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Hypertriglyceridemia in adults: Management

Hypertriglyceridemia in adults: Management
Literature review current through: Jan 2024.
This topic last updated: Feb 15, 2023.

INTRODUCTION — Hypertriglyceridemia is a common clinical condition 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 "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Overview of established risk factors for cardiovascular disease", section on 'Lipids and lipoproteins'.)

This topic reviews the management of hypertriglyceridemia. Other relevant topics include:

(See "Hypertriglyceridemia in adults: Approach to evaluation".)

(See "Hypertriglyceridemia-induced acute pancreatitis".)

(See "Lipoprotein classification, metabolism, and role in atherosclerosis".)

TREATMENT GOALS — Given the association of hypertriglyceridemia with pancreatitis and atherosclerotic cardiovascular disease (ASCVD), the goals of management of patients with hypertriglyceridemia are to lower the risk for both types of conditions, although evidence on the efficacy of triglyceride (TG) lowering is limited:

Reducing risk of pancreatitis – Lowering of serum (or plasma) TG levels is a mainstay of prevention of acute pancreatitis, as the risk of pancreatitis increases progressively with TG levels over 500 mg/dL (5.6 mmol/L), with marked increase in risk in patients with prior recent acute pancreatitis. (See "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Pancreatitis' and "Hypertriglyceridemia-induced acute pancreatitis", section on 'Epidemiology'.)

While nonpharmacologic and pharmacologic lipid-lowering interventions can substantially reduce TG levels , there is only limited evidence on the efficacy of lipid-lowering therapies in reducing pancreatitis risk in individuals with hypertriglyceridemia. (See 'Statin effects' below and 'Fibrate effects' below.)

Reducing ASCVD risk – The efficacy of TG lowering in decreasing ASCVD risk has not been established, in contrast to the established reduction in ASCVD risk with low-density lipoprotein cholesterol (LDL-C) lowering.

Also, LDL-C levels may underrepresent cardiovascular risk in patients with hypertriglyceridemia. High TG levels are associated with small, dense cholesterol-depleted LDL particles that may not be captured by LDL-C measurement. Non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B concentrations are better measures of the excess concentrations of atherogenic lipoproteins in patients with moderate and severe hypertriglyceridemia. (See "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Lipid profile'.)

LDL-C lowering – As patients with hypertriglyceridemia are generally candidates for LDL-C lowering to reduce ASCVD risk, optimal treatment of LDL-C is a cornerstone of therapy for these patients. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

LDL-C lowering agents (such as statins and ezetimibe) generally have mild or moderate TG lowering effects (table 1). (See 'Assess and treat LDL-C' below.)

Targeting TG level – The mechanism by which hypertriglyceridemia is associated with increased ASCVD risk is not known; thus, targeting TG level to reduce ASCVD risk is problematic. The evidence on efficacy for classes of TG lowering agents is conflicting, as discussed below. Relevant studies have been performed over decades and involved different interventions and comparators; as an example, early studies did not involve patients on statins. One explanation for the difficulty in demonstrating a clinical benefit from TG lowering may be that TG levels are not directly involved in the development and clinical impact of atherosclerosis. When we treat to lower TG levels, treatment may reduce the size and number of very low-density lipoprotein (VLDL) particles that carry TG and, to a lesser extent, cholesterol and, thus, both values fall.

As discussed below, there is evidence suggesting that high-dose highly purified marine omega-3 fatty acid (specifically icosapent ethyl) reduces cardiovascular risk, but this clinical benefit is unrelated to the degree of TG lowering. (See 'Effects on cardiovascular outcomes' below.)

GENERAL MEASURES — The management of all individuals with hypertriglyceridemia involves lifestyle modification and management of LDL-C, non-HDL-C, and apolipoprotein B as indicated by ASCVD risk assessment. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)

Additional management is based upon the degree of TG level elevation and clinical factors (prior pancreatitis and ASCVD risk factors), as discussed below. (See 'Additional therapy based upon TG level' below.)

The following first-line general measures apply to all patients with hypertriglyceridemia [1].

Address modifiable causes — Since hypertriglyceridemia is often induced or exacerbated by potentially correctable disorders [2,3], conditions and factors that may cause or exacerbate hypertriglyceridemia should be addressed. For patients with uncontrolled diabetes, improved glycemic control is first-line therapy. Medications that raise serum TG levels should be avoided. (See "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Acquired factors'.)

Nonpharmacologic measures — First-line nonpharmacologic measures include:

Management of ASCVD risk factors is indicated, including optimizing management of hypertension, smoking cessation, and addressing a sedentary lifestyle [1-5]. Recommendations include regular aerobic activity (at least 150 minutes/week of moderate-intensity activity, 75 minutes/week of vigorous intensity activity, or an equivalent combination of both) [1]. (See "Overview of primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Weight loss of 5 to 10 percent body weight is generally recommended for patients with elevated TG [1], although the target weight should be individualized for each patient. (See "Obesity in adults: Dietary therapy".)

Specific recommendations for diet and alcohol consumption differ depending upon the level of hypertriglyceridemia and history of pancreatitis, as discussed below. (See 'Moderate hypertriglyceridemia' below and 'Moderate to severe hypertriglyceridemia' below and 'Severe hypertriglyceridemia' below and 'Prior pancreatitis' below.)

