Amarin Corp Plc (AMRN)

[Cardiologymd]

The first article from November i thought it was gone. It was not. Still there imbedded. I pasted both articles bellow.

The latest MO Bs

Type hyoertriglyceridemia.

It is the 1st result.


Here is copy paste


1st article is under “what’s new”

What's New
Fish oil and cardiovascular outcomes in patients with hypertriglyceridemia (November 2018)

The role of highly purified fish oil in patients with increased cardiovascular risk has been uncertain. In REDUCE-IT, a randomized trial of over 8000 statin-treated patients with elevated triglyceride levels and either established cardiovascular disease or diabetes plus other cardiovascular risk factors, supplementation with 4 g/day icosapent ethyl (a highly purified eicosapentaenoic acid), compared with mineral oil as placebo control, reduced the risk of the composite primary outcome of major cardiovascular events [1]. Because of limitations in this trial (eg, mineral oil may not be a true placebo), confirmation of these findings from ongoing trials is needed before a firm recommendation can be made about the role of fish oil supplementation in this patient population. (See "Hypertriglyceridemia", section on 'Fish oil'.)

Authors:Robert S Rosenson, MDJohn JP Kastelein, MD, PhD, FESCSection Editor:Mason W Freeman, MDDeputy Editors:Jane Givens, MDGordon M Saperia, MD, FACC
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2019. | This topic last updated: Feb 11, 2019.
What's New
Fish oil and cardiovascular outcomes in patients with hypertriglyceridemia (November 2018)

The role of highly purified fish oil in patients with increased cardiovascular risk has been uncertain. In REDUCE-IT, a randomized trial of over 8000 statin-treated patients with elevated triglyceride levels and either established cardiovascular disease or diabetes plus other cardiovascular risk factors, supplementation with 4 g/day icosapent ethyl (a highly purified eicosapentaenoic acid), compared with mineral oil as placebo control, reduced the risk of the composite primary outcome of major cardiovascular events [1]. Because of limitations in this trial (eg, mineral oil may not be a true placebo), confirmation of these findings from ongoing trials is needed before a firm recommendation can be made about the role of fish oil supplementation in this patient population. (See "Hypertriglyceridemia", section on 'Fish oil'.)

Read more
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 "Cardiovascular disease risk assessment for primary prevention: Our approach" and "Overview of 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
In this topic, we categorize patients into one of the following four groups based on their fasting triglyceride level:

?Normal – <150 mg/dL (1.7 mmol/L)

?Mild hypertriglyceridemia – 150 to 499 mg/dL (1.7 to 5.6 mmol/L)

?Moderate hypertriglyceridemia – 500 to 886 mg/dL (5.6 to 10.0 mmol/L)

?Very high or severe hypertriglyceridemia – >886 mg/dL (≥10.0 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.

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 [1].

In individuals with established cardiovascular disease, the prevalence will be higher [2]. Serum triglyceride values above 1000 mg/dL (11 mmol/L) occur in fewer than 1 in 5000 individuals [1].

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 [3,4]. These studies generally show a positive relationship between hypertriglyceridemia and atherosclerotic burden [5-9].

Elevated triglyceride levels are independently associated with increased risk of CVD events [10,11]. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Triglycerides'.)

Mendelian randomization studies support a causal relationship [11]:

?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 [12,13]; other genetic studies suggest that elevated triglyceride levels increase the risk of CHD [11,14-16].

?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) [17].

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) [18].

?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) [19].

?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 [20,21].

?Two large studies found that increased nonfasting triglyceride levels are associated with an increased risk for ischemic stroke [22,23]. (See "Overview of secondary prevention of ischemic stroke".)

One difficulty that has existed in establishing a causal role for hypertriglyceridemia in CHD 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 [24-32].

?Small, dense low density lipoprotein particles [33-36]. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Small dense LDL (LDL phenotype B)'.)

?Atherogenic triglyceride-rich lipoprotein remnants [37,38]. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Intermediate density lipoprotein (remnant lipoproteins)'.)

?Insulin resistance [39,40]. (See "Insulin resistance: Definition and clinical spectrum", section on 'Clinical features'.)

?Increases in coagulability and viscosity [41-43]; triglyceride-mediated hyperviscosity may contribute to endothelial dysfunction, tissue ischemia, and the chylomicronemia syndrome (see below) [43].

