Hypertriglyceridemia in adults: Management

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" 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 goal of management of patients with hypertriglyceridemia is to lower the risk for both types of conditions.

Reducing risk of pancreatitis — Lowering of serum (or plasma) triglyceride (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 was only limited evidence on the efficacy of lipid-lowering therapies in reducing pancreatitis risk in individuals with hypertriglyceridemia prior to trials of apolipoprotein C3 ribonucleic acid (RNA) inhibitors. (See 'Statin effects' below and 'Fibrate effects' below and 'APOC3 inhibitors' below.)

Reducing ASCVD risk — Management of ASCVD risk in patients with hypertriglyceridemia is directed primarily at lowering low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein-cholesterol (non-HDL-C), rather than lowering TG per se. The efficacy of TG lowering in decreasing ASCVD risk has not been established, in contrast to the established reduction in ASCVD risk with LDL-C lowering. (See 'General measures' below and 'Additional therapy based upon TG level' below.)

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 is that TG levels are not directly involved in the development 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. (See 'Specific agents' below.)

There are extensive genetic and epidemiology studies showing that remnant cholesterol in TG-rich lipoproteins is associated with ASCVD risk. On a per-particle basis, remnant cholesterol is four to five times more atherogenic than LDL-C [1-3]. VLDL remnant particles and LDL particles each have one molecule of apolipoprotein B (apo B).

Apo B and non-HDL-C concentrations are better measures of the excess concentrations of atherogenic lipoproteins in patients with moderate and severe hypertriglyceridemia than LDL-C [3]. Apo B levels may be more predictive of ASCVD risk than levels of TG, LDL-C, or non-HDL-C [4,5].

LDL-C levels may underrepresent cardiovascular risk in patients with hypertriglyceridemia because high TG levels are associated with small, dense cholesterol-depleted LDL particles that may not be captured by LDL-C measurement. Variation in the risk associated with non-HDL-C is influenced by the amount of remnant cholesterol [6]. (See "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Lipid profile'.)

In patients with hypertriglyceridemia, the following are the key pharmacologic approaches to reduce ASCVD risk:

●LDL-C and non-HDL-C lowering – As patients with hypertriglyceridemia are generally candidates for LDL-C and non-HDL-C lowering to reduce ASCVD risk, this is a cornerstone of therapy for these patients. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults" 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 low- to moderate-intensity statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors) generally have mild or moderate TG-lowering effects (table 1). However, high-intensity statins (atorvastatin 40 and 80 mg, rosuvastatin 20 and 40 mg) lower triglycerides by 40 to 44 percent in patients with triglycerides as high as 800 to 880 mg/dL [7]. (See 'Assess and treat LDL-C and non-HDL-C' below.)

●High-dose marine omega-3 fatty acid therapy – As discussed below, some evidence suggests that high-dose highly purified marine omega-3 fatty acids (specifically icosapent ethyl) reduce cardiovascular risk, but this clinical benefit is unrelated to the degree of TG lowering caused by these agents. (See 'Marine omega-3 fatty acids' 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 atherosclerotic cardiovascular disease (ASCVD) risk assessment. (See "Overview of primary prevention of cardiovascular disease in adults" and "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults".)

Additional management is based upon the degree of triglyceride (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 [8].

Address modifiable causes — Since hypertriglyceridemia is often induced or exacerbated by potentially correctable disorders [9,10], 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 – This includes optimizing management of hypertension, smoking cessation, and addressing a sedentary lifestyle [8-12]. 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) [8]. (See "Overview of primary prevention of cardiovascular disease in adults" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention)".)

●Weight target – Weight loss of 5 to 10 percent body weight is generally recommended for patients with overweight or obesity with elevated TG [8], although the target weight should be individualized for each patient. (See "Obesity in adults: Dietary therapy".)

●Diet and alcohol consumption – 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 and non-HDL-C — Patients with hypertriglyceridemia should undergo an assessment of their atherosclerotic cardiovascular risk, LDL-C level, and non-HDL-C level. LDL-C levels above goal are treated according to standard recommendations for primary or secondary prevention of ASCVD (generally including a statin). (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults" 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) [7,13]. Ezetimibe lowers TG levels by approximately 7 to 8 percent, and proprotein convertase subtilisin/kexin type 9 inhibitors lower fasting TG levels by 2 to 23 percent. Bempedoic acid has no TG-lowering effects [14].

