Family Medicine Physician, Lebanon, PA
Dr. Orner reports no financial relationships relevant to this field of study.
SYNOPSIS: In a cohort of 15,480 adults with diabetes, there was no significant difference in the risk of serious vascular events when comparing supplementation with 1 g of omega-3 fatty acid vs. an olive oil placebo.
SOURCE: ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-1550.
- This was a 7.5-year randomized, controlled trial that included 15,480 adults with diabetes mellitus in the United Kingdom.
- Participants were randomized to receive a capsule containing 840 mg of marine omega-3 fatty acids (460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) or olive oil (placebo) daily.
- Serious vascular events occurred in 8.9% of patients in the omega-3 fatty acid group and 9.2% in the placebo group.
- Those who received omega-3 fatty acid did not have significantly lower incidences of serious vascular events than those who received the olive oil placebo.
Cardiovascular disease is a major cause of mortality and morbidity. There are an estimated 630,000 deaths per year in the United States from cardiovascular disease.1 The American Heart Association continues to recommend omega-3 fatty acid consumption to the public, preferably through food, and states that it has preventive benefits even in healthy people.2
In the ASCEND (A Study of Cardiovascular Events in Diabetes) trial, researchers assessed the efficacy of daily omega-3 fatty acid supplementation in adults with diabetes and without cardiovascular disease.3
The researchers identified potential trial participants from regional registries and general practice data. They mailed screening questionnaires to eligible patients to determine their willingness to participate. Those interested and eligible then began a prerandomization run-in phase. The researchers requested, but did not require, that patients discontinue over-the-counter fish oil or omega-3 fatty acid supplements prior to and during the study. However, patients were still eligible to participate while taking these supplements as long as the daily dose was less than 1 g.
During the eight- to 10-week run-in phase, participants were asked to notify their doctor of their potential participation in the study; record basic anthropomorphic data, including blood pressure, height, and weight; and provide blood and urine samples. Participants were given capsules containing the olive oil placebo. If participants adhered to the trial regimen, continued to meet the eligibility criteria, and confirmed their willingness to continue, they remained eligible for the trial. (See Table 1.)
The researchers determined the evidence of cardiovascular disease by reviewing the patients’ reported myocardial infarction, angina, stroke, coronary artery bypass surgery, or arterial revascularization.4 Contraindication to aspirin therapy included an allergy to aspirin, recent gastrointestinal bleeding, or being prescribed aspirin, warfarin, or any other blood-thinning agent at the time of the study. Much of this information was gathered from the study screening questionnaire.4
From June 2005 through July 2011, 15,480 participants were randomized to receive 1-g capsules containing either 840 mg of marine omega-3 fatty acids or an olive oil placebo. The marine omega-3 fatty acid included 460 mg of eicosapentaenoic acid (EPA) and 380 mg of docosahexaenoic acid (DHA). Of note, participants were randomized to receive either 100 mg of aspirin or placebo as well. Every six months until the end of the trial, participants were sent follow-up questionnaires regarding serious and nonserious adverse events, adherence to trial regimen, symptomatic bleeding events, and use of nontribal antiplatelet or anticoagulant therapy. Blood and urine samples, blood pressure readings, and weight were requested from 1,800 randomly selected patients after a mean follow-up period of 2.5 years.
The primary endpoint was the first serious vascular event, including nonfatal myocardial infarction, stroke, transient ischemic attack (TIA), or vascular death, excluding intracranial hemorrhage. The secondary endpoint was any serious vascular event or arterial revascularization procedure. Of note, the duration of the follow-up period was extended to 7.5 years, and TIA was included in the definition of serious vascular events during recruitment to increase the power of the trial.
Mean adherence to the trial regimen was 77% for the omega-3 fatty acid group and 76% for the placebo group. There was no significant difference between the groups regarding over-the-counter fish oil supplement use, with 10% of participants reporting use at baseline and 6% reporting use at 6.7 years of follow-up. There was no comment about whether the groups could differentiate between the marine oil and placebo based on eructation.
Serious vascular events occurred in 8.9% (689) of patients in the omega-3 fatty acid group and in 9.2% (712) in the placebo group (rate ratio, 0.97; 95% confidence interval [CI], 0.87-1.08; P = 0.55). The between-group difference was not statistically significant. There was also no significant difference between groups in the secondary outcome. Serious vascular effects or revascularization occurred in 11.4% (882) of the omega-3 group and 11.5% (887) of the placebo group. Rates of death were similar between the two groups, with 9.7% for the omega-3 group and 10.2% for the placebo group (rate ratio, 0.95; 95% CI, 0.86-1.05).
It actually appears that this study is more a comparison of marine oil vs. olive oil, showing that marine oil at low doses is no more beneficial than olive oil at a similar dose. One gram of olive oil is equivalent to approximately 1 mL. This is significantly less than the amount used the studies assessing the Mediterranean diet enriched with extra-virgin olive oil (EVOO), in which participants received approximately 1 L per week of EVOO.5
It is interesting that the study authors did not discuss the possibility of therapeutic benefits from olive oil supplementation for prevention of vascular events in those with diabetes, nor how this would affect the study results. Although these authors have labeled olive oil the placebo, authors of other studies have shown that olive oil has beneficial effects. The authors of a randomized, controlled trial published in 2017 showed that the Mediterranean diet enriched with virgin olive oil improved the atheroprotective functions of human high-density lipoprotein.6 Given that olive oil was used as a placebo in the active phase of the trial and that all participants received it during the run-in phase for eight to 10 weeks, there is certainly concern that it could have affected the study results.
Another factor that could confound the results is that the participants were randomized to receive 100 mg of aspirin or a placebo. Antiplatelet agents, such as aspirin, play a major role in the prevention of vascular events, such as myocardial infarction and ischemic stroke. There was no discussion in the study about how this may have affected the study outcome.
Although this study is thought-provoking in evaluating fish oil for primary prevention of cardiovascular disease in a high-risk group, before changing clinical practice, it would be prudent to have a trial with a true placebo, that did not contain active substances that could affect health. Based on this study, I would not recommend abandoning the American Heart Association’s recommendation that supports omega-3 supplementation as secondary prevention of sudden cardiac death and coronary heart disease for patients with a history of coronary heart disease or heart failure.
- Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation 2017;135:e146-e603.
- Fish and Omega-3 Fatty Acids. American Heart Association. Available at: . Published 2019. Accessed Aug. 7, 2019.
- ASCEND Study Collaborative Group, Bownman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-1550.
- Aung T, Haynes R, Barton J, et al. Cost-effective recruitment methods for a large randomised trial in people with diabetes: A study of cardiovascular events in diabetes (ASCEND). Trials 2016;17:286.
- Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med 2018;378:e34.
- Hernáez Á, Castañer O, Elosua R, et al. Mediterranean diet improves high-density lipoprotein function in high-cardiovascular-risk individuals: A randomized controlled trial. Circulation 2017;135:633-643.