Hypertriglyceridemia 

Updated: Dec 19, 2019
Author: Mary Ellen T Sweeney, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP 

Overview

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). Elevated triglycerides are determined by direct laboratory analysis of serum or plasma after a 10- to 12-hour fast. Determining which lipoprotein abnormality is the cause of hypertriglyceridemia is less straightforward.

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.[1]

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[2]

  • 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.[3] 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.[3]

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.[4] 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),[3] 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."[4] 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.[4] 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

Nonpharmacotherapeutic management

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, icosapent, 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.

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,[5] 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.[6, 4, 7]

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.[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.[8, 9] Apo E has 3 isoforms that are present in slightly varying proportions, depending on race and geographic location.[6] 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.[10]

Most animals, including primates, possess an apo E4 equivalent.[11] 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.[11] 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.[6]

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[12] :

  • 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[13] :

  • 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.[14]

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.

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[14] :

  • 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.[15]

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.[16]

Familial hypertriglyceridemia is also an autosomal dominant trait.[17] 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).[18] Genome-wide association studies (GWAS) have identified several loci associated with blood lipid traits, including hypertriglyceridemia.[19]

Hypertriglyceridemia is associated with several genes (in aggregate) including apoAV, GCKR, LPL, and APOB.[20] 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.[21] 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.[22]

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.[23]

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.

A study by Zhang et al indicated that obesity and uric acid elevation have a strong additive interaction that increases the risk for nonalcoholic fatty liver disease and hypertriglyceridemia. The interaction was reportedly responsible for 27% and 26% of the expanded hypertriglyceridemia risk in men and women, respectively.[24]

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.

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.[14] 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.[25]

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.[11] 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.[11]

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.[14] 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.[11]

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.[11] 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).[11]

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.[26] 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%).[27] 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.[15, 25]

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.

Prognosis

Patients with hyperlipidemia are at extremely high risk of developing premature coronary artery disease (CAD) (30%).[28] 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.

Using data from the National Health and Nutrition Examination Survey (2007-2014), Fan et al estimated that in adult statin users with triglyceride levels in the range between greater than 150 and 500 mg/dL, the mean 10-year risk of atherosclerotic cardiovascular disease is 11.3-19.1%, while in non–statin users falling within the same parameters, the mean 10-year risk is 6.0-15.6%.[29]

Pancreatitis

Extreme elevations of triglycerides, usually well above 1000 mg/dL, may cause acute pancreatitis and all the sequelae of that condition. (A study by Pedersen et al indicated that even nonfasting mild to moderate hypertriglyceridemia [177 mg/dL or above] raises the risk for acute pancreatitis; the investigators found, for example, the multivariable adjusted hazard ratio for acute pancreatitis to be 2.3 for persons with triglyceride levels of 177-265 mg/dL.[30] ) However, many patients tolerate triglycerides of 4000 mg/dL or higher without developing symptoms.[31]

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines indicate 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.[14] 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[32, 33] 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.

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.

 

Presentation

History

The US Preventive Services Task Force (USPSTF) includes the following as risk factors for a 10-year risk of cardiovascular events in patients with dyslipidemias, including hypertriglyceridemia and hyperlipoproteinemia[34] :

  • Diabetes

  • History of coronary heart disease (CHD) or noncoronary atherosclerosis (eg, abdominal aortic aneurysm, peripheral artery disease, carotid artery stenosis)

  • Family history of cardiovascular disease before age 50 years in male relatives or age 60 years in female relatives

  • Tobacco use

  • Hypertension

  • Obesity (body mass index [BMI] >30 kg/m2)

In addition to the risk factors above, the American Association of Clinical Endocrinologists (AACE) includes the following as major risk factors for dyslipidemia and atherosclerosis[35] :

  • Elevated serum total cholesterol levels

  • Elevated levels of non–high-density lipoprotein (non–HDL) levels

  • Elevated low-density lipoprotein (LDL) levels

Gastrointestinal symptoms

Hypertriglyceridemia is usually asymptomatic until triglycerides are greater than 1000-2000 mg/dL. Patients may report pain, which is commonly mid epigastric but may occur in other regions, including the chest or back.

A history of recurrent episodes of acute pancreatitis is common in patients with severe and uncontrolled hypertriglyceridemia.[36] Triglyceride levels often exceed 5000 mg/dL at the onset of pancreatitis.

A study by Vipperla et al indicated that in patients with hypertriglyceridemia-related acute pancreatitis, secondary risk factors, including diabetes, high-risk drinking, obesity, and specific medications, are highly prevalent, with at least one secondary risk factor occurring in 78% of the study’s patients.[37]

Patients with recurrent episodes of abdominal pain that is less severe than acute pancreatitis may experience the chylomicronemia syndrome.[38] Affected patients usually have triglyceride elevations greater than 2000 mg/dL at the onset of symptoms and provide a history of recurrent episodes of abdominal pain, sometimes with nausea, vomiting, or dyspnea. Pancreatitis is not necessarily present. The presentation of hyperchylomicronemia may be confused with conditions such as acute myocardial syndromes or biliary colic.

Dermatologic symptoms

Severe hypertriglyceridemia may cause skin lesions called xanthomas. Patients may report the appearance of any of the following types of xanthomas:

  • Xanthoma striata palmaris: Orange-yellow discolorations of the palmar creases, which in some cases are raised; considered pathognomonic for dysbetalipoproteinemia

  • Tuberoeruptive xanthomas: Nonpainful, raised, erythematous, nodular lesions approximately 0.5 cm in diameter; may be present on the elbows and knees

  • Tuberous xanthomas: Larger, coalesced tuberoeruptive xanthomas; raised, moderately firm, nontender lesions predominantly on the elbows and knees

  • Tendon xanthomas: Occur infrequently; more common in familial hypercholesterolemia

  • Eruptive xanthomas: Small nodular papules commonly seen over the trunk, buttocks, and thighs; associated with chylomicronemia syndrome

Ophthalmologic symptoms

Uncommonly, patients may also note the presence of a corneal arcus, which is a grayish white opacification at the periphery of the cornea and/or xanthelasmas, which are pale yellow, raised lesions around the eyelids.

Physical Examination

When triglycerides are less than 1000 mg/dL, the physical findings are normal unless the underlying condition is dysbetalipoproteinemia, type III hyperlipoproteinemia. In this condition, palmar xanthomas may be discerned infrequently.

When triglycerides are acutely and massively elevated, physical findings may be absent except on funduscopic examination. Therefore, physical findings in patients with severe hypertriglyceridemia are variable, ranging from normal to one or more of the findings discussed below.

In patients with peripheral vascular disease, the pedal pulses or ankle/brachial index may be decreased.

Gastrointestinal

If pancreatitis or the chylomicronemia syndrome is present, the mid epigastric area or upper right or left quadrants are tender to palpitation. Hepatomegaly and, less commonly, splenomegaly may be appreciated.

Dermatologic

Eruptive xanthomas (see the images below) are sometimes found when sustained elevated triglycerides are well above 1000 mg/dL. These are 1- to 3-mm yellow papules on an erythematous base that are most prominent on the back, buttocks, chest, and proximal extremities. The lesions are caused by accumulations of chylomicrons within macrophages and disappear gradually when triglycerides are kept below 1000 mg/dL.

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.
Close-up of eruptive xanthomas. Close-up of eruptive xanthomas.

Patients with dysbetalipoproteinemia (type III) may have palmar xanthomas (yellowish creases of the palms). This type of xanthoma is considered pathognomonic for this disorder. Tuberous or tuberoeruptive xanthomas, which also may occur in other hyperlipidemias, may arise on the elbows, knees, or buttocks.

Ophthalmologic

Corneal arcus, lipemia retinalis, and xanthelasma are the most common ocular abnormalities.[2] Triglyceride levels of 4000 mg/dL or higher may cause lipemia retinalis, in which funduscopic examination reveals retinal blood vessels (and occasionally the retina) that have a pale pink, milky appearance.

The ocular changes are usually not seen until the triglyceride level reaches at least 2000 mg/dL in the early stages; they are best observed in the peripheral fundus. The vessels initially appear salmon-pink, but when the triglyceride level rises further, they become whitish. These changes, which begin in the periphery, progress toward the posterior pole as the triglyceride level rises. In severe cases, the vessels are creamy white, and differentiating the arteries from the veins is difficult. The findings can fluctuate widely from day to day, depending on the triglyceride level.