ADDITIONAL THERAPY BASED UPON TG LEVEL — 

Additional therapy beyond the general approach is based upon triglyceride (TG) level as well as history of prior pancreatitis. For purposes of management, we classify fasting TG levels according to the following criteria:

●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-3 fatty acids in patients meeting these criteria. 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 the risk of cardiovascular disease [15,16]. 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 key goal of therapy is to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) events. These patients generally do not require treatment to reduce the risk of pancreatitis. We use the following approach. We initiate management with ASCVD risk assessment, LDL-C management, and nonpharmacologic measures, as described above (see 'General measures' above). After 4 to 12 weeks of general measures, we assess the need for further TG-lowering therapy.

●Lifestyle modification

•Diet – Dietary management should focus on attaining and maintaining a healthy weight and reducing the 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 [17]. 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 [18]. 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 12 weeks of 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

General approach — For patients with moderate to severe hypertriglyceridemia (500 to 999 mg/dL; 5.65 to 11.3 mmol/L), the following approach is applied in addition to the general measures described above (see 'General measures' above). The goal of therapy for this TG range is to reduce the risk 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 [8]. A change in the types of fat (ie, reducing saturated versus poly- and monounsaturated fats) is recommended [17]. 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 [8]. 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 12 weeks of the above lifestyle modification 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 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, we suggest treatment with 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-3 fatty acid preparation can be used. (See 'Marine omega-3 fatty acids' below.)

An alternative approach for patients without high risk of ASCVD is to begin with marine omega-3 fatty acid therapy and add fibrate therapy as needed.

Niacin not routinely used — 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 [19]. The management approach varies depending upon whether or not familial chylomicronemia syndrome (FCS) is present.

General measures for severe hypertriglyceridemia — The following measures apply to all patients with severe hypertriglyceridemia:

●Role of testing for familial chylomicronemia syndrome – As discussed separately, most patients with severe hypertriglyceridemia (>1000 mg/dL; 11.3 mmol/L) have multifactorial chylomicronemia (polygenic determinants (table 4) [20,21] along with environmental influences [12,22]); rare cases are caused by biallelic loss of function variants in lipoprotein lipase (LPL) or LPL-regulating genes (FCS).

Indications for genetic testing to confirm a diagnosis of FCS are discussed separately. (See "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Diagnostic evaluation'.)

●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 [8].

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 [8].

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

●Avoid omega-3 fatty acids – We avoid omega-3 fatty acid use in patients with chylomicronemia (fasting TG >880 mg/dL) because fat restriction is essential in these individuals.

Without familial chylomicronemia syndrome — The following is our approach for patients with severe hypertriglyceridemia without FCS:

●Limited effectiveness of drug therapy – When the TG level is >1000 mg/dL, drugs used to lower TG have limited effectiveness.

When TG levels increase above 800 to 1000 mg/dL, LPL (the major enzyme for TG clearance) cannot work any harder. At these TG levels, chylomicrons are the major lipoproteins present, with lesser contribution from VLDL. Since fibrates and omega-3 fatty acids reduce TG levels primarily by reducing VLDL production, little TG lowering is accomplished with these agents in the setting of severe hypertriglyceridemia.

•For most patients – Drug therapy for hypertriglyceridemia (aside from treatment of LDL-C) is likely to be ineffective for most patients without FCS until the TG level is lowered to ≤1000 mg/dL. Thus, drug therapy (fibrate) may be deferred until the TG level is ≤1000 mg/dL, although this therapy can be initiated or continued at TG levels >1000 mg/dL without harm. (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 (fibrate) within days. (See 'Monitoring therapy' below.)

•For hospitalized patients with acute pancreatitis – For hospitalized patients recovering from acute pancreatitis induced by severe hypertriglyceridemia caused by a multifactorial syndrome (and not FCS), we treat with a fibrate to reduce TG levels along with the above lifestyle measures. The need for continued fibrate therapy is reassessed during subsequent outpatient management.

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

With familial chylomicronemia syndrome — For patients with FCS, we recommend treatment with olezarsen. The typical dose is 80 mg subcutaneously once monthly. (See 'Olezarsen' below.)

Indications for genetic testing to confirm a diagnosis of FCS are discussed separately. (See "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Diagnostic evaluation'.)

