Prescription omega-3 fatty acid medication reduces triglyceride levels by 20-30% among the majority of people who require treatment for high triglyceride levels, according to a science advisory from the American Heart Association.
“From our review of the evidence from 17 randomized, controlled clinical trials on high triglyceride levels, we concluded that treatment with 4 grams daily of any of the available prescription choices is effective and can be used safely in conjunction with statin medicines that lower cholesterol,” said Ann Skulas-Ray, Ph.D., an author of the new science advisory published in the American Heart Association journal Circulation.
There are two prescription omega-3 fatty acid medications available.
One combines two types of fatty acids, EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid).
The other medication provides EPA only.
Since there have been no head-to-head comparisons of the two different formulations at prescription dosing, the advisory does not recommend one over the other.
Triglycerides are fats that circulate in the blood.
Some studies have shown that elevated levels of triglycerides (above 200 mg/dL) can lead to atherosclerosis (narrowing of the arteries) which increases the risk of heart attack and stroke.
In addition to cardiovascular risk, very high levels of triglycerides (above 500 mg/dL) can also cause pancreatitis, an inflammation of the pancreas.
Skulas-Ray points out that people with high triglyceride levels should not try to treat the condition themselves with non-prescription, omega-3 fatty acid fish oil supplements.
“Dietary supplements containing omega-3 fatty acids are not regulated by the FDA.
They should not be used in place of prescription medication for the long-term management of high triglycerides,” said Skulas-Ray, who is an assistant professor in the Department of Nutritional Sciences at the University of Arizona in Tucson.
In a 2017 science advisory, the American Heart Association noted that there is a lack of scientific research to support clinical use of omega-3 fatty acid supplements to prevent heart disease in the general population.
The effective dose for prescription omega-3 fatty acids is four grams per day taken with food.
Currently, the FDA has approved prescription omega-3 fatty acid medications only for treating very high triglyceride levels above 500 mg/dL.
Healthy lifestyle choices, such as getting regular physical activity, losing weight, avoiding sugar and refined carbohydrates, limiting alcohol as well as choosing healthier fats from plants in place of saturated fats can help reduce triglycerides.
It is also important to treat or eliminate conditions such as poorly controlled type 2 diabetes, hypothyroidism and obesity that may contribute to high triglyceride levels before turning to medication.
Fish is a good source of omega-3 fatty acids, and the American Heart Association recommends eating fatty fish—such as salmon, mackerel, herring and albacore tuna—at least two times per week.
In analyzing the current scientific data, the advisory panel found:
- For most people with high triglycerides (200 to 499 mg/dL), prescription doses of omega-3 fatty acids using drugs with either EPA+DHA or EPA alone can reduce triglyceride by 20 to 30%.
- Contrary to common perception, the formula that contains both EPA and DHA does not increase the “bad” form of cholesterol (LDL-C) among most people with high triglyceride levels (200-499 mg/dL). However, when the drug is given to people with very high triglyceride levels at 500 mg/dL or greater, LDL-C may increase.
- The panel’s review found that the prescription omega-3 drugs are effective in reducing triglyceride levels regardless of whether people are on statin therapy.
- In a recent large, randomized placebo-controlled study called REDUCE-IT, researchers found that the EPA-only medication combined with statin medication resulted in a 25% reduction in major cardiovascular events (heart attack, stroke and cardiovascular death) among people with high triglycerides.
Elevated triglycerides are relatively common among people in the United States, and the prevalence is increasing due to growing rates of obesity and diabetes.
Both of those conditions raise triglyceride levels.
About 25% of adults in the U.S. have a triglyceride level above 150 mg/dL, which is considered borderline high.
Fish Oil Supplements as a Source of O3FAs for Cardiovascular Disease
There is considerable debate about fish oil dietary supplements (FODS) and whether or not they contain levels of quality O3FAs adequate for treating patients with cardiovascular risk and/or elevated TGs.
