Omega-3 and Omega-6 Fatty Acids — Measuring Blood Levels To Help Manage Cardiovascular Risk
While recommendations for dietary intake of omega-3 fatty acids to reduce cardiovascular disease risk are well established, debate continues about the benefits of omega-3 supplementation.1-4
Dr. Robert Superko, Chief Medical Officer, Celera, reviews the evidence relating to omega-3 intake and discusses why measuring blood concentration levels can provide a basis for reducing cardiovascular risk.
Omega-3 and omega-6 are fatty acids, also called n-3 and n-6 polyunsaturated fatty acids (n-3 and n-6 PUFAs). They are involved in digestion, coagulation, muscle function, cellular transport, and cell division and growth. The three major omega-3 fatty acids are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid. Fish oil and fatty fish such as salmon, mackerel, herring, and tuna are the primary dietary sources of EPA and DHA. Alpha-linolenic acid is found in plant-based foods such as green leafy vegetables, beans, and vegetable oils and is converted to EPA and DHA after being ingested.5
“These fatty acids are important,” says Dr. Superko, “because of their involvement in the process of prostaglandins, which are vasodiltory, and thromboxanes, which are vasoconstrictive. The EPA and DHA of omega-3 fatty acids become prostaglandins, while omega-6 fatty acids include arachidonic acid (AA), which moves through the pathway to become a thromboxane. This gives a sense of why the EPA to AA ratio has significance.”
Does Omega-3 Supplementation Provide a Benefit? The Debate
The benefits of Omega-3 fatty acids were originally established by various studies, which used dietary analysis to show that those who consume more fish in relation to red meat have less heart disease.6-7 “The conclusion was that because fish have a high level of omega-3 fatty acids, and beef has arachidonic acid, it must be the fish oils that are beneficial,” notes Dr. Superko. “This hypothesis was then challenged by a series of studies where people were randomized to placebo or fish oil capsules. Some studies showed a little benefit, while some showed none. This has led to the controversy we have today.”3-4
The shortcoming of the fish oil studies is that they assume everybody responds the same to the dose they’re given, observes Dr. Superko. “This is like giving everybody the same statin dose and expecting them to respond the same. In fact, when we looked at the studies, which measured blood levels, we found some important findings. Firstly, the blood level an individual achieves based on a set omega-3 dose varies tremendously within the population. So, you may give one person 1,000 mg of fish oil, and their omega-3 index goes from 0.2 to 0.3. You may give someone else exactly the same amount of fish oil and they go from 0.2 to 0.6.”
The variability of individual response to omega-3 is largely due to a series of genes, the FADS genes, which determine how someone metabolizes oral fish oil capsules. Based on genetics some people will generate high blood levels, and others with exactly the same dose will only increase slightly. “A recent meta-analysis did not find a statistically significant relationship between omega-3 consumption and CVD mortality, but it failed to take into account the implications of variability in individual blood levels of omega-3 fatty acids,” says Dr. Superko.3-4
Association with Reduced CVD Risk – The Evidence
A review of 29 studies by Dr. Superko and others , which had measured omega-3 plasma levels and the impact on cardiovascular disease, demonstrated the relationship between omega-3 levels and CVD risk: the higher the levels in the population, the lower the number of heart attacks.8 “The important point was not whether or not you took one gram of fish oil per day but the blood level you achieved. This helps explain part of the controversy of whether one gram of fish oil works or not, because for 50 to 75% of the population one gram of fish oil doesn't achieve the therapeutic threshold.”
A 2004 study showed that the omega-3 Index (% of blood total fatty acids, which are EPA and DHA) was inversely associated with risk for CHD mortality.8 Another significant study, the Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study (JELIS), was based on 20,000 people who were randomized to pravastatin 10 mg/day or simvastatin 5 mg/day (control group) or the same statin doses with EPA 1800 mg/day. This study showed that an EPA/AA ratio of over 0.75 corresponded to a statistically significant reduction in cardiovascular events.9
Clinical Application of Omega-3 Blood Measurement
“The therapeutic goal that a physician might want to achieve is based on the blood level identified in the 29 clinical trials we analyzed,” notes Dr. Superko. “An individual patient’s blood level response can be tracked with the omega-3 index and the EPA/AA ratio.” An omega-3 index of >3.3% reflects low CVD risk, while <1.1% reflects high risk. An EPA/AA ratio of >0.8 indicates lower risk for major coronary events.
Having established the benefit of omega-3 intake the question is: should it be applied in primary prevention or secondary prevention? “The JELIS study showed there is a significant reduction in cardiovascular events in people with a prior history of heart disease linked to omega-3 blood level,” says Dr Superko. “So firstly, anybody with atherosclerosis or coronary heart disease should seriously consider having their omega-3 blood levels determined, and if they're below a therapeutic threshold, consider taking omega-3. It’s critical, however, that clinicians measure blood levels to determine the impact being achieved – prescribing a supplement and assuming that dose will be effective is not sufficient.” The second group of people to consider are those with a significant family history of coronary disease and the third group are those with dietary patterns that cause concern.
Given the evidence that an increased intake of omega-3 fatty acids can protect from sudden cardiac death (SCD) and other major adverse cardiac events, it has been suggested that the omega-3 Index is “a good candidate for a biomarker to assess risk for SCD and other major adverse cardiac events. Important criteria like standardization, availability, and safety are fulfilled by the Omega-3 Index.”10
“Whereas in the past the decision to recommend fish oil to a patient was rather subjective, the availability of tests to measure blood levels equips a physician with a tool to determine objectively whether or not to do so,” summarizes Dr. Superko.
Once a patient is taking fish oil their levels are normally checked after a month, with a follow-up two months later. “I like to have three measurements to determine if my patient is consistently at an acceptable level,” says Dr. Superko. “So, I would also test again three months after the second test.” As well as monitoring a patient’s response, repeat testing verifies compliance and indicates the integrity of the supplement. “Finally, there is an economic benefit: a blood test costs a fraction of fish oil supplementation, so it may well be worthwhile for a patient to test their level before embarking on a regimen of supplementation.”
- Perk J, De Backer G, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012;33:1635-1701.
- Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124:2458-2473.
- Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardio- vascular disease events: a systematic review and meta-analysis. JAMA. 2012;308:1024–1033.
- Superko HR, etal. Omega-3 Fatty Acid Blood Levels: Clinical Significance and Controversy. Circulation. 2013; 128:2154.
- Kris-Etherton PM, Taylor DS, Yu-Poth S, et al. Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr. 2000;71:179S-188S.
- Dyerburg et al, “Fatty Acid Composition of the plasma lipids in Greenland Eskimos”. Am J Clin Nutr s8(9): 958-66
- Appel et al (1993). “Does supplementation of diet with “fish oil” reduce blood pressure? A meta-analysis of controlled clinical trials” Archives of Internal Medicine 153 (12): 1429-1438
- Harris WS, Von Schacky C. Prev Med. 2004 Jul;39(1):212-20 http://www.fda.gov/ohrms/dockets/dailys/00/Nov00/110200/let0003.pdf
- Matsuzaki M, Yokoyama M, Saito Y, Origasa H, Ishikawa Y, OikawaS, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, Matsuzawa Y; JELIS Investigators. Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease. Circ J. 2009;73:1283–1290.
- von Schacky C. Omega-3 Index and Sudden Cardiac Death Nutrients 2010, 2, 375-388;