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Hypertriglyceridemia

  • Author: Mary Ellen T Sweeney, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
 
Updated: Jul 26, 2016
 

Practice Essentials

Hypertriglyceridemia, a condition in which triglyceride levels are elevated, is a common disorder in the United States. It is often caused or exacerbated by uncontrolled diabetes mellitus, obesity, and sedentary habits, all of which are more prevalent in industrialized societies than in developing nations. In epidemiologic and interventional studies, hypertriglyceridemia is a risk factor for coronary artery disease (CAD).

Hyperlipoproteinemia is a metabolic disorder characterized by abnormally elevated concentrations of specific lipoprotein particles in the plasma.

Hyperlipidemia (ie, elevated plasma cholesterol or triglyceride levels or both) is present in all hyperlipoproteinemias. The primary form includes chylomicronemia, hypercholesterolemia, dysbetalipoproteinemia, hypertriglyceridemia, mixed hyperlipoproteinemia, and combined hyperlipoproteinemia. Other diseases, such as diabetes mellitus, pancreatitis, renal disease, and hypothyroidism, cause the secondary form.

Signs and symptoms

Hypertriglyceridemia is usually asymptomatic until triglycerides are greater than 1000-2000 mg/dL. Signs and symptoms may include the following:

  • GI: Pain in the mid-epigastric, chest, or back regions; nausea, vomiting
  • Respiratory: Dyspnea
  • Dermatologic: Xanthomas
  • Ophthalmologic: Corneal arcus, xanthelasmas

See Clinical Presentation for more detail.

Diagnosis

On examination, findings may be normal, or they may include the following:

  • GI: Tenderness to palpation over mid-epigastric or upper right/left quadrants; hepatomegaly
  • Dermatologic: Eruptive xanthomas on back (see the image below), buttocks, chest, proximal extremities; palmar xanthomas in dysbetalipoproteinemia
    Eruptive xanthomas on the back of a patient admitt Eruptive xanthomas on the back of a patient admitted with a triglyceride level of 4600 mg/dL and acute pancreatitis.
  • Cardiovascular: Decreased pedal pulses or ankle/brachial index in presence of peripheral vascular disease
  • Ophthalmologic: Corneal arcus, lipemia retinalis, xanthelasmas [1]
  • Neurologic: Memory loss, dementia, and depression in the presence of chylomicronemia syndrome

Testing

Laboratory studies used to evaluate hypertriglyceridemia include the following:

  • Lipid analysis
  • Chylomicron determination
  • Fasting blood glucose level
  • TSH level
  • Urinalysis
  • Liver function studies

Procedures

If the diagnosis of eruptive xanthomas is in doubt, obtaining a biopsy of the suspicious lesions will reveal accumulations of fat (not cholesterol). A biopsy of cutaneous lesions suspected to be either planar or tuberous xanthomas will reveal cholesterol deposition.

See Workup for more detail.

Fredrickson classification

Hyperlipidemia has been defined by the Fredrickson classification, which is based on beta-quantification, a process involving ultracentrifugation followed by electrophoresis.[2] In this system, shown in Table 1, below, all categories except type IIa are forms of hypertriglyceridemia.

Table 1. Fredrickson Classification of Hyperlipidemia (Open Table in a new window)

Type Serum Elevation Lipoprotein Elevation
I Cholesterol and triglycerides Chylomicrons
IIa Cholesterol LDL
IIb Cholesterol and triglycerides LDL, VLDL
III Cholesterol and triglycerides IDL
IV Triglycerides VLDL
V Cholesterol and triglycerides VLDL, chylomicrons
IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein.



Source:  Fredrickson DS, Lees RS. A system for phenotyping hyperlipidaemia. Circulation. Mar 1965;31:321-7.[2]



Type I is a rare disorder characterized by severe elevations in chylomicrons and extremely elevated triglycerides, always reaching well above 1000 mg/dL and not infrequently rising as high as 10,000 mg/dL or more. It is caused by mutations of either the lipoprotein lipase gene (LPL), which is critical for the metabolism of chylomicrons and very low-density lipoprotein (VLDL), or the gene's cofactor, apolipoprotein (apo) C-II.

Counterintuitively, despite exceedingly high elevations of triglyceride and, in some cases, of total cholesterol, these mutations do not appear to confer an increased risk of atherosclerotic disease. This fact may have contributed to the unfounded belief that hypertriglyceridemia is not a risk factor for atherosclerotic disease. Although chylomicrons contain far less cholesterol than other triglyceride-rich lipoproteins do, when serum triglyceride levels are severely elevated, cholesterol levels can also be quite high.

Type IIb is the classic mixed hyperlipidemia (high cholesterol and triglyceride levels), caused by elevations in low-density lipoprotein (LDL) and VLDL.

Type III is known as dysbetalipoproteinemia, remnant removal disease, or broad-beta disease due to an individual’s decreased ability to convert VLDL and intermediate-density lipoprotein (IDL), a VLDL remnant, to LDL particles in the blood and because of a decreased clearance of chylomicron remnants.[3] Typically, patients with this rare condition have elevated total cholesterol (range, 300 600 mg/dL) and triglyceride levels (usually >400 mg/dL; may exceed 1000 mg/dL),[2] and these individuals are easily confused with patients with type IIb hyperlipidemia. Patients with type III hyperlipidemia have elevations in IDL.

Dysbetalipoproteinemia is the result of 2 "hits."[3] First, most affected individuals are homozygous for the apo E isoform, apo E2. Second, affected individuals usually have a metabolic disorder such as diabetes, obesity, or hypothyroidism. Consequently, those who are homozygous for apo E2 have a 1-2% risk of developing dysbetalipoproteinemia, and they are at high risk for atherosclerotic cardiovascular and peripheral vascular disease.[3] The condition responds well to treatment of the causative medical condition and to lipid-lowering medications.

Type IV is characterized by abnormal elevations of VLDL, and triglyceride levels are almost always less than 1000 mg/dL. Serum cholesterol levels are normal.

Type V is characterized by elevations of chylomicrons and VLDL. Triglyceride levels are invariably greater than 1000 mg/dL, and total cholesterol levels are always elevated. The LDL cholesterol level is usually low. Given the rarity of type I disease, when triglyceride levels above 1000 mg/dL are noted, the most likely cause is type V hyperlipidemia.

