Another Bust For Omega-3 Fatty Acids – It’s Time To Go Fishing Elsewhere

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Written By

Tonya Coles, Pharm.D.
Dave L. Dixon, Pharm.D., BCPS, CDE, CLS

Reviewed By

Dawn Fuke, Pharm.D., BCPS
Joseph Saseen, Pharm.D., BCPS, CLS

Citation

The ORIGIN Trial Investigators. n–3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia. N Engl J Med 2012; 367: 309-318.

The biggest superstar in the dietary supplement industry is fish oil.  It is available over-the-counter and you can even buy orange juice fortified with it. Unfortunately, most of these products contain very low amounts of omega-3 fatty acids (O3FA). The most concentrated source of omega-3 fatty acids is found in the prescription product, Lovaza®, which enjoys $1 billion in sales annually in the US alone.1 And yet, it’s only FDA-approved indication is for lowering triglycerides in patients with severe hypertriglyceridemia (greater than 500 mg/dL).2  It's reasonable to assume there is A LOT of off-label use of Lovaza®.

We’ve been hooked on O3FA ever since we associated the low rate of cardiovascular disease in the Eskimo population with their high intake of O3FA. Then the GISSI-Prevenzione study found that 1g of O3FA reduced death, non-fatal myocardial infarction (MI), and stroke in patients with a recent MI.3 However, this study had several notable flaws including it’s open-label study design. Several meta-analyses have come to mixed conclusions regarding the cardiovascular benefits of O3FA.4,5 Lovaza® was approved in 2004 based on its ability to lower triglycerides – not outcome data.  A previous study sought to determine if Lovaza® 4g daily could reduce atrial fibrillation recurrence in patients with paroxysmal atrial fibrillation.6  But, alas, no benefit was found. The ORIGIN study is long overdue.  It was designed to prove what we’d assumed was true – that 1gram of O3FA (Lovaza®) could improve cardiovascular outcomes.

The ORIGIN trial was a 2-by-2 factorial, randomized, prospective, multi-center, double blind study designed to evaluate two separate interventions, insulin glargine and omega-3 fatty acids (O3FA). The aim of ORIGIN was to determine if O3FA would reduce death from cardiovascular causes in high-risk individuals with dysglycemia compared to standard of care and placebo. Secondary outcomes included MI, stroke, death from any cause, and death from arrhythmia. 

Dysglycemia was defined as impaired glucose tolerance, impaired fasting glucose, or having a diagnosis of diabetes. Standard of care was determined by the 573 clinics that were represented in the study. Participants eligible for the study included those greater than 50 years of age and taking no more than 1 oral diabetes medication, if diagnosed with diabetes. Exclusion criteria included HbA1c more than 9%, severe heart failure, cancer, or a CABG within the previous 4 years. 

The trial enrolled 12,536 patients from 40 countries who were randomized to receive 1g of O3FA or a placebo containing 1 g of olive oil daily. No differences were noted between the groups at baseline. The mean age was 64 years and the majority of participants were men. According to baseline patient questionnaires, the estimated dietary consumption of DHA and EPA rich foods was similar, about 210 mg per day.

After a mean follow-up of approximately six years, no significant differences were found between the study groups for the primary or secondary outcomes.  See Table 1.  As expected, patients in the O3FA group had a greater reduction in triglycerides compared to placebo (23.4 mg/dL versus 9 mg/dL, p<0.01). The study authors concluded that 1g of O3FA daily does not reduce cardiovascular death or cardiovascular-related events in high-risk patients with dysglycemia. 