Prior pancreatitis — For patients 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 TG-lowering medications (eg, fibrate plus an omega-3 fatty acid for those without FCS; olezarsen for those with FCS), we evaluate for other causes of pancreatitis, particularly if TG level is <500 mg/dL. As noted above, omega-3 fatty acids are avoided in patients with TG level >880 mg/dL. (See 'Treatment goals' above and 'General measures for severe hypertriglyceridemia' above and "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 triglyceride (TG) level monitoring depends upon the severity of hypertriglyceridemia.

●For patients with severe hypertriglyceridemia (TG level >1000 mg/dL or 11.3 mmol/L) 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 (TG level 500 to 999 mg/dL; 5.65 to 11.3 mmol/L), 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):

●Dietary modification – 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 [23].

●Statin – As noted above, a moderate to high dose of a high-intensity statin lowers triglycerides by 40 to 44 percent over a period of four to six weeks. (See 'Assess and treat LDL-C and non-HDL-C' above.)

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

●Fibrates – A response to fibrates is seen as early as two weeks into therapy, with a maximal effect in six to eight weeks [24-26]. (See 'Fibrates' below.)

●Olezarsen – In patients with familial chylomicronemia syndrome (baseline mean TG level approximately 2600 mg/dL), olezarsen 80 mg subcutaneously once monthly reduced TG level by approximately 40 percent at 5 weeks [27]. (See 'Olezarsen' below.)

●Niacin – The majority of the response to niacin (nicotinic acid) is seen in two weeks. However, we do not routinely use niacin. (See 'Niacin not routinely used' above.)

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 atherosclerotic cardiovascular disease (ASCVD) risk, high doses of high-intensity statins also have some triglyceride (TG)-lowering effects by reducing VLDL production and potentially reducing 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 "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 and non-HDL-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) [28].

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 [29,30]. Fibrates are associated with muscle toxicity [31,32], an effect that is more pronounced in patients also treated with a statin [33,34]. Gemfibrozil has a higher risk of muscle toxicity, especially when administered with a statin [35]. Glucuronidation, which is an important pathway for renal excretion of lipophilic statins, appears to be significantly inhibited by gemfibrozil but not fenofibrate [36]. 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 [37]. (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 [33]. 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 (dose 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) [24]. 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 kidney function.

●Gemfibrozil – Gemfibrozil 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 [38]. 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.

●Mechanism of action – Fibrates downregulate apolipoprotein C3 (APOC3; an inhibitor of lipoprotein lipase [LPL]) and upregulate apolipoprotein A-1, fatty acid transport protein, and LPL. These actions increase VLDL catabolism, fatty acid oxidation, and elimination of triglyceride-rich particles.

●Effects on lipid levels – Fibrate therapy reduces serum TG levels by as much as 50 to 70 percent [12,39] and elevates HDL-C by 5 to 20 percent (table 1) [37,40]. 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]) [40-44]. 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 (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) [42]. 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/dL), and HDL-C levels of 40 mg/dL or lower were assigned either pemafibrate or placebo [45]. 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) [28].

●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 [46]. 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 [47]. 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 [48]. 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 acids in patients with moderate or moderate to severe hypertriglyceridemia are discussed above. (See 'Moderate hypertriglyceridemia' above and 'Moderate to severe hypertriglyceridemia' above and 'Without familial chylomicronemia syndrome' 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 prefer to use fibrates in these patients. (See 'Safety' below.)

●In patients without high ASCVD risk, any of the available prescription marine omega-3 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-3 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 [49]; 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) [50].

●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 — Marine omega-3 fatty acids reduce hepatic secretion of triglyceride-rich lipoproteins [51]. High-dose marine omega-3 fatty acid therapy reduces serum TG by approximately 20 to 50 percent, depending on the baseline TG level [22,50,52].

However, omega-3 fatty acids may increase LDL cholesterol (generally mildly), which may be more pronounced with DHA than EPA [53]. (See "Overview of primary prevention of cardiovascular disease in adults", section on 'Omega-3 fatty acids' and "Lipid management with diet or dietary supplements", section on 'Omega-3 fatty acids' and "Fish oil: Physiologic effects and administration", section on 'Potential effects on cardiovascular and metabolic systems'.)

Evidence is lacking on the effects of omega-3 fatty acid therapy on risk of acute pancreatitis. In patients who are highly susceptible to acute pancreatitis, there is concern that increased fat consumption associated with omega-3 fatty acid therapy might increase the risk of acute pancreatitis.