Triglyceride levels greater than 1000 mg/dL increase the risk of acute pancreatitis, and because triglycerides are so labile, levels of 500 mg/dL or greater must be the primary focus of therapy. If a patient also has a high risk for a cardiovascular event, LDL-lowering therapy should be considered.

Management

Nonpharmacotherapy

Nonpharmacologic management of hypertriglyceridemia is generally the initial treatment for patients with this condition. This primarily involves lifestyle modifications such as diet, exercise, weight reduction, smoking cessation, and limiting alcohol intake.

Pharmacotherapy

Medications used in the management of hypertriglyceridemia include the following:

  • Fibric acid derivatives (eg, gemfibrozil, fenofibrate)
  • Niacin (slow-release, immediate-release, extended-release formulations)
  • Omega-3 fatty acids (eg, omega-3-acid ethyl esters)
  • HMG-CoA reductase inhibitors (eg, atorvastatin, fluvastatin, pitavastatin, pravastatin, lovastatin, simvastatin, rosuvastatin)

Surgical option

In general, surgical intervention is not necessary to treat hypertriglyceridemia. Plasmapheresis can be used in the setting of severe hypertriglyceridemia to reduce triglycerides in the acute setting. Ileal bypass surgery has been shown to improve all lipid parameters but should be reserved for severe hypertriglyceridemia refractory to all treatment.

See Treatment and Medication for more detail.

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Pathophysiology

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 (as described below); the triglycerides are subsequently transported throughout the circulation by triglyceride-rich lipoproteins.

By dry weight, triglycerides make up approximately 86%, 55%, and 23% of chylomicrons, very low-density lipoproteins (VLDLs), and intermediate-density lipoproteins (IDLs), respectively,[4] as represented in the image below. Triglycerides are present in low-density lipoprotein (LDL) and high-density lipoprotein (HDL), but in much smaller quantities of 10% or less.

The following image shows composition of triglyceride-rich proteins.

Composition of triglyceride (TG)-rich lipoproteins Composition of triglyceride (TG)-rich lipoproteins. IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein.

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 reesterified 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.

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 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.[5, 3, 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.

Apo Es

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.[3]

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.[3] 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 [3]

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]

Lipoprotein lipase (LPL) releases free fatty acids 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, TGS = triglycerides.
Once very low-density lipoprotein (VLDL) has been 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. Chol = cholesterol; TGs = triglycerides.

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.

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Etiology

Hypertriglyceridemia has many causes, including familial and genetic syndromes, metabolic disease, and drugs. Risks appear to include diet, stress, physical inactivity, and smoking.

CHD risk factors

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) identifies the 2 or more of the following as risk factors for coronary heart disease (CHD) that can lead to the need for more aggressive intervention[13] :

  • Older age: In men, age 45 years or older, whereas in women, 55 years or older; the incidence of CHD is higher in the elderly than the young and in men more than women of the same age
  • Family history of premature CHD: Paternal or male primary relative with myocardial infarction (MI) before age 55 years or sudden death, or in maternal or female primary relative before age 65 years
  • Active tobacco use
  • Hypertension: Blood pressure higher than 140/90 mm Hg or current use of antihypertensive agents
  • Low level of high-density lipoprotein (HDL) cholesterol: Lower than 40 mg/dL

Genetic causes

Abnormalities of the enzyme pathway for chylomicron metabolism are the best-characterized genetic causes of hypertriglyceridemia. Lipoprotein lipase deficiency and apo C-II deficiency are caused by homozygous autosomal recessive genes present at conception.

Type I hyperlipoproteinemia is the best-characterized genetic cause of hypertriglyceridemia and is caused by a deficiency or defect in either the enzyme lipoprotein lipase or its cofactor, apo C-II. Lipoprotein lipase hydrolyzes triglycerides in chylomicrons and very low-density lipoprotein (VLDL), releasing free fatty acids. The enzyme is found in the endothelial cells of capillaries and can be released into the plasma by heparin. Lipoprotein lipase is essential for the metabolism of chylomicrons and VLDL, transforming them into their respective remnants. Apo C-II, an apolipoprotein present in both chylomicrons and VLDL, acts as a cofactor in the action of lipoprotein lipase.

The above pathway is affected by other genetic disorders, particularly type 1 or type 2 diabetes, because lipoprotein lipase requires insulin for full activity. That is, a secondary cause of hyperlipidemia, “second hit,” must be present for the dysbetalipoproteinemia to develop. In addition, the patient may be taking medications, such as protease inhibitors or tricyclic antidepressants, that exacerbate hyperlipidemia.

Two more recently described syndromes include mutations in ApoAV leading to a truncated ApoAV devoid of a lipid-binding domain and glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GP1HBP1) causing decreased binding to LPL and reduced hydrolysis of chylomicrons.[14]

Genetic predisposition for dysbetalipoproteinemia is present in approximately 1% of the population, but only 1-2% of individuals with apolipoprotein (apo) E-2 actually develop this condition. More than 90% of patients with dysbetalipoproteinemia are homozygous for apo E2. Extremely rare forms are associated with other genetic mutations in the apo E gene or the complete absence of apo E.

Familial combined hyperlipidemia and familial hypertriglyceridemia

Two triglyceride disorders, familial combined hyperlipidemia and familial hypertriglyceridemia, are genetically controlled, but the mechanisms are not clearly defined but are likely associated with overproduction and decreased of apo B–containing particles.

Familial combined hyperlipidemia is an autosomal dominant disorder characterized by patients and their first-degree relatives who may have either isolated triglyceride or low-density lipoprotein (LDL) cholesterol elevations or both. Diagnosis of the disorder in a particular patient requires a family history of premature coronary artery disease (CAD) in 1 or more first-degree relatives and a family history for elevated triglycerides with or without elevated LDL cholesterol levels. The diagnosis is important for prognosis; 14% of patients with premature CAD have familial combined hyperlipidemia.[15]

Familial hypertriglyceridemia is also an autosomal dominant trait.[16] These patients and their families have isolated triglyceride elevations and may have an increased risk of premature CAD.