Assess and treat LDL-C — Patients with hypertriglyceridemia should undergo an assessment of their atherosclerotic cardiovascular risk and LDL-C levels. LDL-C levels above goal are treated according to standard recommendations (generally including a statin). (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

While the primary goal of LDL-C lowering therapy is to reduce ASCVD risk, most LDL-C-lowering drugs also reduce fasting TG levels (table 1). Statins typically lower TG levels by 5 to 15 percent; however, high-intensity statin therapy can lower TG levels by 25 to 30 percent in patients with fasting TG levels <400 mg/dL. Larger reductions in TG levels of 40 percent have been reported in patients with fasting TG levels as high as 800 mg/dL with treatment with a moderate- to high-dose high-intensity statin (atorvastatin 80 mg per day, rosuvastatin 20 or 40 mg per day) [6,7]. Ezetimibe lowers TG levels by approximately 7 to 8 percent, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower fasting TG levels by 2 to 23 percent. Bempedoic acid has no TG-lowering effects [8].

ADDITIONAL THERAPY BASED UPON TG LEVEL — Additional therapy beyond the general approach is based upon the TG level as well as history of prior pancreatitis. For purposes of management, we classify fasting TG levels according to the following criteria (to convert from mg/dL to mmol/L, divide by 88.5):

Normal – <150 mg/dL (<1.7 mmol/L)

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

Moderate to severe hypertriglyceridemia – 500 to 999 mg/dL (5.65 to 11.3 mmol/L)

Severe hypertriglyceridemia – ≥1000 mg/dL (≥11.3 mmol/L)

A more stringent definition for hypertriglyceridemia is a fasting TG level >200 mg/dL without an accompanying elevation in LDL-C (with or without statin therapy), as limited evidence suggests cardiovascular benefit of fibrates and marine omega fatty acids in this setting. This is based upon subgroup analyses of plasma TG and TG/HDL-C ratios in randomized controlled trials, in which fibrates and omega-3 fatty acids (particularly icosapent ethyl) may have some beneficial effects on risk of cardiovascular disease [9,10]. In contrast, for patients with TG levels of 150 to 200 mg/dL and elevated LDL-C, treatment with moderate- to high-dose statin treats the LDL-C elevation and generally lowers the TG levels to normal levels (<150 mg/dL or 1.7 mmol/L).

Moderate hypertriglyceridemia — For patients with moderate hypertriglyceridemia (150 to 499 mg/dL; 1.7 to 5.6 mmol/L) , the following approach is applied (algorithm 1) in addition to the general measures described above (see 'General measures' above). In patients with moderate hypertriglyceridemia, after 4 to 12 weeks of general measures, we assess the need for further TG-lowering therapy. The key goal of therapy for this TG range is to reduce the risk of ASCVD events as these patients generally do not require treatment to reduce the risk of pancreatitis.

Lifestyle modification

Diet – Dietary management should focus on attaining and maintaining a healthy weight and reduction of intake of simple carbohydrates, especially high-glycemic and high-fructose foods and beverages (table 2) with a target of <6 percent calories of added sugar and ≤30 to 35 percent calories of total fat. Dietary fat is not a primary source for liver TG, and higher-fat diets do not raise fasting plasma TG levels in most people. Nevertheless, a change in the types of fat (ie, reducing saturated versus poly- and monounsaturated fats) is recommended [11]. We suggest increased consumption of fish that contain high amounts of omega-3 fatty acids (table 3).

Alcohol use – For patients with moderate hypertriglyceridemia (without prior pancreatitis), we advise limiting alcohol consumption to no more than two drinks per day in males and to no more than one drink per day for females. The effects of moderate alcohol consumption in patients with moderate hypertriglyceridemia are less clear than with severe hypertriglyceridemia and the effect on TG levels may be limited [12]. However, alcohol consumption is an often underappreciated source of excess calories that may undermine efforts at weight loss. (See "Cardiovascular benefits and risks of moderate alcohol consumption" and "Etiology of acute pancreatitis", section on 'Etiology'.)

Alcohol avoidance is advised for patients with prior hypertriglyceridemia-induced pancreatitis. (See 'Prior pancreatitis' below.)

Assess and treat LDL-C levels as discussed above. (See 'General measures' above.)

Additional therapy based upon ASCVD risk – In this context, "high ASCVD risk" is defined as established ASCVD or diabetes mellitus plus two additional ASCVD risk factors (age ≥50 years, cigarette smoking, hypertension, HDL-C ≤40 mg/dL for males or ≤50 mg/dL for females, high-sensitivity C-reactive protein [hs-CRP] >3 mg/L [0.3 mg/dL], creatinine clearance <60 mL/min, retinopathy, micro- or macroalbuminuria, and ankle-brachial index [ABI] <0.9).

For patients with high risk of ASCVD For patients with high ASCVD risk whose TG levels remain >150 mg/dL after lifestyle interventions and optimal therapy to lower LDL-C, we suggest treatment with high-dose marine omega-3 fatty acid. For this indication, we suggest icosapent ethyl rather than other marine omega-3 fatty acids. (See 'Marine omega-3 fatty acids' below.)

For patients without high risk of ASCVD For patients without high ASCVD risk, management focuses on continuing the above general measures including lifestyle modification and optimizing treatment of LDL-C. (See 'General measures' above.)

Moderate to severe hypertriglyceridemia — For patients with moderate to severe hypertriglyceridemia (500 to 999 mg/dL; 5.65 to 11.3 mmol/L), the following approach is applied (algorithm 1) in addition to the general measures described above (see 'General measures' above). Goals of therapy for this TG range are to reduce the risks of ASCVD and pancreatitis. However, randomized trials of TG-lowering agents have largely focused on ASCVD outcomes and there is limited available evidence of the effects of TG-lowering drugs on risk of pancreatitis. (See 'Specific agents' below.)