According to a 2008 report by the United States Department of Health and Human Services on complementary and alternative medicine use among adults and children, FODS are the most commonly used supplements among adults in the USA [31].
There is a general public perception that consumption of fish is a healthy dietary habit [32].
Indeed, fish consumption is recommended in the 2015–2020 Dietary Guidelines for Americans and by the American Heart Association [33••].
This view has led to a dramatic increase in the use of FODS, particularly among older adults in the USA.
Although widely available, FODS are not subject to approval and oversight by the FDA, as for over-the-counter (OTC) drugs, so their content and chemical integrity are not regulated in a rigorous manner [34].
FODS are not in the same category or regulated as OTC or prescription drugs by the FDA. Additionally, their efficacy and safety are not assessed prior to marketing as they are classified by the FDA as a food product [34].
And the low EPA and DHA content of various FODS may require patients to take 10 or more capsules per day in order to attempt to reach the same therapeutic dose (up to 4 g/day) available in a prescription form of O3FA.
Unlike the purification processes used for prescription products, oils extracted from marine animals through large-scale industrial production are a common source for FODS.
The fish oil is often a by-product generated during the isolation of protein for animal feed [35, 36].
Due to their chemical structure that includes multiple unsaturated double bonds, O3FAs are highly vulnerable to damage from oxygen free radicals during such extraction procedures. For example, the harvested fish are subjected to 100 °C temperatures in order to isolate the protein components [36].
As a result, O3FAs undergo significant oxidative modification in a manner that is only accelerated in the presence of light and contaminants [36].
Free radical modification of O3FAs would be expected to negate their biologic activity and interfere with any potential clinical benefits associated with the dietary use of FODS [37, 38].
Independent studies from various laboratories have verified concerns about the O3FA content and chemical integrity of FODS.
A study funded by the U.S. Department of Agriculture and published in 2015 reported that, of 47 FODS examined, only ten had EPA levels at or above that indicated on their labels, while only 12 had reported amounts of DHA; 74% of the supplements contained less than the stated label amounts of EPA or DHA [39].
In a similar study conducted in New Zealand, 32 FODS were analyzed for fatty acid content of which only 9% had O3FA levels consistent with stated label amounts [40].
In addition, more than 80% of the supplements were found to have unacceptably high levels of lipid peroxides, an indication of lipid decomposition.
Of the products tested, only three (8%) met international standards for acceptable peroxide and total oxidation levels [40].
FODS sold in North America have also been shown to have unacceptably high levels of lipid peroxides [41].
Such elevated peroxide values compromise the biological benefits of O3FAs as recently reported [42•].
The fatty acid content of leading FODS (by sales) in the USA was recently analyzed with respect to EPA, DHA, and other oils such as saturated fats [42•].
The extent of oxidative damage of the oils in these FODS was also measured and compared to those in an FDA-approved prescription product [42•].
The results of this analysis showed that more than 30 fatty acids were identified in these popular FODS, including as many as ten to 14 different saturated fatty acids, comprising more than a third of the total fatty acid content.
Additionally, O3FA levels varied widely among the FODS, including levels of EPA and DHA by several fold.
This study also measured primary and secondary products of oxidation associated with fatty acids containing multiple double bonds, such as O3FAs [42•].
All of the widely available FODS exceeded recommended maxima for these oxidation products. By contrast, no significant levels of oxidation products or other unfavorable oils such as saturated fat were found in the O3FA prescription product.
The biological activity of the O3FAs isolated from a leading FODS was compared to non-oxidized and oxidized preparations of EPA and DHA to determine their effects on atherogenic small dense LDL-C (sdLDL) oxidation [42•].
Oxidation of sdLDL was inhibited by more than 95% (p < 0.001) when treated with non-oxidized O3FAs but was not inhibited by oxidized O3FAs or the FODS isolate, which contained both oxidized and non-oxidized O3FAs.