Genetic susceptibility factor effects

Known genetic susceptibility factor effects account for approximately 10-15% of the trait variances in blood lipid levels (LDL cholesterol, HDL cholesterol, triglycerides).[17] Genome-wide association studies (GWAS) have identified several loci associated with blood lipid traits, including hypertriglyceridemia.[18]

Hypertriglyceridemia is associated with several genes (in aggregate) including apoAV, GCKR, LPL, and APOB.[19] Patients with single nucleotide polymorphisms (SNPs) 40 kilobases (kb) from TRIB1 (a gene known to be strongly associated with dyslipidemia) have abnormal levels of triglycerides, as well as HDL cholesterol and LDL cholesterol.[20] In a large study of Japanese and Korean individuals, investigators reported that genetic variants of APOA5 (-1131T→C polymorphism [rs662799]) and BTN2A1 (C→T polymorphism [rs6929846]) synergistically affect the prevalence of dyslipidemia in East Asian populations and metabolic syndrome in Japanese individuals.[21]

Certain genetic variants can further predispose a patient with hypertriglyceridemia and certain environmental factors to consequences, such as CAD and MI. For example, the genetic variant R952QP of LRP8 (a gene at 1p31-32 that is associated with familial and premature CAD as well as high-level platelet activation) is associated with high triglyceride levels in patients who are have a history of being overweight, smoke, and have premature CAD/MI.[22]

Metabolic causes

Uncontrolled diabetes mellitus, both type 1 and type 2, is one of the most common causes of hypertriglyceridemia, and it is often severe in patients presenting with ketosis. Patients with type 1 diabetes mellitus are insulin deficient, and lipoprotein lipase is largely ineffective. Control of these patients' diabetes mellitus with insulin will restore lipoprotein lipase function, reducing triglyceride levels and restoring diabetes mellitus control.

In patients with uncontrolled type 2 diabetes mellitus and hyperinsulinemia, triglycerides are elevated for several reasons, including the following:

  • Lipoprotein lipase is less effective in the insulin-resistant state
  • Overproduction of VLDL by the liver is common in patients with diabetes who are often overweight
  • Diabetes mellitus is one of the conditions that leads to incomplete metabolism of VLDL, causing increased remnant VLDL or IDL observed in dysbetalipoproteinemia (see Dysbetalipoproteinemia).

Mild to moderate elevations in triglycerides are common in obese patients, largely secondary to reduced efficacy of LPL and overproduction of VLDL.

Hypothyroidism commonly causes LDL cholesterol elevations, but it also may lead to mixed hyperlipidemia or isolated triglyceride elevations. Reduced hepatic lipase activity slows VLDL remnant catabolism. As with diabetes mellitus, untreated hypothyroidism may cause dysbetalipoproteinemia in patients with homozygous apo E-2.

Nephrotic syndrome is thought to increase hepatic synthesis of VLDL and may also slow catabolism of both LDL and VLDL. As in hypothyroidism, elevated LDL cholesterol levels are more common in this condition, but mixed hyperlipidemia or isolated triglyceride elevations may be observed. Higher levels of proteinuria are correlated with more severe hyperlipidemia.

Drugs

Medications that can cause hypertriglyceridemia include the following:

  • High-dose thiazide diuretics or chlorthalidone
  • High-dose beta-adrenergic blocking agents, excluding those with intrinsic sympathomimetic activity
  • Unopposed oral estrogen replacement therapy
  • Oral contraceptives with high estrogen content
  • Tamoxifen
  • Glucocorticoids
  • Oral isotretinoin
  • Antiretroviral therapy (including some protease inhibitors, nonnucleoside reverse transcriptase inhibitors)
  • Atypical antipsychotics

Other causes

Excessive alcohol intake and high-carbohydrate diets (>60% of caloric intake) are frequent causes of hypertriglyceridemia.

Acute pancreatitis may cause substantial elevations in triglycerides by unknown mechanisms. However, much more frequently, severe hypertriglyceridemia causes acute pancreatitis. In patients presenting with acute pancreatitis and triglycerides greater than 1000 mg/dL, it is prudent to not assume that the triglycerides are the cause of the pancreatitis. Other causes, such as common bile duct obstruction and alcoholism, must be considered as possible etiologies.

In pregnant patients with a history of mildly to moderately elevated triglycerides in the nonpregnant state, hypertriglyceridemia (sometimes severe) may occur. Such patients should be monitored closely, particularly in the third trimester. In fact, simply looking for laboratory notation of lipemic serum in routine blood tests during pregnancy will avoid unexpected complications resulting from unrecognized and untreated hypertriglyceridemia during pregnancy.

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Epidemiology

United States statistics

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) defined elevated triglycerides as 150 mg/dL and higher.[13] Using that criterion, the Third National Health and Nutrition Examination Survey (NHANES) found that the prevalence of hypertriglyceridemia in US adults aged 20 years and older was approximately 35% in men and 25% in women. Triglyceride levels in black men and women were 21% and 14%, respectively; 40% and 35% in Mexican American men and women, respectively; and in 37% and 25% in white American men and women, respectively.[23]

In black individuals, the frequency of the alleles for apolipoprotein (apo) E2 is 12%; apo E3, 65%; and apoE4, 23%; in the white population, the frequencies are approximately 13%; 76%; and 11%, respectively.[10] The frequency of homology for apo E2 is 1.3%, but because of the necessary "second hit," only about 5% of homologous individuals have overt hyperlipidemia.[10]

Prevalence of severe hypertriglyceridemia, defined as triglycerides greater than 2000 mg/dL, is estimated to be to be 1.8 cases per 10,000 white adults, with a higher prevalence in patients with diabetes or alcoholism.[13] The most severe form of hypertriglyceridemia, lipoprotein lipase deficiency, occurs in approximately 1 case per 1 million; the frequency of apo C-II deficiency is even lower. The frequency of dysbetalipoproteinemia is less than 5 persons per 5,000 in the overall population.[10]

International statistics

Hyperlipoproteinemia has a high frequency in developed countries. The worldwide incidence of lipoprotein lipase deficiency is similar to that in the United States with the exception of small populations—such as in Quebec, Canada, where the number is significantly higher, probably due to the founder effect. Apo C-II deficiency is infrequent in all populations studied to date.

Globally, the frequency of all 3 major apoE alleles varies by racial group. The incidence of the apo E2 allele, however, is always far lower than that of the apo E3 allele. Frequencies as low as 4.1% and 4.6% were found in Finland and in Singhalese of Indian descent, respectively.[10] In addition to the US, the highest frequencies were found in New Zealand (12.0%) and in Malaysian Singhalese (11.4%). Frequencies in other populations ranged from 6.1% (Iceland) to 9.7 (Chinese Singhalese).[10]

Race-, sex-, and age-related demographics

As noted above, although the frequency of apo E2 varies somewhat by race, the prevalence of dysbetalipoproteinemia appears to be similar among races. The racial differences are a consequence not only of apo E2 frequency but also of the prevalence of the metabolic abnormalities necessary to cause dysbetalipoproteinemia.

