Hypertriglyceridemia Treatment & Management

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

In general, lifestyle modifications (eg, smoking cessation, diet, exercise, weight reduction) are initiated before any pharmacologic therapy in the treatment of primary and secondary dyslipidemia, particularly in patients who are asymptomatic. ^{[49, 38, 45, 50, 46]} Weight reduction and a diet low in saturated fat and cholesterol are advocated. Patients should avoid alcohol and estrogen in certain types of hyperlipoproteinemias.

The patient’s low-density lipoprotein (LDL) cholesterol level response is measured in 6 weeks to 6 months, depending on the patient's cardiovascular risk factors. Consider an LDL cholesterol goal of less than 70 mg/dL in patients with established coronary artery disease (CAD) or CAD risk equivalents, including clinical manifestations of noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease, transient ischemic attacks or stroke of carotid origin or 50% obstruction of a carotid artery), diabetes, or a Framingham 10-year CAD risk score of greater than 20%. ^[51]

Consider pharmacologic therapy if the LDL-C level remains above the following thresholds ^[51] :

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

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

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

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

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

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

In managing secondary dyslipidemia, consider statin therapy for all patients, as these agents reduce mortality and coronary heart disease/atherosclerotic cardiovascular disease (CHD/ASCVD) endpoints. ^[49] High-potency statins (atorvastatin, rosuvastatin) at high doses have greater efficacy in reduction of cardiovascular events than low potency statins or high-potency statins at low doses. ^[49] However, patients treated with lipid-lowering medications should be carefully monitored for the development of myositis or liver disease. In addition, statin monotherapy is not recommended for severe or very severe hypertriglyceridemia. ^[46]

A study by Shimabukuro et al found that the impact on lipoprotein subclass profiles varies between pitavastatin and atorvastatin. Determining the lipoprotein subclass profile and selecting the appropriate statin in patients with diabetes and an additional cardiovascular risk, such as low HDL cholesterol or hypertriglyceridemia may be beneficial. ^{[52, 53, 54, 55]}

Other considerations

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

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

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

If the primary care provider cannot control a patient's triglycerides, referral should be made to a lipidologist or endocrinologist with expertise in treating severe and difficult-to-manage lipid disorders. ^[56]

FDA warnings

On March 1, 2012, the US Food and Drug Administration (FDA) issued updates to the prescribing information concerning interactions between protease inhibitors (such as those used to treat hepatitis C or human immunodeficiency virus infection) and certain statin drugs, notably that the combination of these agents taken together may raise the blood levels of statins and increase the risk for myopathy. ^[57] The most serious form of myopathy, rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal. ^[57]

Two days earlier, on February 28, 2012, the FDA approved important safety label changes for statins, including removal of routine monitoring of liver enzymes from drug labels. ^[58] Information about the potential for generally nonserious and reversible cognitive side effects and reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels were added to the statin labels. In addition, the lovastatin label was extensively updated with new contraindications and dose limitations when this agent is taken with certain medicines that can increase the risk for myopathy. ^[58]

On June 8, 2011, the FDA recommended limiting the use of the highest approved dose of simvastatin (Zocor) (80 mg) due to the increased risk of myopathy. ^[59] The agency also required changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines. ^[59]

High doses of a strong statin (simvastatin, atorvastatin, rosuvastatin) lower triglycerides, by as much as approximately 50%, and raise high-density lipoprotein (HDL) cholesterol. ^[45] The greater the baseline level of triglycerides the greater the percent triglyceride reduction will be with statin treatment. ^[60] In addition to statins, 3 classes of medications are appropriate for the management of major triglyceride elevations: fibric acid derivatives, niacin, and omega-3 fatty acids. ^{[45, 50, 60]}

Nicotinic acid combined with a statin generally improves low-density lipoprotein (LDL) cholesterol, HDL cholesterol, and triglyceride levels. However, the use of fibric acids has a variable effect on LDL cholesterol despite reducing triglyceride levels and increasing HDL cholesterol levels. ^{[45, 60]} In patients with diagnosed coronary artery disease (CAD) at very high risk of recurrent cardiovascular events, it may be necessary to use the combination of a cholesterol-lowering drug with a triglyceride-lowering drug to reach the non-HDL cholesterol goal. ^[45]