Lifestyle modification

Diet – Dietary management should focus on attaining and maintaining a healthy weight, reduction of intake of simple carbohydrates, especially high-glycemic and high-fructose foods and beverages (table 2), with a target of <5 percent calories of added sugar, and limiting dietary total fat intake to ≤20 to 25 percent calories [1]. A change in the types of fat (ie, reducing saturated versus poly- and monounsaturated fats) is recommended [11]. We suggest increased consumption of fish that contain high amounts of omega-3 fatty acids (table 3).

Alcohol use – For patients with moderate to severe hypertriglyceridemia (with or without prior pancreatitis) we advise abstaining from alcohol consumption [1]. In this setting, alcohol can increase VLDL-TG secretion and further increase TG levels, which might precipitate pancreatitis.

Assess and treat LDL-C levels as discussed above. (See 'General measures' above.)

Additional therapy For patients with moderate to severe hypertriglyceridemia (500 to 999 mg/dL; 5.65 to 11.3 mmol/L) despite the above measures, the following therapy is added.

In this context, "high ASCVD risk" is defined as established ASCVD or diabetes mellitus plus two additional ASCVD risk factors (age ≥50 years, cigarette smoking, hypertension, HDL-C ≤40 mg/dL for males or ≤50 mg/dL for females, hs-CRP >3.00 mg/L [0.3 mg/dL], creatinine clearance <60 mL/min, retinopathy, micro- or macroalbuminuria, and ABI <0.9).

Patients with high risk of ASCVD For patients with high ASCVD risk with TG level of 500 to 999 mg/dL despite lifestyle interventions and optimal therapy to lower LDL-C, the suggested initial additional agent is icosapent ethyl. (See 'Marine omega-3 fatty acids' below.)

For patients with persistent TG level of 500 to 999 mg/dL despite treatment with icosapent ethyl, we suggest adding fibrate therapy. (See 'Fibrates' below.)

For patients without high risk of ASCVD – For patients with moderate to severe hypertriglyceridemia despite lifestyle interventions and optimal LDL-C lowering therapy, the suggested initial additional agent is a fibrate. Fibrate therapy is started after discussing the benefits and risks with the patient. (See 'Fibrates' below.)

If the TG level remains 500 to 999 mg/dL despite fibrate therapy, we suggest addition of marine omega-3 fatty acid therapy. In this setting, any prescription high-dose marine omega fatty acid preparation can be used. (See 'Marine omega-3 fatty acids' below.)

An alternative approach is to begin with marine omega-3 fatty acid therapy and add fibrate therapy as needed.

We do not routinely treat patients with hypertriglyceridemia with niacin (nicotinic acid) given limited benefit and risk of adverse effects (including worsening of insulin resistance). For selected patients with moderate to severe hypertriglyceridemia despite lifestyle interventions, optimal therapy to lower LDL-C, treatment with high-dose marine omega-3 fatty acid and fibrate therapy, and low estimated risk of glucose intolerance (ie, no history of diabetes mellitus or glucose intolerance and normal or low body mass index), some clinicians treat with niacin. (See 'Niacin' below.)

Severe hypertriglyceridemia — We define severe hypertriglyceridemia as >1000 mg/dL or 11.3 mmol/L. Some experts use a lower cutpoint (ie, 880 mg/dL or 10 mmol/L) given that the risk of acute pancreatitis is substantially increased at this lower threshold [13]. The following is our approach for patients with severe hypertriglyceridemia:

Lifestyle modification – The following lifestyle modifications apply in addition to the general measures above (see 'General measures' above):

Diet – In this setting (particularly for those with prior acute pancreatitis), it is crucial to restrict dietary fat to ≤10 to 15 percent (preferably <5 percent) of total calories with the goal of reducing the TG level to <1000 mg/dL [1].

Patients should be reminded that even "good fat" such as vegetable oils and nuts, and fat contained in chips and pastries, can raise their TG levels and cause pancreatitis. At fasting TG levels >500 to 1000 mg/dL (5.6 to 11.3 mmol/L), the clearance of chylomicrons from the blood becomes slower, such that chylomicrons from the previous night's meal may still be present in morning fasting blood. This sets the stage for accumulation of chylomicron TG derived from dietary fat, leading to a risk of pancreatitis and other manifestations of fasting chylomicronemia. (See "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Pancreatitis' and "Hypertriglyceridemia-induced acute pancreatitis", section on 'Epidemiology'.)

Alcohol use – For patients with severe hypertriglyceridemia (with or without prior pancreatitis), we advise avoiding alcohol, which may further increase the risk of pancreatitis [1].

Assess and treat LDL-C levels as described above. (See 'General measures' above.)

Generally defer drug therapy for hypertriglyceridemia – When the TG level is >1000 mg/dL, drugs used to lower TG have limited effectiveness. These agents work primarily by reducing hepatic TG synthesis and secretion as VLDL-TG and thus are relatively ineffective when TG level is severely elevated.

For most patients – Drug therapy for hypertriglyceridemia (aside from treatment of LDL-C) is deferred for most patients (including all outpatients) until the TG level is lowered to ≤1000 mg/dL. (See 'Moderate to severe hypertriglyceridemia' above and 'Moderate hypertriglyceridemia' above.)

Given the rapid rate of TG level lowering achievable with stringent dietary fat restriction, with close monitoring it may be possible to initiate drug therapy for hypertriglyceridemia within days. (See 'Monitoring therapy' below.)

For in patients with acute pancreatitis – For inpatients with pancreatitis and severe hypertriglyceridemia, a fibrate is a component of therapy to reduce TG levels along with the above measures. The need for continued fibrate therapy is reassessed during subsequent outpatient management.