Xanthelasma is a deposition of lipid in the eyelid, usually the upper medial lid. The lesions may be excised, but recurrences are common. Current treatments include serial excisions, the use of carbon dioxide and erbium lasers, and trichloroacetic acid peels. With primary excisions, recurrences of up to 40% have been reported, and secondary excision recurrences are even higher.[39] Of the initial failures, 20% are within the first year.[40]

The fundus abnormalities, which improve as the triglyceride levels return to normal, provide a method of following the patient's course and response to therapy.

Neurologic

Memory loss, dementia, and depression have been reported in patients with the chylomicronemia syndrome.

 

DDx

Diagnostic Considerations

When triglycerides are noted to be elevated, always check a fasting blood sugar and HbA1c to rule out uncontrolled diabetes—one of the most frequent causes of hypertriglyceridemia. Management of this condition may make medication to lower the triglycerides unnecessary or, at least, make it easier to normalize.

A diet high in refined carbohydrates can cause hypertriglyceridemia. Although cakes, candy, cookies, etc, are an obvious source, the quantity of liquid calories (nondiet soda, juice, alcohol) should also be determined.

In addition, consider conditions such as hypertriglyceridemia with elevations of very low-density lipoprotein (VLDL) with or without chylomicronemia, as well as mixed hyperlipidemia (type IIb hyperlipidemia) with elevations of both low-density lipoprotein (LDL) and VLDL. Note that use of oral contraceptives, beta-blockers, and thiazide diuretics can also raise plasma triglyceride and VLDL levels.

First-degree relatives should be screened for hyperlipidemia.

Differential Diagnoses

 

Workup

Approach Considerations

Rule out secondary causes of hypertriglyceridemia, including diabetes mellitus (fasting or random glucose levels), hypothyroidism (thyroid-stimulating hormone [TSH] levels), chronic renal failure (urinalysis, creatinine, and microalbumin), alcohol abuse, hormone replacement therapy, and/or oral contraceptives.[41, 42]

Measure plasma lipid and lipoprotein levels while the patient is on a regular diet after an overnight fast. The Endocrine Society also recommends using fasting triglyceride levels over nonfasting triglyceride levels for the diagnosis of hypertriglyceridemia.[42]

Abnormal lipoprotein patterns can often be identified after determining serum cholesterol and triglyceride levels and visual inspection of the plasma sample (stored at 4°C). In some cases, performing electrophoresis and ultracentrifugation of whole plasma specimens may be necessary to help establish a diagnosis.

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.

Although some studies have shown that tests such as C-reactive protein (CRP) and total homocysteine levels have some predictive value in screening for vascular disease, and thus are emerging as nontraditional risk factors for coronary heart disease, further investigation is need to determine their value.[41] Nonfasting triglyceride levels may reflect the level of atherogenic remnant lipoproteins and may even be stronger predictors of cardiovascular events than traditional fasting lipids.[43]

Lipid Analysis

Elevated triglycerides are determined by direct laboratory analysis of serum or plasma after a 10- to 12-hour fast. Determining which lipoprotein abnormality is the cause of hypertriglyceridemia is less straightforward.

Moderately elevated total cholesterol and triglyceride levels accompanied by the presence of palmar crease xanthomas confirm the diagnosis dysbetalipoproteinemia. Further laboratory workup may not be necessary.

Very low-density lipoproteins (VLDLs) are increased and chylomicrons are absent when triglyceride levels are elevated but below 1000 mg/dL. If triglyceride levels are above 1000 mg/dL, both VLDL and chylomicrons are usually present.

A standard lipid profile using the Friedewald equation to calculate the LDL cholesterol is not useful if the triglyceride level is more than 400-500 mg/dL. The excess cholesterol present in beta-VLDL is included in the LDL cholesterol value. If the triglycerides are elevated but less than 1000 mg/dL and the total cholesterol is elevated, the lipoprotein abnormality may be caused by either: (1) elevations of both low-density lipoprotein (LDL) and VLDL, which is type IIb or mixed hyperlipoproteinemia, or (2) increased remnant VLDL or intermediate-density lipoprotein (IDL), which is type III hyperlipidemia or dysbetahyperlipoproteinemia (total cholesterol levels, about 300-600 mg/dL; triglyceride levels, about 400-800 mg/dL). The 2 disorders may be distinguished by obtaining a direct LDL cholesterol analysis (enzymatic analysis), which is available at most commercial laboratories. If the direct LDL cholesterol is significantly lower than the calculated LDL cholesterol, a diagnosis of type IIIhyperlipoproteinemia is likely. Furthermore, if the cholesterol-to-triglyceride ratio in isolated VLDL is greater than 0.3, dysbetalipoproteinemia is likely (normal ratio, 0.2).

The only procedure that reliably distinguishes between a mixed hyperlipoproteinemia (increased LDL cholesterol and triglycerides) and type III hyperlipoproteinemia (increased IDL) is beta quantification (lipoprotein electrophoresis). This expensive analysis involves ultracentrifugation followed by electrophoresis. However, it is not performed by most commercial or hospital laboratories. Studies that can isolate and measure VLDL and IDL include density-gradient ultracentrifugation and nuclear magnetic resonance spectroscopy. These tests are reliable in helping diagnose dysbetalipoproteinemia, but they may be available only at lipid specialty laboratories.

Specialized lipid centers should be contacted if type IIb or III must be confirmed. In most clinical settings, however, distinguishing between these entities is rarely necessary, because the treatment of both conditions is essentially the same. Diet modification, exercise, and appropriate weight loss improve both. Type IIb and III also respond to the same medications—niacin and/or fibric acid derivatives.[44] Therefore, no matter which diagnosis applies to a given patient, the treatment is the same.

The Endocrine Society does not recommend routinely measuring lipoprotein particle heterogeneity in patients with hypertriglyceridemia, suggesting that although apolipoprotein B (apo B) or lipoprotein(a) [Lp(a)] levels may be useful, results of other apolipoproteins are generally not clinically useful.[42] However, apo E genotyping or phenotyping can be used to determine if the patient is homozygous for apo E-2, but this finding is not sufficient for the diagnosis of dysbetalipoproteinemia without clinical or lipid abnormalities consistent with the disorder.

Chylomicron Determination

If the triglyceride levels are greater than 1000 mg/dL and the presence of chylomicrons must be confirmed, the simplest and most cost-effective test involves overnight refrigeration of an upright tube of plasma or serum. If a creamy supernatant is seen the next day, chylomicrons are present. If the infranatant is cloudy, high levels of very low-density lipoprotein (VLDL) are present (type V hyperlipidemia). If the infranatant is clear, the VLDL content is normal and type I hypercholesterolemia (elevated chylomicrons only) should be suspected.

Type I hyperlipoproteinemia (pure hyperchylomicronemia)

To make a definitive diagnosis of type I hyperlipidemia, a deficiency of either lipoprotein lipase or apo C-II must be confirmed. The presence of lipoprotein lipase activity may be measured in plasma following intravenous heparin administration (50 IU of heparin per kg body weight) or by analysis of muscle or adipose tissue biopsy samples.

Defective or absent apo C-II must be determined at a lipid center that performs 1 of the 3 following assays: (1) gel electrophoresis, (2) radioimmunoassay, or (3) confirmation that lipoprotein lipase added to the patient's plasma is not active.

 

Treatment

Approach Considerations

Even without a definitive diagnosis from the workup, treatment of presumed dysbetalipoproteinemia may proceed, because other lipid disorders, such as type IIb hyperlipidemia produce similar elevations in cholesterol and triglyceride levels and will respond to the same medical interventions.

In general, lifestyle modifications (eg, smoking cessation, diet, exercise, weight reduction) are initiated before any pharmacologic therapy in the treatment of primary and secondary dyslipidemia, particularly in patients who are asymptomatic.[45, 34, 41, 46, 42] Weight reduction and a diet low in saturated fat and cholesterol are advocated. Patients should avoid alcohol and estrogen in certain types of hyperlipoproteinemias.

The patient’s low-density lipoprotein (LDL) cholesterol level response is measured in 6 weeks to 6 months, depending on the patient's cardiovascular risk factors. Consider an LDL cholesterol goal of less than 70 mg/dL in patients with established coronary artery disease (CAD) or CAD risk equivalents, including clinical manifestations of noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease, transient ischemic attacks or stroke of carotid origin or 50% obstruction of a carotid artery), diabetes, or a Framingham 10-year CAD risk score of greater than 20%.[47]

Consider pharmacologic therapy if the LDL-C level remains above the following thresholds[47] :

  • Patients with low risk, 190 mg/dL or greater

  • Patients with moderate risk, 160 mg/dL or greater

  • Patients with moderately high risk, 130 mg/dL (option 100 mg/dL) or greater

  • Patients with high risk, 100 mg/dL (option 70 mg/dL) or greater

Because of the possibility of adverse effects and the question of whether the triglyceride level is an independent risk factor for atherosclerosis, many physicians use drugs to reduce the triglyceride level only when the level exceeds 500 mg/dL. Patients with triglyceride concentrations greater than 1000 mg/dL should receive diet and drug therapy and be closely monitored to prevent pancreatitis.