Fibrates

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

Delayed-release fenofibric acid was approved by the FDA for an indication in which it was coadministered with statin in patients with mixed dyslipidemia and CHD or a CHD risk equivalent in whom optimal statin therapy has been achieved. However, the FDA withdrew approval for this indication when the agency found that, in light of several large trials, "scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events." ^{[61, 62]}

A review of gemfibrozil, fenofibrate, and bezafibrate described their beneficial lipid effects and the association of these drugs with reductions in coronary morbidity and mortality (although no substantial effect on total mortality was found). ^[63]

Clinical trials have shown that some fibrates cause reversible increases in serum creatinine levels but either have no impact on or slightly decrease albumin excretion. ^[64] Moreover, the kidney is the primary route for elimination of most fibrates, and dose reductions are indicated for reduced creatinine clearance. The half-life of gemfibrozil is independent of renal function, and it is the drug of choice for patients with chronic kidney disease. ^[65]

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

All manufacturers provide high- and low-dose fenofibrate tablets. The standard adult dose is always more than 100 mg/d; the lower dose is indicated for patients with renal dysfunction (creatinine clearance < 80). Fibrates are contraindicated in patients with creatine clearance of less than 30. The formulation known as fenofibric acid (Trilipix) was approved by the FDA for use with a statin in mixed dyslipidemia. ^{[66, 67, 63, 64, 65]} The older fenofibrate formulation also appears to be safe when combined with a statin.

Niacin

High-dose niacin (vitamin B-3) (1500 or more mg/d) decreases triglyceride levels by at least 40% and can raise HDL cholesterol levels by 40% or more. ^[46] Niacin also reliably and significantly lowers LDL cholesterol levels, which the other major triglyceride-lowering medications do not. In the Coronary Drug Project, niacin, in comparison with placebo, reduced coronary events. ^[68]

Although extended-release niacin had been approved by the FDA for coadministration with statin for treatment of primary hyperlipidemia and mixed lipidemia, the FDA withdrew approval for this indication when the agency found that, in light of several large trials, "scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events." ^{[61, 62]}

Precautions

Niacin has multiple adverse effects, the worst of which is chemical hepatitis. However, at doses of 1.5-2 g/d, complications are unusual. Sustained-release niacin is more hepatotoxic than immediate-release niacin but is better tolerated. ^[69] Flushing, itching, and rash are expected adverse effects that are less common with long-acting formulations. These symptoms are an annoyance but are not life threatening and may be minimized by starting at low doses and increasing slowly. Switching from immediate-release niacin to an equal dose of time-release preparation has been reported to cause severe hepatotoxicity. Niacinamide, also called vitamin B-3, has no lipid-lowering effects; nor does inositol hexanicotinate.

If niacin is prescribed for patients with type 2 diabetes, glucose control should be carefully monitored, modest increases in insulin resistance can occur. ^[70] In addition, because uncontrolled diabetes can cause hypertriglyceridemia, patients with diabetes mellitus should be treated aggressively to reduce the HbA1c level to less than 7%. Niacin is the best available agent to increase HDL cholesterol. It also lowers lipoprotein (a).

Omega acids

Omega-3 fatty acids are attractive because of their low risk of major adverse effects or interaction with other medications. At high doses (≥4 g/d), triglycerides are reduced. The triglyceride-lowering impact of fish oils is entirely dependent on the omega-3 content, and, therefore, the number of capsules required for a total dose of 4 g/d requires determining the content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per capsule. A recent study of nonprescription fish and krill oil capsules available in the United States as dietary supplements showed that the content of DHA ranges from 0.05 to 0.22 mg/g and of EPA from 0.08 to 0.45 mg/g. The labels of the most common fish oil supplement capsules in the United States claim to provide 180 mg of EPA and 120 mg of DHA per capsule. Therefore, a minimum dose of 4 g of omega-3 fatty acids per day may require at least 8-12 capsules. ^[71]

