DHA/EPA Institute Comments on Recent Review: Omega-3 Supplementation and Cardiovascular Events

Without intending to refute the peer-reviewed publication of the present authors, the following brief commentary is offered. In any long-term intervention trial (whether with medication or nutritional supplements), incomplete compliance poses a major challenge such that monitoring compliance with recognized biomarkers is highly recommended . Such a monitoring protocol can identify poor or incomplete compliance. Also, potential minor side-effects and other factors can compromise compliance. The measurement of fatty acid levels (incl. DHA, EPA , others) in plasma lipid (or whole blood or serum phospholipid or erythrocytes) can serve as reliable indicators to determine the level of compliance. Such monitoring needs to become a standard protocol in essentially all clinical trials which valuate the effect of fish oil or DHA/ EPA intervention on outcomes. Such monitoring to evaluate compliance has been absent in most of the studies as reviewed herein by the present authors and others. An example of a published study wherein such fatty acid profiles were measured is that by Burr et al. (Eur. J. Clin. Nutr., 57: 193-200 (2003)) as utilized in the recent review by Rizos and colleagues . In the study by Burr et al., which did not support a beneficial effect of increasing DHA/EPA intakes from fish or fish oil on cardiac death in men with angina, measurements of EPA levels in plasma lipid were performed. Interestingly, the reported intake of EPA omega-3 in the fish/fish oil-supplemented group was increased to 474 mg/day during intervention . However, the plasma lipid levels of EPA rose by only 37 % by 6 months whereas EPA intakes of much less (such as only 276 mg/ day) have resulted in elevations above 80 % within 6 weeks in the plasma lipid (Castro et al., Nutrition, 23: 127-137 (2007)). Thus, the apparent failure of the subjects in the trial of Burr et al. to fulfill compliance to the target intakes of DHA/EPA is a significant shortcoming which likely prevails amongst many of the omega-3 intervention trials.

Strong support for the need to measure circulating omega-3 levels for compliance and expected efficacy of omega-3 supplementation on cardiac events in clinical trials also comes from the newly-released blood data from the Japan EPA Lipid Intervention Study known as JELIS (Itakura et al., J. Atheroscler. Thromb., 18: 99-107 (2011). In this study, a very wide variance in the elevated circulating concentrations of EPA omega-3 was found between subjects in the treatment group despite assigning all subjects in the EPA group to receive a fixed daily dose of 1800 mg EPA/day. Those EPA-supplemented subjects showing much higher levels of blood plasma EPA levels exhibited a 20 % reduced risk (relative to controls) in the risk of major coronary events whereas those EPA-supplemented subjects who exhibited much lesser levels of blood plasma EPA did not show any reduction in risk.

Despite the various shortcomings, the current review reported the overall risk for cardiac death, sudden death, and myocardial infarction to have relative risks which were lower in the omega- 3 supplemented groups (relative to placebo controls) by 9, 13, and 11 %, respectively (although not reaching statistical significance). It should also be pointed out that not having information on background dietary intakes of (DHA plus EPA) on individual subjects or the groups (and their blood levels of omega-3) does not allow for an assessment of the ‘deprived’ versus ‘non- deprived’ subjects and their relative responses/benefits from omega-3 supplementation. In this regard, the most recent intervention trial included in the analyses by Rizos et al. in their review was the so-called ORIGIN trial (New Engl. J. Med., 367: 309-318 (2012)) wherein supplementation with DHA/EPA omega-3 or ‘placebo’ (controls) to those with (or at risk for) type 2 diabetes did not show a significant difference in outcomes. Interestingly, the intake of fish/other marine products were not restricted (unlike what is commonly done in such intervention trials) throughout the supplement trial such that the median intake of DHA plus EPA from dietary sources was already substantial at 210 mg/day with a considerable portion of the subjects consuming up to 570 mg/day or more. Interestingly, an extensive review on dose- benefit relations for DHA/EPA intakes and human health from the Harvard School of Public Health (Mozaffarian and Rimm, J. Am. Medical Assoc., 296: 1885-1899 (2006) concluded that an intake approaching at least 250 mg/day ‘appears sufficient for primary prevention‘.

For general health and disease prevention, 500 mg (EPA plus DHA) per person daily is recommended as the Position of the American Dietetic Association and the Dietitians of Canada (Journal of the American Dietetic Association, 207 : 1599-1611 (2007)).

For those with coronary disease , the American Heart Association Dietary Guidelines (Revision 2000: A Statement for Healthcare Professionals from the Nutrition Committee of the American

Heart Association) states : “Consumption of one fatty fish meal per day (or alternatively, a fish oil supplement) could result in an omega-3 intake (ie, EPA and DHA) of approx. 900 mg/day, an amount shown to beneficially affect coronary heart disease rates in patients with coronary disease”(Circulation , 102: 2284-2299 (2000).

An elevated triglyceride level is a very significant risk factor for cardiovascular disease and associated mortality. Even moderately-elevated levels of circulating triglyceride (150-199 mg/ 100 ml or 1.7-2.2 mmol/litre), which are highly prevalent in the population including many people on statin treatment for cholesterol-lowering , carry a significantly increased risk for heart disease and are considered ‘borderline-high’ in the recent Scientific Statement from the Amer. Heart Assoc. on ‘Triglycerides and Cardiovascular Disease’ (Circulation, 123: 292-2333 (2011). In fact , the latter review indicates that , by the age of 40 years, almost half of US males and a considerable portion of females do not have triglyceride levels designated as ‘desirable’ (below 150 mg/100 ml ). As reviewed herein on www.dhaomega3.org , the degree of triglyceride- lowering typically amounts to approx. 7-10 % per 1000 mg of (EPA plus DHA) daily such that 2000 mg or 3000 mg can be expected to lower blood triglycerides by approx. 14-20 % and 21- 35 % , respectively. Such triglyceride-lowering is usually attained within 3-4 weeks and can be maintained for years pending ongoing supplementation.

It should also be pointed out that, in addition to any cardio-protective effects, higher intakes of DHA/EPA omega-3 via diet or supplementation throughout various stages of life (motherhood , childhood, middle age, elderly) have been found to offer enhanced health and complementary disease prevention and management (including risk factor improvements) related to optimal cognitive development/performance and visual acuity, anti-inflammatory effects , immunological support, reducing the risk and progression of certain cancers and ocular disorders, beneficial effects on depression , plus other favourable effects based on both epidemiological and interventional studies as published in peer-reviewed medical and nutrition journals. Interestingly, many of the latter clinical trials have been conducted in Japan showing considerable benefits on cardiac-related events (major coronary event, stroke recurrence) and other health outcomes with supplementary levels of long-chain omega-3 fatty acids in a population with daily intakes of DHA plus EPA averaging approx. 1000-1200 mg as compared to only 120-150 mg in North America.