Hypertriglyceridemia Medication

Three classes of medications are appropriate for the management of major triglyceride elevations: fibric acid derivatives, niacin, and omega-3 fatty acids. High doses of a strong statin (simvastatin, atorvastatin, rosuvastatin) also lower triglycerides, by as much as approximately 50%.

Currently, 4 fibrates are used clinically; 2 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 US Food and Drug Administration (FDA). A new fenofibrate formulation known as fenofibric acid (Trilipix) has been approved by the FDA with a specific indication for use with a statin in patients with mixed dyslipidemia.^[11] No head-to-head trials have been performed, and the older fenofibrate formulation also appears to be safe when combined with a statin. When combined with a statin, gemfibrozil is not as safe as fenofibrate, and if at all possible, fenofibrate should be used in patients treated with a statin.^[12]

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).^[13] The oldest fibrate, clofibrate, is no longer used, because of increased morbidity and mortality rates in large, placebo-controlled studies (a World Health Organization [WHO] study and the Coronary Drug Project [a randomized, placebo-controlled trial of secondary prevention in men]). Moreover, tumorigenicity has been demonstrated in rodents.

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.^[14] Moreover, the kidney is the primary route for elimination of most fibrates, and dose reductions are indicated for reduced creatinine clearance. Gemfibrozil's half-life is independent of renal function, and it is the drug of choice for patients with chronic kidney disease.^[15]

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 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/day; 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) has been approved by the FDA for use with a statin in mixed dyslipidemia. The older fenofibrate formulation also appears to be safe when combined with a statin, whereas gemfibrozil does not.

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

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.^[16] 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.

Omega-3 fatty acids are attractive because of their low risk of major adverse effects or interaction with other medications. At very high doses (4 or more 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 (EPA) and docosahexaenoic (DHA) per capsule. Over the counter fish oil capsules vary in concentration from approximately 0.4 g to 1.0 g of EPA +DHA per capsule. Therefore, a minimum dose of 4 g of omega-3 fatty acids per day may require 8 or more capsules.^[17]

A prescription fish oil capsule was approved by the FDA for triglyceride levels greater than 400 mg/dL. Originally called Omacor, it was renamed Lovaza in 2007. One 1-g capsule contains approximately 465 mg of EPA and 375 mg of DHA. High-dose fish oil increases LDL-C levels; the impact on HDL-c levels is variable. The cost is substantially higher than that of over the counter fish oil and is usually not covered by insurance companies.

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.

For patients with mixed hyperlipidemias (elevations of both LDL-c 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, rosuvastatin, or cerivastatin (recalled from US market 8/8/01), lower triglycerides approximately 40%, but such doses are not appropriate unless the LDL-c is at least 30% above the desired level.

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.

Class Summary

Fibric acid derivatives lower triglycerides approximately 40% and increase HDL-c about 20%. Fenofibrate is reported to lower LDL-c levels more reliably than either clofibrate or gemfibrozil, but none of the drugs in this class should be used for isolated LDL-c elevations. The fibrates are commonly used to treat hyperlipidemias types IV (high VLDL) and V (high VLDL and chylomicrons), as well as type III dysbetalipoproteinemia (IDL or VLDL remnant disease).

They can also be used to treat type IIb mixed hyperlipidemia if used in conjunction with an LDL-lowering medication such as a resin.

Gemfibrozil (Lopid)

Lowers TGs and raises HDL-c. LDL-c is usually is unaffected but may increase if initially low or decrease if initially high. Available in generic formulation, most cost-effective fibrate at this time. FDA-approved indications are for type IV and V hyperlipidemia, ie, elevations in VLDL only or both VLDL and chylomicrons.

Fenofibrate (Tricor)

Similar to other fibric acid derivatives in TG-lowering and HDL-raising effects. Differs in that modest LDL-lowering can be expected with greater frequency than with gemfibrozil. The FDA-approved indications are for hypertriglyceridemia and hypercholesterolemia, but this difference does not qualify fenofibrate for treatment of isolated LDL-c elevations. Taken once a day. May increase compliance.

Class Summary

At least 1.5 g/d decreases triglycerides by as much as 50%. HDL-c increases of 30% or more can be achieved, particularly at higher doses. LDL-c will decrease by 15-25%. Whether purchased OTC or by prescription, niacin costs less than any other lipid-lowering medication. For reasons not clearly understood, changing brands during treatment is more likely to cause hepatotoxicity, occurring more so with time-release than immediate-release niacin. Insulin resistance may increase; nevertheless, niacin is a useful medication in patients with type 2 diabetes.^[18]

Niacin (Slo-Niacin, Niaspan)

More hepatotoxic than immediate-release niacin. Patients strongly advised against switching formulations or brands during treatment. Both OTC and prescription formulas are available. OTC brands cost less, but only reliable manufacturers should be recommended. Slo-Niacin is OTC formulation available in 250-mg, 500-mg, and 750-mg tablets. Sundown is another manufacturer. Prescription ER niacin (Niaspan) is available in 500-mg, 750 mg, and 1000-mg tabs.

Niacin (Niacor and Nicolar)

Less hepatotoxic than SR niacin but less well tolerated by patients due to prostaglandin-mediated flushing, itching, and rash. Therapy started at a low dose, such as 100 mg tid pc, and increased gradually over several weeks will allow some patients to accommodate adverse effects. At high doses (4-6 g/d), it is less hepatotoxic than SR niacin. Changing formulation at high dose may increase risk of hepatotoxicity. Niacor and Nicolar are prescription formulations that, while more expensive than OTC brands, may have an advantage in making it less likely that the patient switches brands.

Class Summary

These agents reduce triglyceride biosynthesis.^[17]

Omega-3-acid ethyl esters (Lovaza)

First prescription omega-3-acid. Each 1-g cap contains at least 900 mg of omega-3-acid ethyl esters, predominantly a combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Theorized to reduce triglyceride synthesis in the liver. EPA and DHA are poor enzyme substrates for triglyceride synthesis in the liver, and they inhibit esterification of other fatty acids. Potential mechanisms of action include acyl CoA:1,2-diacylglycerol acyltransferase inhibition, increased hepatic mitochondrial and peroxisomal beta-oxidation, decreased hepatic lipogenesis, and increased plasma lipoprotein lipase activity.

Clinical trials show significant reduction in non–high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol, very low-density lipoprotein cholesterol (VLDL-C), and apolipoprotein B levels from baseline when combined with simvastatin compared with simvastatin and placebo. Monotherapy with omega-3-acid ethyl esters reduce median triglyceride, VLDL-C, and non–HDL-C levels from baseline.

Indicated as adjunctive treatment to diet to reduce very high triglyceride levels (ie, >500 mg/dL).