Hypertriglyceridemia

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2017. | This topic last updated: Feb 28, 2017.

INTRODUCTION Hypertriglyceridemia is most often identified in individuals who have had a lipid profile as part of
cardiovascular risk assessment. (See "Screening for lipid disorders in adults", section on 'Choice of tests' and "Estimation
of cardiovascular risk in an individual patient without known cardiovascular disease" and "Overview of the risk equivalents
and established risk factors for cardiovascular disease", section on 'Lipids and lipoproteins'.)

This topic reviews the evidence that hypertriglyceridemia contributes to the development of adverse cardiovascular
events, the mechanisms by which this might occur, the disorders of triglyceride metabolism that have been identified, and
recommendations for the management of hypertriglyceridemia. The pathways involved in triglyceride synthesis and
metabolism are discussed separately. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on
'Endogenous pathway of lipid metabolism'.) The management of patients with hypertriglyceridemia who have acute or
prior pancreatitis is also discussed separately. (See "Hypertriglyceridemia-induced acute pancreatitis".)

INDICATIONS FOR MEASUREMENT The indications for the measurement of serum triglyceride are presented
separately. (See "Measurement of blood lipids and lipoproteins", section on 'Indications for measurement'.)

DEFINITION AND PREVALENCE One widely used definition of hypertriglyceridemia is described in a table (table 1).
The serum triglyceride concentration can be stratified in terms of population percentiles and/or coronary risk [1]:

Normal <150 mg/dL (1.7 mmol/L)

Borderline high 150 to 199 mg/dL (1.7 to 2.2 mmol/L)
High 200 to 499 mg/dL (2.3 to 5.6 mmol/L)
Very high 500 mg/dL (5.6 mmol/L)

To convert from mg/dL to mmol/L, divide by 88.5.

In this topic, when discussing management, we refer to the range of fasting triglyceride levels from 150 to 500 mg/dL (1.7
to 5.6 mmol/L) as "mild to moderate" hypertriglyceridemia and levels 886 mg/dL (10.0 mmol/L) as "severe"
hypertriglyceridemia [2].

Hyperlipidemia is common but varies with the population being studied. In the United States, the National Health and
Nutrition Examination Surveys (NHANES) from 1999 to 2004 found that the percentage of adults with triglyceride levels
above 150 mg/dL (1.7 mmol/L), 200 mg/dL (2.3 mmol/L), 500 mg/dL (5.7 mmol/L), and 1000 mg/dL (11.3 mmol/L) was 33,
18, 1.7, and 0.4 percent, respectively [3].

In individuals with established cardiovascular disease, the prevalence will be higher [4]. Serum triglyceride values above
1000 mg/dL (11 mmol/L) occur in fewer than 1 in 5000 individuals [3].

TRIGLYCERIDES AND CVD RISK Atherosclerosis is the most common underlying pathology in patients with
cardiovascular disease (CVD). The effect of abnormal triglyceride metabolism on atherosclerosis has been studied by
evaluating the incidence of coronary events, the contribution of triglyceride-containing lipoproteins to atherosclerosis
progression, and the incidence of cerebrovascular ischemic events [5,6]. These studies generally show a positive
relationship between hypertriglyceridemia and atherosclerotic burden [7-11].

Elevated triglyceride levels are independently associated with increased risk of CVD events [12,13]. (See "Lipoprotein
classification, metabolism, and role in atherosclerosis", section on 'Triglycerides'.)

Mendelian randomization studies support a causal relationship [13]:

In one study, triglyceride-mediated pathways were found to be causally involved in coronary heart disease (CHD),
though the study could not directly assess whether triglycerides themselves cause CHD [14,15]; other genetic
studies also suggest that elevated triglyceride levels increase the risk of CHD [13,16-18].
 In a study that used multiple independent single nucleotide polymorphisms as variables (n= 62,199), unrestricted
and restricted allele scores for triglycerides were associated with CHD events (odds ratio 1.62, 95% CI 1.24-2.11
and 1.61, 95% CI 1.00-2.59, respectively) [19].