Nonhispanic blacks often have lower triglyceride levels, possibly related to an increase in LPL activity.[24] Racial predisposition has not been described for lipoprotein lipase deficiency or apo CII deficiency.

In the Prospective Cardiovascular Munster study (PROCAM), a large observational study, mild hypertriglyceridemia (triglycerides >200 mg/dL) was more prevalent in men (18.6%) than in women (4.2%).[25] Genetic mutations in both lipoprotein lipase and apo CII affect males and females in equal numbers.

Dysbetalipoproteinemia primarily affects older adults and is rare in children and premenopausal women. However, in the United States and some other Western populations, the increasing incidence of childhood obesity and type 2 diabetes may presage the emergence of dysbetalipoproteinemia in children. Estrogen improves the clearance of very low-density lipoprotein (VLDL) remnants, and estrogen treatment appears to improve dysbetalipoproteinemia in some postmenopausal women.

Triglycerides increase gradually in men until about age 50 years and then decline slightly. In women, they continue to increase with age. Mild hypertriglyceridemia (triglycerides >150 mg/dL) is slightly more prevalent in men beginning at age 30 years and women starting at age 60 years.[14, 23]

The manifestations of lipoprotein lipase and apo C-II deficiency (severe hypertriglyceridemia) are usually detected in childhood, although defective apo C-II sometimes presents in early adulthood.

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Prognosis

Patients with hyperlipidemia are at extremely high risk of developing premature coronary artery disease (CAD) (30%).[26] If the disease is inadequately managed, the prognosis is poor, especially if other cardiovascular risk factors are present. If the patient complies with lipid-lowering therapy, dietary modification, and lifestyle modification and if therapy is successful, outcome is improved significantly.

Cardiovascular disease

Hypertriglyceridemia is correlated with an increased risk of cardiovascular disease (CVD), particularly in the setting of low high-density lipoprotein (HDL) cholesterol levels and/or elevated low-density lipoprotein (LDL) cholesterol levels. When low HDL cholesterol levels are controlled for, some studies demonstrate that elevated triglycerides do not correlate with risk of CVD. Others suggest that high triglyceride levels are an independent risk factor.

Because metabolism of the triglyceride-rich lipoproteins (chylomicrons, very low-density lipoprotein [VLDL]) and metabolism of HDL are interdependent and because triglycerides are very labile, the independent impact of hypertriglyceridemia on CVD risk is difficult to confirm. However, randomized clinical trials using triglyceride-lowering medications have demonstrated decreased coronary events in both the primary and secondary coronary prevention populations.

An understanding of lipoprotein catabolism provides an explanation for the absence of increased risk of CVD in patients with the most severe form of hypertriglyceridemia, type I hyperlipoproteinemia. The atherogenicity correlated with elevated triglyceride levels is thought to be secondary to increased levels of chylomicron and VLDL remnants. Remnants are smaller, richer in cholesterol, and more readily taken up by macrophages, which are converted to plaque-forming foam cells. The chylomicrons in patients with type I disease cannot be converted to remnants and, therefore, should not be atherogenic.

Pancreatitis

Extreme elevations of triglycerides, usually well above 1000 mg/dL, may cause acute pancreatitis and all the sequelae of that condition. However, many patients tolerate triglycerides of 4000 mg/dL or higher without developing symptoms.[27] The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines indicates that triglycerides are so labile that a level between 500 and 1000 mg/dL may in certain settings increase dramatically and should be a target of treatment even before ensuring that the LDL goal is reached.[13] Thus, these guidelines stipulate that if triglycerides are 500 mg/dL or greater, the initial management should be to lower the triglycerides to prevent pancreatitis. Only when the triglyceride level is below 500 should LDL-lowering be addressed.

The risk of recurrent pancreatitis secondary to hypertriglyceridemia can be avoided entirely by ensuring that levels are maintained well below 700 mg/dL. Because triglyceride levels are so labile, simply moderating levels to less than 1000 mg/dL does not decrease risk substantially, because the slightest metabolic imbalance or dietary indiscretion may push levels several hundred points higher.

Chylomicronemia syndrome

The chylomicronemia syndrome[28, 29] is an often unrecognized and less severe condition than pancreatitis that is usually caused by triglyceride levels greater than 1000 mg/dL. Recurrent episodes of ill-defined abdominal pain that may be accompanied by nausea and vomiting are the most common presenting symptom, but chest pain and dyspnea may sometimes occur. A papular rash may be present on the trunk, thighs, and buttocks, which resolves with treatment. Amylase and lipase are minimally, if at all, elevated. Symptoms resolve when triglyceride levels decrease well below 1000 mg/dL.

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Patient Education

Patients often do not understand that triglycerides are a blood lipid that may be analyzed along with cholesterol. They should be informed about the risks of hypertriglyceridemia, including the increased risk of a cardiovascular event and risk of pancreatitis if levels are close to or above 1000 mg/dL.

Patients should be informed that triglycerides respond to the simple interventions of diet control, exercise, and appropriate weight loss. A trained dietitian should provide thorough diet instructions. Exercise counseling or monitoring may be helpful to treat the dyslipidemia and reduce the risk of symptomatic cardiovascular disease.

In addition, the provider should stress the importance of alcohol intake of no more than 1 drink per day, provide instructions on the use of medications, and provide comprehensive diabetes education to diabetic patients.

For patient education resources, Medscape Reference’s Cholesterol Center and Heart Health Center, as well as High Cholesterol, Understanding Your Cholesterol level, Lifestyle Cholesterol Management, Understanding Cholesterol-Lowering Medications, and Statins and Cholesterol.

