Omega-3 Fatty Acid Therapy: What Comes Next?

The proposed beneficial role of omega-3 fatty acids in the reduction of cardiovascular (CV) events seemed to take a hit this summer when results of the ORIGIN trial¹ (n–3 fatty acids and cardiovascular outcomes in patients with dysglycemia) were announced.

In patients with CV disease or who were at high risk for developing disease and who had dysglycemia or a diagnosis of type 2 diabetes, a combination of DHA and EPA did reduce triglyceride levels but failed to reduce the risk of death, the primary cardiovascular endpoint, or to reduce secondary ischemic endpoints.

On the other hand, the FDA just announced its approval of a new icosapent ethyl formulation for treatment of severe hypertriglyceridemia-making it the second prescription fish oil preparation available.
• Just what are the expectations for omega-3 fatty acid therapy?
• In the absence of outcome trials, how should these formulations be prescribed and which patients will benefit most?

Omega-3 Fatty Acid Therapy

In this short podcast, CardiologyNow host Dr Payal Kohli asks Harvard cardiologist and preventive cardiology expert Dr Deepak Bhatt to address these and other questions and to help put fish oil therapy in to context for primary care practitioners. Dr Bhatt is Chief of Cardiology at VA Boston Healthcare System and Director of the Integrated Interventional Cardiovascular Program at Brigham and Women's Hospital and VA Boston Healthcare System. He is also a Senior Investigator in the TIMI Study Group and Professor of Medicine at Harvard Medical School. Dr. Kohli graduated from Harvard Medical School, completed her internal medicine training in Boston, and is currently a fellow in cardiovascular medicine at the University of California San Francisco.

Take-home points
1. The ORIGIN trial failed to show a reduction in primary endpoint of cardiovascular death or secondary ischemic endpoints using fish oils in patients with dysglycemia, followed for a median of ~6 years. There could be several reasons for this:

a. Low baseline triglycerides in this patient population, which minimized benefits of additional reductions
b. Concentration of EPA, the cardiovascularly “active” component of the formulation of fish oil used, was relatively low
c. The dose of fish oil may have been too low.

2. The FDA has approved 2 prescription fish oil formulations: omega-3-acid ethyl esters (Lovaza) and icosapent ethyl (Vascepa). The primary difference between them is the amount in each of EPA, the “active” component of the fish oil. No safety signals have been associated with these formulations and they have been well-tolerated.
3. In patients receiving statin therapy to reduce LDL-C, reducing triglycerides has not yet been shown to directly decrease the risk of adverse outcomes. In patients with very high triglycerides, who are at increased risk for pancreatitis, prescription fish oils have proven to be effective and are recommended.
4. Use of over-the-counter fish oil supplements should be discouraged because these formulations are not regulated.

Reference
1. Bosch J, Gerstein HC, Dagenais GR, et al. The ORIGIN Trial Investigators. n–3 fatty acids and cardiovascular outcomes in patients with dysglycemia.N Engl J Med. 2012; 367:309-331.

Additional reading
• Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098. Accessed August 13, 2012, at: http://www.ncbi.nlm.nih.gov/pubmed/17398308.

• Amarin Pharma Inc. A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. (REDUCE-IT). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2012 Aug 20]. Available from: http://clinicaltrials.gov/ct2/show/study/NCT01492361?term=REDUCE-IT&rank=1&show_locs=Y#locn. NLM identifier: NCT01492361.