinic acid are common, bothersome, and often severe (see Table 63-6). Flushing may be ameliorated by taking aspirin 80 to 325 mg 30 to 60 minutes before taking nicotinic acid, but aspirin may cause gastrointestinal adverse effects in the elderly. Fast-release formulations of nicotinic acid are preferable because hepatotoxicity appears to be more common and more severe with slow-release formulations. If possible, nicotinic acid should not be used concurrently with a statin, because risk of myositis and hepatotoxicity is increased.

HMG-CoA reductase inhibitors (statins) block intracellular cholesterol biosynthesis and force cells to synthesize more LDL receptors, thus increasing the catabolism of LDL cholesterol. Statins include atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. Statins are becoming the cholesterol-lowering drugs of choice because they are generally safe, have a relatively favorable adverse effect profile, and effectively lower TC levels (by 15 to 45%) and LDL-C levels (by 20 to 40%) and increase HDL-C levels (by 5 to 15%). Statins also effectively lower TG levels (by 10 to 35%). Lovastatin should be taken with food. The others do not have this restriction and are usually taken at bedtime.

Adverse effects are relatively rare and usually transient. Because liver enzyme (particularly transaminase) levels may increase, liver function tests should be performed before treatment, at 6 and 12 weeks after initiation of treatment or after elevation in dose, and at 6-month intervals thereafter. Increases in transaminase levels should be monitored until levels return to normal. Usually, a statin is not discontinued unless the liver enzyme elevations exceed three times the upper limit of normal.

A statin may be the drug of choice for patients with a high LDL-C level and a TG level > 300 mg/dL and for those with severe hemorrhoids or a history of bowel resection or severe constipation. Gemfibrozil may be added if the TG level remains > 300 mg/dL and the patient is at high risk of or has had an atherosclerotic event.

Statins can be used effectively with resins but probably should not be used with nicotinic acid because the risks of myopathy and hepatotoxicity are increased.

The concurrent use of a statin and cyclosporine commonly produces myopathy and may also produce rhabdomyolysis and myoglobinuria. This drug combination should thus be restricted to situations in which other lipid-lowering regimens are ineffective, and patients should be closely monitored.

Erythromycin and its derivatives should not be given concurrently with a statin because the risk of myopathy is increased.

Gemfibrozil, a fibric acid derivative, increases the hydrolysis of VLDL-TG and the synthesis of HDL-C and apolipoprotein A-I. Gemfibrozil lowers LDL-C and TG levels and reduces CAD morbidity and mortality rates in appropriate patients. It is the drug of choice for elderly patients with hypertriglyceridemia or hypoalphalipoproteinemia. Gemfibrozil should be considered for patients with a high TG level (> 300 mg/dL), a low HDL-C level (< 35 mg/dL [< 0.91 mmol/L]), and a moderately high LDL-C level (< 190 mg/dL [< 4.92 mmol/L]). Well tolerated by most patients, gemfibrozil rarely causes gastrointestinal upset or myopathy, although myopathy is more common when the drug is given to patients with impaired renal function. For such patients, especially if they are also receiving cyclosporine, the dose should be reduced.

Combined gemfibrozil-statin therapy may be necessary for patients at highest risk of CAD who have evidence of atherosclerosis. Such patients often have combined hyperlipidemia, usually with high TC, high TG, and low HDL-C levels, which are maintained despite significant dietary, weight, and exercise modification. When these patients are treated with gemfibrozil alone, TG levels can usually be normalized and HDL-C levels can often be increased to > 35 mg/dL (> 0.91 mmol/L), but TC and LDL-C levels may not be adequately lowered and often increase. Conversely, when these patients are treated with a statin alone, LDL-C levels can usually be normalized, but TG levels often remain high, and HDL-C levels often remain low (< 35 mg/dL).

Because myopathy, rhabdomyolysis, myoglobinuria, and renal injury have been reported in patients taking combined gemfibrozil-statin therapy, the following guidelines are recommended:

• It should be reserved for secondary prevention.
• It should not be used if patients have a very low creatinine clearance rate, because the risk of myopathy is increased.
• It should not be used concurrently with cyclosporine or nicotinic acid, because the risk of myopathy is increased.
• It can be used if patients are reliable and are well informed about the possibility of myopathy.
• Creatine kinase levels should be measured and liver function tests should be performed at baseline and every 6 to 8 weeks thereafter.
• Patients should take gemfibrozil 1.2 g/day po and the lowest starting dose of the statin. The statin dose should be adjusted to the lowest dose that will lower LDL-C levels to the target range.

Probucol appears to increase the rate of LDL-C catabolism, probably through pathways not mediated by LDL receptors. One hypothesis is that the antioxidant effect of probucol may reduce atherosclerosis by reducing the atherogenic effect of oxidized LDL-C. The effect of probucol on CAD risk has not been established.

Probucol is considered a second-line drug in the NCEP guidelines. Probucol usually lowers LDL-C levels by about 8 to 15%, but because it also lowers HDL-C levels by as much as 25%, its role in treating patients with a high LDL-C level is uncertain. Xanthoma regression has been reported as HDL-C levels decrease.