The following studies also demonstrate the association between hypertriglyceridemia and CVD events:

In a 2007 report of two large prospective studies, the combined adjusted odds ratio for CHD comparing individuals
in the top third of serum triglyceride levels with those in the bottom third was 1.7 (95% CI 1.6-1.9) [20].
In a 2007 study of nearly 14,000 untreated younger males, aged 26 to 45 years who had serum triglycerides
measured five years apart, triglycerides at first measurement were strongly and independently associated with CHD
risk when comparing those in the highest quintile to those in the lowest (multivariate hazard ratio 4.1) [21].
Hypertriglyceridemia is associated with increased mortality in patients with known CHD, and both increased
mortality and reduced event-free survival after coronary artery bypass graft surgery [22,23].
Two large studies found that increased nonfasting triglyceride levels are associated with an increased risk for
ischemic stroke [24,25]. (See "Overview of secondary prevention of ischemic stroke".)

One difficulty that has existed in establishing a causal role for hypertriglyceridemia is that it is associated with other
abnormalities that predispose to atherosclerosis or are associated with increased CVD risk. These include:

Low levels of high density lipoprotein cholesterol [26-34].

The presence of small, dense low density lipoprotein particles [35-38]. (See "Inherited disorders of LDL-cholesterol
metabolism", section on 'Small dense LDL (LDL phenotype B)'.)
The presence of atherogenic triglyceride-rich lipoprotein remnants [39,40]. (See "Lipoprotein classification,
metabolism, and role in atherosclerosis", section on 'Intermediate density lipoprotein (remnant lipoproteins)'.)
Insulin resistance [41,42]. (See "Insulin resistance: Definition and clinical spectrum", section on 'Biochemical
markers'.)
Increases in coagulability and viscosity [43-45]; triglyceride-mediated hyperviscosity may contribute to endothelial
dysfunction, tissue ischemia, and the chylomicronemia syndrome (see below) [45].

At least two studies have shown that increasing size and concentration of lipoproteins that carry triglycerides are
associated with incident type 2 diabetes [46,47].

CAUSES Hypertriglyceridemia may occur in the setting of other diseases or treatments (acquired) or may be
genetically based.

Acquired disorders The following acquired disorders, conditions, and therapies raise serum triglycerides and this
change may be particularly pronounced in patients with underlying defects in triglyceride metabolism (table 2):

Obesity, often in association with an elevation in serum cholesterol [48]. (See "Obesity in adults: Health
consequences".)
Diabetes mellitus, where there is a relationship to poor glycemic control and, in type 2 diabetes, obesity [49,50].
(See "Treatment of lipids (including hypercholesterolemia) in secondary prevention", section on 'Treatment in
diabetes'.)
Nephrotic syndrome, often in association with hypertriglyceridemia, and renal failure [51,52]. (See "Lipid
abnormalities in nephrotic syndrome", section on 'Hypertriglyceridemia'.)
Hypothyroidism, often in association with hypertriglyceridemia [53]. (See "Lipid abnormalities in thyroid disease",
section on 'Pathophysiology'.)
Pregnancy. (See "Maternal endocrine and metabolic adaptation to pregnancy", section on 'Lipid metabolism'.)
Estrogen replacement, which is often associated with a fall in low density lipoprotein cholesterol (LDL-C) [54,55].
The elevation in serum triglycerides may not be seen with transdermal estrogen delivery [56]. Oral contraceptives
may also increase serum triglyceride concentrations. (See "Menopausal hormone therapy and cardiovascular
risk" and "Risks and side effects associated with estrogen-progestin contraceptives".)
Tamoxifen can cause marked hypertriglyceridemia in a minority of women [57]. (See "Managing the side effects of
tamoxifen", section on 'Coronary heart disease'.)
 Beta blockers. On the other hand, alpha blockers lower serum triglycerides, while low-dose diuretics, angiotensin
converting enzyme inhibitors, calcium antagonists, and carvedilol have little or no effect [58,59].
(See "Antihypertensive drugs and lipids".)
Immunosuppressive medications, such as glucocorticoids and cyclosporine [60,61]. The effect of glucocorticoids is
associated with insulin resistance and appears to be mediated in part by suppression of corticotropin [60].
(See "Major side effects of systemic glucocorticoids".)
HIV antiretroviral regimens [62]. (See "Epidemiology of cardiovascular disease and risk factors in HIV-infected
patients", section on 'Dyslipidemia'.)
Retinoids. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Other side effects'.)

