Research over the past 4 decades has consistently shown the burden of dyslipidemia to be very high in terms of morbidity, mortality, and medical costs. Dyslipidemia is an important major risk factor for coronary heart disease (CHD), which is the leading cause of death in the United States. The World Health Organization estimates that dyslipidemia is associated with more than half of global cases of ischemic heart disease and more than 4 million deaths per year.(1,2)
A study among rural adults in Pakistan (n = 1658), reported the prevalence of hypercholesterolemia, hypertriglyceridemia, low HDL-C (high-density lipoproteins cholesterol) and high LDL-C (high-density lipoproteins cholesterol) as 30.6%, 29.4%, 79.6% and 41.2% respectively. A survey in Pakistan revealed that a large proportion of the population had lipid abnormalities and females had significantly greater values of total cholesterol.(3)
TRIGLYCERIDES: Triglycerides are fats consisting of 3 fatty acids covalently bonded to a glycerol molecule. These fats are synthesized by the liver or, in the case of those derived from dietary sources, are ingested by the liver; the triglycerides are subsequently transported throughout the circulation by triglyceride-rich lipoproteins.
Triglyceride-rich lipoproteins come from 2 sources, often described as the endogenous and exogenous pathways. In the exogenous pathway, dietary fats (triglycerides) are hydrolyzed to free fatty acids (FFAs) and monoglycerides and are absorbed, with cholesterol, by intestinal cells. They are then re-esterified and combined with apolipoproteins and phospholipids to form a nascent chylomicron, a process requiring microsomal triglyceride transfer protein (MTP). The initial apolipoproteins are apolipoprotein (apo) A, which are soluble and can transfer to HDL; and apo B48, a structural apolipoprotein that is not removed during catabolism of the chylomicron. Chylomicrons enter the plasma via the thoracic duct, where they acquire other soluble apolipoproteins, including apo CI, apo CII, apo CIII, and apo E, from HDL.
VERY LOW DENSITY LIPOPROTEINS (VLDLS) AND APOLIPOPROTEINS: VLDLs are produced by a process analogous to the exogenous pathway. Triglycerides may derive from de novo FFA synthesis in the liver and are metabolized by lipoprotein lipase to intermediate-density lipoprotein (IDL), also called VLDL remnants. Lipoprotein lipase hydrolyzes triglycerides, releasing FFAs, which are taken up by myocytes and hepatocytes. Some apo Cs, phospholipids, and apo Es are lost, and triglycerides are transferred to HDL in exchange for cholesterol esters. IDL is, thus, cholesterol-enriched and triglyceride-poor compared to unmetabolized VLDL. As IDL is metabolized by hepatic lipase to LDL, the remaining surface apolipoproteins are lost.(4,5,6)
Triglycerides may also derive from the uptake of remnant chylomicrons, VLDL, or FFAs from the plasma. Precursor VLDL combines triglycerides, the structural or transmembrane apo B100, and phospholipids, as well as cholesterol and some apo Cs and Es. The formation of the immature VLDL requires microsomal transfer protein (MTP). Once secreted into the plasma, VLDLs acquire more apo Cs and Es.
APOES: Apoes are ligands that have greater affinity for the LDL receptor than does apo B100. In fact, the LDL receptor is more accurately designated the B/E receptor. Apo E also binds with high affinity to the LDL receptor-related protein, which takes up chylomicron remnants, VLDL, and IDL. In addition, apo E binds to cell-surface heparan sulfate proteoglycans (HSPGs), which assists in the hepatic uptake of remnant lipoproteins.(4)
The apo E gene has been cloned, sequenced, and mapped to chromosome 19. Genetically altered apo E–deficient mice develop severe dyslipidemia with accelerated atherosclerosis, whereas transgenic mice overexpressing apo E appear to be protected from atherosclerosis.(7,8) Apo E has 3 isoforms that are present in slightly varying proportions, depending on race and geographic location.(5) Apo E3 is the most prevalent allele and for that reason was considered the “wild type” allele from which apo E2 and apo E4 were derived. Newer data, however, suggest that apoA4 was the earliest form of the protein.(9)
Most animals, including primates, possess an apo E4 equivalent.(10) Compared with apo E3, apo E2 has less affinity for the receptor, and apo E4 has more. The alleles differ in 2 amino acid positions, 112 and 158. Apo E2 is most commonly caused by cysteine substituted for arginine at position 158 in apo E3. In apo E4, an arginine is substituted for cysteine at position 112 in apo E3. The substitutions are recessive in that dysbetalipoproteinemia requires the presence of 2 apo E-2 isoforms.(10) Other very rare genetic variants of apo E exist, and several of these have been shown to have defective binding to the LDL receptor and LDL receptor-like protein. These variants act in a dominant fashion in that only 1 copy of apo E is necessary for susceptibility to development of type III hyperlipidemia. White populations, approximately 1% of these individuals are homozygous for apo E2 (“first hit”); however, only 10% of those will develop the condition. A “second hit” is necessary, most commonly metabolic abnormalities that cause increases in VLDL.(4) Other, less common genetic conditions can also predispose people to dysbetalipoproteinemia.