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Contributor Information and Disclosures
Author

Mary Ellen T Sweeney, MD Associate Professor of Medicine (Endocrinology, Diabetes, and Metabolism), Department of Medicine, Emory University School of Medicine; Physician, Division of Endocrinology, Veterans Administration Medical Center; Physician, Lipid Metabolism Clinic, Emory Healthcare, The Emory Clinic

Mary Ellen T Sweeney, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, National Lipid Association

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Additional Contributors

Hampton Roy, Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy, Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Acknowledgements

Steve Charles, MD Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine; Adjunct Professor of Ophthalmology, Columbia College of Physicians and Surgeons; Clinical Professor Ophthalmology, Chinese University of Hong Kong

Steve Charles, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Retina Specialists, Club Jules Gonin, Macula Society, and Retina Society

Disclosure: Alcon Laboratories Consulting fee Consulting; OptiMedica Ownership interest Other; Topcon Medical Lasers Consulting fee Consulting

Karen E Friday, MD, FACP Clinical Core Director of Tulane Xavier National Center of Excellence, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Tulane University School of Medicine

Karen E Friday, MD, FACP is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Heart Association, American Society for Clinical Nutrition, and Endocrine Society

Disclosure: AstraZeneca own AstraZeneca stock None; Merck own Merck stock None; Schering Plough own Schering Plough stock None; Medco Health own Medco Health stock None

Robert A Gabbay, MD, PhD Associate Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism, Laurence M Demers Career Development Professor, Penn State College of Medicine; Director, Diabetes Program, Penn State Milton S Hershey Medical Center; Executive Director, Penn State Institute for Diabetes and Obesity

Robert A Gabbay, MD, PhD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, and Endocrine Society

Disclosure: Novo Nordisk Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching

Steven R Gambert, MD Professor of Medicine, Johns Hopkins University School of Medicine; Director of Geriatric Medicine, University of Maryland Medical Center and R. Adams Cowley Shock Trauma Center

Steven R Gambert, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American Geriatrics Society, Association of Professors of Medicine, Endocrine Society, and Gerontological Society of America

Disclosure: Nothing to disclose.

Romesh Khardori, MD, PhD Professor and Director, Division of Endocrinology, Metabolism, and Molecular Medicine, Southern Illinois University School of Medicine

Romesh Khardori, MD, PhD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society of Andrology, Endocrine Society, and Illinois State Medical Society

Disclosure: Nothing to disclose.

Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. Wu CW, Lin PY, Liu YF, Liu TC, Lin MW, Chen WM, et al. Central corneal mosaic opacities in Schnyder's crystalline dystrophy. Ophthalmology. 2005 Apr. 112(4):650-3. [Medline].

  2. FREDRICKSON DS, LEES RS. A SYSTEM FOR PHENOTYPING HYPERLIPOPROTEINEMIA. Circulation. 1965 Mar. 31:321-7. [Medline].

  3. Mahley RW, Rall SC Jr. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal metabolism. Scriver CR, Beaudet AR, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001. 2835-62.

  4. Kane JP. Structure and function of the plasma lipoproteins and their receptors. Fuster V, Ross R, Topol EJ, eds. Atherosclerosis and Coronary Artery Disease. Philadelphia, Pa: Lippincott-Raven; 89-103. 1996: .

  5. Mahley RW, Huang Y, Rall SC Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res. 1999 Nov. 40(11):1933-49. [Medline].

  6. Smelt AH, de Beer F. Apolipoprotein E and familial dysbetalipoproteinemia: clinical, biochemical, and genetic aspects. Semin Vasc Med. 2004 Aug. 4(3):249-57. [Medline].

  7. Huang Y, Schwendner SW, Rall SC Jr, Sanan DA, Mahley RW. Apolipoprotein E2 transgenic rabbits. Modulation of the type III hyperlipoproteinemic phenotype by estrogen and occurrence of spontaneous atherosclerosis. J Biol Chem. 1997 Sep 5. 272(36):22685-94. [Medline].

  8. Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992 Oct 16. 258(5081):468-71. [Medline].

  9. Corbo RM, Scacchi R. Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a 'thrifty' allele?. Ann Hum Genet. 1999 Jul. 63:301-10. [Medline].

  10. Feussner G, Piesch S, Dobmeyer J, Fischer C. Genetics of type III hyperlipoproteinemia. Genet Epidemiol. 1997. 14(3):283-97. [Medline].

  11. Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988 Jan-Feb. 8(1):1-21. [Medline].

  12. Hassing HC, Surendran RP, Mooij HL, Stroes ES, Nieuwdorp M, Dallinga-Thie GM. Pathophysiology of hypertriglyceridemia. Biochim Biophys Acta. 2012 May. 1821(5):826-32. [Medline].

  13. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16. 285(19):2486-97. [Medline].

  14. Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011 May 24. 123(20):2292-333. [Medline].

  15. Pajukanta P, Porkka KV. Genetics of familial combined hyperlipidemia. Curr Atheroscler Rep. 1999 Jul. 1(1):79-86. [Medline].

  16. Kolovou GD, Anagnostopoulou KK, Kostakou PM, Bilianou H, Mikhailidis DP. Primary and secondary hypertriglyceridaemia. Curr Drug Targets. 2009 Apr. 10(4):336-43. [Medline].

  17. Pilia G, Chen WM, Scuteri A, Orrú M, Albai G, Dei M, et al. Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet. 2006 Aug 25. 2(8):e132. [Medline]. [Full Text].

  18. Willer CJ, Mohlke KL. Finding genes and variants for lipid levels after genome-wide association analysis. Curr Opin Lipidol. 2012 Apr. 23(2):98-103. [Medline]. [Full Text].

  19. Johansen CT, Wang J, Lanktree MB, Cao H, McIntyre AD, Ban MR, et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet. 2010 Aug. 42(8):684-7. [Medline]. [Full Text].

  20. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009 Jan. 41(1):56-65. [Medline]. [Full Text].

  21. Hiramatsu M, Oguri M, Kato K, Horibe H, Fujimaki T, Watanabe S, et al. Synergistic effects of genetic variants of APOA5 and BTN2A1 on dyslipidemia or metabolic syndrome. Int J Mol Med. 2012 Jul. 30(1):185-92. [Medline].

  22. Shen GQ, Li L, Wang QK. Genetic variant R952Q in LRP8 is associated with increased plasma triglyceride levels in patients with early-onset CAD and MI. Ann Hum Genet. 2012 May. 76(3):193-9. [Medline].

  23. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002 Jan 16. 287(3):356-9. [Medline].

  24. Sumner AE, Cowie CC. Ethnic differences in the ability of triglyceride levels to identify insulin resistance. Atherosclerosis. 2008 Feb. 196(2):696-703. [Medline].

  25. Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Münster study. Am J Cardiol. 1992 Sep 15. 70(7):733-7. [Medline].

  26. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986 Nov 28. 256(20):2823-8. [Medline].

  27. Athyros VG, Giouleme OI, Nikolaidis NL, Vasiliadis TV, Bouloukos VI, Kontopoulos AG, et al. Long-term follow-up of patients with acute hypertriglyceridemia-induced pancreatitis. J Clin Gastroenterol. 2002 Apr. 34(4):472-5. [Medline].