Hereditary disorders The following disorders with a genetic basis are discussed in detail elsewhere:

Chylomicronemia Fasting chylomicronemia is characterized by triglyceride levels above the 99 (880 mg/dL or
th

10 mmol/L) percentile in association with a creamy plasma supernatant and cloudy infranatant due to increases in
chylomicrons and very low density lipoprotein (VLDL) (picture 1 and table 3) [63,64]. The clinical manifestations
include hepatosplenomegaly and occasional eruptive xanthomas. However, patients with marked
hypertriglyceridemia (886 mg/dL [10.0 mmol/L]) may develop the chylomicronemia syndrome. Manifestations of
this disorder include recent memory loss, abdominal pain and/or pancreatitis, dyspnea, eruptive xanthoma (picture
2), flushing with alcohol, and lipemia retinalis [65].
Most patients have a secondary form in which some other dyslipidemia (eg, familial hypertriglyceridemia due to
partial lipoprotein lipase [LPL] deficiency) is exacerbated by the administration of exogenous triglyceride-elevating
therapies such as estrogen, tamoxifen, glucocorticoids, or protease inhibitors [55,57], or by poorly-controlled
diabetes. There is also a primary form of type V hyperlipoproteinemia in which there is no deficiency in LPL or its
ligand apo C-II [63,64]. The underlying defect in this disorder is uncertain but apo E4, which is a ligand for the
hepatic chylomicron and VLDL remnant receptor, may play a role [64].
Fasting chylomicronemia can be diagnosed by confirming the presence of chylomicrons and excess VLDL on
agarose gel electrophoresis or ultracentrifugal analysis. A simple technique is to refrigerate plasma overnight and
examine the specimen for a creamy supernatant from chylomicrons and a turbid VLDL-rich infranatant.
This latter finding of a turbid infranatant is not seen in patients with type I hyperlipoproteinemia, in which only
chylomicrons accumulate and the infranatant is clear. Patients with type I hyperlipoproteinemia generally have
complete absence of either LPL activity (type Ia), apo C-II, lipoprotein maturation factor 1 (LMF1), apolipoprotein 5,
or glycosylphosphatidylinositol-anchored high density lipoprotein (HDL) binding protein 1 [65-67]. This is in contrast
to partial LPL deficiency, where the type V phenotype (in which chylomicrons are present in the supernatant, and the
infranatant is cloudy due to VLDL particles) is brought out be one of the exacerbating factors discussed above.
Type Ia hyperlipoproteinemia is an extremely rare genetic disorder that results from homozygous deficiency in LPL
activity. It is characterized by eruptive xanthomas, lipemia retinalis, and frequent episodes of pancreatitis. The only
effective therapy has been a strict low-fat diet. A gene therapy for this condition, LPL(S447X) gene variant, in an
adeno-associated viral vector of serotype 1 (alipogene tiparvovec [Glybera]), has been approved for use in Europe
[68], making it the first gene therapy approved for use in people. A study in three patients of an inhibitor
of APOC3 messenger RNA showed large reductions in triglyceride levels [69]; this finding was somewhat
unexpected, as it had been presumed that the effects of apolipoprotein C3 (APOC3) on triglycerides were mediated
by APOC3 inhibition of LPL.
Familial hypertriglyceridemia Familial hypertriglyceridemia (type IV hyperlipoproteinemia phenotype) is an
autosomal dominant disorder associated with moderate elevations in the serum triglyceride concentration (200 to
500 mg/dL [2.3 to 5.6 mmol/L]). It is often accompanied by insulin resistance, obesity, hyperglycemia, hypertension,
and hyperuricemia.
Patients with familial hypertriglyceridemia are heterozygous for inactivating mutations of the LPL gene and, as noted
above, typically have low serum HDL-C (hypoalphalipoproteinemia) [26,67]. The common LPL mutations raise
serum triglycerides by 20 to 80 percent [26]. More marked elevations require some other factor such as one of the
drugs or acquired disorders noted above, such as estrogen replacement therapy in postmenopausal women [55].
(See 'Acquired disorders' above.)
Familial combined hyperlipidemia Familial combined hyperlipidemia is a disorder caused by overproduction of
hepatically-derived apolipoprotein B-100 associated with VLDL [70]. (See "Inherited disorders of LDL-cholesterol
metabolism", section on 'Familial combined hyperlipidemia'.)
 Familial dysbetalipoproteinemia Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is a multifactorial
disorder that is inherited as an autosomal recessive trait. It is characterized by the presence of two apo E2 alleles
[71,72]. Premature coronary heart disease and peripheral vascular disease are common. Physical findings include
tuberoeruptive xanthomas (picture 3) and xanthomas of the palmar creases (xanthomata palmare striatum) (picture
4). Laboratory findings are characterized by increased concentrations of triglyceride and cholesterol. An additional
genetic or acquired factor that increases lipoprotein production or impairs lipoprotein removal is typically required for
full clinical expression; examples include diabetes mellitus, hypothyroidism, obesity, or gout [71] (see 'Acquired
disorders' above); a similar effect is seen in an animal model of the disorder [73].