More than 90% of patients with dysbetalipoproteinemia are homozygous for apo E2; the remainder have a rare, usually dominant, defect in apo E2. In addition to the apoE2 homology or defect, and combined with a metabolic condition, other genetic factors have been suggested that increase the likelihood of developing dysbetalipoproteinemia. Polymorphisms in the apo A5, lipoprotein lipase and apo C3 have all been mentioned as possible cofactors for the condition.(5)
Accumulation of IDL is caused by the poor affinity of apo E2 to LDL receptors, whereas LDL uptake via apo B100 is unaffected. In fact, total cholesterol, LDL cholesterol, and apo B are usually low compared with those with apo E3. HDL cholesterol levels may be normal or decreased. The following 3 mechanisms have been postulated for the hypocholesterolemic effect of apo E2:(11)
- Increased upregulation of LDL receptors due to decreased binding of lipoproteins containing apo E2
- Increased hepatic LDL uptake due to lower LDL receptor affinity of apo E2 and consequent decreased competition with the apo B100 born by LDL (its sole apolipoprotein)
- Apo E2 interference with lipolysis of VLDL to LDL(4)
CHYLOMICRON AND VLDL METABOLISM: Any disturbance that causes increased synthesis of chylomicrons and / or VLDLs or decreased metabolic breakdown causes elevations in triglyceride levels. That disturbance may be as common as dietary indiscretion or as unusual as a genetic mutation of an enzyme in the lipid metabolism pathway. Essentially, hypertriglyceridemia occurs through 1 of the following 3 processes:(12)
- Abnormalities in hepatic VLDL production, and intestinal chylomicron synthesis
- Dysfunctional lipoprotein lipase -mediated lipolysis
- Impaired remnant clearance
As shown in the images below, chylomicrons and VLDLs are initially metabolized by lipoprotein lipase, which hydrolyzes the triglycerides, releasing FFAs; these FFAs are stored in fat and muscle. With normal lipoprotein lipase activity, the half-lives of chylomicrons and VLDLs are about 10 minutes and 9 hours, respectively. Because of the large size of unmetabolized chylomicrons, they are unlikely to be taken up by macrophages, which are the precursors of foam cells. Foam cells promote fatty streak formation, the precursor of atherosclerotic plaque. Lipoprotein lipase activity produces chylomicron remnants that are small enough to take part in the atherosclerotic process. Chylomicron remnants are taken up by the LDL receptor or the LDL receptor-related protein.(13)
Chol = cholesterol; TGS = triglycerides.
(Courtesy by Medscape)
Lipoprotein lipase (LPL) releases free fatty acids (FFAs) from chylomicrons (chylo) and produces chylomicron remnants that are small enough to take part in the atherosclerotic process.
Chol = cholesterol; TGs = triglycerides.
(Courtesy by Medscape)
Once very low-density lipoprotein (VLDL) has been metabolized by lipoprotein lipase, VLDL remnants in the form of intermediate-density lipoprotein (IDL) can be metabolized by hepatic lipase, producing low-density lipoprotein (LDL), or they can be taken up by the LDL receptor via either apolipoprotein B (apo B) or apo E.
VLDL REMNANTS HAVE 1 OF 2 FATES: They can be metabolized by hepatic lipase, which further depletes triglycerides, producing LDL, or they can be taken up by the LDL receptor via either apo B or apo E. VLDL remnants are not only triglyceride-poor, they are also cholesterol enriched, having acquired cholesterol ester from HDL via the action of cholesterol ester transfer protein (CETP), which facilitates the exchange of VLDL triglycerides for cholesterol in HDL. This pathway may promote HDL's reverse cholesterol transport activity, but only if VLDL and LDL return cholesterol to the liver. If these lipoproteins are taken up by macrophages, the CETP transfer results in increased atherogenesis.
Chylomicron remnants, VLDL, VLDL remnants, and LDL are all atherogenic.