At least two studies have shown that increasing size and concentration of lipoproteins that carry triglycerides are associated with incident type 2 diabetes [44,45]. In addition, elevated triglycerides (>70 mg/dL) predict incident diabetes. Large VLDL particle concentration is the lipoprotein subclass most strongly associated with future risk of type 2 diabetes.

The Copenhagen General Population Study (2003 to 2015) attempted to quantify the magnitude of the cardiovascular risk attributable to triglycerides in 58,547 individuals aged 40 to 65 years and free of atherosclerotic cardiovascular disease, diabetes, and statin use [46]. Patients were classified at baseline by guideline-based statin eligibility and triglyceride level: 14 percent were statin eligible, 7 percent were not statin eligible and had triglycerides ≥264 mg/dL (3.0 mmol/L), and 79 percent were not statin eligible and had triglycerides <264 mg/dL. The estimated 10-year risk of the primary combined end point of cardiovascular death, nonfatal myocardial infarction, unstable angina, or stroke was 7.6, 5.7, and 2.8 percent in the three groups, respectively. That is, patients with triglyceride levels >264 mg/dL (and not statin eligible) had a level of cardiovascular risk, approaching that of statin-eligible patients who did not receive statin.

Our approach to reducing this increase in risk attributable to triglycerides or triglyceride-containing (also called triglyceride rich) lipoproteins is presented below. (See 'Management' below.)

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 1):

?Obesity, often in association with an elevation in serum cholesterol [47]. (See "Overweight and obesity in adults: Health consequences".)

?Diabetes mellitus, where there is a relationship to poor glycemic control and, in type 2 diabetes, obesity [48,49]. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

?Nephrotic syndrome, often in association with hypercholesterolemia, and renal failure [50,51]. (See "Lipid abnormalities in nephrotic syndrome", section on 'Hypertriglyceridemia'.)

?Hypothyroidism, often in association with hypercholesterolemia [52]. (See "Lipid abnormalities in thyroid disease", section on 'Pathophysiology'.)

?Serum total cholesterol and triglyceride concentrations normally increase markedly during pregnancy (table 2).

?Estrogen replacement administered orally. The elevation in serum triglycerides may not be seen with transdermal estrogen replacement [53]. Estrogen in both oral and transdermal contraceptives may also increase serum triglyceride concentrations. (See "Menopausal hormone therapy and cardiovascular risk" and "Risks and side effects associated with combined estrogen-progestin oral contraceptives".)

?Tamoxifen can cause marked hypertriglyceridemia in a minority of women [54]. (See "Managing the side effects of tamoxifen", section on 'Coronary heart disease'.)

?Beta blockers, with the exception of carvedilol, which has little effect on serum triglycerides. Alpha blockers lower serum triglycerides, while low-dose diuretics, angiotensin converting enzyme inhibitors, and calcium antagonists have little or no effect [55,56]. (See "Antihypertensive drugs and lipids".)

?Immunosuppressive medications, such as glucocorticoids and cyclosporine [57,58]. The effect of glucocorticoids is associated with insulin resistance and appears to be mediated in part by suppression of corticotropin [57]. (See "Major side effects of systemic glucocorticoids".)

?HIV antiretroviral regimens [59]. (See "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients", section on 'Dyslipidemia'.)

?Retinoids. (See "Oral isotretinoin therapy for acne vulgaris".)

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

?Chylomicronemia – Fasting chylomicronemia is characterized by triglyceride levels above the 99th (880 mg/dL or 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) [60,61]. 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 [62].

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 [54,63], 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 [60,61]. 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 [61].

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 [62,64,65]. 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 by 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 [66], 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 [67]; 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) [24,65]. The common LPL mutations raise serum triglycerides by 20 to 80 percent [24]. 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 [63]. (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 [68]. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Familial combined hyperlipidemia'.)

?Familial dysbetalipoproteinemia – Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) most often results from inheritance of two apo E2 alleles [69,70]. 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 [69]. (See 'Acquired disorders' above.) A similar effect is seen in an animal model of the disorder [71].

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 [72]. 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 1) [48,54,63].

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. Specifically, there have been no large randomized trials that have evaluated the effect of triglyceride lowering for primary prevention in patients with mild-to-moderate hypertriglyceridemia.

We recommend adoption of healthy lifestyle behaviors for all patients to lower cardiovascular risk and use lipid lowering therapies in some individuals, primarily 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 [5,73]. (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 [5,48,73]. 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) as well as 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 [74]. 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 [74]. 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 [75]. 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 pancreatitis and CVD risk reduction. Treatment is initiated at higher triglyceride levels for prevention of pancreatitis than for CVD risk reduction.