CLINICAL MANIFESTATIONS Most patients with hypertriglyceridemia have no symptoms or signs associated with the
biochemical abnormality. The following are exceptions:

In patients with acquired disorders such as diabetes or obesity, clinical manifestations are usually due to the
underlying disorder rather than the lipid abnormality.
In patients with hereditary disorders, skin lesions such as xanthomas and xanthelasmas may be present.
(See "Cutaneous xanthomas", section on 'Clinical variants'.)
In patients with very high triglyceride levels (above 1000 mg/dL [11 mmol/L]), pancreatitis may develop [74]. It
should be kept in mind that the diagnosis of triglyceride-mediated pancreatitis cannot be made in the absence of
chylomicronemia. (See "Etiology of acute pancreatitis", section on 'Hypertriglyceridemia' and "Clinical manifestations
and diagnosis of acute pancreatitis", section on 'Clinical features' and "Lipoprotein classification, metabolism, and
role in atherosclerosis", section on 'Chylomicrons'.)

The serum in patients with hypertriglyceridemia may be opalescent due to an increase in very low density lipoprotein; at
higher levels, it may be milky due to hyperchylomicronemia. Most of these patients have one of the dyslipidemias
described below with an additional condition known to raise serum triglycerides (eg, diabetes mellitus, alcohol abuse, or
estrogen or tamoxifen therapy) (table 2) [49,55,57].

DIAGNOSTIC APPROACH For all patients who are found to have an elevated triglyceride level, an attempt should be
made to identify a cause. In patients where a likely cause is not evident such as obesity or alcohol excess, we obtain a
serum blood glucose, creatinine, and thyroid-stimulating hormone as well as a urinalysis (albumin/protein). If no secondary
cause is evident, the patient likely has a hereditary cause. (See 'Causes' above.)

MANAGEMENT There are limited data regarding which patients with hypertriglyceridemia require treatment and which
therapies provide the best outcomes. We recommend adoption of healthy lifestyle behaviors for all patients to lower
cardiovascular risk and use lipid lowering therapies in some individuals to lower the risk of pancreatitis.

Lifestyle modifications We recommend adoption of lifestyle modifications similar to those recommended for
individuals at high risk of cardiovascular disease. (See "Overview of primary prevention of coronary heart disease and
stroke", section on 'Major components'.)

Hypertriglyceridemia is often induced or exacerbated by potentially correctable disorders [7,75]. (See 'Acquired
disorders' above.). Thus, nonpharmacologic interventions such as weight loss in obese patients; aerobic exercise;
avoidance of concentrated sugars, alcohol, and medications that raise serum triglyceride levels; and strict glycemic control
in diabetics should be first-line therapy [7,49,75]. Other risk factors for cardiovascular disease, such as hypertension and
smoking, should also be addressed.