Hypercholesterolemia develops as a consequence of abnormal lipoprotein metabolism, mainly reduction of LDL receptor expression or activity, and consequently diminishing hepatic LDL clearance from the plasma. It is a major predisposing risk factor for the development of atherosclerosis. This mechanism is classically seen in familial hypercholesterolemia and when excess saturated or trans-fat is ingested. In addition, excessive production of VLDL by the liver, as seen in familial combined hyperlipidemia and insulin resistance states such as abdominal obesity and type 2 diabetes, can also induce hypercholesterolemia or mixed dyslipidemia.
A current theory for the initiating event in atherogenesis is that apoprotein B-100-containing lipoproteins are retained in the subendothelial space, by means of a charge-mediated interaction with extracellular matrix and proteoglycans.(14) This allows reactive oxygen species to modify the surface phospholipids and unesterified cholesterol of the small LDL particles. Circulating LDL can also be taken up into macrophages through unregulated scavenger receptors. As a result of LDL oxidation, isoprostanes are formed. Isoprostanes are chemically stable, free radical-catalyzed products of arachidonic acid, and are structural isomers of conventional prostaglandins. Isoprostane levels are increased in atherosclerotic lesions, but they may also be found as F2 isoprostanes in the urine of asymptomatic patients with hypercholesterolemia.(15)
A strong association exists between elevated plasma concentrations of oxidized LDL and CHD.(16) The mechanisms through which oxidized LDL promotes atherosclerosis are multiple and include damage to the endothelium, induction of growth factors, and recruitment of macrophages and monocytes.
Vasoconstriction in the setting of high levels of oxidized LDL seem to be related to a reduced release of the vasodilator nitric oxide from the damaged endothelial wall as well as increased platelet aggregation and thromboxane release.
Smooth muscle proliferation has been linked to the release of cytokines from activated platelets.(17)
The state of hypercholesterolemia leads invariably to an excess accumulation of oxidized LDL within the macrophages, thereby transforming them into "foam" cells. The rupture of these cells can lead to further damage of the vessel wall due to the release of oxygen free radicals, oxidized LDL, and intracellular enzymes.
The burden of hypercholesterolemia is related to its link to atherosclerosis and coronary heart disease (CHD). In adults, elevations in total cholesterol (TC), LDL-C and non-HDL-C are risk factors for atherosclerotic cardiovascular disease, specifically CHD,(18) which may lead to sudden coronary death and myocardial infarction (MI). The association of triglyceride levels with CHD is unclear.
Hypertriglyceridemia can be associated with pancreatitis when the triglyceride levels are markedly elevated (i.e. when the triglyceride concentration is greater, and often very much greater, than 1000 mg/dl or 12 mmol/l).
SIGN AND SYMPTOMS:
The onset of dyslipidemia may be presented with several signs and symptoms that can help in diagnosing the blood disorder.
Some of the common symptoms that may be encountered in relation to dyslipidemia may include the following:
CORNEAL OPACIFICATION: is among the ocular findings that may be exhibited to people with dyslipidemia. The ophthalmologic sign is the result of very low level of high density lipoprotein due to a mutation in the regulatory genes.
CORNEAL ARCUS: is also among the ophthalmologic sign that may be exhibited by a person with dyslipidemia. This clinical manifestation associated with dyslipidemia is common to people below the age of 50 years.
LIPEMIA RETINALIS: Severe hypertriglyceridemia (> 2000 mg / dL [> 22.6 mmol / L]) can give retinal arteries and veins a creamy white appearance (lipemia retinalis). Extremely high lipid levels also give a lactescent (milky) appearance to blood plasma.
XANTHOMAS: is the most common dermatologic sign of dyslipidemia. These are firm and non-tender deposit of cutaneous that are cholesteryl ester-enriched foam cells that are commonly observed in people with high levels of low density lipoproteins.
Planar xanthomas are flat or slightly raised yellowish patches. Tuberous xanthomas are painless, firm nodules typically located over extensor surfaces of joints. Patients with severe elevations of Triglycerides (TGs) can have eruptive xanthomas over the trunk, back, elbows, buttocks, knees, hands, and feet.
The mentioned are just a few of the condition that are associated with dyslipidemia and other signs and symptoms may also include the following:
- Balance impairment
- Pain in the calf when walking
- Abdominal pain
- Difficulty in speaking
After a prolonged period, following conditions may appear:
- Coronary artery disease (CAD)
- Ischemic heart disease
- Peripheral vascular disease
- Cerebrovasular disease and kidney disease
High levels of TGs (> 1000 mg / dL [> 11.3 mmol / L]) can cause acute pancreatitis.
Primary lipid disorders are suspected when patients have physical signs of dyslipidemia, onset of premature atherosclerotic disease (at <60 yr), a family history of atherosclerotic disease, or serum cholesterol > 240 mg / dL (> 6.2 mmol/L). Dyslipidemia is diagnosed by measuring serum lipids. Routine measurements (lipid profile) include total cholesterol (TC), TGs, HDL cholesterol, and LDL cholesterol.
