DHA and EPA Have Differential Effects on LDL-Cholesterol

[Guest guest]

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<http://www.medscape.com/viewcollection/32023>,

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 son* (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 * (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,

GlaxoKline) is currently approved for the treatment of elevated

triglyceride levels, but its use often results in an increase in LDL

cholesterol. 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 . " 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

Blumenthal *(s 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 , 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 son,

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.*

*www.medscape.com

*

--

Ortiz, MS, RD

*The FRUGAL Dietitian* <http://www.thefrugaldietitian.com>

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