Patients first should be treated for the metabolic condition that is causing or exacerbating their hyperlipidemia. If diabetes is present, glucose levels and glycosylated hemoglobin (HbA1c) should be normalized with treatment that meets or exceeds the guidelines of the American Diabetes Association (ADA), if possible. If hypothyroidism is diagnosed, thyroid stimulating hormone (TSH) should be normalized.

In managing secondary dyslipidemia, consider statin therapy for all patients, as these agents reduce mortality and coronary heart disease/atherosclerotic cardiovascular disease (CHD/ASCVD) endpoints.[45] High-potency statins (atorvastatin, rosuvastatin) at high doses have greater efficacy in reduction of cardiovascular events than low potency statins or high-potency statins at low doses.[45] However, patients treated with lipid-lowering medications should be carefully monitored for the development of myositis or liver disease. In addition, statin monotherapy is not recommended for severe or very severe hypertriglyceridemia.[42]

A study by Shimabukuro et al found that the impact on lipoprotein subclass profiles varies between pitavastatin and atorvastatin. Determining the lipoprotein subclass profile and selecting the appropriate statin in patients with diabetes and an additional cardiovascular risk, such as low HDL cholesterol or hypertriglyceridemia may be beneficial.[48, 49, 50, 51]

Other considerations

Do not start medications that may cause severe hypertriglyceridemia without first checking baseline triglycerides. These drugs may be used in patients with mildly elevated triglycerides and are not absolutely contraindicated in patients with significantly elevated triglycerides. Patients must be closely monitored, and a triglyceride-lowering medication should be instituted, if necessary.

Ileal bypass surgery and plasmapheresis to lower elevated serum lipids are used in selected cases of familial hypercholesterolemia. Only experienced physicians should use these therapies.

Normally, in patients with acute pancreatitis secondary to severe hypertriglyceridemia, triglyceride levels rapidly decrease, often by 1000 mg/dL each day when treated with standard medical therapy: nothing by mouth (NPO), intravenous (IV) hydration, and if needed, parenteral insulin to reduce plasma glucose levels. If triglyceride levels do not decrease or, more ominously, if they increase, more aggressive intervention with plasmapheresis is probably warranted.

If the primary care provider cannot control a patient's triglycerides, referral should be made to a lipidologist or endocrinologist with expertise in treating severe and difficult-to-manage lipid disorders.[52]

FDA warnings

On March 1, 2012, the US Food and Drug Administration (FDA) issued updates to the prescribing information concerning interactions between protease inhibitors (such as those used to treat hepatitis C or human immunodeficiency virus infection) and certain statin drugs, notably that the combination of these agents taken together may raise the blood levels of statins and increase the risk for myopathy.[53] The most serious form of myopathy, rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.[53]

Two days earlier, on February 28, 2012, the FDA approved important safety label changes for statins, including removal of routine monitoring of liver enzymes from drug labels.[54] Information about the potential for generally nonserious and reversible cognitive side effects and reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels were added to the statin labels. In addition, the lovastatin label was extensively updated with new contraindications and dose limitations when this agent is taken with certain medicines that can increase the risk for myopathy.[54]

On June 8, 2011, the FDA recommended limiting the use of the highest approved dose of simvastatin (Zocor) (80 mg) due to the increased risk of myopathy.[55] The agency also required changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines.[55]

Pharmacologic Therapy

High doses of a strong statin (simvastatin, atorvastatin, rosuvastatin) lower triglycerides, by as much as approximately 50%, and raise high-density lipoprotein (HDL) cholesterol.[41] The greater the baseline level of triglycerides the greater the percent triglyceride reduction will be with statin treatment.[56] In addition to statins, 3 classes of medications are appropriate for the management of major triglyceride elevations: fibric acid derivatives, niacin, and omega-3 fatty acids.[41, 46, 56]

Nicotinic acid combined with a statin generally improves low-density lipoprotein (LDL) cholesterol, HDL cholesterol, and triglyceride levels. However, the use of fibric acids has a variable effect on LDL cholesterol despite reducing triglyceride levels and increasing HDL cholesterol levels.[41, 56] In patients with diagnosed coronary artery disease (CAD) at very high risk of recurrent cardiovascular events, it may be necessary to use the combination of a cholesterol-lowering drug with a triglyceride-lowering drug to reach the non-HDL cholesterol goal.[41]

Fibrates

Currently, four fibrates are used clinically; two are available in the United States, both in generic formulations: gemfibrozil (Lopid) and fenofibrate (multiple brand names). Bezafibrate and ciprofibrate, available in Europe and elsewhere, have not been approved by the FDA.

Delayed-release fenofibric acid was approved by the FDA for an indication in which it was coadministered with statin in patients with mixed dyslipidemia and CHD or a CHD risk equivalent in whom optimal statin therapy has been achieved. However, the FDA withdrew approval for this indication when the agency found that, in light of several large trials, "scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events."[57, 58]

A review of gemfibrozil, fenofibrate, and bezafibrate described their beneficial lipid effects and the association of these drugs with reductions in coronary morbidity and mortality (although no substantial effect on total mortality was found).[59]

Clinical trials have shown that some fibrates cause reversible increases in serum creatinine levels but either have no impact on or slightly decrease albumin excretion.[60] Moreover, the kidney is the primary route for elimination of most fibrates, and dose reductions are indicated for reduced creatinine clearance. The half-life of gemfibrozil is independent of renal function, and it is the drug of choice for patients with chronic kidney disease.[61]

Fenofibrate has been marketed in the United States under multiple brand names, each with different doses; generic fenofibrate is also available in different doses. In addition, micronized and nonmicronized formulations are produced; whether one formulation has any advantage over the other is not clear.

All manufacturers provide high- and low-dose fenofibrate tablets. The standard adult dose is always more than 100 mg/d; the lower dose is indicated for patients with renal dysfunction (creatinine clearance < 80). Fibrates are contraindicated in patients with creatine clearance of less than 30. The formulation known as fenofibric acid (Trilipix) was approved by the FDA for use with a statin in mixed dyslipidemia.[62, 63, 59, 60, 61] The older fenofibrate formulation also appears to be safe when combined with a statin.

Niacin

High-dose niacin (vitamin B-3) (1500 or more mg/d) decreases triglyceride levels by at least 40% and can raise HDL cholesterol levels by 40% or more.[42] Niacin also reliably and significantly lowers LDL cholesterol levels, which the other major triglyceride-lowering medications do not. In the Coronary Drug Project, niacin, in comparison with placebo, reduced coronary events.[64]

Although extended-release niacin had been approved by the FDA for coadministration with statin for treatment of primary hyperlipidemia and mixed lipidemia, the FDA withdrew approval for this indication when the agency found that, in light of several large trials, "scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events."[57, 58]

Precautions

Niacin has multiple adverse effects, the worst of which is chemical hepatitis. However, at doses of 1.5-2 g/d, complications are unusual. Sustained-release niacin is more hepatotoxic than immediate-release niacin but is better tolerated.[65] Flushing, itching, and rash are expected adverse effects that are less common with long-acting formulations. These symptoms are an annoyance but are not life threatening and may be minimized by starting at low doses and increasing slowly. Switching from immediate-release niacin to an equal dose of time-release preparation has been reported to cause severe hepatotoxicity. Niacinamide, also called vitamin B-3, has no lipid-lowering effects; nor does inositol hexanicotinate.

If niacin is prescribed for patients with type 2 diabetes, glucose control should be carefully monitored, modest increases in insulin resistance can occur.[66] In addition, because uncontrolled diabetes can cause hypertriglyceridemia, patients with diabetes mellitus should be treated aggressively to reduce the HbA1c level to less than 7%. Niacin is the best available agent to increase HDL cholesterol. It also lowers lipoprotein (a).

