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Omega-3 Heart Trial Fails the Test
6/14/2012
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We just returned from a conference featuring presentations by leading researchers in the field of omega-3s and heart disease, from Harvard University, the American Heart Association, (AHA) and Europe.
 
All agreed that the evidence showing cardiovascular health benefits from omega-3s is overwhelming.
 
(You'll find the official positions of various public health authorities in the section of our Omega-3 Facts & Sources page titled “Omega-3 EPA and DHA: Key heart-health allies”.)
 
And the AHA’s William Harris, Ph.D., deplored the undue attention paid to three recent trials whose small size, short durations, and/or other flaws rendered their “no benefit” conclusions unreliable.
 
Now, another flawed clinical trial is the subject of worldwide headlines … to the detriment of public health and those diagnosed with or concerned about heart disease and/or diabetes.
 
For a very well-informed, scientific perspective, we interviewed leading omega-3 chemist Dr. Doug Bibus, Ph.D., who performs the omega-3 and full blood-fat analyses for users of our Vital Omega-3 and 6 HUFA Test™.
 
Dr. Bibus is a widely recognized expert in fatty acid nutrition and the impacts of fatty acids and other lipids on human health.
 
We recommend that you read his comments … which echo and expand on the flaws and limitations acknowledged by the authors of the new clinical trial.
 
Well start by describing the trial’s design and outcomes, and quote the authors’ own critiques of its design.
 
Clinical trial in diabetics finds no cut in heart-related deaths or hospitalizations
This six-year-long clinical trial was part of the larger Outcome Reduction with Initial Glargine Intervention (ORIGIN) study.
 
The ORIGIN trial was conducted by researchers from Canada’s McMaster University and Hamilton Health Sciences, and was published online this week in The New England Journal of Medicine (Gerstein HC et al. 2012).
 
The authors recruited 12,536 adults deemed at high risk for cardiovascular disease due to a diagnosis of either type-2 diabetes or pre-diabetes (impaired fasting glucose or impaired glucose tolerance).
 
Their average age was 64 years and 35 percent were women.
 
The participants were randomly assigned to one of two groups:
  • The Omega-3 Group took fish oil capsules providing 900mg of omega-3 fatty acids (EPA + DHA).
  • The Placebo Group took capsules containing 1 gram of olive oil.
After six years, the Omega-3 Group did not show reduced rates of heart-related deaths, heart attacks, stroke, or hospitalizations for any cardiovascular cause
 
However, the patients in the Omega-3 Group enjoyed a bigger drop in their triglyceride levels, which was 14.5 mg/dL larger than the reduction seen among those receiving placebo pills. There was no significant impact on other blood fats.
 
The researchers said that their findings should not be taken to lessen the value of dietary recommendations to eat more fish.
 
They explained that eating fish “… not only increases the intake of foods containing omega–3 fatty acids but is also associated with a reduction in the consumption of foods such as red meats, which may be harmful.” (Gerstein HC et al. 2012)
 
Authors acknowledge their study's limitations and flaws
We applaud the care the researchers took to point out the inherent limitations and flaws of their study design … and as you’ll see below, omega-3 expert Dr. Doug Bibus sees others that they didn’t mention.
 
First, both groups were taking either glargine (a long-acting synthetic form of insulin) or receiving standard care for diabetes or high blood sugar, which would reduce their risk for adverse heart health outcomes.
 
And, unlike previous studies that showed cardiovascular benefits from supplemental fish oil, some of the participants in the ORIGIN trial were also taking various cardio-protective drugs (e.g., statins) ... a fact that likely diminished their ability to detect beneficial effects in the omega-3 group.
 
The researchers also acknowledged that the dose of omega-3 fatty acids used in the study may have been too low to detect any effect … especially since the participants were already taking various heart drugs that reduce risk.
 
The authors summarized those limitations of their trial this way:
These two possibilities are supported by the results of a recent trial, which did not show a beneficial effect of omega–3 fatty acids in patients who had had a myocardial infarction [heart attack] and were receiving concomitant therapies [heart drugs] at proportions similar to those in our study.” (Gerstein HC et al. 2012)
 
In addition, as they said, other, successful trials involved patients who'd recently suffered a heart attack or been diagnosed with heart failure.
 
Compared with the ORIGIN trial participants, those people might have been more likely to benefit from any potential anti-arrhythmic effect of omega-3s (i.e., omega-3s tend to normalize heart rhythms).
 
Further, they noted that the, participants in successful clinical trials may have had lower daily “background” intakes of omega-3s (from seafood) than the 210mg per day estimated for the ORIGIN trial’s subjects … which might explain why those earlier trials detected substantial benefits from supplemental omega-3s.
 
The researchers also pointed out that their study involved patients with pre-diabetes or diabetes, and “omega-3 fatty acids may not be effective in such patients” (Gerstein HC et al. 2012).
 
Finally, they acknowledged that in other trials, participants with diabetes or other blood-sugar control problems did show benefits from omega-3 supplements.
 
Omega-3 expert offers a cogent critique of the ORIGIN trial
We spoke with Dr. Bibus to get his perspective on the findings of the ORIGIN trial, and are pleased to present his responses here.
 
As we noted, Dr. Bibus performs the omega-3 and full blood-fat analyses for users of our Vital Omega-3 and 6 HUFA Test™, and is a recognized expert in fatty acids and their impacts on human health.
 
