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Nissen SE. Omega-3 Fatty Acids and Cardiovascular Outcomes: Anatomy of a Fish Story. Presented at: American Association of Clinical Endocrinology Annual Scientific and Clinical Conference; 26.-29. May 2021 (virtual meeting).

Disclosure:
AstraZeneca funded the STRENGTH study. Nissen reports that he has received institutional research grants from AbbVie, Amgen, AstraZeneca, Eli Lilly, Esperion, Ethicon Endosurgery, Medtronic, Novartis, Orexigen, Pfizer, Resverlogix, Takeda, and The Medicines Company; and that he does not accept personal or industry fees.

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The evidence that eating fish can reduce the risk of cardiovascular events is “weak,” and data from several large studies suggests that supplementing fish oil is cardiovascular neutral and, according to a spokesman, even risk for atrial fibrillation can increase.

Data from a secondary analysis of the STRENGTH study presented at the American College of Cardiology scientific meeting in May showed that higher blood levels of eicosapentaenoic acid (EPA) 1 year after daily omega-3 carboxylic acid supplementation did not result in lower cardiovascular levels Risk associated with hypertriglyceridemia and high risk of cardiovascular disease in adults, Steven E. Nissen, MD, MACC, Chief Academic Officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, said during a presentation at the American Association of Clinical Endocrinology virtual meeting. STRENGTH’s data comparing 4 g omega-3 carboxylic acid daily to corn oil placebo were similar to the neutral results seen in large, low-dose omega-3 fatty acid studies such as VITAL, ASCEND, and ORIGIN. However, the debate about omega-3 supplementation continues after the REDUCE-IT study presented in 2018, which showed that a pharmaceutical-grade omega-3 fatty acid containing pure EPA, icosapentethyl (Vascepa, Amarin), reduced the risk for ischemic events in a similar patient population.

Nits is that Chief Academic Officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic.

In addition, researchers observed a higher incidence of new atrial fibrillation in the omega-3 groups in several studies including STRENGTH and REDUCE-IT, Nissen said.

“We are faced with a dilemma and clinicians have to decide what to do,” Nissen, also director of the STRENGTH study, told Healio. “If you put this in the context of the very strong increase in atrial fibrillation that can now be observed in three studies – REDUCE-IT, STRENGTH and ONEMI – the question arises as to whether one should do one of them [fish oil] Products more benefit than harm? I am not convinced that they will. “

Comparison of studies

As Healio previously reported, data from STRENGTH, first presented at the American Heart Association’s virtual scientific sessions in November, showed that administration of high-dose omega-3 carboxylic acid, a combination of EPA and docosahexaenoic acid (DHA), was compared to Corn oil placebo did not reduce the risk for the primary endpoint, a combination of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina that required hospitalization. The post-hoc STRENGTH analysis, unveiled in May, showed that scores remained unchanged when evaluating participants in the highest tertile of EPA blood levels – those who saw an average increase of 443%. The new analysis also showed no evidence of damage in participants in the top tertile of the DHA level.

The STRENGTH results were in stark contrast to the REDUCE-IT study, which showed that icosapentethyl, a pharmaceutical-grade omega-3 fatty acid that contains EPA but no DHA, was superior to placebo in terms of risk of ischemic events in adults with hypertriglyceridemia at high risk of CV.

Nissen and other researchers have suggested that the placebo used could explain the difference. In REDUCE-IT, the researchers used 4 g of mineral oil placebo as a comparison substance with significant side effects, said Nissen. In year 2 of REDUCE-IT, participants who were assigned mineral oil had an average increase in LDL cholesterol of 11.4% and an average increase in highly sensitive C-reactive protein of 32.3%. In STRENGTH, participants who were assigned corn oil saw an average decrease in LDL cholesterol of 1.1% and an average decrease in highly sensitive C-reactive protein of 6%.

“Mineral oil has a tremendous adverse effect on lipids,” said Nissen. “When REDUCE-IT came onto the market, I was skeptical from day one, that is a really positive result. Then I saw the lipid and inflammation effects and was quickly convinced it was a false positive study. The 32% increase in C-reactive protein in the mineral oil group is not trivial. Nobody will ever be able to prove whether it is enough to drive the results forward. “

“I don’t think we have the answer to fish oil, but I don’t think that REDUCE-IT can be accepted without repeating the study with a neutral placebo,” said Nissen during his presentation.

Dealing with mixed news

Clinicians are now hearing two “fish stories,” said Nissen: That a pure EPA omega-3 fatty acid formulation used in REDUCE-IT is superior to a combination of EPA / DHA formulations such as those used in STRENGTH and that DHA has some of the benefits of EPA, which led to the neutral CV results in other studies.

Nissen disagrees.

“If EPA is beneficial, we should have seen something in the participants who saw a huge EPA increase in STRENGTH,” Nissen told Healio. “EPA is EPA. We often hear that a certain version of a product has pleotropic effects or a particular benefit. That was generally not very well received. “

Given the available data on the risk of developing atrial fibrillation, Nissen said he could “not justify” prescribing fish oil products to patients, barring very specific circumstances.

“I use the drug on people whose triglyceride levels are above 500 mg / dL because there is at least some reasonable evidence of it [supplementation] could prevent pancreatitis, ”Nissen told Healio. “That’s a very small number of people. In the absence of this, I do not feel comfortable prescribing these drugs. “

“I’ll leave you with a little ironic comment,” said Nissen at the end of his presentation. “Forget about fish oil. Just use olive oil for cooking and for your salads. “

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Annual meeting of the American Association of Clinical Endocrinology

Annual meeting of the American Association of Clinical Endocrinology

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