Omega-3-Acid Ethyl Esters Capsules (Omacor)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA has approved a new lipid regulating agent—the ethyl esters of omega-3 fatty acids for the treatment of high triglyceride levels. Marketed under the trade name "Omacor," the drug is a combination of eicosapentaenoic acid and docosahexaenoic acid. The Ross Division of Abbott Laboratories will market Omacor^TM.

Indications

Omega-3-acid ethyl esters (OAEE) are approved as an adjunct to diet to reduce very high (500 mg/dL) triglyceride levels in adult patients. Diseases and/or drugs that may be contributory to hypertriglyceridemia should be evaluated and adequately treated.¹

Dosage

The daily dose of OAEE is 4 g per day taken as a single 4 g dose or 2 divided 2-g doses. In clinical trials OAEE was taken with meal(s).¹ Each 1-gram capsule contains approximately 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid as ethyl esters (a total of at least 900 mg).

Potential Advantages

OAEE has been reported to reduce triglyceride levels by a median value of 44.9% and a difference of 51.6% compared to placebo. In addition high density lipoprotein cholesterol (HDL-C) was increased by a median value of 9.1%, non-HDL-C was reduced by 13.8%, and very low-density lipoprotein cholesterol (VLDL-C) was reduced by 41.7%.¹ Drug interaction involving CYP isoenzymes are not expected with OAEE.

Potential Disadvantages

OAEE may increase LDL-C levels and non-HDL-C in some patients.^1,2 An increase in LDL-C of 44.5% has been reported. Periodic monitoring of LDL-cholesterol is recommended.¹ Short-term increases in fasting glucose levels have been reported.³ However no alteration in glycemic parameters were detected at 6 months at dose of 2 g per day in a large (n = 935) study that included patients with type 2 diabetes and glucose intolerance.⁴ Adverse events associated with OAEE compared to placebo were flu symptoms (3.5% vs 1.3%), infection (4.4% vs 2.2%), eructation (4.9% vs 2.2%), and taste perversion (2.7% vs 0%).¹

Comments

OAEE appears to be effective in lowering high triglyceride levels. Its approval was based on 2 randomized, placebo-controlled, double-blind studies in 84 adults.¹ In 10 studies cited in a systemic review, 5 involving Omacor, omega-3 fatty acid at doses 3 g or higher showed mean reduction in triglycerides of 29%, VLDL of 30.2%, and a 10% increase in HDL-C although the authors cited methological flaws in these studies.² Only 3 of 10 studies found significant increases in LDL-C. The mechanism(s) of action of OAEE is/are not clear. Inhibition of acylCoA:1,2-diacylglycerol acyltranferase, increased peroxisomal -oxidation in the liver, and inhibition of esterification of other fatty acids has been proposed.¹ The addition of OAEE (4g daily) to patients (n = 59) with coronary heart disease and on simvastatin therapy resulted in additional 20-30% reduction in triglycerides (mean baseline of 406 mg/dL) with no adverse effect on LDL-cholesterol.⁵ In another small study (n = 28), OAEE (4 g/d) was found have a similar reduction in triglyceride levels to gemfibrozil (1200 mg/d).⁶ In addition reduction in VLDL and increase in HDL-C and LDL-C were also similar. Increase in LDL-C was due to increase in cholesterol contents in the more buoyant LDL subfractions compared to the more dense subfractions. However, OAEE appears to increase the susceptibility of LDL-C to oxidative modification in vitro compared to gemfibrozil.

The clinical relevance of this observation in not known. Adverse effects appear to be minimal. The cost of Omacor was not available at the time of this review.

Clinical Implications

Epidemiological evidence has suggested cardiovascular benefit of omega-3-acids.^7,8 However, randomized controlled trials are less convincing.⁹ Omega-3-acid supplements were considered food supplements prior to the approval of Omacor. This concentrated preparation now provides an alternative to fibrates or niacin in the treatment of high triglycerides particularly those that cannot tolerate these agents or due to adverse events or drug-drug interactions. It may also be a possible add on to statin therapy as low HDL-cholesterol and high triglycerides may modulate the capacity of statins to decrease cardiovascular risk in primary and secondary prevention.¹⁰

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.

References

1. Omacor Product Information. Reliant Pharmaceuticals, Inc. November 2004.

2. Lewis A, et al. J Am Acad Nur Pract. 2004;16(9):384-395.

3. Woodman RJ, et al. Am J Clin Nutr. 2002;76(5): 1007-1015.

4. Sirtori CR, et al. Atherosclerosis. 1998;137(2):419-427.

5. Durrington PN, et al. Heart. 2001;85:544-548.

6. Stalenhoef AF, et al. Atherosclerosis. 2000;153(1): 129-138.

7. Holub DJ, Holub BJ. Mol Cell Biochem. 2004;263: 217-225.

8. Siddiqui RA, et al. Mini Rev Med Chem. 2004;4:859-871.

9. Hooper L, et al. Cochrane Database Syst Rev. 2004; Oct 18;(4):CD003177.

10. Fruchart JC, Duriez P. Curr Opin Lipidol. 2002;13: 605-616.