N-3 fatty acids did not reduce major cardiovascular events in patients with dysglycaemia
- Correspondence to: Daan Kromhout
Division of Human Nutrition, Wageningen University and Research Centre, Biotechnion, Bomenweg 2, 6703 HD Wageningen, The Netherlands;
Commentary on Bosch J, Gerstein HC, Dagenais GR, et al. ORIGIN Trial Investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309–18
N-3 fatty acids have beneficial effects on elevated triglyceride levels, impaired endothelial function, inflammation, atherosclerotic plaque and severe arrhythmias. Prospective cohort studies have shown a lower risk of cardiovascular events among persons who consumed fish regularly. These studies were followed by clinical trials evaluating the effects of supplements with the fish fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in patients with a history of cardiovascular disease. The ORIGIN trial was the first large trial testing the hypothesis that long-term supplementation with n-3 fatty acids reduces cardiovascular events in dysglycaemic patients.
Patients with type 2 diabetes, impaired fasting glucose or impaired glucose tolerance were recruited from September 2003 through December 2005. A total of 12 536 patients (mean age: 64 years, 35% women) from 573 centres in 40 countries were followed for a median of 6.2 years. At baseline, 59% of the patients had had a myocardial infarction or stroke or had undergone revascularisation. Participants were excluded if they were unwilling to discontinue their use of n-3 fatty acids supplements, had a glycated haemoglobin level ≥9%, severe heart failure or cancer. The primary outcome was death from cardiovascular causes. Secondary endpoints included different composites of cardiovascular outcomes.
Participants were randomised after a 10 day run in period and received either a supplement with 1 g of n-3 fatty acids containing 465 mg EPA and 375 mg DHA or a placebo with 1 g of olive oil. Specific dietary recommendations were not given for the consumption of fish or other marine products. However, the use of n-3 fatty acids outside the study was discouraged. The study was double-blind and power calculations showed that 12 500 patients had to be included for at least 6 years to detect a 16.4% reduction in the risk of death from cardiovascular causes. Data were analysed according to intention-to-treat.
The median dietary intake of EPA–DHA was 210 mg/d (IQR: 40–568). The primary endpoint deaths from cardiovascular causes did occur in 1155 patients. Supplementation with n-3 fatty acids did not significantly reduce deaths from cardiovascular causes (HR 0.98; 95% CI 0.87 to 1.10 (p=0.72)). There was no significant difference in the primary endpoint in key subgroups defined by baseline consumption of n-3 fatty acids, triglyceride level and glycaemic status. In addition, the secondary endpoints did not differ between the n-3 fatty acid and the placebo group.
This study showed that a daily dose of 1 g of n-3 fatty acids did not prevent any cardiovascular outcome in patients who had or were at high risk of diabetes. This result is in accord with the two recent meta-analyses that also showed no significant effect of additional amounts of n-3 fatty acids ranging from 0.4 to 4.8 g/day in cardiac patients.1 ,2
Earlier trials did show a significant effect of n-3 fatty acids on major cardiovascular outcomes, in particular, on non-sudden and sudden coronary death.
The more recent trials differed from the older ones in cardioprotective drug treatment. Patients now receive state-of-the-art drug treatment for hypertension, hypercholesterolaemia and thrombosis. These therapies reduce the event rate of death from cardiovascular causes, making it harder to detect the effect of n-3 fatty acids. Subgroup analyses of the Alpha Omega Trial showed that in patients who had had a myocardial infarction in combination with diabetes, an additional amount of 400 mg EPA–DHA per day reduced fatal coronary heart disease significantly.3 An additional amount of 400 mg EPA–DHA in combination with 2 g of the n-3 fatty acid alpha linolenic acid also reduced severe arrhythmia-related events significantly in this trial.4
The recently reported results from randomised double-blind placebo-controlled trials showed that supplementation with n-3 fatty acids did not reduce cardiovascular outcome in patients with a history of cardiovascular disease or diabetes. However, there are suggestions that the results differ by the level of cardiovascular risk of the patients, their baseline intake of n-3 fatty acids and the dose of the supplements used. Therefore, the next step would be to carry out a meta-analysis using individual patient data.
The negative results in the recent trials do not justify the recommendation to use an increased dose of n-3 fatty acids in secondary prevention. However, the recommendation to eat fatty fish at least once a week as a component of a nutritionally adequate diet can be justified based on the results obtained in prospective cohort studies and intervention studies with different markers of cardiovascular risk.5