Effects on cardiovascular outcomes — Randomized controlled trials examining effects of marine omega-3 fatty acids on ASCVD outcomes have yielded mixed results [15,47,54-59]. 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 [58]. In a multivariable meta-regression model, the risk ratio 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 [15] 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 [15]. 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 and 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 composite cardiovascular 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 [15]. Two prespecified analyses showed reductions in the rates of both first and subsequent (ie, total) ischemic events [60] as well as the need for subsequent first and second revascularizations [61]. Icosapent ethyl showed similar 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) [62].

●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 [apo 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 [63,64], another study that expanded the biomarkers from LDL-C and CRP to non-HDL-C and apo B suggested that the effects of mineral oil may partially explain most of the differences in the study outcomes [65].

•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 [66,67].

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) [68]. 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 [56].

The STRENGTH trial (published after the meta-analysis cited above [58]), 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 [59]. 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 [69]. 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 [67].

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) [70]. However, there were two important study limitations. 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 [71]) accounted for the competing risk of death [72]. 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 [71].

APOC3 inhibitors

Mechanism of action — Apolipoprotein C3 (APOC3) is a primarily liver-produced glycoprotein that circulates on triglyceride rich lipoproteins (TRL, such as chylomicrons and VLDLs). APOC3 increases TG levels by inhibiting LPL activity, inhibiting hepatic clearance of TRL remnants, and stimulating hepatic secretion of VLDLs, which compete with chylomicrons for LPL-mediated clearance [73]. Olezarsen, volanesorsen and plozasiran are antisense oligonucleotides that target messenger RNA for APOC3 and decrease inhibition of LPL and other effects of APOC3 and, thus, reduce serum TG levels.

Agents

Olezarsen — Olezarsen is small interfering RNA for APOC3 that is approved for clinical use in the United States as an adjunct to diet in patients with familial chylomicronemia syndrome (FCS) [74].

●For familial chylomicronemia syndrome – In a phase 3 trial, 66 patients with FCS (most with prior history of acute pancreatitis) were randomly assigned to receive one of the following doses subcutaneously every four weeks for a total of 49 weeks: olezarsen 80 mg, olezarsen 50, or placebo [27]. The baseline mean TG level was 2630 mg/dL.

•The 80 mg olezarsen dose significantly reduced TG levels at six months compared with placebo (-43.5 percentage points; 95% CI -69.1 to -17.9). The 50 mg olezarsen dose also reduced TG levels in most patients, but the change in TG levels did not reach statistical significance (−22.4 percentage points; 95% CI -47.2 to 2.5). APOC3 levels at six months were reduced by both olezarsen doses compared with placebo.

•Incidence of acute pancreatitis by 53 weeks was lower with olezarsen (one episode in each of the olezarsen dose groups versus 11 episodes with placebo; rate ratio for pooled olezarsen groups versus placebo 0.12, 95% CI 0.02-0.66).

•Adverse events considered to be related to the trial drug occurred in seven patients (32 percent) in the olezarsen 80 mg group, six patients (29 percent) in the olezarsen group, and five patients (22 percent) in the placebo group. The most common adverse reactions with olezarsen were injection site reactions (19 versus 9 percent), decreased platelet count (12 versus 4 percent) (see 'Effects on platelet count' below), and arthralgia (9 versus 0 percent).

●For moderate or severe hypertriglyceridemia – In a phase 2b trial, 154 patients with either moderate hypertriglyceridemia (TG level 150 to 499 mg/dL) plus elevated cardiovascular risk or severe hypertriglyceridemia (TG level ≥500 mg/dL) were randomly assigned to receive monthly subcutaneous olezarsen (50 or 80 mg) or placebo [75]. The baseline median TG level was 241.5 mg/dL. The 50 mg olezarsen dose reduced TG levels by 49.3 percentage points and the 80 mg dose reduced TG levels by 53.1 percentage points compared with placebo. Olezarsen also reduced levels of APOC3, apo B, and non-HDL-C, but not LDL-C. Rates of adverse events were similar with olezarsen and placebo, although mild elevations in ALT or AST were more common in patients taking olezarsen.