Table 1. Primary and Secondary Outcomes

Outcome

Hazard Ratio (95% CI)

Primary

 

   CV death

0.98 (0.87-1.1)

Secondary

 

   MI, stroke, or CV death

1.01 (0.93-1.10)

   Death from any cause

0.98 (0.89-1.07)

   Death from arrhythmia

1.10 (0.93-1.30)

   Fatal and nonfatal MI

1.09 (0.93-1.27)

   Fatal and nonfatal stroke

0.92 (0.79-1.08)

   Hospitalization for HF

1.02 (0.88-1.19)

   Revascularization procedure

0.96 (0.87-1.05)

                            CV=cardiovascular; MI=myocardial infarction; HF=heart failure

Overall, the ORIGIN trial was well designed and had reliable patient follow up. There are a few things to note, however. Close to 60% of the study population had a history of myocardial infarction, stroke, or revascularization.  Nearly 80% had hypertension and 82% a diagnosis of diabetes. Thus, a majority of study participants were already receiving cardioprotective therapies (e.g., ACE-Inhibitors or ARBs, statins, beta-blockers, and aspirin). And their baseline A1c, blood pressure, and cholesterol levels were fairly well controlled. Compared to the GISSI-Prevenzione and GISSI-HF7 trials, more of the ORIGIN trial participants were receiving statins at baseline.  In other words, there probably wasn’t much room for improvement.                                       

But why did O3FA provide a benefit in the GISSI-Prevenzione and GISSI-HF studies but fail to do so in ORIGIN?  It has been hypothesized that the reduction in sudden cardiac death observed with O3FA in the post-MI and heart failure populations was related to the antiarrhythmic properties of O3FA, resulting in a reduction in fatal arrhythmias. The American Heart Association recommends 1g of O3FA for secondary prevention8, so perhaps the addition of O3FA was simply too late for the ORIGIN population.  After all, the majority of these patients had already had a CV event.  Perhaps there would have been a benefit if the study had included only primary prevention patients.

The O3FA dose in this study was 1g daily and some contend that this dose may have been too low. While this is plausible, the “cardioprotective benefits” of O3FA have only been observed with lower doses. The only FDA-approved dose is 4 grams daily, which is utilized to lower triglycerides in patients with severe hypertriglyceridemia. Furthermore, one study which followed 3,114 men with angina who ate oily fish twice a week or took ~1g of O3FA from a non-prescription fish oil supplement found an increase in mortality.9

ORIGIN follows recent studies (e.g., ACCORD Lipid, AIM-HIGH) evaluating combination lipid lowering therapies that have found no additional benefit over statins alone. And ORIGIN validates the findings from two previously published O3FA studies:  the SU.FOL.OM3 study conducted in France and the Alpha Omega Trial conducted in the Netherlands.10,11  Off-label use of prescription O3FA is excessive and will likely increase once the EPA-only prescription product, Vascepa®, becomes available. Over-the-counter “fish oil” use by our patients is ubiquitous and they are being used for a wide variety of purported health benefits, despite their low amounts of actual O3FA and lack of supportive evidence. In this population of individuals with dysglycemia, O3FA provided no additional benefit beyond what can be obtained with other, well-established cardioprotective therapies. The excessive off-label use of Lovaza® and overuse of OTC “fish oil” is a major concern and ORIGIN reminds us to limit O3FA use to those with severe hypertriglyceridemia. How do YOU see the ORIGIN trial impacting your practice?

Comments

2

"American Heart Association recommends 1g of O3FA for secondary prevention, so perhaps the addition of O3FA was simply too late for the ORIGIN population. After all, the majority of these patients had already had a CV event. Perhaps there would have been a benefit if the study had included only primary prevention patients." For me, this is the impact statement of your review. I wouldn't expect O3FA to have a major impact on patients who are already on all of the recommended prescription meds. Where these products/foods could benefit the population might be BEFORE they have CV events or need all of the prescriptions. Do you think that we will get a large scale study on that?

Thank you for your comment Kelly. I doubt we will ever get that type of data because of the associated cost and large study population that would be required. Primary prevention is expensive and difficult in this day and age. What we could do is study patients at high CVD risk (Framingham >20%). That might be doable. I'm not aware of any ongoing studies looking at this.