Prior pancreatitis — For patient with prior hypertriglyceridemia-induced pancreatitis, management of hypertriglyceridemia is as described above except that avoidance of alcohol is recommended, regardless of current TG level. (See 'Moderate hypertriglyceridemia' above and 'Moderate to severe hypertriglyceridemia' above and 'Severe hypertriglyceridemia' above.)

For patients with recurrent acute pancreatitis while taking fibrate and an omega-3 fatty acid, we evaluate for other causes of pancreatitis, particularly if TG level is <500 mg/dL. (See "Etiology of acute pancreatitis" and "Hypertriglyceridemia-induced acute pancreatitis".)

The management of hypertriglyceridemia-induced acute pancreatitis is discussed separately. (See "Hypertriglyceridemia-induced acute pancreatitis".)

MONITORING THERAPY — The frequency of TG level monitoring depends upon the severity of hypertriglyceridemia.

For patients with severe hypertriglyceridemia treated with stringent dietary fat restriction (<5 percent dietary fat per day), we measure TG levels frequently (eg, every three days) to guide prompt initiation of TG-lowering drugs.

For patients with moderate or moderate to severe hypertriglyceridemia, we typically check TG levels six to eight weeks after starting or altering drug therapy.

Pharmacologic therapies and lifestyle modifications vary in how quickly and effectively they reduce TG levels (table 1):

With TG levels ≥500 to 1000 mg/dL (5.6 to 11.3 mmol/L), the expected reduction in fasting TG with <5 percent dietary fat is 25 percent per day [14].

The majority of TG reduction with marine omega-3 fatty acid therapy is seen in two weeks. (See 'Effects on lipid levels' below.)

A response to fibrates is seen as early as two weeks into therapy, with a maximal effect in six to eight weeks [15-17].

The majority of the response to niacin (nicotinic acid) is seen in two weeks.

SPECIFIC AGENTS

Statins

Choice of agent and administration — Statin use is discussed separately. (See "Statins: Actions, side effects, and administration", section on 'Administration'.)

Statin effects — While statins are used primarily to reduce ASCVD risk, statins also have some TG-lowering effects that may reduce the risk of pancreatitis:

Reducing ASCVD risk and LDL- C – In patients with hypertriglyceridemia, the primary goal of statin therapy is to reduce ASCVD risk though LDL-C lowering and perhaps pleiotropic effects. The effects of statins on ASCVD risk are discussed separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Reducing pancreatitis risk and TG – Statins generally have mild to moderate TG-lowering effects (table 1), as discussed above (see 'Assess and treat LDL-C' above). There is some evidence that statins may help lower the risk of pancreatitis, although evidence is lacking in patients with moderate to severe or severe hypertriglyceridemia. A meta-analysis that included 16 statin trials with 113,800 participants with baseline normal TG levels or low moderate hypertriglyceridemia found that statin therapy was associated with a reduced risk of pancreatitis compared with placebo or standard care (risk ratio [RR] 0.77; 95% CI 0.62-0.97) [18].

Fibrates — The indication for fibrate therapy is discussed above. (See 'Moderate to severe hypertriglyceridemia' above.)

Choice of agent — When choosing fibrate therapy, we generally prefer fenofibrate to gemfibrozil since it has fewer drug interactions, is generally better tolerated, and patient compliance is better due to its once-daily dose. Fenofibrate is also the preferred fibrate in patients who require combined therapy with a statin and fibrate [19,20]. Fibrates are associated with muscle toxicity [21,22], an effect that is more pronounced in patients also treated with a statin [23,24]. Gemfibrozil has a higher risk of muscle toxicity, especially when administered with a statin [25]. Glucuronidation, which is an important pathway for renal excretion of lipophilic statins, appears to be significantly inhibited by gemfibrozil but not fenofibrate [26]. 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 a randomized trial of fenofibrate, there was a low incidence of myopathy whether or not patients were also taking a statin [27]. (See "Statins: Actions, side effects, and administration", section on 'Drug interactions'.)

Both fenofibrate and gemfibrozil infrequently cause liver injury; a US Food and Drug Administration (FDA) alert warns of potential for severe liver injury with fenofibrate. (See 'Fibrate effects' below.)

Adminstration — When treating with a fibrate, we aim for a TG level <500 mg/dL (5.6 mmol/L) to minimize the large (two- to threefold) postprandial elevations in TG concentrations that may occur after a meal in which fat, carbohydrate, and/or alcohol intake is excessive, which may lead to the development of pancreatitis.

Fibrates interfere with the metabolism of warfarin [23]. 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 per day taken without regard to meals), micronized capsules (dosage and administration are product dependent), nonmicronized capsules or tablets (dose is product dependent; taken with food), or as fenofibric acid (also called choline fenofibrate; 145 mg per day without regard to meals) [15]. Prescribers should become familiar with one available formulation and follow prescribing information for that product. We generally prefer to use the maximum dose unless dose reduction is required for adverse effects or reduced renal function.

GemfibrozilGemfibrozil is prescribed at a dose of 600 mg twice per day and is given before breakfast and dinner.

Bezafibrate Bezafibrate is prescribed in doses of 200 mg three times per day or a sustained-release daily dose of 400 mg per day [28]. Bezafibrate is not approved in the United States but is approved in many other regions of the world.

Ciprofibrate – Ciprofibrate is prescribed at a dose of 100 mg per day. It is not approved for use in the United States but is approved in many other countries.

Pemafibrate – This is prescribed at a dose of 0.2 mg twice per day. This drug is approved for use in Japan but not elsewhere.

Fibrate effects — Despite the favorable effects of fibrates on lipid levels, there is limited evidence that these drugs have favorable effects on clinical outcomes.