The clinical translation of the lack of biological effect from oxidized FODS has been reported to include negative therapeutic effects on blood lipid levels [37] and a lack of intended effectiveness on lipid or inflammatory parameter levels [43].Go to:
Distinct Roles of EPA and DHA in Cellular Function and Atherosclerosis
O3FAs play an essential role in the structure and function of cellular membranes in various tissues throughout the human body.
These molecules influence membrane organization, including lipid raft formation, as well as membrane fluidity.
O3FAs are metabolized for energy and serve as precursors to important lipid mediators that influence inflammation.
These bioactive lipids include eicosanoids, prostaglandins, leukotrienes, and resolvins [44]. Recent research has demonstrated that EPA and DHA have distinct tissue distributions where they influence target organs in different ways (Fig. 1).
EPA has been shown to associate with atherosclerotic plaque membranes in blood vessels where it interferes with lipid oxidation and various signal transduction pathways linked to inflammation and endothelial dysfunction [45] as reviewed in Table Table2.
The basis for these benefits may be, in part, the result of direct effects of EPA on plaque development and stability [17•].
In particular, its lipophilic structure and molecular space dimensions allow EPA to insert efficiently into lipoprotein particles and cell lipid membranes where it scavenges free radicals. In contrast to EPA, DHA serves essential functions in nervous tissues where it is abundant and has pronounced effects on neuronal and retinal membrane organization [46, 47].
Hypothesized effects of EPA and DHA on endothelial and neuronal cell membrane structural organization, respectively, based on model membrane experiments. DHA is proposed to undergo rapid conformational changes in the neuronal cell plasma membrane where it may promote the formation of cholesterol-rich lipid domains and fluidity—a structural feature shown to be essential to neuronal function. EPA, by contrast, is proposed to intercalate into the membrane phospholipid hydrocarbon core region where it inhibits free radical propagation while preserving a more homogenous cholesterol distribution [13••, 14, 43, 44, 47, 48•, 49•]. Note: This figure contains graphic elements that were modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License
Table 2
Effects of EPA on plaque progression [2•, 45]
| Under conditions of… | EPA increases… | EPA decreases… |
|---|---|---|
| Endothelial dysfunction and oxidative stress | • Endothelial function • NO bioavailability | • Cholesterol crystalline domains • oxLDL • RLP-C • Adhesion of monocytes • Macrophages • Foam cells |
| Inflammation and plaque growth | • EPA/AA ratio • IL-10 | • IL-6 • ICAM-1 • hsCRP • Lp-PLA2 |
| Unstable plaque | • Fibrous cap thickness • Lumen diameter • Plaque stability | • Plaque volume • Arterial stiffness • Plaque vulnerability • Thrombosis • Platelet activation |
AA arachidonic acid, EPA eicosapentaenoic acid, hsCRP high-sensitivity C-reactive protein, ICAM-1intercellular adhesion molecule 1, IL-6 interleukin 6, IL-10 interleukin 10, Lp-PLA2 lipoprotein-associated phospholipase A, MMPs matrix metalloproteinases, oxLDL oxidized low-density lipoprotein, RLP-Cremnant lipoprotein cholesterol
Several lines of evidence show that EPA and DHA differ in their antioxidant properties as well as in their apparent effects on membrane lipid structure and dynamics.
The antioxidant effects of EPA are attributed to its ability to quench reactive oxygen species associated with cellular membranes and lipoproteins.
Following intercalation into the lipid particle or membrane, the multiple double bonds associated with EPA facilitate electron stabilization mechanisms that inhibit free radical propagation.
The antioxidant effects of EPA could not be reproduced with vitamin E or other FDA-approved, TG-lowering agents, under normal or hyperglycemic conditions in vitro [13••, 48•, 49•].
We also observed that the antioxidant activity of EPA could not be reproduced over time with DHA in lipoprotein particles [48•].
To elucidate the basis for these differences in antioxidant function, small angle x-ray diffraction approaches were used to demonstrate that EPA occupies a distinct area in the membrane as compared with DHA [50•].