A general discussion of the dietary approach to elevated lipid levels is found elsewhere. (See "Lipid lowering with diet or
dietary supplements".) Appropriate dietary management of hypertriglyceridemia differs between mild-to-moderate and
severe hypertriglyceridemia. Dietary management of mild-to-moderate hypertriglyceridemia should focus on "eating less"
with a goal of weight loss, and also on reduction of carbohydrates, especially high glycemic and high fructose foods.
Dietary fat is not a primary source for liver triglyceride, and higher fat diets do not raise fasting plasma triglyceride levels in
most people. For patients with mild-to-moderate hypertriglyceridemia who are above their ideal body weight, we suggest a
hypocaloric diet in combination with regular moderate-to-intense aerobic exercise. The diet should restrict consumption of
high glycemic index/load foods (table 4) including refined sugars, fruit juices, and high fructose beverages; we suggest
increased consumption of fish that contain high amounts of omega-3 fatty acids (table 5).
At fasting triglyceride levels above 500 to 1000 mg/dL (5.6 to 11.3 mmol/L), the clearance of chylomicrons from the blood
becomes very slow, such that chylomicrons from the previous night's meal are still present in morning fasting blood. This
sets the stage for accumulation of chylomicron triglyceride derived from dietary fat, leading to a risk of pancreatitis and
other manifestations of fasting chylomicronemia. Therefore, at very high fasting triglyceride levels (especially above
886 mg/dL [10.0 mmol/L]), it is crucial to restrict dietary fat greatly, to less than 25 to 40 g daily [ 76]. Patients need to be
reminded that even "good fat" such as vegetable oils and nuts, as well as fat contained in chips and pastries, can raise
their triglyceride levels and cause pancreatitis. (See "Lipid lowering with diet or dietary supplements".)

Diets aimed at weight loss should be used cautiously, if at all, in patients with severe hypertriglyceridemia, and weight loss
should generally be avoided until other therapies have reduced fasting triglyceride levels [76]. This is because when the
weight-loss diet ends and refeeding begins, such patients are likely to develop very high triglyceride levels with a resultant
increased risk of pancreatitis.

Alcohol overuse must be avoided in patients with severe hypertriglyceridemia, as it can cause large increases in
triglyceride levels, which might precipitate pancreatitis. The effects of moderate alcohol consumption in patients with mild-
to-moderate hypertriglyceridemia are less clear and may have only a limited effect on triglyceride levels [77]. This
observation may be important in those with other risk factors for cardiovascular disease (CVD) in whom moderate alcohol
consumption may improve coronary risk. (See "Cardiovascular benefits and risks of moderate alcohol consumption".)
Given the potential risks of alcohol consumption in patients with hypertriglyceridemia, and while awaiting further study, we
suggest that in patients with mild to moderate hypertriglyceridemia, men limit their alcohol consumption to no more than
two drinks per day and women limit their consumption to no more than one drink per day.

Indications for drug therapy The two potential indications for pharmacologic therapy to lower triglyceride levels are
prevention of episodes of pancreatitis and lowering of cardiovascular risk.

For patients with triglyceride levels persistently above 886 mg/dL (10.0 mmol/L), we start drug therapy to lower the risk of
pancreatitis. The rationale is that there is a risk of postprandial triglyceride elevations that may result in a triglyceride level
>1600 mg/dL to 2000 mg/dL in these individuals, levels that are associated with the development of pancreatitis. Although
we are unaware of clinical trial data that specifically address this issue, we advise lowering triglyceride levels to less than
500 mg/dL. We rarely treat at levels below 886 mg/dL (10.0 mmol/L), as the risk of pancreatitis from hypertriglyceridemia
appears to be quite small [78-80]. In patients with lower triglyceride levels, it is reasonable to consider drug therapy in
patients with a prior episode of pancreatitis. (See "Hypertriglyceridemia-induced acute pancreatitis".)

Despite the evidence linking hypertriglyceridemia to CVD risk (see 'Triglycerides and CVD risk' above), most of our
contributors rarely start drug therapy to lower cardiovascular risk, as there is no strong evidence that targeting
hypertriglyceridemia improves CVD outcomes. Studies have not clearly demonstrated an overall benefit of fibrates for
reduction of cardiovascular or total mortality [81-83].