Effects on lipid levels – Fibrate therapy reduces serum TG levels by as much as 50 to 70 percent [5,29] and elevates HDL-C by 5 to 20 percent (table 1) [27,30]. Fibrates reduce LDL particle number but mildly increase LDL-C. The effects of fibrates on LDL-C and HDL-C are discussed separately. Fibrates are more potent (ie, provide greater TG lowering) and have a better side-effect profile than nicotinic acid (niacin). (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Fibrates' and "HDL cholesterol: Clinical aspects of abnormal values", section on 'Effect of increasing HDL cholesterol on clinical outcome' and 'Niacin' below.)

Effects on cardiovascular outcomes – Unlike statins, which have demonstrated clinical efficacy across a broad range of LDL-C levels, fibrates have shown reductions in cardiovascular events primarily in subsets of patients with high TG (above 200 mg/dL [2.2 mmol/L]) and/or low HDL-C (below 40 mg/dL [1 mmol/L]) [30-34]. A meta-analysis of 18 fibrate trials (45,058 participants) conducted over a mean of 4.1 years found no effect on all-cause mortality (relative risk [RR] 1.00, 95% CI 0.93-1.08) or cardiovascular mortality (RR 0.97, 95% CI 0.85-1.02), and a trend toward increased noncardiovascular mortality (RR 1.10, 95% CI 0.995-1.21) [32]. Fibrate therapy reduced the risk of coronary events (RR 0.87, 95% CI 0.81-0.93), but not stroke (RR 1.03, 95% CI 0.91-1.16).

In a prospective clinical trial of the selective peroxisome proliferator-activated receptor alpha agonist pemafibrate, patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level 200 to 499 mg per deciliter), and HDL-C levels of 40 mg per deciliter or lower were assigned either pemafibrate or placebo [35]. First CVD events (nonfatal myocardial infarction, stroke, coronary revascularization, or death) were similar in those assigned pemafibrate compared with placebo (10.9 versus 10.7 percent).

Effects on risk of pancreatitis – Evidence is lacking on the impact of fibrate therapy on the risk of pancreatitis in patients with moderate to severe hypertriglyceridemia, as the available evidence is largely limited to patients with lower TG levels. A meta-analysis of seven fibrate trials (40,162 participants), conducted over a mean of 5.3 years in patients with high normal TG levels to low moderate hypertriglyceridemia, identified a trend toward increased risk of pancreatitis with fibrate therapy, but the total number of pancreatitis events was small (84 with fibrate therapy, 60 with placebo; RR 1.39, 95% CI 1.00-1.95) [18].

Safety:

Fenofibrate – The main toxicity of fenofibrate is an increase in liver enzymes with occasional increases in creatine phosphokinase and, rarely, rhabdomyolysis. In 2021, the US FDA revised the warnings for fenofibrate to describe reports of serious drug-induced liver injury, including liver transplantation and death [36]. The product label suggests monitoring of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin at baseline and periodically during therapy, with discontinuation of the medication if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST >3 times the upper limit of normal, or if accompanied by elevation of bilirubin).

Fenofibrate-associated nephrotoxicity is an adverse effect that is often not recognized [37]. Although mechanisms remain unclear, the increase in serum creatinine could be prerenal from fenofibrate effects on skeletal muscles or on renal hemodynamics via defects in vasodilatory prostaglandin production. This effect of fenofibrate is often reversible [38]. In patients with fenofibrate-induced increases in serum creatinine, gemfibrozil is an alternative.

The relatively low risk of myopathy with fenofibrate therapy is discussed above. (See 'Choice of agent' above.)

Gemfibrozil – The risk of myopathy with gemfibrozil, particularly when combined with statin therapy, is discussed above. (See 'Choice of agent' above.)

Gemfibrozil therapy is associated with mild and transient serum aminotransferase elevations and, rarely, acute liver injury.

Bezafibrate and ciprofibrate – The major adverse effects of bezafibrate and ciprofibrate are myopathy and hepatic injury.

Marine omega-3 fatty acids — Indications for high-dose marine-derived omega-3 fatty acid in patients with moderate or moderate to severe hypertriglyceridemia are discussed above. (See 'Moderate hypertriglyceridemia' above and 'Moderate to severe hypertriglyceridemia' above.)

Choice of agent — Marine-derived omega-3 fatty acid preparations contain omega-3-acid ethyl esters eicosapentaenoic acid (EPA) with or without docosahexaenoic acid (DHA). The choice of agent varies depending upon the level of ASCVD risk (as defined above) (see 'Moderate hypertriglyceridemia' above and 'Moderate to severe hypertriglyceridemia' above and "Fish oil: Physiologic effects and administration"):

For patients with high ASCVD risk (as defined above), we prefer prescription-strength icosapent ethyl (the ethyl ester of EPA; Vascepa). (See 'Moderate hypertriglyceridemia' above and 'Moderate to severe hypertriglyceridemia' above.)

A possible exception to this is if a patient has paroxysmal atrial fibrillation. Due to concern for worsening the atrial fibrillation, we would prefer to use fibrates in these patients. (See 'Safety' below.)

In patients without high ASCVD risk, any of the available prescription marine omega fatty acid preparations can be used. Options include omega-3 fatty acid ethyl esters (EPA and DHA) in generic or brand (Lovaza) form or icosapent ethyl (Vascepa). (See 'Marine omega-3 fatty acids' above.)

The recommended prescription omega fatty acid preparations differ from many fish oil supplements which contain only 30 to 50 percent omega-3 fatty acids and are taken at low doses. By comparison, the commercial preparation Vascepa contains more than 95 percent icosapent ethyl [39]; the dose of icosapent ethyl in the REDUCE-IT trial was 4 g per day. Epanova, used in the STRENGTH trial, is a carboxylic acid formulation containing 4 g per day of omega-3 fatty acids (EPA and DHA). These trials are discussed below. (See 'Marine omega-3 fatty acid effects' below.)

