Since the first report by Bang and Dyerberg regarding the apparent beneficial effects of a fish oil-enriched diet on the incidence of atherosclerotic heart disease in Greenland eskimos, a considerable number of studies have been performed regarding the effects of omega-3 polyunsaturated fatty acids on the prevention and treatment of a variety of disease states not necessarily related to atherosclerosis. From the beginning, the discussion remained open whether these effects were due to a completely different diet with food products rich in omega-3 polyunsaturated fatty acids (omega-3 PUFA’s) or to the omega-3 PUFA’s per se. Observational studies have mainly concentrated on total diet, whereas intervention studies have mainly concentrated on the addition of various amounts of purified omega-3 PUFA’s, whilst maintaining the dietary habits. Purified fish oil is derived mostly from cold water oily fishes like mackerel and salmon, and contains rather high contenctrions of long chain omega 3 fatty acids, primarily eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoicacid (22:6 n-3).
Already in the eighties and nineties of the last century, studies were performed using fish oil (omega-3 PUFAs) supplements in healthy volunteer , and in patients with hyperlipidemia, atherosclerotic vascular disease, diabetes, asthma, psoriasis, renal transplant patients, renal replacement therapy, and chronic renal insufficiency, amongst others. Positive effects on platelet activity, lipid profile, blood rheology and blood pressure--all factors which are presumably of importance in the pathogenesis of atherosclerotic disease were noted in these studies, albeit with a wide range of variability. Some negative effects also appeared to exist. Amongst others, when studying lipid changes, especially triglyceride concentration were lowered (to a certain extent in a dose-response curve), but LDL cholesterol levels increased, although the particles formed when using fish oil were of the larger and “fluffy” kind.
Longer term studies
Many studies in those days were already ongoing (and have been performed since) concentrating on assessing the long term effects of fish oil on especially outcome in various atherosclerotic vascular disease states and diabetes including its microvascular and macrovascular complications. This continuing drive to perform studies using omega-3 polyunsaturated fatty acids is remarkable in the light of the generally quite uniform negative findings on hard endpoints.
Primary end point information
Although the initial changes in secondary end points (improved rheological properties with increased erythrocyte deformability, improvements in prostaglandin profiles, lower fibrinogen levels) boded well, a Cochrane analysis in 2009concluded that no effects on cardiovascular endpoints could be observed.
The results of this analysis were confirmed in a meta-analysis in the JAMA in 2012, in which it was concluded that overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association . One possible exception on this general conclusion might be the rather weak beneficial effect in post-MI patients, who did not use statins. In cohort of 413 statin non-users and a history of myocardial infarction, only 9% of those who received of 400 mg eicosapentaenoic acid plus docosahexaenoic acid (i.e.fish oil) and 2 g a-linolenic acid experienced an event compared with 18% in the placebo group after an average follow-up period of 41 months (HRadj 0.46; 95% CI: 0.21, 1.01; P = 0.051; ). In a recent study assessing the possible effects of omega-3 PUFA on postoperative atrial fibrillation, no beneficial effects were seen .
In some contrast with the findings using fish oil supplements are the results of analyses focusing on fish consumption; again, in a recent meta-analysis , where the available observational data indicated a moderate and inverse associations of fish consumption and long chain omega 3 fatty acids with cerebrovascular risk. When analyzing these outcomes to long chain omega 3 fatty acids measured as circulating biomarkers in observational studies or supplements in primary and secondary prevention trials, the authors concluded that these were not associated with cerebrovascular disease. They suggest that the beneficial effect of fish intake on cerebrovascular risk is likely to be mediated through the interplay of a wide range of nutrients abundant in fish.
When investigating fish oil in (especially) type 2 diabetes mellitus, the latest Cochrane review on this subject concluded, that although some types of lipids (especially triglycerides) in the blood are reduced through omega-3 supplementation, others including LDL cholesterol were increased. Control of blood glucose levels was not affected by the treatment. No other significant adverse effects of the interventions were noted. The results of this Cochrane analysis do not suggest a major harmful effect on the balance of blood lipids and confirm that it has no adverse effect on blood glucose control.
When studying the effects of omega-3 PUFA’s in subjects with impaired fasting glucose, impaired glucose tolerance, or diabetes and a high cardiovascular risk profile, again no effects on CV incidents were seen after supplementation of 900 mg of ethyl esters of n-3 fatty acids for an average of 6.2 years . When looking at possible effects of omega-3 PUFA’s on markers of renal damage in diabetes in a short term study, some encouraging effects could be found . Still, long term results lack in this aspect, and should be awaited before firm conclusions regarding its possible use can be drawn.
Despite initial encouraging short term results and effects, ingestion of Omega-3 PUFA’s supplements has not shown any long term effects on incidence of cardiovascular disease in the majority of studies. Beneficial results are lacking as well in subjects either prone to diabetes or already having diabetes in general. Some niche groups might benefit, like subjects who use ciclosporin, or subjects who can not or will not use a statin post-MI. Use of omega-3 PUFA’s cannot be recommended in subjects with diabetes. If any advices should be given in relation to ingestion of omega-3 PUFA rich products, eating fish several times weekly instead of eating meat would probably result in more beneficial effects than addition of supplements.
^ Montori VM, Farmer A, Wollan PC, Dinneen SF. Fish Oil Supplementation in Type 2 Diabetes. A quantitative systematic review. Diabetes Care2000; 23:1407–1415
^ Hooper L, Harrison RA, Summerbell CD, Moore H, Worthington HV, Ness A, Capps N, Davey Smith G, Riemersma R, Ebrahim S Omega 3 fatty acids for prevention and treatment of cardiovascular disease (Review). Cochrane review, 2009
^ Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events. A Systematic Review and Meta-analysis. JAMA. 2012;308(10):1024-1033
^ Eussen SRBM, Geleijnse JM, Giltay EJ, Rompelberg CJM, Klungel OH, Daan Kromhout D. Effects of n-3 fatty acids on major cardiovascular events in statin users and non-users with a history of myocardial infarction. European Heart Journal (2012) 33, 1582–1588
^ Mozaffarian D, PH Roberto Marchioli R, Macchia A, et alFish Oil and Postoperative Atrial Fibrillation. The Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) Randomized Trial. JAMA 2012;308(19):2001-2011
^ Chowdhury R, Stevens S, Gorman D, Pan A, Warnakula, Chowdhury S, Ward H, Johnson L, Crowe F, Hu FB, Franco OH. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. BMJ 2012;345:e6698 doi: 10.1136/bmj.e6698 (Published 30 October 2012)
^ Hartweg J, Perera R, Montori VM, Dinneen SF, Neil AHAWN, Farmer AJ. Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus (Review) Cochrane review, 2009
^ The ORIGIN Trial Investigators. n–3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia N Engl J Med 2012 (10.1056/NEJMoa1203859)
^ Miller ER, Juraschek SP, Anderson CA, et al. The Effects of n-3 Long-Chain Polyunsaturated Fatty Acid Supplementation on Biomarkers of Kidney Injury in Adults With Diabetes. Results of the GO-FISH trial. Diabetes Care Published Ahead of Print, published online January 24, 2013