LIPID PROFILE MEASUREMENT: TC, TGs, and HDL cholesterol are measured directly. TC and TG values reflect cholesterol and TGs in all circulating lipoproteins, including chylomicrons, VLDL, intermediate-density lipoprotein (IDL), LDL, and HDL. TC and HDL cholesterol can be measured in the nonfasting state, but most patients should have all lipids measured while fasting (usually for 12 h) for maximum accuracy and consistency.
Testing should be postponed until after resolution of acute illness because TG and lipoprotein(a) levels increase and cholesterol levels decrease in inflammatory states. Lipid profiles can vary for about 30 days after an acute MI; however, results obtained within 24 h after MI are usually reliable enough to guide initial lipid-lowering therapy.
OTHER TESTS: Patients with premature atherosclerotic cardiovascular disease, cardiovascular disease with normal or near-normal lipid levels, or high LDL levels refractory to drug therapy should probably have Lp(a) levels measured. Lp(a) levels may also be directly measured in patients with borderline high LDL cholesterol levels to determine whether drug therapy is warranted. C-reactive protein may be considered in the same populations. Measurements of LDL particle number or apoprotein B-100 (apo B) may be useful in patients with elevated TGs and the metabolic syndrome. Apo B provides similar information to LDL particle number because there is one apo B molecule for each LDL particle. Apo B measurement includes all atherogenic particles, including remnants and Lp(a).
TEST FOR SECONDARY CAUSES: Tests for secondary causes of dyslipidemia including measurements of fasting glucose, liver enzymes, creatinine, thyroid-stimulating hormone (TSH), and urinary protein, should be done in most patients with newly diagnosed dyslipidemia and when a component of the lipid profile has inexplicably changed for the worse.
UNIVERSAL SCREENING: Universal screening using a fasting lipid profile (TC, TGs, HDL cholesterol, and calculated LDL cholesterol) should be done in all children between age 9 and 11 (or at age 2 if children have a family history of severe hyperlipidemia or premature CAD). Adults are screened at age 20 yr and every 5 yr thereafter. Lipid measurement should be accompanied by assessment of other cardiovascular risk factors, defined as
- Diabetes mellitus
- Cigarette use
- Family history of CAD in a male 1st-degree relative before age 55 or a female 1st-degree relative before age 65
A definite age after which patients no longer require screening has not been established, but evidence supports screening of patients into their 80s, especially in the presence of atherosclerotic cardiovascular disease.
Patients with an extensive family history of heart disease should also be screened by measuring Lp(a) levels.
PATIENT SELECTION FOR TREATMENT:
The importance of treating dyslipidemias based on cardiovascular risk factors is highlighted by the National Cholesterol Education Program guidelines. The first step in evaluation is to exclude secondary causes of hyperlipidemia. Assessment of the patient's risk for coronary heart disease helps determine which treatment should be initiated and how often lipid analysis should be performed.
The target LDL cholesterol value in patients with coronary heart disease or other atherosclerotic disease is 100 mg per dL (2.60 mmol per L) or lower. If the LDL level does not exceed 100 mg per dL in a patient with coronary heart disease, the patient should begin the step I diet, regularly participate in physical activity and stop smoking. Annual lipoprotein analysis is indicated for this group.
The NCEP guidelines recommend that patients at higher risk of coronary heart disease receive more intensive interventions for dyslipidemia than patients at lower risk. Persons at highest risk for future coronary events have a history of coronary heart disease or extracoronary atherosclerotic disease. For all practical purposes, treatment of patients with multiple risk factors for coronary heart disease but without a history of coronary disease should be as aggressive as that for patients with coronary heart disease.
The NCEP guidelines recommend dietary modification, exercise and weight control as the foundation of treatment of dyslipidemia.(19) A reduction in total cholesterol by 1 percent may decrease a person's risk of developing coronary heart disease by 2 percent.(20) Cessation of cigarette smoking and reduction of other modifiable risk factors are essential aspects of prevention of coronary heart disease.
EXERCISE AND WEIGHT REDUCTION: Obesity frequently elevates cholesterol levels in both very-low-density lipoprotein (VLDL) and LDL fractions, raises triglyceride levels, lowers HDL cholesterol levels, raises blood pressure and promotes glucose intolerance. Weight loss lowers total cholesterol and its LDL and VLDL fractions, lowers triglycerides and raises HDL cholesterol.(21) Weight loss also lowers blood pressure and improves glycemic control.