Administration — The dose of prescription omega-3 fatty acids (EPA+DHA or EPA-only) for reducing TG levels in patients with hypertriglyceridemia is 4 g per day (>3 g per day total of EPA+DHA) [40].

The dose of icosapent ethyl (Vascepa, which contains only the ethyl ester of EPA) is 2 g twice per day with meals. The icosapent ethyl product is ≥96 percent EPA so there is 3.8 g EPA per 4 g dose.

The dose of omega-3 fatty acid ethyl esters (EPA+DHA) in generic or brand (Lovaza) form is 4 g once per day or 2 g twice per day with food. Lovaza contains 425 mg EPA and 345 mg DHA per 1000 mg capsule, so there is 3.1 g EPA+DHA per 4 g dose.

Marine omega-3 fatty acid effects

Effects on lipid levels — High-dose marine omega-3 fatty acid therapy reduces serum TG by approximately 20 to 50 percent, depending on the baseline TG level [40-42]. Evidence is lacking on the effects of omega-3 fatty acid therapy on risk of pancreatitis. Omega-3 fatty acids may also increase LDL cholesterol (generally mildly), which may be more pronounced with DHA than EPA [43]. (See "Fish oil: Physiologic effects and administration", section on 'Potential effects on cardiovascular and metabolic systems' and "Overview of primary prevention of cardiovascular disease", section on 'Omega-3 fatty acids' and "Lipid management with diet or dietary supplements", section on 'Omega-3 fatty acids'.)

Effects on cardiovascular outcomes — Randomized controlled trials examining effects of marine omega-3 fatty acids on ASCVD outcomes have yielded mixed results [9,37,44-49]. The hypothesis that TG lowering therapy reduces ASCVD risk was supported by a meta-analysis of trials of the effects of statins (n = 25) and nonstatin (n = 24) therapies (fibrates, niacin, and marine omega-3 fatty acids) on ASCVD outcomes in 197,270 participants [48]. In a multivariable meta-regression model, the relative risk reduction was 0.84 (95% CI 0.75-0.94) per 1 mmol/L or 0.92 per 40 mg/dL reduction in TG. However, the REDUCE-IT trial [9] strongly influenced the results of this analysis. Without this trial, the relative risk was 0.91 (95% CI 0.81-1.01) per 1 mmol/L reduction in TG.

In the REDUCE-IT trial, 8179 patients with elevated TG levels (fasting levels 135 to 499 mg/dL [1.52 to 5.63 mmol/L]) on statin and either established cardiovascular disease or diabetes plus two other cardiovascular risk factors were randomly assigned to supplementation with icosapent ethyl 4 g per day or mineral oil [9]. Cardiovascular risk factors were defined as age ≥50 years, cigarette smoking, hypertension, HDL-C ≤40 mg/dL for males or ≤50 mg/dL for females, high-sensitivity C-reactive protein (hs-CRP) >3.00 mg/L (0.3 mg/dL), creatinine clearance <60 mL/min, retinopathy, micro- or macroalbuminuria, and ankle-brachial index (ABI) <0.9. The following results were reported:

From baseline to one year, the median TG level decreased 18 percent in the treatment group, increased 2.2 percent in the control group, and LDL-C levels increased in both groups (treatment group 3.1 percent, control group 10.2 percent). At two years, CRP levels decreased by 13.9 percent in the treatment group and increased by 32.2 percent in the control group.

Icosapent ethyl reduced the risk of the primary combined cardiovascular disease (CVD) endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina (17.2 versus 22.0 percent; hazard ratio [HR] 0.75, 95% CI 0.68-0.83) after median follow-up of 4.9 years [9]. Two prespecified analyses showed reductions in the rates of both first and subsequent (ie, total) ischemic events [50] as well as the need for subsequent first and second revascularizations [51]. Icosapent ethyl showed similar primary CVD risk reductions in the subset of 1837 REDUCE-IT participants with prior coronary artery bypass graft surgery (22 versus 28 percent; HR 0.76, 95% CI 0.63-0.92) [52].

Limitations of the REDUCE-IT trial include:

Mineral oil as control – Concerns have been raised that mineral oil contributed to increases in atherogenic lipoproteins (LDL-C, non-HDL-C, apolipoprotein B), CRP, and cardiovascular risk in the control group. While some subsequent studies and reviews have suggested that the mineral oil control did not substantially affect the study results [53,54], another study that expanded the biomarkers from LDL-C and CRP to non-HDL-C and apolipoprotein B suggested that the effects of mineral oil may partially explain most of the differences in the study outcomes [55].

Lack of correlation between TG reduction and CVD outcome – The mechanisms for the reduction in cardiovascular events with icosapent ethyl are uncertain, as the modest reductions in fasting TG level are unlikely to account for the magnitude of benefit. Moreover, the amount of TG lowering was not related to favorable outcomes. Pleiotropic effects may include favorable effects on platelet aggregation, endothelial function, oxidative metabolism, and inflammation [56,57].

A similar benefit from icosapent ethyl therapy was observed in the open-label JELIS trial, in which 18,645 hypercholesterolemic patients treated with a statin were randomly assigned to receive icosapent ethyl (1.8 g per day) or control (no additional therapy) [58]. Baseline TG levels were normal to moderately elevated (median 154 mg/dL [1.74 mmol/L]; interquartile range 111 to 220 mg/dL [1.25 to 2.49 mmol/L]). There was a 19 percent reduction in the composite of cardiovascular events in the icosapent ethyl group (2.8 versus 3.5 percent), largely due to decreased hospital admission for unstable angina. The extent of TG lowering was not related to the risk of cardiovascular events [46].