Omega acids

Omega-3 fatty acids are attractive because of their low risk of major adverse effects or interaction with other medications. At high doses (≥4 g/d), triglycerides are reduced. The triglyceride-lowering impact of fish oils is entirely dependent on the omega-3 content, and, therefore, the number of capsules required for a total dose of 4 g/d requires determining the content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per capsule. A recent study of nonprescription fish and krill oil capsules available in the United States as dietary supplements showed that the content of DHA ranges from 0.05 to 0.22 mg/g and of EPA from 0.08 to 0.45 mg/g. The labels of the most common fish oil supplement capsules in the United States claim to provide 180 mg of EPA and 120 mg of DHA per capsule. Therefore, a minimum dose of 4 g of omega-3 fatty acids per day may require at least 8-12 capsules.[67]

Low doses of EPA and DHA (750-1000 mg/d) that do not affect lipid levels have been demonstrated to lower the incidence of fatal coronary events, probably due primarily to its antiarrhythmic properties.[68]

However, the role of omega-3 fatty acid supplements in coronary heart disease (CHD) prevention is controversial, with conflicting results derived from large trials of the fatty acids. For example, a meta-analysis by Aung et al indicated that in high-risk patients, daily supplements of marine-derived omega-3 fatty acids produce no significant reduction in the rate of fatal or nonfatal CHD or other major vascular events. However, a 2017 scientific statement update from the American Heart Association declared it reasonable for omega-3 fatty acid supplementation to be used in patients with prior CHD or heart failure with reduced ejection fraction, while European guidelines state that more evidence is required before use of these supplements can be justified.[69, 70]

A retrospective study by Kim et al found that, using a baseline triglyceride level of 200-500 mg/dL, patients with hypertriglyceridemia who took omega-3 fatty acid experienced a greater reduction in triglyceride levels after 3 months than did those receiving statin monotherapy. However, the investigators found no significant difference in triglyceride decrease between those patients on omega-3 fatty acid monotherapy and those being administered a combination of omega-3 fatty acid and a statin. The study also found that at a baseline triglyceride level of 500 mg/dL or above, triglyceride reduction did not differ significantly between all the three groups. The study included 2071 patients.[71]

A retrospective, observational cohort study by Tatachar et al found that even a suboptimal dose of over-the-counter (OTC) fish oil supplement can significantly lower triglyceride levels. The investigators found that in patients who were prescribed 2 g/day of fish oil supplements, triglycerides were reduced by 29%. However, patients in the study who were prescribed fenofibrate or gemfibrozil achieved greater triglyceride reduction, 48.5% and 49.8%, respectively.[72]

Several prescription fish oil capsules have been approved by the FDA to treat triglyceride levels of more than 500 mg/dL. A report by Hilleman and Smer states that omega-3 fatty acid products available in prescription formulations have been found to significantly reduce triglycerides. In patients with baseline triglyceride levels of 500 mg/dL or greater taking 4 g/day of a prescription product, decreases compared with placebo ranged from 12.2% to 51.6%. Unlike the supplements, the prescription products are subject to FDA approval, and their safety and efficacy must be established prior to marketing. Currently, prescription capsules contain either a combination of EPA and DHA or EPA alone.[73] There is some concern regarding the use of DHA in patients with dyslipidemia, since high-dose omega-3 products containing DHA increase LDL cholesterol levels; the impact on HDL cholesterol levels varies.

Icosapent ethyl (Vascepa), an ultra-pure prescription omega fatty acid, contains an ethyl ester of EPA; capsules have no DHA component. Past studies suggest that highly purified EPA can reduce TG levels without raising LDL cholesterol.[74, 75]

Serving as an adjunct to diet, icosapent has been indicated for lowering TG levels of at least 500 mg/dL. In December 2019, the drug gained FDA approval as adjunctive therapy for cardiovascular event risk reduction in adults whose TG levels are 150 mg/dL or higher and in whom established cardiovascular disease is present (or in whom, in the absence of established cardiovascular disease, diabetes exists, along with two or more additional cardiovascular disease risk factors).

Approval was largely based on the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial). The study involved statin-treated patients, all with a history of atherosclerosis or diabetes, in whom TG levels between 135 to just under 500 mg/dL and LDL levels between just over 40 to 100 mg/dL were found. Of 3146 US patients, the primary endpoint—cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina—was reached by 24.7% of those on placebo, compared with 18.2% of patients treated with icosapent ethyl, by median 4.9-year follow-up.[76]

Other examples of prescription products include Lovaza. A 1-g capsule contains at least 900 mg of ethyl esters of omega-3 fatty acids (~465 mg of EPA and 375 mg of DHA). Another prescription omega-3 fatty acid product, Omtryg, was approved by the FDA in 2014 and contains EPA and DHA in the same amounts as Lovaza.[77]

The Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension (MARINE) trial randomized 229 diet-stable patients with fasting TG levels from 500-2000 mg/dL (with or without background statin therapy) to icosapent 4 g/day, icosapent 2 g/day, or placebo. Results showed that icosapent significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels. Icosapent 4 g/day reduced the placebo-corrected TG levels by 33.1% (n = 76; P< 0.0001) and icosapent 2 g/day by 19.7% (n = 73; P = 0.0051). For a baseline TG level >750 mg/dL, icosapent 4 g/day reduced the placebo-corrected TG levels by 45.4% (n = 28; P = 0.0001) and icosapent 2 g/day by 32.9% (n = 28; P = 0.0016).[78]

An omega-3 carboxylic acid product (Epanova) was approved by the FDA in May 2014.[79] It is the first prescription omega-3 product in free fatty acid form. It is indicated as an adjunct to diet to reduce triglyceride levels in adults with severe hypertriglyceridemia (TGs ≥500 mg/dL).

Approval was based on data from the Phase III EVOLVE (EpanoVa fOr Lowering Very High triglyceridEs) trial. The trial showed a significant decrease in non-HCL-C, ratio of total cholesterol to HDL-C, VLDLs, Apo-C, phospholipase A2, and arachidonic acid with omega-3 carboxylic acids over a 12-week period compared with olive oil in patients with TGs ≥500 mg/dL.[80]

Vascazen, a medical food derived from fish oil, is also available. Each 1-g Vascazen capsule contains at least 900 mg of ethyl esters of omega-3 fatty acids sourced from fish oils and includes approximately 680 mg of EPA and approximately 110 mg of DHA.

Note that although fatty fish (eg, salmon, tuna, trout, mackerel, sardines) are good sources of omega-3 fatty acids, they also usually contain high concentrations of mercury and polychlorinated biphenyls (PCBs). Fish oil supplements that can be obtained without a prescription have negligible amounts of mercury. [86] The advantage of prescription fish oil is that fewer capsules are necessary to achieve a therapeutic dose, facilitating adherence. Additionally, the prescription products have been thoroughly tested in phase 3 trials to show safety and efficacy (particularly for lowering very high TGs).[78, 80] [77, 79] Consistency of potency is ensured with the prescription fish oil products.

HMG-CoA reductase inhibitors (statins)

For patients with mixed hyperlipidemias (elevations of both LDL cholesterol and triglycerides), a moderate dose of a hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor may be appropriate if the amount of triglyceride lowering necessary is only about 20%. Maximum doses of the strongest statins, atorvastatin, simvastatin, and rosuvastatin, lower triglycerides approximately 40%, but such doses are not appropriate first-line therapy unless triglycerides are less than 500 mg/dL and LDL-C is elevated.[42, 81]

It is recommended that patients intolerant to one statin (eg, owing to myalgias) try the other statins before excluding the entire class, particularly in secondary prevention of dyslipidemias.[41] If the patients cannot take statins other agents suitable for management of mixed dyslipidemia may be tried, either alone or in combination therapy, including niacin, fibric acids, and ezetimibe.[41] Bile acid sequestrants can raise triglycerides and are contraindicated in patients with very high triglycerides.[56]

Note the following[41] :

  • Statins are more effective when taken at bedtime or in the evening

  • Although lovastatin should be taken with food to maximize its absorption, the sustained-release formulation should be taken on an empty stomach

  • A major reduction in HDL may occur in some patients on combined therapy with fibrates and thiazolidinediones (check HDL levels 1-2 mo following initiation of this combination therapy)

  • Do not adjust dosing regimens more often than every 4 weeks after a fasting lipid panel has been obtained

A study by Jun et al found that treatment with omega-3 fatty acid and atorvastatin more effectively lowered triglyceride levels in patients than did atorvastatin therapy alone. The report involved adults with fasting triglyceride levels of 200 mg/dL or above but less than 500 mg/dL, and low-density lipoprotein (LDL) cholesterol levels of below 110 mg/dL. Patients underwent 8 weeks of daily treatment consisting of either 4000 mg of omega-3 fatty acid and atorvastatin calcium 20 mg or atorvastatin calcium 20 mg plus placebo. The report found that 62.9% of individuals in the omega-3/atorvastatin group achieved triglyceride levels of less than 200 mg/dL, compared with 22.3% of the monotherapy group.[82]

 

Other agents

Bile acid sequestrants (cholestyramine or colestipol) raise triglyceride levels and are not appropriate therapy for hypertriglyceridemia. However, in patients with a mixed hyperlipidemia, resins may be combined with niacin or a fibrate.

