Clinical Question

In patients with diabetes mellitus, what is the safety and efficacy of daily supplementation with omega-3 fatty acids for the prevention of cardiovascular events?

Bottom Line

In this study, there was no significant difference in the likelihood of a composite vascular outcome or all-cause mortality in patients given an omega-3 fatty acid supplement compared with those given an olive oil placebo. Although olive oil has been associated with better cardiovascular outcome in studies of the Mediterranean diet, those studies used approximately 1 liter per week compared with only 7 grams per week in the current trial. The reduction in vascular deaths is intriguing, but the authors urge caution given multiple comparisons. (Level of Evidence = 1b)

Synopsis

This study recruited adults 40 years and older with diabetes, no known cardiovascular disease, no contraindications to aspirin, and no major comorbidity that would keep them from participating in the study for at least five years. After a placebo run-in period to assure adherence, 15,480 participants were randomized to receive omega-3 fatty acids or placebo (olive oil) in identical 1-gram capsules. This was a factorial design study with patients also randomized to receive aspirin; those results are reported separately. The groups were balanced at the start of the study. The patients had a mean age of 63 years, 63% were men, and 96% were white. Almost all (94%) had type 2 diabetes. A validated risk score determined that approximately 40% of participants were at low risk of vascular events (less than 5% at five years), 40% had a five-year risk of 5% to 10%, and the remainder were at high risk. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke (excluding hemorrhagic stroke), vascular death, or transient ischemic attack. Transient ischemic attack was added after recruitment had begun, and the length of the trial was increased after lower-than-expected rates of the composite outcome were observed. Although the authors do not specifically state that the analysis was by intention to treat, for all practical purposes it was, because 99.1% of patients had completed follow-up. After a mean of 7.4 years of follow-up, there was no difference between groups for the primary composite outcome (8.9% in the omega-3 group and 9.2% in the placebo group; hazard ratio [HR] = 0.97; 95% CI, 0.87 to 1.08). There were no differences for any of the individual components of the composite, with the exception of vascular deaths (2.4% for omega-3 vs. 2.9% for placebo; HR = 0.81; CI, 0.67 to 0.99; number needed to treat = 200 for 7.4 years). All-cause mortality did not differ significantly between the groups, although the absolute difference of 0.5% mirrored that for the subset of vascular deaths.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry and foundation

Allocation: Concealed

Setting: Outpatient (any)

Reference: Bowman L, Mafham M, Wallendszus K, et al.; ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379(16):1540–1550.

Editor's Note: Dr. Ebell is Deputy Editor for Evidence- Based Medicine for AFP and cofounder and Editor-in-Chief of Essential Evidence Plus.