The STRENGTH trial (published after the meta-analysis cited above [48]), randomly assigned 13,078 statin-treated patients at high cardiovascular risk to a carboxylic acid formulation of omega-3 fatty acids (omega-3 CA, which included EPA and DHA) or corn oil [49]. All patients had TG baseline levels between 180 and 500 mg/dL (median level of 240 mg/dL), as well as HDL-C <42 mg/dL for males and <47 mg/dL for females.

After a median treatment period of 38.2 months, the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization was similar in both groups (12.0 versus 12.2 percent, respectively; HR 0.99, 95% CI 0.90-1.09). There were no significant differences in the individual components of the composite. The trial was stopped early for futility.

A secondary analysis of the STRENGTH trial evaluated the relationship between plasma omega-3 fatty acid levels and the primary composite endpoint in 10,382 participants with plasma levels of EPA or DHA at baseline and 12 months after randomization [59]. Patients achieving the highest tertile of EPA and DHA levels did not have better outcomes than those given the corn oil placebo (HR 0.98, 95% CI 0.83-1.16 for EPA and HR 1.02, 95% CI 0.86-1.20 for DHA).

A limitation of the STRENGTH trial is that EPA levels on omega-3 CA were substantially lower than those in the REDUCE-IT and JELIS trials (89.6 versus 144, and 169 mcg/mL), so there is concern that the dose of omega-3 CA may have been inadequate. Also, DHA has different biophysical effects on membranes that might contribute to reducing the effect of EPA alone [57].

Safety

Gastrointestinal symptoms – In the STRENGTH trial, there were more gastrointestinal disorders (mainly diarrhea) in the omega-3 CA group than in the corn oil group (24.7 versus 14.7 percent). In the REDUCE-IT trial, gastrointestinal disorders were common in both treatment groups with a slightly lower incidence rate in the icosapent ethyl group compared with the mineral oil group (33.0 versus 35. 1 percent).

Atrial fibrillation – Although omega-3 fatty acids have been associated with an increased risk of atrial fibrillation, prior studies have important limitations. A meta-analysis of the published findings from seven randomized controlled trials (RCTs) of 81,000 people showed that participants assigned to omega-3 fatty acid supplementation versus placebo were at increased risk of atrial fibrillation (n = 2905; HR 1.25; 95% CI 1.07-1.46) [60]. However, two important study limitations were that AF was not a prespecified primary composite endpoint of any of the RCTs analyzed. In addition, only one of the seven RCTs, (the VITAL study [61]) accounted for the competing risk of death [62]. Among the studies not accounting for competing risk of death, the incidence of death was 1.5 to 5 times as high as the risk of atrial fibrillation. Thus, the failure to account for the competing risk of death could have led to a falsely increased association between omega-3 fatty acids and atrial fibrillation. In the VITAL study, rates of incident atrial fibrillation were similar among patients who received omega-3 fatty acids and those who received placebo [61].

Niacin — A limited possible indication for niacin for hypertriglyceridemia is described above. (See 'Moderate to severe hypertriglyceridemia' above.)

Niacin dosing is discussed separately. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Use'.)

At doses of 1500 to 2000 mg per day, nicotinic acid can reduce TG levels by 15 to 25 percent [29]. However, no study has shown that nicotinic acid improves cardiovascular outcomes. Niacin has a number of adverse side effects, including worsening of insulin resistance that may result in new onset type 2 diabetes or worsening of diabetes control in patients with type 2 diabetes. Additional side effects include hyperuricemia (and associated risk of gout), infection risk, elevations in serum transaminases and bilirubin, and gastrointestinal symptoms. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Nicotinic acid (niacin)'.)

Emerging and investigational therapies — The following emerging therapies are aimed at increasing lipoprotein lipase-mediated clearance of TG by decreasing the activity of proteins that inhibit lipoprotein lipase such as apolipoprotein C-III (APOC3) and angiopoietin-like protein (ANGPTL) 3:

APOC3 inhibitor – Volanesorsen, an antisense oligonucleotide inhibitor of APOC3, is approved for use in Europe for patients with genetically confirmed monogenic chylomicronemia but is not approved for clinical use in the United States. The following studies demonstrated that it reduces APOC3 and serum TG levels:

Monogenic chylomicronemia – In the APPROACH trial, 66 patients with monogenic chylomicronemia (table 4) (formerly type I hyperlipoproteinemia or familial chylomicronemia syndrome; baseline mean plasma APOC3 level of 30.2 mg/dL and mean fasting TG level of 2209 mg/dL) were randomly assigned to volanesorsen (300 mg subcutaneously once a week) or placebo [63]. Volanesorsen lowered TG levels below 750 mg/dL in 77 percent of patients at three months, compared with 10 percent of patients taking placebo. Volanesorsen reduced APOC3 levels by 84 percent and TG levels by 77 percent in these patients deficient in lipoprotein lipase, suggesting that the drug promotes TG clearance through lipoprotein lipase-independent pathways as well as via lipoprotein lipase. (See "Lipoprotein classification, metabolism, and role in atherosclerosis".)

Less severe hypertriglyceridemia – A randomized trial of this agent in patients with less severely elevated APOC3 and TG levels demonstrated reductions in these levels with or without concomitant fibrate therapy [64]. The mean baseline levels for APOC3 and TG were 22.8 mg/dL and 581 mg/dL in the patients not receiving other TG-lowering therapies and 17.6 mg/dL and 376 mg/dL in patients also treated with fibrates. In the monotherapy cohort the 300 mg dose reduced APOC3 levels by a mean of 79.6 percent (compared with a 4.2 percent increase with placebo) and TG by 70.9 percent (compared with an increase of 20.1 percent in the placebo group). In the add-on to fibrate group, the 300 mg dose reduced APOC3 levels by a mean of 70.9 percent (compared with a 2.2 percent reduction in the placebo group) and TG levels by 64.0 percent (compared with a 7.7 percent reduction in the placebo group).

