Hypertriglyceridemia is associated with an increased risk of cardiovascular events and acute pancreatitis. Along with lowering low-density lipoprotein cholesterol levels and raising high-density lipoprotein cholesterol levels, lowering triglyceride levels in high-risk patients (e.g., those with cardiovascular disease or diabetes) has been associated with decreased cardiovascular morbidity and mortality. Although the management of mixed dyslipidemia is controversial, treatment should focus primarily on lowering low-density lipoprotein cholesterol levels. Secondary goals should include lowering non–high-density lipoprotein cholesterol levels (calculated by subtracting high-density lipoprotein cholesterol from total cholesterol). If serum triglyceride levels are high, lowering these levels can be effective at reaching non–high-density lipoprotein cholesterol goals. Initially, patients with hypertriglyceridemia should be counseled about therapeutic lifestyle changes (e.g., healthy diet, regular exercise, tobacco-use cessation). Patients also should be screened for metabolic syndrome and other acquired or secondary causes. Patients with borderline-high serum triglyceride levels (i.e., 150 to 199 mg per dL [1.70 to 2.25 mmol per L]) and high serum triglyceride levels (i.e., 200 to 499 mg per dL [2.26 to 5.64 mmol per L]) require an overall cardiac risk assessment. Treatment of very high triglyceride levels (i.e., 500 mg per dL [5.65 mmol per L] or higher) is aimed at reducing the risk of acute pancreatitis. Statins, fibrates, niacin, and fish oil (alone or in various combinations) are effective when pharmacotherapy is indicated.

STATINS

The primary target of lipid therapy is to reach low-density lipoprotein cholesterol (LDL-C) goals. Statins have an important role in reducing the risk of cardiovascular events in patients with elevated LDL-C levels, particularly in high-risk patients (e.g., those with cardiovascular disease or diabetes). If hyper-triglyceridemia is a comorbidity, statins can lower triglyceride levels by 20 to 40 percent.7

FIBRATES

Fibrates can markedly lower triglyceride levels (40 to 60 percent) and modestly raise HDL-C levels (15 to 25 percent).In patients with cardiovascular disease and moderately elevated triglyceride levels and low HDL-C levels, fibrates have been shown to decrease the risk of cardiovascular events (secondary prevention). Fibrate therapy also has been shown to decrease angiographic progression of coronary heart disease in patients with type 2 diabetes.

Because data show decreased cardiovascular mortality rates with triglyceride reduction (more than that achieved with LDL-C reduction alone),there is increasing interest in fibrate use in patients with hypertriglyceridemia and in combination fibrate/statin therapy in patients with mixed dyslipidemia. However, despite several large studies, no fibrate has been shown to decrease all-cause mortality rates, and some trials have shown an increase in all-cause mortality rates. A recent primary prevention trial of fenofibrate (Tricor), which included 9,795 patients with type 2 diabetes, did not significantly decrease the primary end points of coronary events or all-cause mortality but decreased the secondary end point of total cardiovascular events (i.e., coronary heart disease events, stroke, or revascularization).

Combination therapy raises safety concerns. All statins (especially at higher doses) increase the risk of rhabdomyolysis; this risk may be compounded by fibrate use. Cerivastatin (Baycol) was withdrawn from the market because of reports of fatal rhabdomyolysis, often in patients also taking gem-fibrozil (Lopid). An increased risk also has been shown with rosuvastatin (Crestor). When combined with statins, gemfibrozil may increase serum statin levels by inhibiting statin metabolism.

Compared with gemfibrozil/statin therapy, fenofibrate/statin therapy has a lower incidence and reported rate of rhabdomyolysis and may be safer. However, long-term safety and outcome data for fibrate/statin combinations are lacking, and combination therapy should be used with caution. Patients should receive the lowest possible statin dosage, be monitored closely for side effects (e.g., muscle pain, brown urine), and be given the opportunity for proper informed consent.

NIACIN

Niacin lowers triglyceride levels by 30 to 50 percent, raises HDL-C levels by 20 to 30 percent, and lowers LDL-C levels by 5 to 25 percent. Niacin is not as potent as fibrates for lowering triglyceride levels but is more effective at raising HDL-C levels.

Studies evaluating niacin’s effect on cardiovascular and all-cause mortality are limited. The largest study (the Coronary Drug Project) revealed that patients treated with niacin had a modest decrease in nonfatal myocardial infarction (8.9 versus 12.2 percent) but no difference in all-cause mortality after five years. A nine-year, nonrandomized, nonblinded follow-up study to the Coronary Drug Project revealed a decrease in all-cause mortality rates in the original cohort treated with niacin (52 versus 58 percent;P = .004; number needed to treat = 17 patients for 15 years).

Concerns over worsening glycemic control may limit the use of niacin in patients with diabetes. However, a study of patients taking lipid-lowering doses of niacin demonstrated that niacin is beneficial without significantly affecting glycemic control. A consensus report recommended that niacin therapy be considered for high-risk patients with elevated triglyceride and low HDL-C levels, even with coexistent diabetes.

The use of niacin is limited because of the risk of vasomotor side effects and elevation of liver enzyme levels. Flushing and hepatotoxicity can be minimized by starting with low doses and slowly titrating upward using extended-release formulations and by concurrent use of aspirin taken 30 minutes before niacin. Low-dose niacin combined with a statin has been associated with a significant decrease in cardiovascular events, however, this combination has not been compared with either agent alone.

FISH OIL

Fish oil contains high amounts of the essential fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); these acids also are known as omega-3 fatty acids. A systematic review showed that fish oil is effective at lowering triglyceride levels. Fish oil with 2 to 4 g of total EPA/DHA daily can lower triglyceride levels by 30 to 50 percent.7, Randomized controlled trials have shown that, along with statins, fish oil is the only other lipid-lowering agent that can decrease all-cause mortality in patients with known heart disease.1

The GISSI-Prevenzione trial showed a 15 percent reduction in all-cause mortality in patients with a recent myocardial infarction who were taking fish oil. This reduction was in addition to optimal management with lipid-lowering therapy, antiplatelet agents, beta blockers, and angiotensin-converting enzyme inhibitors. These results must be interpreted with caution because a systematic review that combined data from primary and secondary prevention studies showed no mortality benefit. If there are benefits to using fish oil in patients with heart disease, they are most likely multifactorial and go beyond triglyceride effects alone.

Studies of fish oil/statin combinations demonstrate an additional 30 percent triglyceride reduction. Side effects are minimal and include a fishy aftertaste and mild gastrointestinal upset. Bleeding effects are theoretical and have not been shown to be clinically significant even in large doses. Omacor, a newly approved prescription medication for hypertriglyceridemia, is a highly concentrated form of omega-3-acid ethyl esters and is available in 1-g capsules (840 mg EPA/DHA). Over-the-counter capsules are readily available, but physicians should make certain that patients receive 2 to 4 g of total EPA/DHA per day. Most over-the-counter preparations only contain 300 mg of EPA/DHA per capsule.