n 3 Fatty Acids and Cardiovascular Outcomes in Patients with DysglycemiaLiterature - The ORIGIN Trial Investigators. N Engl J Med 2012. June 11
n–3 Fatty Acids and Cardiovascular Outcomes in Patients with DysglycemiaThe ORIGIN Trial Investigators
NEJM 2012 (published online before print) DOI: 10.1056/NEJMoa1203859
BackgroundThe use of n–3 fatty acids may have beneficial effects on arrhythmias, elevated triglyceride levels, atherosclerotic plaque, impaired endothelial function, platelet aggregation, and inflammation. Epidemiologic studies have shown a reduced risk of cardiovascular events among persons who consume fish regularly or who take supplements containing n–3 fatty acids [1-4], further warranting clinical trials to evaluate the effect on cardiovascular events and death. Various trials, either open-label or placebo-controlled, have been performed. No large trials have been performed in patients with type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance. The Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial evaluated the effect of long-term supplementation with n-3 fatty acids on cardiovascular events in these patients.
In a 2 x 2 factorial design, more than 12,500 patients with impaired fasting glucose, impaired glucose tolerance, or diabetes were randomized to either omega-3 fatty acids or placebo.
Omega-3 fatty acids versus placebo:
- CV death (primary endpoint): 9.1% versus 9.3% (HR 0.98, CI 0.87 – 1.10, p = 0.72)
- Major vascular events: 16.5% versus 16.3% (HR 1.01,CI 0.93 – 1.10, p = 0.81)
- Death from any cause: 15.1% versus 15.4% (HR 0.98, CI 0.89 – 1.07, p = 0.63)
- Death from arrhythmia: 4.6% versus 4.1% (HR 1.10, CI 0.93 – 1.30, p = 0.26)
ConclusionThe administration of 1 g of n-3 fatty acids did not reduce the rate of death from cardiovascular causes or other outcomes during a period of 6 years in patients with dysglycemia and additional cardiovascular risk factors.
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2. Hu FB, Cho E, Rexrode KM, Albert CM, Manson JE. Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women. Circulation 2003;107:1852-7.
3. Calder PC. n-3 Fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clin Sci (Lond) 2004;107:1-11.
4. Saravanan P, Davidson NC, Schmidt EB, Calder PC. Cardiovascular effects of marine omega-3 fatty acids. Lancet 2010;376:540-50.
The use of n–3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown.
In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n–3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n–3 fatty acids and placebo are reported here.
During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n–3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n–3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n–3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups.
Daily supplementation with 1 g of n–3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events.