Safety – Common adverse side effects with volanesorsen therapy are injection-site reactions (61 versus 0 percent with placebo) and thrombocytopenia (33 versus 3 percent with placebo) [63]. The development of N-acetyl-galactosamine antisense oligonucleotide conjugates for delivery to the liver may provide a means to avoid the thrombocytopenic risk [65,66].

ANGPTL 3 inhibitors – ANGLPT3 inhibitors under investigation include a monoclonal antibody (evinacumab) [67] and an antisense oligonucleotide [68].

Gene therapy – Alipogene tiparvovec, gene therapy for lipoprotein lipase deficiency delivered in an adeno-associated viral vector, reduces TG levels in patients with monogenic chylomicronemia (table 4) [69]. This therapy was approved for clinical use in Europe, but not in the United States. It is no longer available.

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 (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Treatment goals – The goals of management of patients with hypertriglyceridemia are to lower the risk for pancreatitis and atherosclerotic cardiovascular disease (ASCVD), although evidence on the efficacy of triglyceride (TG) lowering is limited. (See 'Treatment goals' above and 'Specific agents' above.)

General measures – For all patients with hypertriglyceridemia, first-line management includes (see 'General measures' above) (algorithm 1):

Address causes – Factors that may cause or exacerbate hypertriglyceridemia should be addressed. (See 'Address modifiable causes' above.)

Lifestyle modification – Diet and alcohol restrictions depend upon the level of hypertriglyceridemia. (See 'Moderate hypertriglyceridemia' above and 'Moderate to severe hypertriglyceridemia' above and 'Severe hypertriglyceridemia' above.)

Additional measures include aerobic exercise and management of ASCVD risk factors [2-4]. (See 'General measures' above and "Overview of primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Optimize treatment of LDL-C – Assessment of ASCVD risk and management of low-density lipoprotein cholesterol (LDL-C) level is performed according to standard recommendations. (See 'General measures' above and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Summary and recommendations' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Our approach'.)

Additional management – For patients whose TG levels remain >150 mg/dL despite the above general measures, additional management depends on the TG level, ASCVD risk factors, and history of pancreatitis. (See 'Additional therapy based upon TG level' above.)

In the discussion below, "high ASCVD risk" is defined as established ASCVD or diabetes mellitus plus two additional ASCVD risk factors (age ≥50 years, cigarette smoking, hypertension, high-density lipoprotein cholesterol [HDL-C] ≤40 mg/dL for males or ≤50 mg/dL for females, high sensitivity C-reactive protein [hs-CRP] >3 mg/L [0.3 mg/dL], creatinine clearance <60 mL/min, retinopathy, micro- or macroalbuminuria, and ankle-brachial index [ABI] <0.9).

Our approach is as follows (algorithm 1):

Moderate hypertriglyceridemia (fasting TG 150 to 499 mg/dL [1.7 to 5.6 mmol/L]) (see 'Moderate hypertriglyceridemia' above):

-Patients with high ASCVD risk – For patients with moderate hypertriglyceridemia who have high ASCVD risk, we suggest adding marine omega-3 fatty acid therapy (Grade 2B). In this setting, we suggest icosapent ethyl rather than other marine omega-3 fatty acid preparations (Grade 2C). (See 'Marine omega-3 fatty acids' above.)

-Patients not at high ASCVD risk – For patients with moderate hypertriglyceridemia who lack the above ASCVD risk factors, management focuses on continuing general measures. (See 'General measures' above.)

Moderate to severe hypertriglyceridemia (fasting TG 500 to 999 mg/dL [5.65 to 11.3 mmol/L]):

-Patients with high ASCVD risk The preferred initial agent to add for patients with moderate to severe hypertriglyceridemia and high ASCVD risk is icosapent ethyl. If TG level remains ≥500 mg/dL despite treatment with icosapent ethyl, unless the patient has chylomicrons, we suggest adding fibrate therapy for the prevention of or to lower the risk of acute pancreatitis (Grade 2C). (See 'Marine omega-3 fatty acids' above and 'Fibrates' above.)

-Patients not at high ASCVD risk – For patients without the above ASCVD risk factors, we suggest adding fibrate therapy (Grade 2C). If TG level remains ≥500 mg/dL despite treatment with fibrate therapy, we suggest adding a marine omega-3 fatty acid agent (Grade 2C). In this setting, any of the available prescription high-dose marine omega-3 fatty acid preparations may be used. (See 'Fibrates' above and 'Marine omega-3 fatty acids' above.)

Severe hypertriglyceridemia (fasting TG ≥1000 mg/dL [≥11.3 mmol/L]) – Patients with severe hypertriglyceridemia are managed with extreme dietary fat restriction, alcohol abstinence, and LDL-lowering therapy with the goal of reducing the TG level to <1000 mg/dL. For most patients with severe pancreatitis (including all outpatients), addition of TG-lowering agents is deferred until the TG level is ≤1000 mg/dL. For patients with acute pancreatitis, a fibrate is a component of therapy to reduce TG levels along with the above measures. (See 'Severe hypertriglyceridemia' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thanks John J P Kastelein, MD, PhD, FESC, for his past contributions as an author to prior versions of this topic review.

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Topic 4570 Version 82.0

References

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