In addition, most patients at increased CVD risk will have therapy, usually with a statin, targeting low density lipoprotein
cholesterol (LDL-C). No trials of statins have looked specifically at patients with normal LDL-C and elevated triglycerides.
High-intensity statin therapy is more effective than low-intensity statin therapy for lowering triglyceride levels [ 84]. Among
patients with triglycerides levels 200 mg/dL to 880/mg/dL,atorvastatin 80 mg daily and rosuvastatin 20 mg daily reduce
fasting triglyceride levels by 43 to 44 percent [85,86]. Some of our contributors start high-intensity statin therapy, which
can reduce triglycerides by about 40 percent, in patients with triglyceride levels above 500 mg/dL and less than
886 mg/dL. Their rationale is that statin therapy may reduce cardiovascular risk. (See "Treatment of lipids (including
hypercholesterolemia) in primary prevention", section on 'Deciding whom to treat'.)

Several subgroup analyses of randomized trials performed in patients with coronary heart disease (CHD) or coronary risk
equivalents raise the possibility that pharmacologic treatment targeting triglycerides, either alone or in combination with
statins, could provide clinical benefit:

In the Helsinki Heart Study, CHD risk was highest in the cohort with a triglyceride level
>201 mg/dL (2.3 mmol/L) and an LDL-C/HDL-C ratio >5.0 (figure 1) [31]. A benefit from gemfibrozil therapy was
confined to this high-risk subgroup.
The VA-HIT trial assessed the efficacy of gemfibrozil therapy in patients with low HDL-C
(40 mg/dL [1.0 mmol/L]), relatively low LDL-C (140 mg/dL or 3.6 mmol/L), and triglyceride levels
 300 mg/dL (3.4 mmol/L) [87]. Gemfibrozil raised HDL-C by 6 percent, lowered triglycerides by 31 percent, and had
no significant effect on LDL-C. At five years, there was an absolute risk reduction of 4.4 percent [7].
In the ACCORD Lipid trial, fenofibrate showed no overall benefit when added to a statin in patients with type 2
diabetes, but tended to improve outcomes in the subset of patients with both elevated triglyceride levels
(>204 mg/dL [2.30 mmol/L]) and low HDL-C levels [88]. In an open label extension of the ACCORD and
ACCORDION trials, fenofibrate therapy in statin-treated patients reduced the risk of CVD events [89]. This subset
analysis was pre-planned because of similar suggestions of benefit with fenofibrate in such subgroups that had
previously been seen in the Helsinki Heart Study [31], the FIELD trial [81], and The Bezafibrate Infarction Prevention
(BIP) trial [82].

Pharmacologic therapy As discussed above, the principal indication for pharmacologic therapy to lower triglyceride
levels is to prevent pancreatitis in individuals with very high levels (>886 mg/dL [10.0 mmol/L]). (See 'Indications for drug
therapy' above.) We start treatment with a fibrate due to the common concurrent or potential later use of statins in many of
these individuals.

Randomized trials have not directly compared agents for prevention of CVD events or pancreatitis in patients with
hypertriglyceridemia. In the absence of such trials agents are typically chosen based on their ability to reduce triglyceride
levels and based on their side effects. A number of drugs such as fibrates, niacin, and statins reduce triglyceride levels
(table 6); fibrates are the most potent.

The goal of therapy is to lower triglyceride levels below 886 mg/dL (10.0 mmol/L). We aim for a triglyceride level below
500 mg/dL in order to minimize large (two- to threefold increase) post-prandial elevations in triglyceride concentrations that
may occur after a meal where fat, carbohydrate, or alcohol intake may be excessive.

Pharmacologic therapies vary in how quickly they reduce triglyceride levels. A response to fibrates is seen as early as two
weeks into therapy with a maximal effect in six to eight weeks [90-92]. We typically check triglyceride levels six to eight
weeks after starting or altering therapy. The majority of the response with nicotinic acid is seen in six weeks and with fish
oil in two weeks.

For the majority of patients with refractory hypertriglyceridemia there is a significant lifestyle component that requires
managing. Often the diet is suboptimal, the patients remain very overweight, or there is excessive alcohol or carbohydrate
intake.

In these patients, combinations of fibrates, fish oil (n-3 fatty acids), and nicotinic acid are used but rarely. For recurrent
pancreatitis due to hypertriglyceridemia, we advocate a strict reduction in refined carbohydrate, complete avoidance of
alcohol, and caloric restriction to obtain an ideal body weight. In the setting of acute pancreatitis, plasma exchange is an
option.