EPA increased membrane hydrocarbon core electron density over a broad area, indicating an energetically favorable and extended orientation for EPA.
By contrast, DHA interacted with the phospholipid head group region with coincident decreases in the hydrocarbon core electron density, a confirmation of its increased molecular volume or disorder. These differences in membrane distribution are attributed to the additional carbon atoms and double bond of DHA, which produces rapid molecular changes that lead to increased lipid disorder that correspond to limitations in its antioxidant capacity [13••, 14, 15, 48•, 51].
The interaction between O3FAs and cholesterol is of particular importance because cholesterol content and organization have profound effects on the overall structure and function of the cell membrane.
DHA, for example, has been shown to isomerize through each of its possible confirmations within 50 ns after being added to biological membranes [52].
High acyl chain flexibility and rapid conformational changes are thought to interfere with the close association of O3FAs with cholesterol molecules, which have a rigid steroid ring structure and are less flexible in their membrane disposition [53].
By contrast, EPA does not undergo the same rapid conformational changes as DHA, allowing it to freely distribute with cholesterol and other lipids throughout the membrane bilayer.
As a result of this differential lipid interaction, DHA has been observed to promote cholesterol-rich domains in model membranes while EPA has no such effect [13••].
In dietary and cellular models of atherosclerosis, cholesterol has been shown to accumulate and form distinct domains in cellular membranes [54, 55].
These domains are believed to precipitate the formation of toxic extracellular crystals that induce cell apoptosis and necrosis, hallmark features of the unstable atherosclerotic plaque [56–60].
Along with oxidized LDL, cholesterol crystals are also a primary activator of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasomes, which regulate caspase-1 and its associated processing of pro-interleukin 1 beta (IL-1β) into an active cytokine that initiates inflammation in atherosclerosis [61].
We have also observed that the antioxidant effects of EPA in model membranes and various ApoB particles could not be reproduced by other TG-lowering agents such as niacin, gemfibrozil, and fenofibrate [48•, 49•].
The antioxidant effects of EPA in highly atherogenic LDL-C subfractions such as sdLDL from human subjects were actually enhanced in combination with atorvastatin under in vitro conditions [48•].
This unexpected finding indicates a shared location for these two amphipathic molecules where their intermolecular interactions further stabilize unpaired lipid free radicals and thereby reduce oxidative damage.
Thus protected, the non-oxidized LDL-C particle would be less atherogenic and more efficiently cleared from the circulation.
In patients with coronary artery disease (CAD), treatment with EPA has also been shown to improve HDL function. Specifically, HDL isolated from these patients showed enhanced cholesterol efflux and improved HDL activities, including antioxidant and anti-inflammatory effects [62].
In a recent study using isolated human endothelial cells, EPA-enriched HDL inhibited cytokine-stimulated vascular cell adhesion molecule 1 (VCAM-1) expression and increased resolvin E3 production [63•].
HDL treatment also enhanced cholesterol efflux following EPA incorporation [63•]. The lipophilic structure and molecular space dimensions of EPA allow it to insert more efficiently into the HDL particle, with improved antioxidant function, as compared to DHA [64•].
Thus, EPA has direct vascular effects that have been well characterized in cellular and animal models of atherosclerosis and corroborated by various clinical investigations.
These studies show that EPA treatment is associated with reduced inflammation and improved plaque stabilization [45].
The distinct location of EPA in the membrane and lipoprotein particles may explain certain differences in its vascular effects when compared to other TG-lowering agents and even DHA. EPA intercalates into the membrane with its long axis parallel to the phospholipid acyl chains, potentially allowing EPA to concentrate efficiently in endothelial and other membranes associated with atherosclerotic plaque.
These findings support a mechanistic basis for a potential benefit with EPA in reducing cardiovascular risk as is being currently tested in ongoing clinical trials.
More information: Ann C. Skulas-Ray et al, Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association, Circulation (2019). DOI: 10.1161/CIR.0000000000000709
Journal information: Circulation
Provided by American Heart Association