Generally, probucol is well tolerated; diarrhea is the most common adverse effect. Because the drug can prolong the QT interval, it is probably contraindicated in patients with ventricular irritability and an initially prolonged QT interval and in those taking other drugs that prolong the QT interval. The combination of probucol and a resin is effective; the reduction in the HDL-C level is less than that with probucol alone, and constipation is much less common than with a resin alone.

Fish oils containing omega-3 fatty acids are available over the counter but can also be obtained in reasonable amounts by eating a 3-oz (cooked) portion of oily fish (eg, herring, mackerel, salmon, shad, trout). Data about the long-term effectiveness and adverse effects of fish oil supplements are scarce; however, for short-term use, doses of <= 15 g/day appear to be safe and can lower TG levels, but they are not useful in lowering cholesterol levels. They may increase the hydrolysis of VLDL-TG. In patients with hypertriglyceridemia, fish oils may increase HDL-C levels by 10 to 15%. At much higher doses (usually > 50 g/day), they may be associated with thrombocytopenia and increased bleeding time; such doses are almost never used clinically. In rare cases when doses of > 20 g/day are used, platelet counts and bleeding time should be monitored. At such doses, fish oils may interfere with glucose control in patients with diabetes.

Estrogen replacement therapy: Postmenopausal women who receive unopposed estrogen replacement therapy have lower LDL-C levels (by 15 to 25%) and higher HDL-C levels (by 16 to 21%) than those who do not receive this therapy; as a result the LDL-C/HDL-C ratio is substantially decreased. Such therapy also lowers Lp(a) levels. Unopposed estrogen therapy appears to reduce the risk of cardiovascular death. The addition of a progestin to reduce the risk of endometrial hyperplasia and endometrial cancer may limit or eliminate the benefit observed with unopposed estrogen, and may even initially increase the risk of coronary artery disease.

Estrogen replacement therapy can be used alone or with other lipid-modifying treatments. Estrogen substantially elevates TG levels in women with preexisting hypertriglyceridemia, occasionally to levels that can cause lethal pancreatitis. Consequently, fasting TG levels should be measured before initiating estrogen replacement therapy (with or without a progestin). Estrogen replacement therapy is contraindicated in women with familial hypertriglyceridemia and a TG level > 300 mg/dL after modification of diet and alcohol intake.

Antioxidant therapy: The toxicity of LDL-C may be reduced by the use of antioxidants. According to one hypothesis, atherosclerosis progresses because "toxic LDL" triggers the development of fatty streaks. Toxic LDL is formed when the lipid component of the lipoprotein is oxidized by endothelial cells and smooth muscle cells. Oxidation occurs via a free radical mechanism involving superoxide anions and hydrogen peroxide. The oxidized LDL functions as a chemotactic agent for monocytes, transforming them to macrophages, which stimulate cholesterol esterification and the formation of foam cells.

-Tocopherol (vitamin E) inhibits the oxidation of LDL in vitro. In several studies, vitamin E consumption appeared to be strongly and inversely correlated with CAD risk. Vitamin E supplementation for short periods produced no benefit, but supplementation for at least 2 years was associated with a lower risk of CAD in men and women.

Vitamin A, a -carotenoid, may affect atherosclerosis by scavenging oxidizing free radicals. In observational studies, the CAD mortality rate appeared to be strongly and inversely correlated with dietary carotene intake.

Ascorbic acid (vitamin C) is considered a secondary antioxidant; it works synergistically with vitamin E, regenerating vitamin E from the vitamin E radical. Vitamin C may also enhance the transformation of cholesterol into bile acids.

Treatment of special conditions: Treating elderly patients with an isolated low HDL-C level (usually well below 35 mg/dL [0.91 mmol/L]), a TC level < 200 mg/dL (< 2.26 mmol/L), and a TG level < 250 mg/dL (< 2.82 mmol/L) is a challenge. If lifestyle changes (weight loss, increased aerobic exercise, cessation of cigarette smoking) do not increase the HDL-C level and particularly if the patient has had an atherosclerotic event or is at high risk because of primary hypoalphalipoproteinemia or other CAD risk factors, drug treatment is warranted. However, the best approach has not been established. Nicotinic acid 1.5 to 6.0 g/day or gemfibrozil 1.2 g/day may be effective, particularly if the Lp(a) level is also high. If these drugs are ineffective or cannot be tolerated, a statin may be given to lower the TC level to < 160 mg/dL (< 4.14 mmol/L) or the LDL-C level to < 100 mg/dL (< 2.59 mmol/L); the HDL-C level usually does not change, but the TC/HDL-C ratio is usually substantially decreased.

High Lp(a) levels cannot be lowered by diet and can be lowered only modestly by nicotinic acid. Most other drugs that lower LDL-C levels do not substantially alter Lp(a) levels. Therefore, aggressive modification of other CAD risk factors, if present, is important.