Fibrates Fibrates available in the United States include gemfibrozil and fenofibrate. Other fibrates that are available
worldwide include bezafibrate and ciprofibrate. Fibrate therapy can reduce triglyceride levels by as much as 50 percent or
more [36].

Fibrates have been associated with muscle toxicity [93], an effect that is more pronounced in patients also treated with a
statin [94,95]. This effect may be mediated by competitive inhibition of CYP3A4, leading to a reduction in statin metabolism
(table 7). Pravastatin and fluvastatin are not extensively metabolized by the CYP3A4; as a result, they may be safer when
combination therapy is required with a fibrate, but this is uncertain [96]. (See "Statin myopathy", section on 'Risk factors'.)
Glucuronidation, which is an important pathway for renal excretion of lipophilic statins, appears to be significantly inhibited
by gemfibrozil but not fenofibrate [97]. In clinical studies, serum levels of statins increase 1.9- to 5.7-fold in gemfibrozil-
treated subjects but are unchanged in fenofibrate-treated subjects. In the randomized trial of fenofibrate discussed above,
there was a low incidence of myopathy whether or not patients were also taking a statin [ 81]. Thus, fenofibrate is the
preferred fibrate in patients who require combined therapy with a statin and fibrate [98,99].

Fibrates also interfere with the metabolism of warfarin [94]. As a result, the warfarin dose should be reduced by 30 percent
in patients treated with this drug.

The following are the commonly used fibrates:

 Fenofibrate Fenofibrate can be prescribed as a nanocrystal formulation (145 mg daily taken without regard to
meals), as micronized capsules (200 mg daily taken with dinner), or as fenofibric acid (also called choline
fenofibrate; 145 mg daily without regard to meals) [91]. Prescribers should become familiar with one available
formulation and follow prescribing information for that product.
Gemfibrozil Gemfibrozil is prescribed at a dose of 600 mg twice daily.
Bezafibrate Bezafibrate is prescribed in doses of 200 mg three times daily or a sustained-release daily dose of
400 mg daily [100].

Nicotinic acid Although nicotinic acid at doses of 1500 to 2000 mg daily can reduce triglyceride levels by 15 to 25
percent [36], we rarely use it as monotherapy to reduce triglyceride levels as fibrates are more potent and have a better
side effect profile. Nicotinic acid may worsen glucose tolerance in diabetic patients, although not all studies have found
this effect [101-104]. Glycemic control should be monitored carefully in diabetic patients treated with nicotinic acid.
(See "Treatment of lipids (including hypercholesterolemia) in secondary prevention", section on 'Treatment in diabetes'.)

Reductions in triglyceride levels are typically smaller with nicotinic acid than with fibrates, and there are data suggesting
that nicotinic acid, particularly when used in combination with statin therapy, may have harmful effects. (See "Lipid
lowering with drugs other than statins and fibrates".) Thus, we rarely use nicotinic acid in the management of
hypertriglyceridemia. One exception might be a patient without diabetes who had refractory hypertriglyceridemia and was
at high risk for pancreatitis or had a prior history of pancreatitis.

Fish oil Fish oil supplements that contain eicosapentaenoic acid/docosahexaenoic acid concentrate reduce VLDL
production [105-107] and can lower the serum triglyceride concentration by as much as 50 percent or more [106].
However, their use is often limited by metabolic and gastrointestinal side effects. (See "Lipid lowering with diet or dietary
supplements", section on 'Fish oil and omega-3 fatty acids'.)

Active n-3 fatty acids constitute only 30 to 50 percent of many fish oil supplements. In comparison, a prescription
preparation (Lovaza in the United States and Omacor elsewhere) is 85 percent omega-3 fatty acids. In patients with
severe hypertriglyceridemia, Lovaza (4 g/day) reduced triglyceride levels by 45 percent but raised LDL-C levels by 31
percent [108]. Another commercial preparation, Vascepa, is more than 95 percent icosapent-ethyl, the ethyl ester of
eicosapentaenoic acid [109]. Icosapent-ethyl (4 g/day) also reduced triglyceride levels by up to 45 percent, but did not
significantly affect LDL-C levels [110]. This differential effect on LDL-C levels appears large enough to be potentially
clinically meaningful, but larger trials comparing preparations in appropriate target populations are needed before we can
recommend this newer and more expensive preparation over dual omega-3 fatty acid products. Additionally, trials with
clinical end points will help determine whether these LDL-C effects translate into differences in clinical outcomes.