Patients are more likely to comply with exercise programs that are tailored to meet individual goals, interests and needs. Most patients benefit from aerobic exercise that targets large muscle groups, performed for 30 minutes four or more times a week.(21) Shorter, but more frequent, aerobic exercise sessions provide similar benefits. Overweight patients should engage in low-intensity exercise more frequently and for longer durations.
ALCOHOL INTAKE: Alcohol exerts several effects on lipid levels, including raising the serum triglyceride and HDL cholesterol levels. Its effect on LDL cholesterol appears to be minimal. Since excessive alcohol causes numerous adverse effects, including hepatic toxicity, cardiomyopathy, motor vehicle crashes and extensive psychosocial consequences, it is not recommended for the prevention of coronary heart disease.(19)
STEP I AND STEP II DIETS: Dietary therapy should be initiated in patients who have borderline-high LDL cholesterol levels (130 to 159 mg per dL [3.35 to 4.10 mmol per L]) and two or more risk factors for coronary heart disease and in patients who have LDL levels of 160 mg per dL (4.15 mmol per L) or greater. The objective of dietary therapy in primary prevention is to decrease the LDL cholesterol level to 160 mg per dL if only one risk factor for coronary heart disease is present and to less than 130 mg per dL if two or more risk factors are identified. In the presence of documented coronary heart disease, dietary therapy is indicated in patients who have LDL values exceeding 100 mg per dL (2.60 mmol per L), with the aim of lowering the LDL level to 100 mg per dL or less.
Step I and Step II diets are designed to progressively reduce intake of saturated fats, cholesterol and total calories to decrease lipoprotein values and promote weight loss in overweight persons.(19) Complex carbohydrates, rather than simple sugars, should be emphasized.
Examples of Foods to Eat and Foods to Avoid in the Step I and Step II Diets(22)
||FOODS TO EAT
||FOODS TO AVOID
|Lean meat, poultry and fish (≤6 oz a day)
||Beef, lamb—lean cuts, well-trimmed before cooking
||Beef, lamb—regular, ground beef, fatty cuts, spare ribs, organ meats
|Poultry, without skin
||Poultry with skin, fried chicken
||Fried fish, fried shellfish
|Processed meat prepared from lean meat
||Regular luncheon meat
|Eggs (step I: ≤4 yolks per week; step II: ≤2 yolks per week)
||Egg whites, cholesterol-free egg substitute
||Egg yolks (including eggs used in cooking and baking)
|Low-fat dairy products (2 to 3 servings a day)
||Milk—skim, ½% or 1% low-fat milk, buttermilk
||Whole milk, 2% low-fat milk, imitation milk
|Non-fat or low-fat yogurt
|Low-fat or processed cheese
|Non-fat or low-fat cottage cheese
||Regular cottage cheese (4% fat)
|Frozen yogurt, ice milk
|Low-fat coffee creamer, non-fat or low-fat sour cream
||Cream, half & half, whipping cream, regular sour cream
|Fats and oils (≤6 to 8 teaspoons a day)
||Unsaturated oils—safflower, sunflower, corn, soybean, canola, olive, peanut
||Coconut oil, palm oil
|Margarine—made from unsaturated oils listed above, soft margarine
||Butter, lard, shortening, bacon fat, hard margarine
|Salad dressings—made from unsaturated oils listed above, fat-free or low-fat dressing
||Salad dressings—made with egg yolk, cheese, whole milk, sour cream
|Seeds and nuts, peanut butter
|Breads and cereals (≥6 servings a day)
||Whole grain breads, English muffins, bagels, corn and flour tortillas
||Croissants, breads in which eggs, fat or butter are major ingredients
|Oat, wheat, corn and multigrain cereals, pasta, rice, dry beans and peas
|Low-fat crackers (graham, animal-type, soda, melba toast, breadsticks)
|Homemade baked goods containing unsaturated oils, skim or 1% milk, egg substitute
||Commercially baked biscuits, pastries, muffins containing whole milk, egg yolks, saturated oils
||Low-fat and reduced-sodium varieties
||Soups containing whole milk, cream, meat fat, poultry fat, poultry skin
|Vegetables (3 to 5 servings a day)
||Fresh, frozen or canned vegetables without added fat or sauce
||Fried vegetables or those prepared with butter, cheese or cream sauce
|Fruits (2 to 4 servings a day)
||Fresh, frozen, canned or dried fruits
||Fried fruit or fruit served with butter or cream sauce
|Sweets and modified-fat desserts
||Beverages, candy made without fat, gelatin
||Candy made with whole milk, chocolate, coconut oil, palm kernel oil, palm oil
|Frozen yogurt, sherbet, sorbet, ice milk, popsicles
|Cookies, cake, pie, pudding prepared with egg substitute, skim or 1% milk, unsaturated oils
||Commercially baked pies, cakes, doughnuts, high-fat cookies prepared with egg yolks, whole milk, saturated oils
DIETARY FIBER: Soluble fiber has been shown to modestly reduce total cholesterol and LDL cholesterol levels.(19) Current dietary guidelines recommend a total daily fiber intake of at least 20 to 30 g for adults, with 25 percent of the fiber being soluble fiber.(19) These levels can be attained with the proposed six or more daily servings of grain products and five or more daily servings of fruits and vegetables. Adding 3 g per day of soluble fiber from oat bran can reduce total cholesterol by 5 to 6 mg per dL.(21) Higher daily intake of soluble fiber promotes a further modest reduction of cholesterol values.
