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Study sends wrong message about omega-3 fatty acids and prostate cancer
Ophthalmologists who treat dry eye disease have to disseminate correct information to counter flawed study conclusions.
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By all accounts we are in the midst of an epidemic of age-related macular degeneration, dry eye disease and meibomian gland dysfunction in the United States. We cannot escape the fact that this coincides with a dramatic drop in the ingestion of omega-3 fatty acids and an increase in omega-6 fatty acids in the typical American diet. Studies have shown a beneficial effect in the treatment of both dry eye disease and meibomian gland dysfunction by increasing omega-3 fatty acid intake. Those of us who treat dry eye disease are now conversant with various types of omega-3 fatty acids and their composition, absorption and measurement. While we have begun to ramp up our use of this supplement, typically in the form of marine or fish oil, some challenges have arisen to make our task more difficult.
Studies cast doubt
Last fall, two published studies cast doubt on the safety and efficacy of omega-3 fatty acid supplementation. In our eye care world, the publication of the AREDS2 confirmed that relatively high doses of antioxidant vitamins with the addition of lutein and zeaxanthin and the removal of beta-carotene were at least as effective at reducing the progression of high-risk AMD as the original AREDS formula. However, omega-3 fatty acid was not found to have any beneficial effect. Numerous commentators have noted that the dose and quality of the fish oil used in the AREDS2 were substantially lower than those in present use. Also noted was the relatively concurrent publication of findings from the epic Women’s Health Study that showed an approximately 27% decrease in vision loss due to AMD in women who consumed the highest levels of omega-3 fatty acids in the triglyceride forms DHA and EPA.
Of greater interest to those of us in the business of dry eye care was the publication of the article “Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial.” In reality this was a reworking of data mined from a study of the risk of selenium and vitamin E ingestion on prostate cancer, a study that was never intended to examine omega-3 fatty acids at all. Despite this flaw present from the outset, the authors went on to the rather sweeping conclusion that omega-3 fatty acids in the triglyceride forms are “involved in tumorigenesis” and caused prostate cancer. This sensational “finding” was naturally trumpeted blindly (pun intended) by all manner of nonscientific media outlets at pretty much the same time that ophthalmologists were beginning to prescribe omega-3 fatty acids for ocular surface disease associated with meibomian gland dysfunction.
Study’s flaws
Because pretty much all of us gathered here take part in the care of dry eye disease, let’s take a few moments to dissect this study and all of its flaws so that we can 1) remain comfortable that prescribing high doses of omega-3 fatty acids is safe and proper and 2) have a ready response for both our patients and their primary care doctors when they express concerns.
Let’s begin with the fact that prior studies that included more than 500,000 subjects have shown that omega-3 fatty acids reduce the risk of prostate cancer. There is a significant disconnect with well-known epidemiological statistics; the study’s conclusion flies in the face of the fact that countries with a high fish-eating diet have significantly lower rates of prostate cancer. Indeed, several population-based studies have shown a benefit of increased omega-3 fatty acid intake to reduce prostate cancer risk.
The study itself is flawed in multiple ways. The cohorts were chosen and controlled for selenium and vitamin E intake. Because the study was not designed to evaluate omega-3 fatty acid intake, there was control of neither the amount nor the source (fish vs. fish oil) of omega-3 fatty acids. The authors based their conclusions on a single blood test of plasma phospholipid fatty acids rather than the more accurate and actionable measurement of omega-3 fatty acids in the cell membranes of red blood cells. Plasma phospholipid fatty acid levels do not measure long-term intake and can be dramatically influenced by a single dose or meal. Red blood cell membrane levels accurately portray the true long-term intake. In addition, no effort was made to control for important known risk factors for prostate cancer, a study design flaw whether one is looking at omega-3 fatty acid or selenium/vitamin E risk.
Finally, let’s take a look at the results and how they were analyzed. The conclusions are based on a 0.18% difference in omega-3 fatty acid level (4.66% in the combined cancer group vs. 4.48% in the control), a difference that did not reach the level of statistical significance when individual omega-3 fatty acids, such as EPA and DHA, were evaluated. Cox proportional hazards, the statistical method chosen for the comparison, is more often used when the substance under consideration is applied in a uniform manner, such as four times a day or continuous dosing. Omega-3 fatty acid ingestion was neither controlled nor even recorded. The numbers in the subgroups are very small. One must wonder if they are sufficient to provide adequate statistical power to the study. Perhaps we will see the data re-explored using a model that takes into account the issues with the study and cohort controls.
Responding to the conclusion
In the end, we, and our patients, are left the victims of sensationalism of a poorly designed study with a boldly proclaimed conclusion that seems to be weakly supported by its own findings. This conclusion has been roundly and soundly refuted by countless previous studies, epidemiological data and a multitude of experts in the field. The publication and subsequent media interest have led to the creation of unwarranted fear and confusion in both our patients and their family doctors, in turn making it more difficult for us to convince our patients that high doses of marine omega-3 fatty acids are a part of an effective treatment regimen for meibomian gland dysfunction and associated ocular surface disease.
How should we respond? Certainly, if asked, we should accept invitations to discuss this with mainstream media outlets. In our offices, a brief written summary of the issue that concludes with a firm denunciation of the article and an equally firm endorsement of marine omega-3 fatty acids is the minimum. At SkyVision, we have found that giving patients this form upfront dramatically reduces the time we need to devote to this issue. Those of you with websites, blogs or other media outlets may wish to address it in these places, too. Nutritional support with high doses of high-grade marine omega-3 fatty acids plays an important role in the treatment of our dry eye patients. Let’s not let suspect science and lazy reporting take it away from us.