Patients with the metabolic syndrome are often treated with metformin, which improves impaired fasting glucose levels, frequently causes modest weight loss, and can lower triglyceride levels.

Ezetimibe (Zetia) is a selective cholesterol-absorption inhibitor that has been used as secondary therapy in the management of dyslipidemia, such as in the following clinical situations[41] :

  • High LDL, low HDL (< 40 mg/dL), and high triglycerides (>200 mg/dL)

  • High LDL, regardless of whether the HDL level is lower than 40 mg/dL or not

Adult Treatment Panel Guidelines

The Adult Treatment Panel guidelines (ATP III) were published in 2001 and reclassified serum triglycerides (TGs), as shown in Table 2 (below). An update to the ATP III guidelines (ATP IV) was published in 2013.[83]

Table 2. Classification of Triglycerides (Open Table in a new window)

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.[14]

If triglycerides are 500 or above, their treatment takes priority over low-density lipoprotein (LDL) treatment to prevent pancreatitis, unless the patient has a high risk for an acute coronary artery disease (CAD) event, in which case simultaneous treatment for both conditions should be considered.

If the secondary conditions that raise triglyceride levels cannot be managed successfully and if triglycerides are 200-499 mg/dL, the non–high-density lipoprotein (HDL) cholesterol (total cholesterol – HDL) can be used as the initial target of using LDL-lowering medication (see Table 3, below). The non–HDL cholesterol is the sum of the cholesterol carried by the atherogenic lipoproteins, LDL, very low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL). The goals for non–HDL levels, similar to those for LDL levels, are dependent on risk and are 30 mg/dL higher than the corresponding LDL goals.

Table 3. Classification of LDL Cholesterol and Non-HDL Cholesterol (Open Table in a new window)

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.[14]

When hypertriglyceridemia is diagnosed, secondary causes should be sought out and controlled. If the triglyceride level is below 500 mg/dL, triglyceride-lowering medication may be withheld while secondary causes are managed. For example, lowering a substantially elevated HbA1c may normalize the triglycerides; or at least facilitate their treatment.

Diet and Exercise

The importance of obesity, a sedentary lifestyle, very high fat diet, and intake of large concentrations of refined carbohydrates should not be underestimated as causes of severe hypertriglyceridemia. A dietitian or knowledgeable physician should counsel the patient. Instituting a program of progressive aerobic and toning exercise, weight loss, and dietary management can significantly lower triglyceride levels and, in some cases, normalize them.

It is recommended that individuals consume less than 20% of calories as fat, with saturated fat reduced to less than 7% of calories, which may be achieved by avoiding trans fats, limiting dietary cholesterol to less than 200 mg/d.[41] Restrict refined carbohydrates, particularly sugar and liquid calories. In addition, lowering low-density lipoprotein (LDL) may be enhanced by adding dietary options such as 2 g/d of plant stanols/sterols and at least 5-10 g/d of viscous soluble fiber to the diet.[41]

Alcohol consumption should also be severely limited or abstained; consuming more than 1 standard alcoholic drink per day may worsen hypertriglyceridemia. In March 2011, the American Dietetic Association published updated evidence-based guidelines for nutrition practice for disorders of lipid metabolism.

Total fat intake

Total fat intake should be restricted if this intervention assists in weight loss. If triglyceride levels are greater than 1000 mg/dL, allowing no more than 10% of total calories from fat will usually lower triglycerides promptly and dramatically.

Fat restriction is a 2-edged sword. Reducing fat intake causes needed weight loss, and triglycerides usually improve. When triglycerides are severely elevated (>1000 mg/dL), suggesting impaired or absent lipoprotein lipase activity, a low-fat diet decreases chylomicron and very low-density lipoprotein (VLDL) production and improves the metabolism of these triglyceride-rich lipoproteins.

However, in the setting of stable weight and moderately elevated triglycerides, a very low-fat diet increases triglycerides and may, in addition, decrease high-density lipoprotein (HDL) levels. Patients who are extremely compliant and motivated may choose to follow such a diet in the hope of improving their cholesterol levels. If they have a mixed hyperlipidemia, their LDL level certainly will decrease. However, such a diet will, if anything, cause further deterioration in the HDL and triglyceride levels. If the patient has an isolated triglyceride elevation and does not lose weight on the diet, the triglyceride levels may increase. In such cases, addition of a healthy fat (monounsaturated or polyunsaturated fat) lowers levels of triglycerides, increases HDL, and sometimes decreases LDL.

Carbohydrate intake

In cases in which dietary intake of sugar and white flour products is substantial, restricting simple carbohydrates and increasing dietary fiber are important adjuncts that can lower triglycerides substantially. Large quantities or fruit juice or nondiet soda can increase triglycerides dramatically.

Again, alcohol should be eliminated or restricted to no more than 1 standard alcoholic beverage per day.

Omega-3 (N-3) fatty acids

The class of polyunsaturated fats known as omega-3 fatty acids, which are derived mainly from fatty fish and some plant products (flax seed), has a unique impact on triglycerides. In large amounts (10 or more g/d), N-3 fatty acids lower triglycerides 40% or more.

To achieve this dose, purified capsules are usually necessary, but some patients may prefer to eat large quantities of fatty fish. The fish highest in N-3 fatty acids are sardines, herring, and mackerel; daily servings of 1 pound or more may be necessary. If weight gain ensues, triglyceride lowering will be compromised.

Exercise

Exercise, particularly sustained aerobic activity, can have a dramatic impact on triglyceride levels and may increase HDL slightly. If patients have no known cardiovascular disease, they should be encouraged to begin an exercise program of graduated aerobics and toning.

The American Heart Association (AHA) recommends 30-60 minutes of aerobic exercise most days of the week and toning for 20-30 minutes twice a week. Frequent and sustained exercise lowers elevated triglyceride levels and may raise HDL cholesterol levels.

Before beginning an exercise program, consider giving a stress test to older patients and patients with multiple risk factors for coronary artery disease, as these patients are at increased risk for cardiovascular disease.

Exercise prescription also has substantial benefits beyond lipid effects as follows:

  • Reduced weight

  • Decreased insulin resistance

  • Decreased blood pressure

  • Improved cardiovascular conditioning

Overall reduction in acute cardiovascular events is also a likely benefit of regular exercise. Toning of large muscles groups (abdomen, back, legs, arms) also improves metabolism of triglyceride-rich lipoproteins and lowers triglycerides.

Pregnant Patients

Women with elevated triglycerides before conception may develop severe hypertriglyceridemia, with triglyceride levels well above 1000 mg/dL, and the concomitant risk of pancreatitis. These women should be counseled regarding diet, exercise, and weight management before becoming pregnant and must be monitored closely during their pregnancies.[84] All pregnancies require occasional triglyceride monitoring. Simple inspection to rule out lipemic serum is all that is necessary.

The use of lipid-lowering drugs in pregnant patients and pediatric patients has not been thoroughly investigated. Thus, most of the medications to treat hypertriglyceridemia are contraindicated during pregnancy, although treatment with gemfibrozil in a patient with severe hypertriglyceridemia and pancreatitis has been reported.[84] Omega-3 fatty acids may be a more acceptable intervention, but the safety of high-dose N-3 fatty acids has not been proven.

Screening and Prevention

To decrease the risk of cardiovascular disease, patients should avoid smoking, obesity, and sedentary lifestyles. Moreover, pursue aggressive treatment of hypertension and diabetes.

Primary and secondary prevention

Patients with hypertriglyceridemia, particularly if the high-density lipoprotein (HDL) level is low, are at risk for cardiovascular events. For primary prevention, it is recommended that men aged 35 and older—and those aged 20-35 if they are at increased risk—are screened for coronary heart disease (CHD) with a fasting lipid profile; screening for women is recommended only for those at increased risk for CHD.[45, 34] For patients who were screened with a nonfasting due to patient convenience, follow-up on abnormal nonfasting lipid levels with a fasting lipid profile. Screening should be repeated every 5 years in patients with normal lipid levels.[45]

In secondary prevention, all patients with CHD, other atherosclerotic cardiovascular disease (ASCVD), diabetes mellitus, or a Framingham 10-year risk of greater than 20% should be screened with a full lipid panel.[45] Evaluate the patient’s risk for cardiovascular events. Patients considered at high risk include those who have CHD without major risk factors or other risks associated with very high risk.