The American Heart Association (AHA) diet may lower total cholesterol by 5 to 7 percent, whereas similar diets that emphasize dietary fiber may reduce total cholesterol by 11 to 32 percent and may exert beneficial effects on LDL and HDL cholesterol levels as well.(23) Moreover, a high-carbohydrate, low-fiber diet typically raises serum triglyceride levels and lowers HDL cholesterol levels. Conversely, a high-carbohydrate, high-fiber diet may lower the serum triglyceride level and raise the HDL cholesterol level.(23) A high-fiber, low-fat diet also provides other beneficial effects, including improved glycemic control, weight reduction and earlier satiety, prevention of diverticular disease and, possibly, prevention of colorectal cancer.(23)
ANTIOXIDANTS: Atherogenicity is promoted by oxidation and glycosylation of LDL cholesterol.(19) Several vitamins, including vitamin C, vitamin E and beta carotene, have antioxidant properties, which may provide protection against atherogenesis. Fruits and dark-green and deep-yellow vegetables are rich sources of antioxidant vitamins.
Because dietary modification rarely reduces LDL cholesterol levels by more than 10 to 20 percent, the NCEP guidelines recommend that consideration be given to the use of cholesterol-lowering agents if lipid levels remain elevated after six months of intensive dietary therapy or sooner under certain circumstances.
HMG-COA REDUCTASE INHIBITORS: Lovastatin , pravastatin simvastatin, fluvastatin, atorvastatin and cerivastatin are HMG-CoA reductase inhibitors, or statins, that inhibit cholesterol synthesis. To varying degrees, all of these agents lower total, LDL and triglyceride cholesterol components and slightly raise the HDL fraction. While these agents are generally well tolerated, a small percentage of patients (fewer than 1 percent) may develop elevated hepatic transaminase levels, which may necessitate discontinuation of the drug.(24) Other adverse effects include myopathy (fewer than 0.1 percent of cases) and gastrointestinal complaints. The gastrointestinal effects often subside with continued therapy.
Statins should generally be taken in a single dose with the evening meal or at bedtime to maximize the LDL lowering effect.
PCSK9 INHIBITORS: PCSK9 inhibitors are a newer class of drug that can also lower LDL cholesterol levels. Drugs in this class can also lower levels of other lipoproteins, such as lipoprotein(a), that can cause buildup of blood vessel plaques. The PCSK9 inhibitors include alirocumab and evolocumab, which are given by injection every two to four weeks. They have been shown to reduce LDL cholesterol by as much as 70 percent, and by as much as 60 percent in patients who are also on statin therapy. Experience with these drugs is limited and more study is needed to understand the longer-term effects; however, it appears that they can substantially reduce cardiovascular events (such as heart attack or stroke) and mortality.
EZETIMIBE: Ezetimibe impairs the body's ability to absorb cholesterol from food as well as cholesterol that the body produces internally. It lowers LDL cholesterol levels and has relatively few side effects. When used in combination with a statin in treatment after an acute coronary syndrome (e.g. heart attack), ezetimibe provides a small additional reduction in cardiovascular events.
BILE ACID–BINDING RESINS: The anion exchange resins cholestyramine and colestipol bind cholesterol-containing bile acids in the intestines, producing an insoluble complex that prevents reabsorption. This results in increased hepatic oxidation of cholesterol to bile acids, fecal cholesterol excretion and LDL receptor activity.(25) These agents decrease LDL cholesterol levels by up to 20 percent. They may be a good choice in patients with hepatic disease because they do not affect hepatic metabolism. They are also a good choice in very young patients and women of childbearing age.(26)
Bile acid–binding resins may cause an increase in triglyceride levels. Because of their gritty texture and side effects, compliance may be a problem. Side effects include constipation, abdominal discomfort, flatulence, nausea, bloating and heartburn. A dosage reduction, increased dietary fiber, taking bile acid sequestrants with meals and letting the resin stand in liquid for 10 minutes before taking it are strategies that minimize the side effects.