  28. Brunzell JD, Bierman EL. Chylomicronemia syndrome. Interaction of genetic and acquired hypertriglyceridemia. Med Clin North Am. 1982 Mar. 66(2):455-68. [Medline].

  29. Chait A, Brunzell JD. Chylomicronemia syndrome. Adv Intern Med. 1992. 37:249-73. [Medline].

  30. US Preventive Services Task Force. Screening for lipid disorders in adults: U.S. Preventive Services Task Force recommendation statement. Rockville, Md: Agency for Healthcare Research and Quality; 2008.

  31. Jellinger PS, Smith DA, Mehta AE, Ganda O, Handelsman Y, Rodbard HW, et al. American Association of Clinical Endocrinologists' Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract. 2012 Mar-Apr. 18 Suppl 1:1-78. [Medline].

  32. Fortson MR, Freedman SN, Webster PD 3rd. Clinical assessment of hyperlipidemic pancreatitis. Am J Gastroenterol. 1995 Dec. 90(12):2134-9. [Medline].

  33. Vipperla K, Somerville C, Furlan A, et al. Clinical Profile and Natural Course in a Large Cohort of Patients With Hypertriglyceridemia and Pancreatitis. J Clin Gastroenterol. 2016 Jun 17. [Medline].

  34. Leaf DA. Chylomicronemia and the chylomicronemia syndrome: a practical approach to management. Am J Med. 2008 Jan. 121(1):10-2. [Medline].

  35. Pandhi D, Gupta P, Singal A, Tondon A, Sharma S, Madhu SV. Xanthelasma palpebrarum: a marker of premature atherosclerosis (risk of atherosclerosis in xanthelasma). Postgrad Med J. 2012 Apr. 88(1038):198-204. [Medline].

  36. Rohrich RJ, Janis JE, Pownell PH. Xanthelasma palpebrarum: a review and current management principles. Plast Reconstr Surg. 2002 Oct. 110(5):1310-4. [Medline].

  37. Institute for Clinical Systems Improvement. Lipid management in adults. Bloomington, Minn: Institute for Clinical Systems Improvement; 2009.

  38. Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012 Sep. 97(9):2969-89. [Medline]. [Full Text].

  39. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007 Jul 18. 298(3):309-16. [Medline].

  40. Haffner SM. Secondary prevention of coronary heart disease: the role of fibric acids. Circulation. 2000 Jul 4. 102(1):2-4. [Medline].

  41. University of Michigan Health System. Screening and management of lipids. Ann Arbor, Mich: University of Michigan Health System; 2009.

  42. Klop B, Wouter Jukema J, Rabelink TJ, Castro Cabezas M. A physician's guide for the management of hypertriglyceridemia: the etiology of hypertriglyceridemia determines treatment strategy. Panminerva Med. 2012 Jun. 54(2):91-103. [Medline].

  43. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. A summary of implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol. 2004 Aug. 24(8):1329-30. [Medline].

  44. Shimabukuro M, Higa M, Tanaka H, Shimabukuro T, Yamakawa K, Masuzaki H. Distinct effects of pitavastatin and atorvastatin on lipoprotein subclasses in patients with Type 2 diabetes mellitus. Diabet Med. 2011 Jul. 28(7):856-64. [Medline].

  45. Hadfield SG, Horara S, Starr BJ, Yazdgerdi S, Marks D, Bhatnagar D, et al. Family tracing to identify patients with familial hypercholesterolaemia: the second audit of the Department of Health Familial Hypercholesterolaemia Cascade Testing Project. Ann Clin Biochem. 2009 Jan. 46:24-32. [Medline].

  46. Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008 Nov 11. 337:a2423. [Medline]. [Full Text].

  47. van der Graaf A, Cuffie-Jackson C, Vissers MN, Trip MD, Gagné C, Shi G, et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J Am Coll Cardiol. 2008 Oct 21. 52(17):1421-9. [Medline].

  48. Schaap-Fogler M, Schurr D, Schaap T, Leitersdorf E, Rund D. Long-term plasma exchange for severe refractory hypertriglyceridemia: a decade of experience demonstrates safety and efficacy. J Clin Apher. 2009. 24(6):254-8. [Medline].

  49. US Food and Drug Administration. Safety: statins and HIV or hepatitis C drugs: drug safety communication - interaction increases risk of muscle injury. Posted: March 1, 2012. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm294294.htm. Accessed: November 1, 2013.

  50. US Food and Drug Administration. Safety: statin drugs - drug safety. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm293670.htm. Accessed: November 1, 2013.

  51. US Food and Drug Administration. Safety: Zocor (simvastatin): label change - new restrictions, contraindications, and dose limitations. Posted: June 8, 2011. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258384.htm. Accessed: November 1, 2013.

  52. Maki KC, Bays HE, Dicklin MR. Treatment options for the management of hypertriglyceridemia: strategies based on the best-available evidence. J Clin Lipidol. 2012 Sep-Oct. 6(5):413-26. [Medline].

  53. Mohiuddin SM, Pepine CJ, Kelly MT, Buttler SM, Setze CM, Sleep DJ, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with simvastatin in patients with mixed dyslipidemia: a phase 3, randomized, controlled study. Am Heart J. 2009 Jan. 157(1):195-203. [Medline].

  54. Wu J, Song Y, Li H, Chen J. Rhabdomyolysis associated with fibrate therapy: review of 76 published cases and a new case report. Eur J Clin Pharmacol. 2009 Dec. 65(12):1169-74. [Medline].

  55. Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P, et al. Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review. Am J Med. 2009 Oct. 122(10):962.e1-8. [Medline].

  56. Sica DA. Fibrate therapy and renal function. Curr Atheroscler Rep. 2009 Sep. 11(5):338-42. [Medline].

  57. Harper CR, Jacobson TA. Managing dyslipidemia in chronic kidney disease. J Am Coll Cardiol. 2008 Jun 24. 51(25):2375-84. [Medline].

  58. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986 Dec. 8(6):1245-55. [Medline].

  59. McKenney JM, McCormick LS, Weiss S, Koren M, Kafonek S, Black DM. A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. Collaborative Atorvastatin Study Group. Am J Med. 1998 Feb. 104(2):137-43. [Medline].

  60. Goldberg RB, Jacobson TA. Effects of niacin on glucose control in patients with dyslipidemia. Mayo Clin Proc. 2008 Apr. 83(4):470-8. [Medline].