Patients considered at very high risk include individuals with CHD or other atherosclerotic vascular disease as well as 1 or more of the following: major risk factors (eg, diabetes, hypertension, metabolic syndrome, active cigarette smoking) or acute coronary syndrome.[45, 47] Thus, these patients should be treated not only for their lipid disorder but also for other modifiable cardiovascular risk factors, such as hypertension, diabetes, smoking, sedentary lifestyle, and obesity.[85, 86]

The Endocrine Society’s 2012 guidelines in evaluating and treating hypertriglyceridemia included screening adults for this condition as part of a lipid panel at least at 5-year intervals.[42] For pediatric patients with dyslipidemia, the American Association of Clinical Endocrinologists (AACE) recommends early diagnosis and management to reduce LDL levels, thereby reducing the risk for cardiovascular events in adulthood.[68]

Diet and exercise

Although the rare inherited disorders of severe hypertriglyceridemia require heroic restrictions in dietary fat, most elevated triglycerides can be controlled, at least partially, by a program of diet, exercise, and weight loss. Lifestyle modification can be more effective than a triglyceride-lowering medication if the habits are in need of intervention and the patient is willing and able to make significant changes. Therefore, prevention entails pursuing an active lifestyle with regular aerobic and toning exercise; adhering to a diet low in simple carbohydrates and alcohol and, if the triglycerides are well above 1000 mg/dL, low in fat; and maintaining a lean body habitus. These habits have the added benefit of reducing the probability of developing type 2 diabetes mellitus and hypertension.

Patients with modest triglyceride elevations may develop severe hypertriglyceridemia and risk of pancreatitis if an aggravating agent is instituted. Drugs such as oral isotretinoin and unopposed oral estrogen replacement therapy should be used with caution.

During pregnancy, severe hypertriglyceridemia is an unusual complication and may cause pancreatitis. Many case reports have been published describing interventions to manage this condition. Most commonly, a very low-fat diet was sufficient to control triglycerides and prevent pancreatitis. Intermittent and, in persistent cases, continuous total parenteral nutrition has been used—usually in the third trimester. Reports also have been published describing plasma exchange or apheresis, as well as early third-trimester termination of pregnancy by cesarean section.

Consultations

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.

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.

In patients with diabetes, aggressive glucose control should be pursued with diet, oral hypoglycemic agents, or insulin.

 

Medication

Medication Summary

Classes of medications that are appropriate for the management of major triglyceride elevations include fibric acid derivatives, niacin, and omega-3 fatty acids. High doses of a strong statin (simvastatin, atorvastatin, rosuvastatin) also lower triglycerides, by as much as approximately 50%.

 

Table 4. Fibric Acid Agents, Omega Acid Ethyl Esters, and Niacin Drug Characteristics [87] (Open Table in a new window)

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.

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

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)

Secondary CV risk prevention; REDUCE-IT trial showed primary endpoint (major CV events) occurred in 24.7% of placebo compared with 18.2% of icosapent ethyl treated patients (p = 0.000001) [76]

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

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 [88] (Open Table in a new window)

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

 

Fibric Acid Agents

Class Summary

Fenofibrate is reported to lower LDL levels more reliably than either clofibrate or gemfibrozil, but none of the drugs in this class should be used for isolated LDL elevations. The fibrates are commonly used to treat hyperlipidemias types IV (high VLDL) and V (high VLDL and chylomicrons), as well as type III dysbetalipoproteinemia (IDL or VLDL remnant disease).

These agents can also be used to treat type IIb mixed hyperlipidemia if used in conjunction with an LDL-lowering medication such as a resin.

Gemfibrozil (Lopid)

Gemfibrozil lowers triglycerides, VLDL, and IDL, but raises HDL. LDL is usually is unaffected but may increase if it is initially low or decrease if it is initially high. This agent increases the activity of lipoprotein lipase, which hydrolyzes triglycerides in triglyceride-rich lipoproteins. Gemfibrozil reduces synthesis of VLDL in the liver and increases the clearance of remnant lipoproteins from blood.

Gemfibrozil is available in generic formulation, most cost-effective fibrate at this time. Its FDA-approved indications are for type IV and V hyperlipidemia (ie, elevations in VLDL only or both VLDL and chylomicrons).

Fenofibrate (Tricor, Lofibra, TriCor, Antara, Triglide)

Fenofibrate is similar to other fibric acid derivatives in triglyceride-lowering and HDL-raising effects. However, this agent differs in that modest LDL-lowering can be expected with greater frequency than with gemfibrozil.

The FDA-approved indications for fenofibrate are for hypertriglyceridemia and hypercholesterolemia, but this difference does not qualify fenofibrate for treatment of isolated LDL elevations. Fenofibrate is taken once a day, which may increase patient compliance. Patients with mild-to-moderate renal disease should receive a reduced dose (about one third of the usual dose), and it is contraindicated in severe renal impairment.

Omega-3 Acids

Class Summary

Prescription omega-3 acids (fish oil) are available and have shown to be effective in lowering very high serum triglycerides (≥ 500 mg/dL).

Icosapent (Vascepa)

Ethyl ester of eicosapentaenoic acid indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia (> 500 mg/dL). It is also indicated as adjunctive therapy for cardiovascular event risk reduction in adults whose TG levels are 150 mg/dL or higher and in whom established cardiovascular disease is present (or in whom, in the absence of established cardiovascular disease, diabetes exists, along with two or more additional cardiovascular disease risk factors). Reduces hepatic VLDL-TG synthesis and/or secretion; enhances TG clearance from circulating VLDL particle; may also increase beta-oxidation, inhibits acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT), decreases lipogenesis in liver, and increases plasma lipoprotein lipase activity. Icosapent does not increase LDL-cholesterol.

Omega-3 fatty acids (Lovaza, Vascazen, Omtryg)

Omega-3-acid ethyl esters were the first prescription omega-3-acid. These are purified fish oil, without heavy metals and polychlorinated biphenyl (PCBs). Content of EPA and DHA vary between each brand.

This agent is theorized to reduce triglyceride synthesis in the liver. EPA and DHA are poor enzyme substrates for triglyceride synthesis in the liver, and they inhibit esterification of other fatty acids. Potential mechanisms of action include acyl CoA:1,2-diacylglycerol acyltransferase inhibition, increased hepatic mitochondrial and peroxisomal beta-oxidation, decreased hepatic lipogenesis, and increased plasma lipoprotein lipase activity.

Omega-3-acid ethyl esters are indicated as adjunctive treatment to dietary changes to reduce very high triglyceride levels (ie, >500 mg/dL).

Clinical trials show significant reduction in non–HDL, triglyceride, total cholesterol, VLDL, and apo B levels from baseline when combined with simvastatin compared with simvastatin and placebo. Monotherapy with omega-3-acid ethyl esters reduces median triglyceride, VLDL, and non–HDL levels from baseline.

Omega-3 carboxylic acids (Epanova)

Omega 3 acids are thought to inhibit acyl CoA:1,2-diacylglycerol acyltransferase. Increased mitochondrial and peroxisomal beta-oxidation in liver , decreased hepatic lipogenesis, and increased activity of plasma lipoprotein lipase activity may also be possible mechanisms. Omega 3 carboxylic acids is the first prescription omega-3 product in free fatty acid form approved in the United States. It is indicated as an adjunct to diet in patients with severe hypertriglyceridemia (ie, TG ≥ 500 mg/dL).

Lipid-Lowering Agents, Other

Class Summary

Niacin (vitamin B-3) inhibits the hepatic secretion of VLDL cholesterol. This agent is effective in most categories of hyperlipidemia. Niacin has been demonstrated to lower LDL cholesterol by 32% (generally, 15-25% decrease), lower triglycerides by 20-50% (≥1.5 g/d decreases triglycerides by as much as 50%), and raise HDL cholesterol by 43%, particularly at higher doses. Niacin lowers lipoprotein (a) levels, which may be of some clinical importance, because lipoprotein (a) levels have been associated with coronary heart disease in numerous epidemiologic studies. The clinical benefit of lowering lipoprotein (a) levels has not been determined.

Whether purchased by prescription or not, niacin costs less than any other lipid-lowering medication. For reasons not clearly understood, changing brands during treatment is more likely to cause hepatotoxicity, occurring more so with time-release than immediate-release niacin. Insulin resistance may increase; nevertheless, niacin is a useful medication in patients with type 2 diabetes.[66]

Niacin (Slo-Niacin, Niaspan, Niacor)

Niacin, or water-soluble vitamin B-3, functions in the body after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. In gram doses, niacin reduces levels of total cholesterol, VLDL, IDL, LDL, and triglycerides but increases HDL. The magnitude of individual lipid and lipoprotein responses may be influenced by the severity and type of underlying lipid abnormality. Thus, although niacin may increase insulin resistance and worsen glucose control, it is useful for the dyslipidemias common in patients with diabetes. This agent should be taken at bedtime after a low-fat snack and individualized according to patient response.

