Combination Therapy with Prescription Omega-3-acid Ethyl Esters and Statin Improves Non-HDL-C More Effectively than Statin Alone

Željko Reiner


Clin Lipidology. 2010;5(3):325-328. 

In This Article


It is well known that omega-3 fatty acids decrease high levels of triglycerides and atherogenic remnant lipoproteins associated with atherogenic dyslipidemia.[6,7] Doses of 2–4 g/day reduce triglycerides levels by 25–30%.[8] This is usually accompanied by a moderate increase in LDL-C and a minor positive or no influence on HDL-C.[8,9] However, a very moderate decrease of total and LDL-C had already also been described several years ago.[10] Therefore, adding the prescription forms of omega-3 fatty acids to a statin, as investigated in this paper, can be appropriate for improving achievement of lipid targets, particularly in patients with combined dyslipidemia. In these patients, non-HDL-C is of particular importance.

In a study published almost a decade ago, therapy with a combination of prescription omega-3 fatty acids 4 g/day plus simvastatin (10–40 mg/day) for up to 1 year led to a stronger reduction of triglyceride concentrations (20–30%) but also to a reduction of VLDL-C by 30–40% without adverse effects on LDL- and HDL-C in coronary heart disease patients with hypertriglyceridemia.[11] In the more recently published Combination of Prescription Omega-3 with Simvastatin (COMBOS) study, treatment with 4 g/day of prescription ethyl esters of omega-3 fatty acids, in other words, the same type of drug as used in the discussed study, administered in combination with simvastatin, also resulted in significantly greater reductions of triglycerides (by 29.5 vs 6.3%) and VLDL-C (27.5 vs 7.2%) and a small but significant increase in HDL-C (3.4% vs decrease by 1.2%) when compared with treatment with simvastatin alone.[12] In another study, it has been demonstrated that the increase in HDL-C could be attributed to a decrease in both catabolism and production of apolipoproteins AI and AII, the main apolipoproteins of HDL particles, induced by omega-3 fatty acids and not by atorvastatin.[13] Similar results were obtained by adding the only ethyl ester of eicosapentaenoic acid to statins.[14] Accordingly, the results of the discussed study fit well with the results of all the other studies published until now as they show a significant improvement in relevant lipid parameters when a combination of prescription omega-3 fatty acid ethyl esters with a statin is applied. However, they also provide new data on the important issue of influencing non-HDL-C, which was not dealt with by other studies so far.

The addition of prescription omega-3 fatty acid ethyl esters to simvastatin 40 mg/day also increases the size of LDL particles, thus changing their atherogenicity in a positive way since it is well known that small, dense LDL particles are particularly atherogenic.[15] Adding omega-3 fatty acids 3.6 g/day to pravastatin 20 mg/day plus micronized fenofibrate 200 mg/day in a triple combination further decreased not only triglycerides concentrations but homocysteine as well (by 29%) and it also decreased microalbuminuria (by 24%) in patients with diabetic dyslipidemia.[16]

All these data suggest that combination treatment with prescription omega-3 fatty acid ethyl esters and statins can be particularly useful in patients with diabetes. Namely, the lifelong CVD risk in patients with diabetes is as high as in nondiabetic individuals with previous CVD, particularly if they have some other risk factors or have microalbuminuria. It is estimated that diabetes is associated with two- to four-fold higher risk of CVD.[17] Therefore, early and intensive prevention using lipid-lowering drugs, particularly in patients with Type 2 diabetes, is of utmost importance.[18] Hence, the discussed combination of prescription omega-3 fatty acid ethyl esters and statins might be one of the solutions for these patients. This might also help in a much broader perspective to improve CVD prevention, which is public health priority number one in many countries of the world.[19]

No significant interactions of any statin with omega-3 fatty acids have been described and the combination of omega-3 fatty acids and statins in many studies, as in the discussed study, has been shown to be safe and well tolerated.

Similarly to all the other lipid-lowering treatments except for statins, there are no firm data on cardiovascular outcomes for such a combination. However, it has to be mentioned that the GISSI Preventione Trial, a large prospective study, demonstrated that administering omega-3 fatty acid ethyl esters l g/day significantly reduces the all-cause mortality in postmyocardial infarction patients and the risk for sudden death caused by cardiac arrhythmias.[20] Nonetheless, this cannot be attributed to their effect in improving dyslipidemia and/or decreasing non-HDL-C but predominantly to their proven antiarrhytmic effects. Potential mechanisms by which omega-3 fatty acids may reduce risk for CVD also include anti-thrombotic and anti-inflammatory effects, improvement of vascular endothelial cell function, reduction of expression of endothelial cells adhesion molecules, inhibition of smooth muscle cells migration and proliferation and very moderate reduction of blood pressure in hypertensive subjects.[7]

To date, only one study was published investigating the effects of combination treatment with a omega-3 fatty acid plus statins on clinical cardiovascular events. In this study, eicosapentaenoic acid combined with low-dose pravastastin or simvastatin compared with statin therapy alone reduced major coronary events without altering rates of sudden cardiac death. These effects were achieved without any significant changes in total, LDL- or HDL-C and just a small decrease in triglycerides, suggesting that eicosapentaenoic acid can lower CVD risk by mechanisms other than LDL-C lowering.[21] In a continuation of this study, the addition of eicosapentaenoic acid to pravastatin or simvastatin reduced also the incidence of coronary heart disease events in high-risk patients with metabolic syndrome and atherogenic dyslipidemia characterized by high triglycerides and low HDL-C.[22]

From the results analyzed in this article, it could be hypothesized that since some patients with dyslipidemia, particularly those with established CVD or diabetes, have therapeutic needs that cannot be met by a simple monotherapy with a statin, achieving target values for non-HDL-C in these patients using a therapeutic approach that incorporates the combination of prescription of omega-3 fatty acid ethyl esters and a statin (precisely atorvastatin), could be used. Such a combination therapy might increase the likelihood of therapeutic success in these patients and the meeting of non-HDL-C goals according to the guidelines.


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