Other There have been case reports of treating patients with marked symptoms with
plasma exchange/plasmapheresis, particularly in patients with acute pancreatitis [65,111]. (See "Hypertriglyceridemia-
induced acute pancreatitis", section on 'Apheresis'.)

An inhibitor of APOC3 messenger RNA was found to decrease triglyceride levels in patients with chylomicronemia.
(See 'Hereditary disorders' above.) A randomized trial of this agent in patients with less severely elevated triglyceride
levels demonstrated large reductions in levels both in patients not receiving other therapies and in patients also being
treated with fibrates [112]. Other emerging therapies for triglyceride lowering include ANGPLT3 inhibitors.

SCREENING We screen adults for lipid abnormalities with a lipid profile, which includes a triglyceride level. In this
setting, triglycerides are not the focal point of screening. (See "Screening for lipid disorders in adults", section on
'Summary and recommendations'.)

While hypertriglyceridemia is frequently an acquired disorder, many of the causes are familial. (See 'Causes' above.)
Thus, we suggest screening first-degree relatives (by measuring a fasting triglyceride level) of patients with triglyceride
levels above 500 mg/dL (5.7 mmol/L) who are otherwise healthy and have nothing to suggest an acquired disorder (eg,
not obese, not diabetic, not hypothyroid). (See 'Acquired disorders' above.)

RECOMMENDATIONS OF OTHERS

The American College of Cardiology/American Heart Association guidelines recommend that adults with a
triglyceride level 500 mg/dL (5.7 mmol/L) be evaluated for secondary causes of hyperlipidemia [113].
 We agree with recommendations made in the 2016 European Society of Cardiology/European Atherosclerosis
Society Guidelines for the Management of Dyslipidaemias [114].
We agree with recommendations made in the 2012 Endocrine Society (United States) guideline on the evaluation
and treatment of hypertriglyceridemia [115].

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and
regions around the world are provided separately. (See "Society guideline links: Lipid disorders in adults".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond
the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they
th th

answer the four or five key questions a patient might have about a given condition. These articles are best for patients who
want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best
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for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to
your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the
keyword(s) of interest.)

Basics topics (see "Patient education: High triglycerides (The Basics)")

Beyond the Basics topics (see "Patient education: High cholesterol and lipids (hyperlipidemia) (Beyond the
Basics)")

SUMMARY AND RECOMMENDATIONS

This topic refers to the range of fasting triglyceride levels from 150 to 500 mg/dL (1.7 to 5.6 mmol/L) as "mild to
moderate" hypertriglyceridemia and levels above 886 mg/dL (10.0 mmol/L) as "severe" hypertriglyceridemia.
Elevated triglyceride levels are independently associated with cardiovascular risk, particularly coronary heart
disease risk and the results of Mendelian Randomization studies make causality likely. (See 'Triglycerides and CVD
risk' above.)
Although it has not been convincingly shown that lowering triglyceride levels reduces risk, we believe it is
reasonable to recommend nonpharmacologic interventions such as weight loss in obese patients, aerobic exercise,
avoidance of concentrated sugars and medications that raise serum triglyceride levels, and strict glycemic control in
diabetics should be first-line therapy in patients with mild to moderate hypertriglyceridemia. Other risk factors for
cardiovascular disease, such as hypertension and smoking, should also be addressed. (See 'Management' above.)
For patients with triglyceride levels persistently above 886 mg/dL (10.0 mmol/L) after nonpharmacologic
interventions, we suggest starting drug therapy to lower the risk of pancreatitis (Grade 2C). (See 'Indications for
drug therapy' above.)

We start therapy with a fibrate. (See 'Fibrates' above.)

For patients with hypertriglyceridemia not clearly associated with a secondary cause, we screen family members
with a fasting triglyceride level. (See 'Screening' above.)