  61. Roth EM, Bays HE, Forker AD, Maki KC, Carter R, Doyle RT, et al. Prescription omega-3 fatty acid as an adjunct to fenofibrate therapy in hypertriglyceridemic subjects. J Cardiovasc Pharmacol. 2009 Sep. 54(3):196-203. [Medline].

  62. Lavie CJ, Milani RV, Mehra MR, Ventura HO. Omega-3 polyunsaturated fatty acids and cardiovascular diseases. J Am Coll Cardiol. 2009 Aug 11. 54(7):585-94. [Medline].

  63. Kim HS, Kim H, Jeong YJ, et al. Comparative analysis of the efficacy of omega-3 fatty acids for hypertriglyceridaemia management in Korea. J Clin Pharm Ther. 2016 Jul 18. [Medline].

  64. Egert S, Kannenberg F, Somoza V, Erbersdobler HF, Wahrburg U. Dietary alpha-linolenic acid, EPA, and DHA have differential effects on LDL fatty acid composition but similar effects on serum lipid profiles in normolipidemic humans. J Nutr 2009;139:861-68.

  65. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis 2006;189:19-30.

  66. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011 Sep 1. 108(5):682-90. [Medline].

  67. Kastelein JJ, Maki KC, Susekov A, Ezhov M, Nordestgaard BG, Machielse BN, et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. J Clin Lipidol. 2014 Jan-Feb. 8(1):94-106. [Medline].

  68. Fletcher B, Berra K, Ades P, Braun LT, Burke LE, Durstine JL, et al. Managing abnormal blood lipids: a collaborative approach. Circulation. 2005 Nov 15. 112(20):3184-209. [Medline].

  69. Hsia SH, Connelly PW, Hegele RA. Successful outcome in severe pregnancy-associated hyperlipemia: a case report and literature review. Am J Med Sci. 1995 Apr. 309(4):213-8. [Medline].

  70. Kuklina EV, Yoon PW, Keenan NL. Trends in high levels of low-density lipoprotein cholesterol in the United States, 1999-2006. JAMA. 2009 Nov 18. 302(19):2104-10. [Medline].

  71. Hudgins LC, Kleinman B, Scheuer A, White S, Gordon BR. Long-term safety and efficacy of low-density lipoprotein apheresis in childhood for homozygous familial hypercholesterolemia. Am J Cardiol. 2008 Nov 1. 102(9):1199-204. [Medline].

  72. Foran SE, Flood JG, Lewandrowski KB. Measurement of mercury levels in concentrated over-the-counter fish oil preparations: is fish oil healthier than fish?. Arch Pathol Lab Med. 2003 Dec. 127(12):1603-5. [Medline].

  73. Pharmacist's Letter. 2010; 26(1): 260101. Available at http://pharmacistsletter.therapeuticresearch.com/. Accessed: October 11, 2013.

  74. Pharmacist's Letter. 2012; 28(6): 280606. Available at http://pharmacistsletter.therapeuticresearch.com/. Accessed: October 11, 2013.

  75. Nainggolan L. FDA Approves Epanova for Severe Hypertriglyceridemia. Medscape Medical News. Available at http://www.medscape.com/viewarticle/824748. Accessed: May 12, 2014.

 
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Eruptive xanthomas on the back of a patient admitted with a triglyceride level of 4600 mg/dL and acute pancreatitis.
Close-up of eruptive xanthomas.
Composition of triglyceride (TG)-rich lipoproteins. IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein.
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, TGS = triglycerides.
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. Chol = cholesterol; TGs = triglycerides.
Table 1. Fredrickson Classification of Hyperlipidemia
Type Serum Elevation Lipoprotein Elevation
I Cholesterol and triglycerides Chylomicrons
IIa Cholesterol LDL
IIb Cholesterol and triglycerides LDL, VLDL
III Cholesterol and triglycerides IDL
IV Triglycerides VLDL
V Cholesterol and triglycerides VLDL, chylomicrons
IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein.



Source:  Fredrickson DS, Lees RS. A system for phenotyping hyperlipidaemia. Circulation. Mar 1965;31:321-7.[2]



Table 2. Classification of Triglycerides
Classification TG level, mg/dL
Normal triglyceride level < 150
Borderline-high triglyceride level 150-199
High triglyceride level 200-499
Very high triglyceride level >500
Source:  National Cholesterol Education Program. Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. May 16 2001;285(19):2486-97.[13]
Table 3. Classification of LDL Cholesterol and Non-HDL Cholesterol
Classification LDL Goal,



mg/dL



Non-HDL Goal,



mg/dL



CHD and CHD risk equivalent, diabetes mellitus, and the following: 10-year risk for CHD >20% < 100 < 130
Two or more risk factors and the following: 10-year risk < 20% < 130 < 160
0-1 risk factor < 160 < 190
CHD = coronary heart disease; LDL = low-density lipoprotein; HDL = high-density lipoprotein.



Source:  National Cholesterol Education Program. Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. May 16 2001;285(19):2486-97.[13]



Table 4. Fibric Acid Agents, Omega Acid Ethyl Esters, and Niacin Drug Characteristics [73]
Drug Lipid Effects Lipid Effects in Combination with Statin Outcomes Data Comments
Bezafibrate LDL decrease: 9.6-25% (400 mg)



HDL increase: 15-24% (400 mg)



Triglyceride decrease: 25-43% (400 mg)



Further LDL decrease: 1.1% (400 mg)



Further HDL increase: 22% (400 mg)



Further triglyceride decrease: 31.7% (400 mg)



Secondary prevention: Prevents composite endpoint of MI and sudden death in a subgroup with triglycerides of 200 mg/dL or higher. No increase in non-CV death First-line option for triglyceride >10 mmol/L



Option for triglyceride 5-10 mmol/L



Option for low HDL



Reversible increase in serum creatinine



Requires renal dose adjustment



Limited data with statins



Ezetimibe LDL decrease: 18% (10 mg/day)



HDL increase: 1% (10 mg/day)



Triglyceride decrease: 8%



Further LDL decrease: 25%, as add-on



Further HDL increase: 3%, as add-on



Further triglyceride decrease: 14%, as add-on



Prevention of CV events in post-acute coronary syndrome patient when added to statin showed a benefit of reducing the primary endpoint (composite of CV death, MI, unstable angina requiring rehospitalization, coronary revascularization or stroke) by 6.4% vs statin alone



In intermediate outcomes studies, ezetimibe did not reduce regression of carotid intima-media thickness (surrogate marker) when added to a statin



Efficacy studied in combination with atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin



Role as statin add-on to reduce LDL if HDL and triglyceride satisfactory



Fenofibrate LDL decrease: 20.6% (145 mg)



HDL increase: 11% (145 mg)



Triglyceride decrease: 23.5-50.6% (greatest drop in patients with highest triglycerides) (145 mg)



Further LDL decrease: 0-6% (200 mg)



Further HDL increase: 13-17% (200 mg)



Further triglyceride decrease: 20-32% (200 mg)



Prevention of CV events in type 2 diabetes: Did not reduce primary composite outcome (nonfatal MI or CV death). Improved outcomes included nonfatal MI (24% decrease), coronary revascularization (21% decrease), progression to albuminuria, and reduced laser treatments for retinopathy. Nonsignificant increase in risk of CV death.