The slow-release formulation is more hepatotoxic than immediate-release niacin; carefully monitor aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels indefinitely in these patients. Patients strongly advised against switching formulations or brands during treatment. Both prescription and nonprescription formulas are available. Nonprescription brands cost less, but only reliable manufacturers should be recommended. Slo-Niacin is a nonprescription formulation that is available in 250-, 500-, and 750-mg tablets. Prescription extended-release (ER) niacin (Niaspan) is available by prescription in 500-, 750-, and 1000-mg tabs.

At high doses (4-6 g/d), the immediate-release formulation of niacin is less hepatotoxic than the sustained-release (SR) formulation, but it is also less well tolerated by patients due to prostaglandin-mediated flushing, itching, and rash. Therapy is best started at a low dose, such as 100 mg tid pc, and increased gradually (titrated) over several weeks, allowing some patients to accommodate adverse effects. Changing formulation at high doses may increase risk of hepatotoxicity.

Niacor and Nicolar are prescription formulations that, although more expensive than nonprescription brands, may have an advantage in making it less likely that the patient switches brands.

Lipid-Lowering Agents, Statins

Class Summary

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors are competitive inhibitors of 3-hydroxy-3-methyl Co-A reductase, an enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis, resulting in upregulation of LDL receptors in response to the decrease in intracellular cholesterol. The HMG-CoA reductase inhibitors are indicated for the secondary prevention of cardiovascular events and for the treatment of hypercholesterolemia and mixed dyslipidemia.

HMG-CoA reductase inhibitors are indicated for patients with primary and familial hypercholesterolemia, as well as combined hyperlipidemia, as an adjunct to other lipid-lowering treatments. Their main differences lie in their metabolism and therapeutic half-life and in their drug interactions.

FDA warnings

On March 1, 2012, the US Food and Drug Administration (FDA) issued updates to the prescribing information concerning interactions between protease inhibitors (such as those used to treat hepatitis C or human immunodeficiency virus infection) and certain statin drugs, notably that the combination of these agents taken together may raise the blood levels of statins and increase the risk for myopathy.[53] The most serious form of myopathy, rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.[53]

Two days earlier, on February 28, 2012, the FDA approved important safety label changes for statins, including removal of routine monitoring of liver enzymes from drug labels.[54] Information about the potential for generally nonserious and reversible cognitive side effects and reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels were added to the statin labels. In addition, the lovastatin label was extensively updated with new contraindications and dose limitations when this agent is taken with certain medicines that can increase the risk for myopathy.[54]

On June 8, 2011, the FDA recommended limiting the use of the highest approved dose of simvastatin (Zocor) (80 mg) due to the increased risk of myopathy.[55] The agency also required changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines.[55]

Atorvastatin (Lipitor)

Fluvastatin

Lovastatin (Mevacor)

Pitavastatin

Pravastatin

Rosuvastatin (Crestor)

Simvastatin (Zocor)

Vytorin

 

Questions & Answers

Overview

What is hypertriglyceridemia (high triglyceride levels)?

What is hypolipoproteinemia?

What is hyperlipidemia?

What are the signs and symptoms of hypertriglyceridemia (high triglyceride levels)?

Which physical findings suggest hypertriglyceridemia (high triglyceride levels)?

Which lab studies are used to evaluate hypertriglyceridemia (high triglyceride levels)?

When is biopsy indicated for diagnosing hypertriglyceridemia (high triglyceride levels)?

How is hypertriglyceridemia (high triglyceride levels) defined by the Fredrickson classification?

What is type I hyperlipidemia?

Does hypertriglyceridemia (high triglyceride levels) increase the risk for atherosclerotic disease?

What is type IIb hyperlipidemia?

What is type III hyperlipidemia?

What is type IV hyperlipidemia?

What is type V hyperlipidemia?

What is included in the nonpharmacological management of hypertriglyceridemia (high triglyceride levels)?

Which medications are used in the management of hypertriglyceridemia (high triglyceride levels)?

When is surgical intervention indicated for hypertriglyceridemia (high triglyceride levels)?

What is the biological composition of triglycerides?

What are the sources of triglyceride-rich lipoproteins?

What is the role of very low-density lipoproteins (VLDLs) in the pathophysiology of hypertriglyceridemia (high triglyceride levels)?

What are apoEs and what is their role in the pathophysiology of hypertriglyceridemia (high triglyceride levels)?

What is the role of chylomicron and VLDL metabolism in the pathophysiology of hypertriglyceridemia (high triglyceride levels)?

What causes hypertriglyceridemia (high triglyceride levels)?

What are the risk factors for coronary heart disease (CHD)?

What are the genetic causes of hypertriglyceridemia (high triglyceride levels)?

What causes type I hyperlipoproteinemia?

Is there a genetic predisposition for dysbetalipoproteinemia?

Which triglyceride disorders are genetically controlled?

What is familial combined hyperlipidemia?

What is familial hypertriglyceridemia?

Which genes are associated with hypertriglyceridemia (high triglyceride levels)?

Does diabetes mellitus cause hypertriglyceridemia (high triglyceride levels)?

Why are triglyceride levels elevated in patients with uncontrolled type 2 diabetes mellitus and hyperinsulinemia?

Does obesity cause hypertriglyceridemia (high triglyceride levels)?

Does hypothyroidism cause hypertriglyceridemia (high triglyceride levels)?

Does nephrotic syndrome cause hypertriglyceridemia (high triglyceride levels)?

Which medications may cause hypertriglyceridemia (high triglyceride levels)?

Which dietary factors may cause hypertriglyceridemia (high triglyceride levels)?

Does acute pancreatitis cause hypertriglyceridemia (high triglyceride levels)?

How do obesity and uric acid elevation cause hypertriglyceridemia (high triglyceride levels)?

Does hypertriglyceridemia (high triglyceride levels) occur during pregnancy?

What is the prevalence of hypertriglyceridemia (high triglyceride levels) in the US?

What is the frequency of apolipoprotein (apo) E among different racial groups in the US?

What is prevalence of severe hypertriglyceridemia (high triglyceride levels) in the US?

What is the global prevalence of hypertriglyceridemia (high triglyceride levels)?

What is the global frequency of apolipoprotein (apo)E?

Does the prevalence of dysbetalipoproteinemia vary among racial groups?

Is hypertriglyceridemia (high triglyceride levels) more prevalent in men or women?

What is the prevalence of dysbetalipoproteinemia among different age groups?

How does age affect the prevalence of hypertriglyceridemia (high triglyceride levels) in men and women?

At what age is hypertriglyceridemia (high triglyceride levels) normally detected?

What is the prognosis of hypertriglyceridemia (high triglyceride levels)?

Does hypertriglyceridemia (high triglyceride levels) increase the risk for cardiovascular disease?

Are hypertriglyceridemia (high triglyceride levels) and acute pancreatitis comorbidities?

At what triglyceride level is treatment to prevent acute pancreatitis required?

How is recurrent pancreatitis secondary to hypertriglyceridemia (high triglyceride levels) prevented?

What is chylomicronemia syndrome?

What patient education should be provided regarding hypertriglyceridemia (high triglyceride levels)?

Presentation

What are the risk factors for cardiovascular events in patients with hypertriglyceridemia (high triglyceride levels) identified by the USPSTF?

What are the risk factors for dyslipidemia and atherosclerosis identified by the AACE?

What are the GI symptoms of hypertriglyceridemia (high triglyceride levels)?

What are the dermatologic symptoms of hypertriglyceridemia (high triglyceride levels)?

What are the ophthalmologic symptoms of hypertriglyceridemia (high triglyceride levels)?

What are the physical findings in patients with hypertriglyceridemia (high triglyceride levels) and triglyceride levels less than 1000 mg/dL?

What are the physical findings in patients with hypertriglyceridemia (high triglyceride levels) and acutely and massively elevated triglycerides?

What are the physical findings in patients with hypertriglyceridemia (high triglyceride levels) and peripheral vascular disease?

What are the GI findings in patients with hypertriglyceridemia (high triglyceride levels) and pancreatitis or the chylomicronemia syndrome?

Which dermatologic findings suggest hypertriglyceridemia (high triglyceride levels)?