Volanesorsen — Volanesorsen is small interfering RNA for APOC3 that is approved for use in Europe, the United Kingdom, and Brazil for patients with genetically confirmed FCS, but is not approved for clinical use in the United States due to concerns about risk of thrombocytopenia, as discussed below. (See 'Effects on platelet count' below.)

The following studies demonstrated that it reduces APOC3 and serum TG levels:

●For familial chylomicronemia syndrome – In the APPROACH trial, 66 patients with monogenic chylomicronemia (table 4) (formerly type I hyperlipoproteinemia or monogenic chylomicronemia (mean baseline fasting TG level of 2209 mg/dL; mean APOC3 25.7 mg/dL) were randomly assigned to subcutaneous once weekly volanesorsen (300 mg) or placebo [76]. 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 LPL, suggesting that the drug promotes TG clearance through LPL-independent pathways as well as via LPL. (See "Lipoprotein classification, metabolism, and role in atherosclerosis".)

●For less severe hypertriglyceridemia – A randomized trial of volanesorsen which enrolled 85 patients with less severely elevated TG and APOC3 levels demonstrated reductions in these levels with or without concomitant fibrate therapy [77]. The mean baseline fasting levels for TG and APOC3 were 581 and 22.8 mg/dL in the patients not receiving other TG-lowering therapies and 376 mg/dL and 17.6 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 reversible thrombocytopenia, as discussed below [76]. (See 'Effects on platelet count' below.)

Plozasiran — Plozasiran is a small interfering RNA for APOC3 [78] that is an investigational agent in the US and Europe.

●For persistent chylomicronemia – Persistent chylomicronemia is caused by FCS and, much more commonly, by multifactorial causes. A trial randomly assigned 75 patients with persistent chylomicronemia (with or without genetically confirmed FCS) to subcutaneous plozasiran (25 or 50 mg) or placebo every 3 months for 12 months [78]. The median TG level declined (from 2044 mg/dL at baseline) to a similar extent with the two doses: 80 percent in the plozasiran 25 mg group and 78 percent in the plozasiran 50 mg group, compared with 17 percent in the placebo group.

The incidence of acute pancreatitis was 4 percent in patients receiving plozasiran and 20 percent in patients receiving placebo (odds ratio 0.17, 95% CI 0.03-0.94). The rate of severe and serious adverse events was lower with plozasiran than with placebo. Mean glycated hemoglobin values were mildly increased with plozasiran in patients with baseline prediabetes or diabetes.

●For mixed hyperlipidemia – A trial randomly assigned 353 patients with mixed hyperlipidemia (TG level of 150 to 499 mg/dL and either a LDL-C of ≥70 mg/dL or a non-HDL-C of ≥200 mg/dL) to treatment with subcutaneous plozasiran (10, 25, or 50 mg) or placebo in four cohorts with quarterly or half-yearly dosing [79]. At week 24, reductions in TG level were greatest in patients treated with the highest and more frequent dose. Worsening glycemic control was seen in some patients receiving the 50 mg dose (quarterly or half-yearly).

●For severe hypertriglyceridemia – A trial randomly assigned 229 patients with severe hypertriglyceridemia (baseline TG level 500 to 4000 mg/dL [mean 897 mg/dL] and baseline APOC3 level 32 mg/dL) to subcutaneous plozasiran (10, 20, or 50 mg) or placebo on day 1 and at week 12 [80]. Patients with FCS or pancreatitis within 12 weeks were excluded. Plozasiran induced reductions in placebo-adjusted least squares mean TG levels (-57 percent; 95% CI -71.9 to -42.1 percent at the highest dose) and APOC3 (-77 percent; 95% CI -89.1 to -65.8 percent at the highest dose) at week 24. Among the participants in the plozasiran treatment group, 90.6 percent achieved a TG level of less than 500 mg/dL at week 24. While the highest dose of plozasiran significantly increased LDL-C, plozasiran decreased non-HDL-C levels at all doses. The two treatment groups had similar rates of adverse events.

Effects on platelet count — As noted above, volanesorsen was not approved for clinical use in the United States due to concerns about risk of thrombocytopenia. Reversible reductions in platelet count are common with volanesorsen therapy (eg, 33 versus 3 percent with placebo) [76]. The risk of thrombocytopenia with volanesorsen therapy was partially mitigated by enhanced platelet count monitoring with rules for reducing drug dose or suspending drug administration. (See 'Volanesorsen' above.)