As statin add-on, did not lower risk of non-fatal MI, nonfatal stroke, or CV death more than statin alone in patients with type 2 diabetes at high risk for CV disease



First-line option for triglyceride >10 mmol/L (about 1000 mg/dL)



Option for triglyceride >500 mg/dL or 5-10 mmol/L



Option for low HDL



Preferred over gemfibrozil for use with statins



Requires renal dose adjustment



Associated with reversible increase in serum creatinine



Gemfibrozil LDL: No effect



HDL increase: 6% (1200 mg/day)



Triglyceride decrease: 33-50% (greatest drop in patients with highest triglycerides) (1200 mg/day)



Further triglyceride decrease: 41%



Further HDL increase: 9%



Primary prevention of coronary heart disease



Secondary prevention of cardiac events in men with low HDL



First-line option for triglyceride >10 mmol/L (about 1000 mg/dL)



Option for triglyceride >500 mg/dL or 5-10 mmol/L



Option for low HDL



Requires renal dose adjustment



Avoid with statin



Icosapent ethyl LDL decrease: 5%



HDL decrease: 4%



Triglyceride decrease: 27%



Further triglyceride decrease: 21.5% (4 g/day), 10.1% (2 g/day)



Further LDL decrease: 6.2% (4 g/day)



A study, REDUCE IT, is underway to look at reduction in CV events with icosapent ethyl Option for triglyceride >500 mg/dL



Safe for use with statins



Use caution with fish or shellfish allergy



Niacin LDL decrease: 14-17% (Niaspan 2 g/day); 12% (niacin immediate-release 1.5 g/day and Niaspan 1.5 g/day)



HDL increase: 22-26% (2 g/day Niaspan); 17% (niacin immediate release 1.5 g/day); 20-22% (Niaspan 1.5 g/day)



Triglyceride decrease: 20-50%



Further LDL decrease: 1-5% (Niaspan 1 g/day); 10% (Niaspan 2 g/day)



Further HDL increase: 24% (Niaspan 2 g/day); 15-17% (Niaspan 1 g/day)



Further triglyceride decrease: 24% (Niaspan 2 g/day); 12-22% (Niaspan 1 g/day)



Secondary MI prevention; in combination with a resin, slows progression or promotes regression of atherosclerosis; reduces mortality



As statin add-on, reduces carotid intima-media thickness (surrogate marker) compared with ezetimibe as statin add-on in patients with lower HDL



No CV event benefit from niacin plus statin versus statin alone in patients with well-controlled LDL, low HDL, and high triglycerides



Option for triglyceride >500 mg/dL (about 5 mmol/L)



Raises HDL more than any other agent



Dose-dependent risk of hyperglycemia (especially in patients with type 2 diabetes) and liver toxicity



May increase risk of statin myopathy



Omega-3 ethyl esters LDL increase: 44.5% (4 g/day)



HDL increase: 9.1% (4 g/day)



Triglyceride decrease: 45% (4 g/day)



LDL increase: 0.7% (4 g/day)



Further HDL increase: 3.4% (4 g/day)



Further triglyceride decrease: 29.5% (4 g/day)



Secondary prevention: Reduces cardiovascular death; sudden death; and combined endpoint of death, nonfatal MI, and nonfatal stroke



Secondary prevention in patients with, or at risk for, type 2 diabetes: did not reduce CV events



Option for triglyceride >500 mg/dL (about 5 mmol/L)



Safe for use with statins



Associated with an increase in risk for recurrence of symptomatic atrial fibrillation or flutter within first 3 months of therapy



Use with caution with fish or shellfish allergy



Table 5. Statin Drug Characteristics [74]
Drug Potency (average LDL decrease) Renal Considerations Liver Function Monitoring
Atorvastatin 10 mg: 35-39%



20 mg: 43%



40 mg: 50%



80 mg: 55-60%



No dose adjustment necessary for reduced renal function Check liver function tests at baseline and when clinically indicated
Fluvastatin 20 mg: 22%



40 mg: 25%



80 mg: 35%



(as XL product)



In severe renal impairment, use daily doses >40 mg with caution Check liver function tests at baseline and when clinically indicated
Lovastatin 10 mg: 21%



20 mg: 24-27%



40 mg: 30-31%



80 mg: 40-42%



(as 40 mg BID)



If CrCl < 30 mL/min, use daily doses over 20 mg with caution Check liver function tests at baseline and when clinically indicated
Pitavastatin 1 mg: 31-32%



2 mg: 36-39%



4 mg: 41-45%



For glomerular filtration rate 15-59 mL/min/1.73 m2, including hemodialysis, initial daily dose is 1 mg, not to exceed 2 mg/day Check liver function tests at baseline and when clinically indicated
Pravastatin 10 mg: 22%



20 mg: 32%



40 mg: 34%



80 mg: 37%



In significant renal impairment, start with 10 mg/day Check liver function tests at baseline and when clinically indicated
Rosuvastatin 5 mg: 45%



10 mg: 46-52%



20 mg: 47-55%



40 mg: 55-63%



If CrCl < 30 mL/min/1.73 m2 (but not on hemodialysis), starting dose is 5 mg/day, not exceed 10 mg/day



Rosuvastatin levels in hemodialysis patients are about 50% higher than levels in normal renal function



Check liver function tests at baseline and when clinically indicated
Simvastatin 5 mg: 26%



10 mg: 30%



20 mg: 38%



40 mg: 29-41%



80 mg: 36-47%



In severe renal impairment, starting dose is 5 mg daily with close monitoring Check liver function tests at baseline and when clinically indicated
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