Our approach — Our approach to treatment is outlined below:

Prevention of pancreatitis — For patients with triglyceride levels persistently above 886 mg/dL (10.0 mmol/L), we start drug therapy to lower the risk of pancreatitis. At levels below this threshold, the risk appears to be quite small [76-78]; however, it is reasonable to consider drug therapy at levels of 500 mg/dL (5.6 mmol/L) or above in patients with a prior episode of pancreatitis.

We aim for a triglyceride level below 500 mg/dL in order to minimize the large (two- to threefold) post-prandial elevations in triglyceride concentrations that may occur after a meal where fat, carbohydrate, or alcohol intake are excessive, and which may lead to the development of pancreatitis.

We start treatment with a fibrate. We recommend using fenofibrate rather than gemfibrozil due to the likelihood of either concurrent or later use of a statin, because gemfibrozil has a higher risk of muscle toxicity.

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 [79-81]. 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 hypertriglyceridemia, there is a significant lifestyle component that requires management. Often the diet is suboptimal, the patients remain overweight, or there is excessive alcohol or carbohydrate intake. (See 'Lifestyle modifications' above.)

For patients with refractory hypertriglyceridemia (not responsive to initial fibrate therapy), a combination of fibrates and fish oil (n-3 fatty acids) can be used. 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. (See "Hypertriglyceridemia-induced acute pancreatitis".)

Cardiovascular disease risk reduction — Despite the clinical trial evidence linking hypertriglyceridemia to CVD risk reduction (see 'Triglycerides and CVD risk' above), most of our contributors rarely start drug therapy to lower cardiovascular risk, as there is limited evidence that targeting hypertriglyceridemia improves CVD outcomes. In addition, most patients at increased CVD risk will be prescribed a therapy (usually with a statin), targeting low-density lipoprotein (LDL) cholesterol, and this therapy will also lower triglyceride levels. Statin therapy is discussed elsewhere. (See "Statins: Actions, side effects, and administration".)

High-intensity statin therapy is more effective than low-intensity statin therapy for lowering triglyceride levels [82]. Among patients with triglycerides levels 200 mg/dL to 880/mg/dL, either atorvastatin 80 mg daily or rosuvastatin 20 mg daily can reduce fasting triglyceride levels by 43 to 44 percent [83,84]. 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. (See "Management of elevated low density lipoprotein-cholesterol (LDL-C) in primary prevention of cardiovascular disease", section on 'Indications'.)

Randomized trials comparing different triglyceride-lowering agents to each other, in order to assess superiority on cardiovascular outcomes, have not been done. The majority of patients are usually treated with a statin. Other agents such as fibrates, niacin, omega-3 fatty acids are rarely added to further reduce CVD risk (table 6).

Evidence for cardiovascular disease risk reduction — 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, can 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 cholesterol/high-density lipoprotein (HDL) cholesterol ratio >5.0 (figure 1) [29]. A benefit from gemfibrozil therapy in lowering the incidence of CHD events was confined to this high-risk subgroup.

?The VA-HIT trial assessed the efficacy of gemfibrozil therapy in patients with low HDL cholesterol (≤40 mg/dL [1.0 mmol/L]), relatively low LDL cholesterol (≤140 mg/dL or 3.6 mmol/L), and triglyceride levels ≤300 mg/dL (3.4 mmol/L) [85]. Gemfibrozil raised HDL cholesterol by 6 percent, lowered triglycerides by 31 percent, and had no significant effect on LDL cholesterol.

?In the ACCORD trial, fenofibrate showed no overall benefit in the primary outcome of first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes, when added to a statin in patients with type 2 diabetes. There was a possible benefit in the subset of patients with both elevated triglyceride levels (>204 mg/dL [2.30 mmol/L]) and low HDL cholesterol levels [86]. In an open label extension of the ACCORD and ACCORDION trials, fenofibrate therapy in statin-treated patients with type 2 diabetes reduced the risk of CVD events among those with hypertriglyceridemia and low HDL cholesterol [87]. 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 [29], the FIELD trial [88], and The Bezafibrate Infarction Prevention (BIP) trial [89].

