DHA and EPA Have Differential Effects on LDL-Cholesterol

May 24, 2011

May 22, 2011 (New York, New York) — New data presented this week provide clues as to why eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)--both components of omega-3 fatty acids--have differential effects on LDL cholesterol.

Presenting the results of the laboratory study here at the National Lipid Association (NLA) 2011 Scientific Sessions, senior investigator Dr Preston Mason (Brigham and Women's Hospital, Boston, MA) said that EPA is an inhibitor of lipid oxidation at normal and elevated cholesterol levels in the presence and absence of DHA, while DHA seems to have no real effect on lipid peroxidation. This trial was one of a number of studies that attempted to address the clinical question as to why LDL-cholesterol levels increase in patients treated with the triglyceride-lowering omega-3 fatty acids. In his trial, Mason et al compared the effects of EPA and DHA--alone or in combination with statins--on lipid peroxidation in polyunsaturated fatty-acid– and cholesterol-enriched vesicles.

"We know that EPA and DHA have different effects on LDL-cholesterol levels," Mason told heartwire . "One of the things that affect LDL clearance is its oxidative state. Oxidized LDL is not cleared. One of the concepts is that EPA might preferentially prevent LDL oxidation, so even though it's not affecting its synthesis, it would help its clearance."

EPA inhibited lipid hydroperoxide (LOOH) formation by 42% and 54% in vesicles with normal and elevated cholesterol levels, respectively. DHA, on the other hand, inhibited LOOH by 28% in vesicles with elevated cholesterol levels only. The separate effects of EPA, DHA, and EPA/DHA were enhanced when used in combination with statin therapy, including atorvastatin, atorvastatin metabolite, simvastatin, or rosuvastatin. The most potent antioxidant capacity was observed with EPA and the active metabolite of atorvastatin.

"Statins are also lipophilic, in general," Mason told heartwire , "and one statin, in particular atorvastatin and its active metabolite, is known to be a very good antioxidant. We've published that separately in the past. This is where we saw the best effect, although we did see excellent effects with all the statins. The concept is that a lot of people are also taking a statin so there might be some opportunity for synergy."

Other Analyses Looking at Similar Questions

In another analysis, Dr Terry Jacobson (Emory University School of Medicine, Atlanta, GA) and colleagues reviewed 21 clinical trials that systematically evaluated the effects of EPA and DHA as monotherapy on LDL-cholesterol, HDL-cholesterol, triglyceride, and non–HDL-cholesterol levels.

In studies that directly compared DHA and EPA, mean placebo-corrected triglyceride levels decreased by 22.4% and 15.6%, respectively. In head-to-head comparisons, DHA increased LDL cholesterol by 2.6% whereas EPA decreased LDL cholesterol by 0.7%. In trials comparing each agent alone, 10 of the 14 monotherapy trials with DHA showed increases in LDL cholesterol ranging from 5.4% to 16.0% vs control, while none of the EPA trials showed any increase. The changes in LDL-cholesterol levels significantly correlated with baseline triglyceride levels for DHA-treated patients, but this was not observed for patients treated with EPA, the group reported.

Speaking with heartwire , Dr William Harris (University of South Dakota, Sioux Falls), who was not involved in the research, said the issue is clinically important because numerous studies have shown that long-chain omega-3 fatty acids lower triglycerides, but randomized, clinical trials with compounds containing EPA and DHA have also shown increases in LDL-cholesterol levels. Lovaza (omega-3 fatty acid ethyl esters, GlaxoSmithKline) is currently approved for the treatment of elevated triglyceride levels, but its use often results in an increase in LDL cholesterol. Harris noted that other drugs, including fibrates, have the potential to increase LDL cholesterol.

"People have been trying to figure whether it's one fatty acid or the other causing the increase in LDL cholesterol," said Harris. "In the context of where we usually see it, it's in patients with very high triglyceride levels, but their LDL-cholesterol levels can often be abnormally low to start with, so it goes up to normal. It often looks like a large relative increase, but nevertheless, I'm not too concerned about it."

Others have noted that most patients treated with omega-3 fatty acids have mixed dyslipidemia and most likely would be treated with a statin anyway. Dr Roger Blumenthal (Johns Hopkins University School of Medicine, Baltimore, MD) previously said that while omega-3 fatty acids can raise LDL cholesterol, they do not affect apolipoprotein B levels, a better measure of the atherogenic particles. Like Harris, he previously said he is not clinically concerned about the increase in LDL cholesterol with omega-3 fatty acids.

In addition to the laboratory and clinical analyses by Mason and Jacobson, results of the MARINE trial, a study of a semisynthetic derivative of omega-3 fatty acids (AMR101, Amarin), were also presented in abstract form at the NLA meeting. The trial, as previously reported by heartwire , is testing whether an isolated semisynthetic EPA lowers triglycerides without a concomitant increase in LDL cholesterol. The results reported here were similar to those presented to the media and financial analysts in November 2010, with Dr Harold Bays (Louisville Metabolic and Atherosclerosis Research Center, KY) and colleagues reporting that the 2-g and 4-g doses of AMR101 reduced triglyceride levels by 20% and 33%, respectively, without a significant increase in LDL-cholesterol levels.

The MARINE trial is sponsored by Amarin.