NICOTINIC ACID: Nicotinic acid, or niacin, decreases the synthesis of LDL cholesterol by reducing the hepatic synthesis of VLDL cholesterol, by increasing the synthesis of HDL cholesterol, by inhibiting lipolysis in adipose tissue and by increasing lipase activity. This agent increases the HDL level by 15 to 35 percent, reduces total and LDL cholesterol levels by 10 to 25 percent, and decreases the triglyceride level by 20 to 50 percent.(24)
Side effects of nicotinic acid include flushing, pruritus, gastrointestinal discomfort, hyperuricemia, gout, elevated liver function tests and glucose intolerance. Taking 325 mg of aspirin 30 minutes before the drug is ingested may minimize flushing.(27) Frequently, however, flushing and pruritus resolve spontaneously with continued use. Nicotinic acid should be taken with meals to reduce the occurrence of gastrointestinal upset. Hepatotoxic side effects are more common with sustained-release nicotinic acid preparations than with regular formulations. A hepatitis-like syndrome, manifested by weakness and a lack of appetite, may develop in patients receiving sustained-release preparations.(28) Other side effects of nicotinic acid include atrial fibrillation, hypotension, transient headaches and activation of peptic ulcer disease. Nicotinic acid therapy should be avoided in patients with diabetes mellitus because it tends to worsen glycemic control.(29)
FIBRIC ACID DERIVATIVES: Fibric acid derivatives, or fibrates, increase the clearance of VLDL cholesterol by enhancing lipolysis and reducing hepatic cholesterol synthesis. These agents have been reported to lower triglyceride levels by 20 to 50 percent, raise HDL levels by up to 20 percent and reduce LDL levels by approximately 5 to 15 percent.(30-32) Some patients with hypertriglyceridemia may have an increase in LDL levels, so such patients should be very closely monitored if fibrates are used. Gemfibrozil is particularly useful in patients with diabetes and familial dysbetalipoproteinemia.
Side effects of gemfibrozil include nausea, bloating, flatulence, abdominal distress and mild liver-function abnormalities. Myositis, gallstones and elevation of the LDL cholesterol level have also been reported.(24,32) Clofibrate has been associated with formation of gallstones and serious gastrointestinal disease, including hepatic malignancy,(24) and therefore should only be used in certain select patients with types II, IV or V hyperlipidemia. Fibrates should generally not be used with HMG-CoA reductase inhibitors because the risk of severe myopathy is greatly increased.(33)
MULTIPLE DRUG THERAPY: As mentioned previously, the National Cholesterol Education Program (NCEP) guidelines define a target LDL cholesterol level of 100 mg per dL (2.60 mmol per L) as a goal for high-risk patients with established coronary heart disease. But this population, even with a step II diet, often cannot achieve such a low LDL level. An LDL level greater than 130 mg per dL (3.35 mmol per L) requires further reduction in patients with coronary heart disease, and combination drug regimens are sometimes required.(33) An additional cholesterol-lowering drug is probably required if the LDL cholesterol level remains above the target level after three months of single-drug therapy. In patients with coronary heart disease and LDL levels between 100 and 130 mg per dL (2.60 and 3.35 mmol per L), clinical judgment is needed to decide whether to initiate cholesterol-lowering medication (or add a second medication) in conjunction with dietary therapy. Although drug therapy is not usually started until patients have undergone a three- to six-month trial of dietary therapy, in some patients with marked hypercholesterolemia or coronary heart disease, it is reasonable to initiate drug therapy earlier.(26)
OTHER THERAPEUTIC MODALITIES:
LIFIBROL: Lifibrol is a lipid-lowering agent presently under investigation. Clinical trials have shown that lifibrol lowers total cholesterol and LDL cholesterol levels with a potency similar to that of high-dose statins.(34) Lifibrol has also been shown to reduce Lp(a), fibrinogen and uric acid levels.(34) Its effects on HDL cholesterol and triglyceride levels are less consistent.
The mechanism of action of this agent is complex and probably multimodal. It appears to act at an earlier level of the cholesterol synthesis pathway than do the statins. Side effects are primarily gastrointestinal.