Hepatically targeted APOC3 inhibitors appear to reduce or avoid the risk of thrombocytopenia:

●Olezarsen is an N-acetyl-galactosamine antisense oligonucleotide targeting the liver. In the above-cited clinical trial in patients with FCS, the rate of decreased platelet count was 12 percent in the olezarsen group and 4 percent in the placebo group [27,74].

●Plozasiran is an N-acetyl-galactosamine antisense small interfering RNA targeting the liver [81,82]. No significant fall in platelet count was observed in clinical trials of plozasiran [78,79].

Niacin — A limited possible indication for niacin for hypertriglyceridemia is described above. (See 'Niacin not routinely used' above.)

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

At doses of 1500 to 2000 mg per day, nicotinic acid can reduce TG levels by 15 to 25 percent [39]. However, no study has shown that nicotinic acid improves cardiovascular outcomes. Niacin has a number of adverse side effects, including worsening of insulin resistance, which may result in new-onset type 2 diabetes or worsening of diabetes control in patients with type 2 diabetes [83]. 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 investigational therapies are aimed at increasing LPL-mediated clearance of TG.

ANGPTL3 inhibitors — Angiopoietin-like 3 protein (ANGPTL3) inhibits both LPL and endothelial lipase [84]. ANGPTL3 inhibitors under investigation include a monoclonal antibody (evinacumab) [85] and small interfering RNA (zodasiran, solbinsiran).

Evinacumab — A phase 2 trial in patients with severe hypertriglyceridemia and prior hospitalization for acute pancreatitis demonstrated median TG lowering of 64.8 percent in patients with multifactorial chylomicronemia syndrome and 81.7 percent in patients with unspecified hypertriglyceridemia [86]. There was no TG lowering in patients with biallelic loss-of-function variants in LPL or LPL-mediated pathways.

Zodasiran — A phase 2b trial was performed in 204 adults with mixed hyperlipidemia (fasting TG 150 to 499 mg/dL and either an LDL cholesterol level of ≥70 mg/dL or a non-HDL-C level of ≥100 mg/dL) who were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 [73]. At 24 weeks, there were dose-dependent decreases in TG levels. LDL-C levels also declined with zodasiran. There was a small transient increase in glycated hemoglobin in patients with diabetes mellitus treated with the highest dose of zodasiran.

Gene therapy — Alipogene tiparvovec, gene therapy for LPL deficiency delivered in an adeno-associated viral vector, reduces TG levels in patients with monogenic chylomicronemia (table 4) [87]. 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 5^th to 6^th 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 10^th to 12^th 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):

•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. (See 'General measures' above and "Overview of primary prevention of cardiovascular disease in adults" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention)".)

•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 'Initial drug therapy to reduce LDL-C'.)

●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:

•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 icosapent ethyl rather than no marine omega-3 fatty acid (Grade 2B) and rather than other marine omega-3 fatty acids (Grade 2C). (See 'Marine omega-3 fatty acids' above.)

-Patients without 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])(see 'Moderate to severe hypertriglyceridemia' above):

-Patients with high ASCVD risk – For patients with moderate to severe hypertriglyceridemia and high ASCVD risk, the therapy of choice is the same as for moderate hypertriglyceridemia (icosapent ethyl). (See 'Marine omega-3 fatty acids' above and 'Fibrates' above.)

-Patients without high ASCVD risk – For patients without the above ASCVD risk factors, we suggest adding fibrate therapy (Grade 2C). If TG level remains 500 to 880 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. (See 'Severe hypertriglyceridemia' above.)

-Without familial chylomicronemia syndrome - For most patients with severe hypertriglyceridemia without familial chylomicronemia syndrome (FCS), addition of TG-lowering agents may be deferred until the TG level is ≤1000 mg/dL, since such agents may not be effective at higher TG levels. (See 'Without familial chylomicronemia syndrome' above.)

An exception is for hospitalized patients recovering from acute pancreatitis induced by hypertriglyceridemia caused by a multifactorial syndrome (not FCS) who are treated with a fibrate along with lifestyle measures. Management of acute hypertriglyceridemia-induced pancreatitis is discussed separately. (See "Hypertriglyceridemia-induced acute pancreatitis".)

-With familial chylomicronemia syndrome – For patients with genetically confirmed FCS, we recommend treatment with olezarsen (Grade 1B). The typical dose is 80 mg subcutaneously once monthly.

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.