Omega-3 Fatty Acids Fail to Reduce CVD Events in Diabetic Patients: ASCEND

MUNICH, Germany— A new study casts yet more doubt on the benefits of omega-3 fatty acid supplementation in diabetic patients who lack established cardiovascular disease, with investigators stating that the emphasis on fish oil in clinical guidelines should be revisited.

Speaking with TCTMD after presenting the ASCEND trial at the European Society of Cardiology Congress 2018, lead investigator Louise Bowman, MD (University of Oxford, England), said the results suggest that “at the dose we tested, it seems hard to justify the use of fish oil supplements for the prevention of cardiovascular disease.

“As with many health supplements, the global health market for omega-3 products—fish oil—has been remarkably successful in recent years,” Bowman continued. Recent estimates suggest sales north of $30 billion US dollars, with roughly 19 million individuals in the United States taking fish oil supplements, she added. “Benefits claimed are very widespread—on the heart, brain, vision, inflammation. The list goes on.”  

The American Heart Association (AHA) does not recommend omega-3 polyunsaturated fatty acid supplementation for the primary prevention of coronary heart disease. Nor does the AHA recommend omega-3 fatty acids for patients at high risk for cardiovascular disease or those with diabetes. In a 2017 scientific advisory, however, the AHA stated that omega-3 fatty acids could be considered a reasonable option in secondary prevention, particularly in individuals who have had an MI. The AHA also recommends one or two seafood meals per week to reduce the risk of congestive heart failure, coronary heart disease, ischemic stroke, and sudden cardiac death.

Both Athena Poppas, MD (Alpert Medical School of Brown University, Providence, RI), and Mariell Jessup, MD (Hospital of the University of Pennsylvania, Philadelphia), who were not involved in the study, said the negative ASCEND results aren’t surprising, telling TCTMD that physicians and patients have continued to hope that some of these health supplements might provide cardiovascular benefit.

“In general, a third of patients are taking supplements,” said Poppas. “It would be nice to have some data behind it.”

Both Poppas and Jessup said that if they learn a patient is taking omega-3 fatty acids from a health food store, they encourage them to find better uses for their money. “You won’t hurt yourself, but you are not doing anything good,” said Poppas. “Spend your money on healthier food or fresh vegetables.”

Ileana Piña, MD (Montefiore Weiler Hospital, New York, NY), agreed, noting: “I have a lot of patients who want to take the omega acids and they spend a lot of money in these health food stores, and I always say, particularly to my women, eat fish three times a week and you will get all the omega fatty acids that you need. Plus, it tastes good.”

‘It Was a Disappointment’

The ASCEND trial was a 2x2 factorial trial that included patients 40 years and older with diabetes and no evidence of cardiovascular disease at baseline. Patients were randomized both to enteric-coated aspirin 100 mg daily or placebo and to supplementation with 1-gram capsules of omega-3 fatty acids or placebo. Bowman reported the fish oil results and the aspirin data were revealed in a separate presentation at the meeting.

Spend your money on healthier food or fresh vegetables. Athena Poppas

With 15,480 patients, ASCEND is the largest trial testing omega-3 polyunsaturated fatty acids to date, and with 7.4 years follow-up, also the longest. Patients in the trial had had diabetes mellitus for a median of 7.0 years, and the majority had low-to-moderate vascular risk. Those in the treatment arm received 1-g capsules containing 460 mg of eicosapentaenoic acid (EPA) and 380 mg of docosahexaenoic acid (DHA).   

Serious vascular events, which was defined as a composite of nonfatal MI or stroke, transient ischemic attacks, or vascular death (excluding intracranial hemorrhage), occurred in 8.9% of patients treated with omega-3 fatty acids and 9.2% of patients who received placebo, a nonsignificant difference. The rate of serious vascular events or coronary revascularization was also no different between the groups. Treatment with omega-3 fatty acids had no impact on the risk of vascular death.

“It was a disappointment because if one could find a cheap and safe supplement that could improve risk in people with diabetes then obviously we would have been very happy,” said Bowman. In subgroup analyses, there did not appear to be any suggestion of benefit with omega-3 fatty acid supplementation, including in those with higher vascular risk.

“Overall, we think guideline recommendations should be reconsidered,” she said.

Although the ASCEND population did not have cardiovascular disease, Bowman said patients with diabetes have two to three times the risk of the general population. Based on the ASCEND findings, “it is hard to put much emphasis now on using supplements even in secondary prevention,” she said. “One could argue this was a primary prevention trial, but when you add it in to the other data that has accumulated over the years, the consistency is very great—we’re not getting clear evidence of benefit.”

In 2012, the ORIGIN study, which included patients with diabetes and prediabetes, failed to show any effect of omega-3 fatty acid supplements on the primary endpoint of cardiovascular death. In secondary prevention, the evidence is conflicting, with GISSI-Prevenzione and JELIS both showing a treatment benefit with EPA/DHA supplements, but several others, including OMEGA, AREDS2, ALPHA-OMEGA, and SU.FOL.OM3, being negative.

‘Fish Oil Capsule Is Not a Fish’

The researchers selected the 1-g dose of omega-3 fatty acids based on earlier studies that showed promise. “The question does remain would a higher dose have been effective,” said Bowman. A much higher dose of prescription omega-3 fatty acid is currently being tested in the REDUCE-IT trial. In that study, investigators are testing a highly purified EPA for the reduction of cardiovascular events in statin-treated patients with high triglyceride levels and cardiovascular disease (or at high risk for cardiovascular disease).

Poppas said there might still be a role for prescription fish oil in the setting of hypertriglyceridemia, but “I’m surprised they continue to do studies on something that continues to show negative results.” As for the AHA recommendation stating fish oil is reasonable in secondary prevention, Poppas suspects that will change based on the new ASCEND data.

Commenting on the observational studies that have shown fish consumption once or twice per week lowers the risk of heart disease, Bowman said a “fish oil capsule is not a fish, and if you’re eating a fish you’re probably not eating a 10-oz steak.” In other words, teasing out confounding variables can be difficult. The bottom line, said Bowman, is that they are not advocating removing fish from the diet.

Francois Schiele, MD, PhD (Université de Franche Comté, Besançon, France), who moderated the press conference, said the ASCEND data provides solid evidence that omega-3 fatty acid supplements are “completely useless.” Instead, the focus should be on getting patients to take and adhere to optimal medical therapy. For diabetics, that therapy includes statins, a drug class that has been vilified in the lay media.   

“It’s a new part of primary and secondary prevention, to explain to the patient each line of treatment and to remind them to be careful about medical information that isn’t coming from physicians,” he told TCTMD.