GENE THERAPY: Gene therapy is several years from clinical use. It may prove ideal for use in patients with genetic disorders such as familial hypercholesterolemia. Gene therapy will probably not be appropriate in dyslipidemic patients whose predominant risks for coronary heart disease are exogenous.(35)
PLASMAPHERESIS: Plasmapheresis has become the most common nonpharmacologic, nondietary treatment of severe hypercholesterolemia.(36) In nonselective plasmapheresis, the patient's plasma is replaced with salt-free human albumin. This action reduces triglyceride levels dramatically and decreases the risk of pancreatitis. In patients with severe, refractory forms of familial hypercholesterolemia, a highly specific LDL cholesterol absorption system is utilized for extended use.(36)
SURGICAL MODALITIES: Partial ileal bypass that eliminates the reabsorption of bile acids at the distal portion of the ileum has been shown to be a viable treatment in some cases of severe dyslipidemia.(37) Portacaval shunt and liver transplantation have been shown to be effective in treating severe hypercholesterolemia. These proceures, of course, are not first-line treatments.
GOALS OF THERAPY:
- To reduce the risk for development of CHD in people without documented CHD and
- To reduce the risk for progression of CHD or to cause regression in people with known CHD.
To review “American College of Cardiology / American Heart Association” guidelines, please click on below link:
To review “American family physician” guidelines, please click on below link:
To review “European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)” guidelines, please click on below link:
To review “American association of clinical endocrinologist” guidelines, please click on below link:
COSULTATION AND LONG TERM MONITORING:
CONSULTATION:A specialist in lipid disorders may be helpful in treating the hyperlipidemia that develops in patients, which can be very severe and difficult to treat, often requiring multiple lipid-lowering agents.
In addition, patients should receive nutrition counseling and should be advised to restrict calories if they are overweight. These individuals also should reduce saturated and trans fats and cholesterol intake.
LONG TERM MONITORING: Follow up with patients who are on diet and lipid-lowering therapy. Periodically monitor their blood cholesterol, triglyceride, and lipoprotein levels. If patients are taking lipid-lowering medications, obtain periodic liver function tests. No data support specific monitoring intervals, but measuring lipid levels 2 to 3 months after starting or changing therapies and once or twice yearly after lipid levels are stabilized is common practice.
If patients are taking fibric acid derivatives or statins, advise them to report unexplained generalized muscle pain, tenderness, or weakness. Perform creatinine kinase determinations in these individuals. Despite the low incidence of liver and severe muscle toxicity with statin use (0.5 to 2% of all users), current recommendations are for baseline measurements of liver and muscle enzyme levels at the beginning of treatment. Routine monitoring of liver enzyme levels is not necessary, and routine measurement of CK is not useful to predict the onset of rhabdomyolysis. Muscle enzyme levels need not be checked regularly unless patients develop myalgias or other muscle symptoms. If statin-induced muscle damage is suspected, statin use is stopped and CK may be measured. When muscle symptoms subside, a lower dose or a different statin can be tried. If symptoms do not subside within 1 to 2 wk of stopping the statin, another cause should be sought for the muscle symptoms (e.g. polymyalgia rheumatica)
In patients with diabetes, aggressive glucose control should be pursued with diet, oral hypoglycemic agents, or insulin.
Offer following preventions to patients:
DIET SUGGESTIONS: It is not necessary to follow a low-fat diet but rather reduce the intake of saturated fat, trans fats, and cholesterol. The diet should consist of a colorful array of whole fruits and vegetables, be high in fiber, and whole grains.
Fast foods, high carbohydrate foods, and any foods that do not offer good nutritional value should be restricted or eliminated.
Regular servings of fish, nuts, and legumes are recommended. When oil is used, it should be olive or another monounsaturated oil.
WEIGHT: Being overweight is a risk factor for hyperlipidemia and heart disease. Losing weight can help lower your LDL, total cholesterol, and lower your triglyceride levels. It can also raise your HDL, which helps to remove the bad cholesterol out of the blood.
PHYSICAL ACTIVITY: Not being physically active is a risk factor for heart disease. Regular exercise and activity can help lower LDL (bad) cholesterol and raise HDL (good) cholesterol levels. It also helps you lose weight. You should try to be physically active for 30 minutes at least 5 days a week. Brisk walking is an excellent and easy choice for exercise.
NO SMOKING: Smoking activates many problems that contribute to heart disease. It promotes plaque buildup on the walls of the arteries, increases the bad cholesterol, and encourages blood clot formations and inflammation. Quitting smoking will result in increases in HDL, which may be part of the reduced cardiovascular disease risk seen after smoking cessation.
RESTRICT ALCOHOL CONSUMPTION: Moderate alcohol consumption increases levels of HDL cholesterol, which decreases the risk of CHD. However, chronic, heavy alcohol use raises triglyceride levels, and is associated with many other harmful effects. Therefore, it is recommended that, on average, women consume no more than one alcoholic beverage per day; men should consume no more than two alcoholic drinks daily. (A drink is considered one 12-ounce beer, 4 ounces of wine, or 1.5 ounces of 80-proof spirits.)
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