Among other professional distinctions, he’s a two-time winner of the American Chemical Society’s Award in Analytical Chemistry.
 
Vital Choices: Dr. Bibus, would you share your observations on the newly published trial, which tested omega-3 fish oil in people with diabetes or pre-diabetes?
 
Dr. Bibus:
I see several problems, some of which the authors acknowledged.
 
First, there was no attempt to prove “compliance” by the participants.
 
Although the subjects in the omega-3 fish oil group claimed that they actually took the supplements, the authors did not test the participants’ blood for omega-3 levels before and after the study period.
 
As they wrote, “… assessment of whether the effect of n–3 fatty acids on death from cardiovascular causes varied according to dietary intake of n–3 fatty acids was based on the use of a dietary questionnaire rather than measurement of serum [blood] levels.” (Gerstein HC et al. 2012)
 
Blood testing would have allowed the researchers to determine the degree of compliance with their assigned daily regimen (fish oil or olive oil) by the test and control groups, or the effects of their normal diet on the omega-3 levels in the fish oil group. 
 
Thus, it was impossible to know the extent of compliance and the degree to which the omega-3 supplements affected the subjects’ blood levels, as opposed to their intake of fish (or unauthorized, unreported consumption of extra fish oil).
 
Second, the test dose may have been too low.
 
A substantial body of research suggests that omega-3 intakes above 900mg per day may be needed to reduce cardiovascular risks for most people.
 
This may be because of their high intakes of competing omega-6 fatty acids, and other risk factors.
 
For example the American Heart Association recommends that heart patients consume at least 1,000mg of omega-3s per day, and up to 4,000mg to lower triglyceride levels.
 
Research by Dr. William Harris – a member of the AHA expert panel that established those recommendations – concluded that many people require 1,000mg per day to raise their omega-3 blood levels enough (minimum of eight percent of red blood cell fatty acids) to reduce cardiovascular risks substantially.
 
A study by his colleague, Dr. Clement von Shacky, found that more than half of the people who took 1 gram (1,000mg) of EPA + DHA daily failed to raise the proportion of omega-3s in their red blood cells to eight percent.
 
This measure of the proportion of omega-3s in red blood cell membranes – called the Omega Index – was co-developed by Drs. Harris and von Shacky.
 
They've shown, based on the results of many studies, that achieving an Omega Index of eight percent reduces the risk of cardiovascular disease substantially, while levels significantly lower than that do not. 
 
Third, the subjects’ regular consumption of fish could blunt the impact of the omega-3 supplements, because doses above a certain level would not increase amount of risk reduction. 
 
The subjects’ average daily intake of EPA and DHA from seafood was estimated at 210mg per day. 
 
Because most Americans consume less than 75mg per day of EPA + DHA, the fact that these folks were consuming three times that amount suggests that many of these patients were already on fish oil supplements. 
 
Again, testing their blood omega-3 levels before and after the study would have shown how many subjects were consuming substantial amounts of omega 3 fatty acids on top of the provided fish oil supplements. 
 
If you are sick, have elevated triglyceride levels (which, by the end of the trial were reduced among those taking the fish oil) and a strong chance of dying from cardiovascular disease, would you be willing to stay on what could be placebo, and avoid taking an omega 3 supplement as “insurance”?
 
Dr. Dariush Mozaffarian from Harvard University’s School of Public Health has led many of the largest studies looking for links between omega-3 intake and risk of heart disease.
 
His team has concluded, based on their analyses of many epidemiological (diet-health) studies, that a minimum daily intake of 250mg of EPA + DHA is required to reduce cardiovascular risks substantially.
 
If this is true, than the subjects’ regular intake of 210mg of EPA + DHA – undoubtedly due to fish and omega 3 supplements in their diet – would almost meet that threshold, and therefore reduce the impact of the added amount (900mg daily) provided by the supplements. 
 
Fourth, the authors did not test the subjects’ blood for levels of omega-6 arachidonic acid, which is strongly linked to higher risk of cardiovascular disease through its generally (not exclusively) pro-inflammatory impacts. 
 
Aspirin is recommended to heart patients because it reduces inflammation by inhibiting the metabolism of this omega-6 fatty acid. 
 
Harvard’s Dr. Charles Serhan and others recently discovered that both aspirin and omega-3 DHA stimulate the release of very powerful DHA-derived inflammation-ending agents called immune resolvants.
 
For these and other reasons, omega-3 fatty acids from fish oil provide a natural way of keeping dietary omega-6 fatty acids from promoting and sustaining chronic inflammation, which is a driving force in cardiovascular disease.
 
And, given the very high levels of omega-6 fatty acids in the average American’s diet, it may take daily intakes of omega-3s even higher than 900mg to fully counter this imbalance.
 
Vital Choices: Do you have any general recommendations to improve the reliability of future trials?
 
Dr. Bibus: This study will hopefully highlight the need to run omega-3 and omega-6 blood tests before and after clinical trials testing the effects of fish oil supplements, at least a subset of patients.
 
The lack of benefit measured in this trial also suggest that researchers should consider using doses that result in healthful balances of omega-6 and omega-3 fatty acids in the blood, which reflects the amounts and proportions in the cell membranes.
 
 
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