Low doses of EPA and DHA (750-1000 mg/d) that do not affect lipid levels have been demonstrated to lower the incidence of fatal coronary events, probably due primarily to its antiarrhythmic properties. ^[72]

However, the role of omega-3 fatty acid supplements in coronary heart disease (CHD) prevention is controversial, with conflicting results derived from large trials of the fatty acids. For example, a meta-analysis by Aung et al indicated that in high-risk patients, daily supplements of marine-derived omega-3 fatty acids produce no significant reduction in the rate of fatal or nonfatal CHD or other major vascular events. However, a 2017 scientific statement update from the American Heart Association declared it reasonable for omega-3 fatty acid supplementation to be used in patients with prior CHD or heart failure with reduced ejection fraction, while European guidelines state that more evidence is required before use of these supplements can be justified. ^{[73, 74]}

A retrospective study by Kim et al found that, using a baseline triglyceride level of 200-500 mg/dL, patients with hypertriglyceridemia who took omega-3 fatty acid experienced a greater reduction in triglyceride levels after 3 months than did those receiving statin monotherapy. However, the investigators found no significant difference in triglyceride decrease between those patients on omega-3 fatty acid monotherapy and those being administered a combination of omega-3 fatty acid and a statin. The study also found that at a baseline triglyceride level of 500 mg/dL or above, triglyceride reduction did not differ significantly between all the three groups. The study included 2071 patients. ^[75]

A retrospective, observational cohort study by Tatachar et al found that even a suboptimal dose of over-the-counter (OTC) fish oil supplement can significantly lower triglyceride levels. The investigators found that in patients who were prescribed 2 g/day of fish oil supplements, triglycerides were reduced by 29%. However, patients in the study who were prescribed fenofibrate or gemfibrozil achieved greater triglyceride reduction, 48.5% and 49.8%, respectively. ^[76]

Several prescription fish oil capsules have been approved by the FDA to treat triglyceride levels of more than 500 mg/dL. A report by Hilleman and Smer states that omega-3 fatty acid products available in prescription formulations have been found to significantly reduce triglycerides. In patients with baseline triglyceride levels of 500 mg/dL or greater taking 4 g/day of a prescription product, decreases compared with placebo ranged from 12.2% to 51.6%. Unlike the supplements, the prescription products are subject to FDA approval, and their safety and efficacy must be established prior to marketing. Currently, prescription capsules contain either a combination of EPA and DHA or EPA alone. ^[77] There is some concern regarding the use of DHA in patients with dyslipidemia, since high-dose omega-3 products containing DHA increase LDL cholesterol levels; the impact on HDL cholesterol levels varies.

Icosapent ethyl (Vascepa), an ultra-pure prescription omega fatty acid, contains an ethyl ester of EPA; capsules have no DHA component. Past studies suggest that highly purified EPA can reduce TG levels without raising LDL cholesterol. ^{[78, 79]}

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

Approval was largely based on the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial). The study involved statin-treated patients, all with a history of atherosclerosis or diabetes, in whom TG levels between 135 to just under 500 mg/dL and LDL levels between just over 40 to 100 mg/dL were found. Of 3146 US patients, the primary endpoint—cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina—was reached by 24.7% of those on placebo, compared with 18.2% of patients treated with icosapent ethyl, by median 4.9-year follow-up. ^[80]

Other examples of prescription products include Lovaza. A 1-g capsule contains at least 900 mg of ethyl esters of omega-3 fatty acids (~465 mg of EPA and 375 mg of DHA). Another prescription omega-3 fatty acid product, Omtryg, was approved by the FDA in 2014 and contains EPA and DHA in the same amounts as Lovaza. ^[81]

The Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension (MARINE) trial randomized 229 diet-stable patients with fasting TG levels from 500-2000 mg/dL (with or without background statin therapy) to icosapent 4 g/day, icosapent 2 g/day, or placebo. Results showed that icosapent significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels. Icosapent 4 g/day reduced the placebo-corrected TG levels by 33.1% (n = 76; P< 0.0001) and icosapent 2 g/day by 19.7% (n = 73; P = 0.0051). For a baseline TG level >750 mg/dL, icosapent 4 g/day reduced the placebo-corrected TG levels by 45.4% (n = 28; P = 0.0001) and icosapent 2 g/day by 32.9% (n = 28; P = 0.0016). ^[82]

An omega-3 carboxylic acid product (Epanova) was approved by the FDA in May 2014. ^[83] It is the first prescription omega-3 product in free fatty acid form. It is indicated as an adjunct to diet to reduce triglyceride levels in adults with severe hypertriglyceridemia (TGs ≥500 mg/dL).

Approval was based on data from the Phase III EVOLVE (EpanoVa fOr Lowering Very High triglyceridEs) trial. The trial showed a significant decrease in non-HCL-C, ratio of total cholesterol to HDL-C, VLDLs, Apo-C, phospholipase A2, and arachidonic acid with omega-3 carboxylic acids over a 12-week period compared with olive oil in patients with TGs ≥500 mg/dL. ^[84]

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

Note that although fatty fish (eg, salmon, tuna, trout, mackerel, sardines) are good sources of omega-3 fatty acids, they also usually contain high concentrations of mercury and polychlorinated biphenyls (PCBs). Fish oil supplements that can be obtained without a prescription have negligible amounts of mercury. [86] The advantage of prescription fish oil is that fewer capsules are necessary to achieve a therapeutic dose, facilitating adherence. Additionally, the prescription products have been thoroughly tested in phase 3 trials to show safety and efficacy (particularly for lowering very high TGs). ^{[82, 84]} [77, 79] Consistency of potency is ensured with the prescription fish oil products.

HMG-CoA reductase inhibitors (statins)

For patients with mixed hyperlipidemias (elevations of both LDL cholesterol and triglycerides), a moderate dose of a hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor may be appropriate if the amount of triglyceride lowering necessary is only about 20%. Maximum doses of the strongest statins, atorvastatin, simvastatin, and rosuvastatin, lower triglycerides approximately 40%, but such doses are not appropriate first-line therapy unless triglycerides are less than 500 mg/dL and LDL-C is elevated. ^{[46, 85]}

It is recommended that patients intolerant to one statin (eg, owing to myalgias) try the other statins before excluding the entire class, particularly in secondary prevention of dyslipidemias. ^[45] If the patients cannot take statins other agents suitable for management of mixed dyslipidemia may be tried, either alone or in combination therapy, including niacin, fibric acids, and ezetimibe. ^[45] Bile acid sequestrants can raise triglycerides and are contraindicated in patients with very high triglycerides. ^[60]

Note the following ^[45] :

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

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

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

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

A study by Jun et al found that treatment with omega-3 fatty acid and atorvastatin more effectively lowered triglyceride levels in patients than did atorvastatin therapy alone. The report involved adults with fasting triglyceride levels of 200 mg/dL or above but less than 500 mg/dL, and low-density lipoprotein (LDL) cholesterol levels of below 110 mg/dL. Patients underwent 8 weeks of daily treatment consisting of either 4000 mg of omega-3 fatty acid and atorvastatin calcium 20 mg or atorvastatin calcium 20 mg plus placebo. The report found that 62.9% of individuals in the omega-3/atorvastatin group achieved triglyceride levels of less than 200 mg/dL, compared with 22.3% of the monotherapy group. ^[86]

 

Other agents

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

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

Ezetimibe (Zetia) is a selective cholesterol-absorption inhibitor that has been used as secondary therapy in the management of dyslipidemia, such as in the following clinical situations ^[45] :

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

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

The Adult Treatment Panel guidelines (ATP III) were published in 2001 and reclassified serum triglycerides (TGs), as shown in Table 2 (below). An update to the ATP III guidelines (ATP IV) was published in 2013. ^[87]