Which ophthalmologic abnormalities suggest hypertriglyceridemia (high triglyceride levels)?

Which neurological findings suggest hypertriglyceridemia (high triglyceride levels)?

DDX

Which disorders should be included in the differential diagnoses of hypertriglyceridemia (high triglyceride levels)?

What are the differential diagnoses for Hypertriglyceridemia?

Workup

How is hypertriglyceridemia (high triglyceride levels) diagnosed?

Which tests should be done to confirm a diagnosis of eruptive xanthomas?

Which test results may predict cardiovascular events in patients with hypertriglyceridemia (high triglyceride levels)?

How are elevated triglyceride levels determined?

What is the role of the standard lipid profile in the diagnosis of hypertriglyceridemia (high triglyceride levels)?

What is the role of beta quantification (lipoprotein electrophoresis) in the diagnosis of hypertriglyceridemia (high triglyceride levels)?

When is the use of a specialized lipid center indicated for the diagnosis of hypertriglyceridemia (high triglyceride levels)?

What are the Endocrine Society recommendations for routine lipoprotein particle heterogeneity measurements in the workup of hypertriglyceridemia (high triglyceride levels)?

How is the presence of chylomicrons confirmed in hypertriglyceridemia (high triglyceride levels)?

How is type I hyperlipidemia diagnosed?

How is defective or absent apo C-II determined in the workup of hypertriglyceridemia (high triglyceride levels)?

Treatment

How frequently is LDL cholesterol level response measured in patients with hypertriglyceridemia (high triglyceride levels)?

What is the initial nonpharmacologic treatment for hypertriglyceridemia (high triglyceride levels)?

When should pharmacologic therapy be considered for hypertriglyceridemia (high triglyceride levels)?

When is pharmacologic therapy indicated to reduce triglyceride levels in patients with hypertriglyceridemia (high triglyceride levels)?

What is the initial treatment for hypertriglyceridemia (high triglyceride levels)?

When is statin therapy indicated in the treatment of hypertriglyceridemia (high triglyceride levels)?

What should be considered before administering medications that may cause severe hypertriglyceridemia (high triglyceride levels)?

When are surgery and plasmapheresis indicated to treat hypertriglyceridemia (high triglyceride levels)?

How is acute pancreatitis treated in patients with hypertriglyceridemia (high triglyceride levels)?

When is a referral to a specialist indicated for the treatment of hypertriglyceridemia (high triglyceride levels)?

What updates have been issued by the FDA concerning interactions between protease inhibitors and statin drugs?

What are the 2012 FDA safety label changes for statins?

What are the FDA recommendations for dose limits of simvastatin (Zocor)?

How much do statins lower triglycerides levels?

Is nicotinic acid combined with a statin effective in lowering triglyceride levels?

Which fibrates are used to treat hypertriglyceridemia (high triglyceride levels)?

Do fibrates reduce the risk of coronary complications in patients with hypertriglyceridemia (high triglyceride levels)?

How do fibrates affect creatinine and albumin levels in patients with hypertriglyceridemia (high triglyceride levels)?

Which formulations of fenofibrate are available in the US for the treatment of hypertriglyceridemia (high triglyceride levels)?

How effective is high-dose niacin in the treatment of hypertriglyceridemia (high triglyceride level) and what is the FDA's stance on niacin-statin coadministration?

What are the possible adverse effects of niacin in the treatment of hypertriglyceridemia (high triglyceride levels)?

Do omega-3 fatty acids effectively treat hypertriglyceridemia (high triglyceride levels) and reduce the risk of coronary heart disease?

Which prescription fish oil capsules are available to treat hypertriglyceridemia (high triglyceride levels)?

Is icosapent effective in reducing triglyceride levels in hypertriglyceridemia (high triglyceride levels)?

Is omega-3 carboxylic acid (Epanova) effective for the treatment of hypertriglyceridemia (high triglyceride levels)?

When are statins indicated for the treatment of hypertriglyceridemia (high triglyceride levels)?

How is hypertriglyceridemia (high triglyceride levels) managed in patients intolerant of statins, and what is the effect of combining omega-3 fatty acid with statins?

When are bile acid sequestrants indicated in the treatment of hypertriglyceridemia (high triglyceride levels)?

When is metformin indicated in the treatment of hypertriglyceridemia (high triglyceride levels)?

When is ezetimibe (Zetia) indicated for the treatment of hypertriglyceridemia (high triglyceride levels)?

What are the ATP III guidelines classification of triglycerides?

According to the ATP III guidelines, when does triglyceride treatment take priority over LDL treatment?

According to the ATP III guidelines, when is non-HDL cholesterol used as the initial target of LDL-lowering medication?

According to the ATP III guidelines, how should secondary causes of hypertriglyceridemia (high triglyceride levels) be managed?

Are lifestyle changes effective treatments for hypertriglyceridemia (high triglyceride levels)?

What are the specific dietary recommendations in the treatment of hypertriglyceridemia (high triglyceride levels)?

Should alcohol be restricted in patients with hypertriglyceridemia (high triglyceride levels)?

Should fat intake be restricted in patients with hypertriglyceridemia (high triglyceride levels)?

What are the risks and benefits of fat restriction in patients with hypertriglyceridemia (high triglyceride levels)?

Should carbohydrate intake be restricted in patients with hypertriglyceridemia (high triglyceride levels)?

What is the effect of omega-3 fatty acids in patients with hypertriglyceridemia (high triglyceride levels)?

How does exercise affect triglyceride levels?

How much exercise does the AHA recommend for patients with hypertriglyceridemia (high triglyceride levels)?

What are the benefits of exercise prescription beyond lipid effects in the treatment of hypertriglyceridemia (high triglyceride levels)?

How is hypertriglyceridemia (high triglyceride levels) managed during pregnancy?

How can the risk for cardiovascular disease be reduced in hypertriglyceridemia (high triglyceride levels)?

What is the primary prevention of cardiovascular events in patients with hypertriglyceridemia (high triglyceride levels)?

What is the secondary prevention for cardiovascular events in patients with hypertriglyceridemia (high triglyceride levels)?

Which patients are at very high risk for hypertriglyceridemia (high triglyceride levels)?

What are the screening guidelines for hypertriglyceridemia (high triglyceride levels)?

How effective are lifestyle changes in the management of hypertriglyceridemia (high triglyceride levels)?

Which drugs can aggravate modest triglyceride elevations?

How is severe hypertriglyceridemia (high triglyceride levels) managed during pregnancy?

What specialist consultations are indicated in the treatment of hypertriglyceridemia (high triglyceride levels)?

What long-term monitoring is indicated in the treatment of hypertriglyceridemia (high triglyceride levels)?

When are creatinine kinase determinations indicated in the treatment of hypertriglyceridemia (high triglyceride levels)?

How should diabetes be managed in patients with hypertriglyceridemia (high triglyceride levels)?

Medications

Which medication classes are used for management of hypertriglyceridemia (high triglyceride levels)?

What is the role of fibrates in the treatment of hypertriglyceridemia (high triglyceride levels)?

Which fibrates are used to treat hypertriglyceridemia (high triglyceride levels)?

What is the role of niacin in the treatment of hypertriglyceridemia (high triglyceride levels)?

What are the adverse effects of niacin in the treatment of hypertriglyceridemia (high triglyceride levels)?

What is the role of omega-3 fatty acids in the treatment of hypertriglyceridemia (high triglyceride levels)?

Which prescription fish oil products are approved by the FDA for the treatment of hypertriglyceridemia (high triglyceride levels)?

What is the role of eicosapentaenoic (EPA) and docosahexaenoic (DHA) in the treatment of hypertriglyceridemia (high triglyceride levels)?

What is the role of bile acid sequestrants in the treatment of hypertriglyceridemia (high triglyceride levels)?

What is the role of statins in the treatment of hypertriglyceridemia (high triglyceride levels)?

When are bile acid sequestrants indicated in the treatment of hypertriglyceridemia (high triglyceride levels)?

How is metabolic syndrome managed in patients with hypertriglyceridemia (high triglyceride levels)?

What are the characteristics of fibric acid agents, omega acid ethyl esters, and niacin drugs?

What are the characteristics of statin drugs?

Which medications in the drug class Fibric Acid Agents are used in the treatment of Hypertriglyceridemia?

Which medications in the drug class Omega-3 Acids are used in the treatment of Hypertriglyceridemia?

Which medications in the drug class Lipid-Lowering Agents, Other are used in the treatment of Hypertriglyceridemia?

Which medications in the drug class Lipid-Lowering Agents, Statins are used in the treatment of Hypertriglyceridemia?