In REDUCE-IT, a randomized trial designed to evaluate the effect of fish oil therapy on cardiovascular disease outcomes in patients with hypertriglyceridemia, a highly purified fish oil (icosapent ethyl) was found to have some effect. In this trial, over 8000 patients with elevated triglyceride levels (fasting 135 to 499 mg/dL [1.52 to 5.63 mmol/L]), on statins, and either established CVD or diabetes plus other cardiovascular risk factors were randomly assigned to supplementation with icosapent ethyl 4 g/day, or mineral oil. Icosapent ethyl reduced the risk of the primary combined CVD endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina (17.2 versus 22.0 percent, HR 0.75, 95% CI 0.68-0.83) after median follow-up of 4.9 years [90]. The rates of each component of the primary composite endpoint were also significantly reduced. From baseline to one year, the median triglyceride level decreased 18 percent in the treatment group and increased 2.2 percent in the control group. LDL cholesterol levels increased in both groups (treatment group 3.1 percent, control group 10.2 percent). At two years, C-reactive protein levels decreased by 13.9 percent in the treatment group and increased by 32.2 percent in the control group.

Limitations of the REDUCE-IT trial include concerns that mineral oil may have caused the increases in atherogenic lipoproteins and C-reactive proteins in the control group and thus did not function as a true placebo. These adverse effects of mineral oil may have raised the risk of cardiovascular events in the control group and may partially account for the favorable risk reduction observed in the treatment group. If so, the true cardiovascular effect of icosapent ethyl may be less than observed in the trial. Another concern is that rates of new-onset atrial fibrillation were significantly higher in the treatment group (5.3 versus 3.9 percent).

The authors and editors of this topic are divided regarding recommendations for use of icosapent ethyl, based on the limitations of the trial. If a fish oil capsule is to be considered for reduction of cardiovascular risk in patients with mild hypertriglyceridemia (149 to 500 mg/dL), we support the use of icosapent ethyl based on the results of REDUCE-IT, if it is used in combination with a statin as in the study population. However, further evaluation of the efficacy and safety of these findings from ongoing trials is recommended before a firm recommendation can be made.

Specific treatments

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 [34].

Fibrates have been associated with muscle toxicity [91], an effect that is more pronounced in patients also treated with a statin [92,93]. 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 [94] (see "Statin muscle-related adverse events", 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 [95]. 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 [88]. Thus, fenofibrate is the preferred fibrate in patients who require combined therapy with a statin and fibrate [96,97].

Fibrates also interfere with the metabolism of warfarin [92]. 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) [80]. 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 [98].

Nicotinic acid — Although nicotinic acid at doses of 1500 to 2000 mg daily can reduce triglyceride levels by 15 to 25 percent [34], 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 [99-102]. Glycemic control should be monitored carefully in diabetic patients treated with nicotinic acid. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

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 "Low density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Nicotinic acid (Niacin)'). 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 very low-density lipoprotein (VLDL) production [103-105] and can lower the serum triglyceride concentration by as much as 50 percent or more [104]. 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'.)

The n-3 fatty acids constitute only 30 to 50 percent of many fish oil supplements. By comparison, a prescription preparation of omega-3 ethyl esters (Lovaza in the United States and Omacor elsewhere) is 85 percent omega-3 fatty acids. In patients with severe hypertriglyceridemia, omega-3 ethyl esters (4 g/day) reduced triglyceride levels by 45 percent but raised LDL-C levels by 31 percent [106].

Another commercial preparation, Vascepa, is more than 95 percent icosapent ethyl, the ethyl ester of eicosapentaenoic acid [107]. In a small trial of patients with very high fasting triglyceride levels, icosapent-ethyl (4 g/day) reduced triglyceride levels by up to 45 percent but did not significantly affect LDL cholesterol levels [108].

Other — There have been case reports of treating patients with marked symptoms with plasma exchange/plasmapheresis, particularly in patients with acute pancreatitis [62,109]. (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 [110]. 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 [111].

?We agree with recommendations made in the 2016 European Society of Cardiology/European Atherosclerosis Society Guidelines for the Management of Dyslipidaemias [112].

?We agree with recommendations made in the 2012 Endocrine Society (United States) guideline on the evaluation and treatment of hypertriglyceridemia [113].

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 5th to 6th grade reading level, and they 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 10th to 12th grade reading level and are best 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 499 mg/dL (1.7 to 5.6 mmol/L) as "mild" hypertriglyceridemia, ≥500 to 886 mg/dL (5.6 to 10.0 mmol/L as "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 advise 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. Patients with more severe triglyceride elevations may need more aggressive nonpharmacologic interventions. (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.)

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