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

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

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

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

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

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

It is recommended that individuals consume less than 20% of calories as fat, with saturated fat reduced to less than 7% of calories, which may be achieved by avoiding trans fats, limiting dietary cholesterol to less than 200 mg/d. ^[45] Restrict refined carbohydrates, particularly sugar and liquid calories. In addition, lowering low-density lipoprotein (LDL) may be enhanced by adding dietary options such as 2 g/d of plant stanols/sterols and at least 5-10 g/d of viscous soluble fiber to the diet. ^[45]

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

Total fat intake

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

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

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

Carbohydrate intake

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

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

Omega-3 (N-3) fatty acids

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

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

Exercise

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

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

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

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

• Reduced weight

• Decreased insulin resistance

• Decreased blood pressure

• Improved cardiovascular conditioning

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

Women with elevated triglycerides before conception may develop severe hypertriglyceridemia, with triglyceride levels well above 1000 mg/dL, and the concomitant risk of pancreatitis. These women should be counseled regarding diet, exercise, and weight management before becoming pregnant and must be monitored closely during their pregnancies. ^[88] All pregnancies require occasional triglyceride monitoring. Simple inspection to rule out lipemic serum is all that is necessary.

The use of lipid-lowering drugs in pregnant patients and pediatric patients has not been thoroughly investigated. Thus, most of the medications to treat hypertriglyceridemia are contraindicated during pregnancy, although treatment with gemfibrozil in a patient with severe hypertriglyceridemia and pancreatitis has been reported. ^[88] Omega-3 fatty acids may be a more acceptable intervention, but the safety of high-dose N-3 fatty acids has not been proven.

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

Primary and secondary prevention

Patients with hypertriglyceridemia, particularly if the high-density lipoprotein (HDL) level is low, are at risk for cardiovascular events. For primary prevention, it is recommended that men aged 35 and older—and those aged 20-35 if they are at increased risk—are screened for coronary heart disease (CHD) with a fasting lipid profile; screening for women is recommended only for those at increased risk for CHD. ^{[49, 38]} For patients who were screened with a nonfasting due to patient convenience, follow-up on abnormal nonfasting lipid levels with a fasting lipid profile. Screening should be repeated every 5 years in patients with normal lipid levels. ^[49]

In secondary prevention, all patients with CHD, other atherosclerotic cardiovascular disease (ASCVD), diabetes mellitus, or a Framingham 10-year risk of greater than 20% should be screened with a full lipid panel. ^[49] Evaluate the patient’s risk for cardiovascular events. Patients considered at high risk include those who have CHD without major risk factors or other risks associated with very high risk.

Patients considered at very high risk include individuals with CHD or other atherosclerotic vascular disease as well as 1 or more of the following: major risk factors (eg, diabetes, hypertension, metabolic syndrome, active cigarette smoking) or acute coronary syndrome. ^{[49, 51]} Thus, these patients should be treated not only for their lipid disorder but also for other modifiable cardiovascular risk factors, such as hypertension, diabetes, smoking, sedentary lifestyle, and obesity. ^{[89, 90]}

The Endocrine Society’s 2012 guidelines in evaluating and treating hypertriglyceridemia included screening adults for this condition as part of a lipid panel at least at 5-year intervals. ^[46] For pediatric patients with dyslipidemia, the American Association of Clinical Endocrinologists (AACE) recommends early diagnosis and management to reduce LDL levels, thereby reducing the risk for cardiovascular events in adulthood. ^[72]

Diet and exercise

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

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

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

A specialist in lipid disorders may be helpful in treating the hyperlipidemia that develops in patients, which can be very severe and difficult to treat, often requiring multiple lipid-lowering agents.

In addition, patients should receive nutrition counseling and should be advised to restrict calories if they are overweight. These individuals also should reduce saturated and trans fats and cholesterol intake.

Follow up with patients who are on diet and lipid-lowering therapy. Periodically monitor their blood cholesterol, triglyceride, and lipoprotein levels. If patients are taking lipid-lowering medications, obtain periodic liver function tests.

If patients are taking fibric acid derivatives or statins, advise them to report unexplained generalized muscle pain, tenderness, or weakness. Perform creatinine kinase determinations in these individuals.

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