July 2018


Cornea editor’s corner of the world
Study shows little effect from omega-3 fatty acids

by Rich Daly EyeWorld Contributing Writer

LipiView (Johnson & Johnson Vision) image of 31-year-old male with emergency presentation for pain and blurring of vision in both eyes. The tear osmolarity was OD 339 and OS 347, the InflammaDry test (Quidel) was positive OU, and he was diagnosed with MGD with OSD and DED.

LipiView image of MGD and DED patient, who was started on preservative-free artificial tears, re-esterified oral omega-3 liquid 1 teaspoon per day with food, a Bruder microwaveable heated mask, lifitegrast OU BID, and a short course of loteprednol etabonate OU BID with no refills. He was scheduled to return for a LipiFlow treatment.
Source (all): Cynthia Matossian, MD

The results of the Dry Eye Assessment and Management (DREAM) study were recently published in the New England Journal of Medicine.1 This was a multicenter, double-blinded prospective clinical trial with dry eye patients randomly assigned to omega-3 fatty acids versus olive oil placebo for 12 months. Omega-3 fatty acids have anti-inflammatory properties and are abundant in some plant oils (walnuts, flaxseed, and canola) and fish. It is commendable that Penny Asbell, MD, et al. have successfully designed and conducted this study. The findings were certainly interesting with no significant difference between groups with respect to Ocular Surface Disease Index scores (both groups had decreased scores) and signs of dry eye.
A few things to keep in mind when interpreting these results include the fact that dry eye studies have a notoriously high placebo effect. All dry eye patients were recruited, not just those with primary blepharitis/meibomian gland deficiency or rosacea-related ocular surface disease, for which omega-3 fatty acids work best. Patient were able to continue all other therapies during the study including cyclosporine, lubrication drops, warm compresses, lid hygiene, etc., and participating in a study could have improved compliance overall in these patients. Olive oil has been touted to be a key component of the “Mediterranean diet,” and ideally, a true placebo would have strengthened the study. Finally, there have been decades of research not just in ophthalmology but also in the cardiovascular literature regarding the positive benefits of omega-3s. In the Women’s Health Study of 32,470 women aged 45–84, a higher dietary intake of omega-3 (versus omega-6) was associated with a decreased incidence of dry eye.2 Cardiovascular research has shown that omega-3 fatty acids decrease risk of arrhythmias, decrease triglyceride levels, slow growth rate of atherosclerotic plaques, and can slightly lower blood pressure.3 Personally, I have continued to advise my patients to take up to 3 grams of omega-3 fatty acids in the re-esterified triglyceride form consistent with the recommendations of the American Heart Association.
In this month’s “Cornea editor’s corner of the world,” Dr. Asbell, Anat Galor, MD, Cynthia Matossian, MD, and John Sheppard, MD, discuss more details of the DREAM study, how they interpret the data, and the impact this study will have in their practice in the management of dry eye patients.


1. Asbell PA, et al. n-3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378:1681–1690.
2. Miljanovic B, et al. Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Clin Nutr. 2005;82:887–93.
3. www.heart.org/HEARTORG/HealthyLiving/HealthyEating/HealthyDietGoals/Fish-and-Omega-3-Fatty-Acids_UCM_303248_Article.jsp#.WxvcTy7wYgA

Clara Chan, MD,
Cornea editor

Recent research finds that placebo had equivalent efficacy as a mainstay dry eye treatment

Clinicians have long recommended the use of supplements of n-3 fatty acids (omega-3 fatty acids) to relieve dry eye symptoms. Recent research has cast doubt on that treatment.
A multicenter, double-blind clinical trial with randomly assigned moderate to severe dry eye patients provided 329 patients with a daily oral dose of 3,000 mg of fish-derived n-3 eicosapentaenoic and docosahexaenoic acids, and 170 patients received an olive oil placebo for 12 months.
The study, known as the Dry Eye Assessment and Management (DREAM) trial, found no significantly different mean change in the score on the Ocular Surface Disease Index between the active supplement group and the placebo group (−13.9 points and −12.5 points).1
The results were consistent across pre-specified subgroups.
Additionally, the study found no significant differences between active and placebo groups in mean changes from baseline in the conjunctival staining score, corneal staining score, tear breakup time, and the Schirmer’s test.
“It definitively showed [an omega-3 fatty acid supplement] was not more beneficial than placebo in the year-long study,” said Penny Asbell, MD, professor of ophthalmology, Icahn School of Medicine at Mount Sinai, New York. “Given those results, I don’t see recommending omega-3 to patients who are symptomatic and have moderate to severe dry eye disease. It doesn’t seem to be any better than placebo.”
Anat Galor, MD, associate professor of ophthalmology, Bascom Palmer Eye Institute, University of Miami, described the research as “well executed,” although there are different interpretations of the results.
“But the fact stands that the active omega-3s did not do any better than the olive oil,” Dr. Galor said.
Fatty acid supplements’ role as the first treatment offered by most clinicians treating dry eye due to its track record and peer-reviewed findings of its safety and efficacy make the study’s finding “borderline shocking,” said John Sheppard, MD, clinical director, Thomas R. Lee Center for Ocular Pharmacology, Eastern Virginia Medical School, Norfolk, Virginia.
“The results were surprising for just about everyone in the dry eye field,” Dr. Sheppard said.

Concerns raised

Among those raising questions about the study was Cynthia Matossian, MD, in private practice in New Jersey and Pennsylvania. Dr. Matossian said the study failed to provide the scientific structure required to define conclusive outcomes because patients were permitted to use a wide variety of treatments for their dry eye including topical cyclosporine and could change adjunctive therapies at will.
“As a result, I think there were too many variables allowed to derive a strong conclusion,” Dr. Matossian said.
Dr. Galor understands that there are criticisms regarding the use of other medications during the trial. However, this design was chosen in order to study the use of omega- 3s in a “real world setting.” While some view this as a weakness, it can also be considered a strength of the study. Other strengths included the large number of patients enrolled and lack of commercial interests as the study was funded by the National Eye Institute at the National Institutes of Health.
Dr. Asbell said the patients were chosen to reflect the typical dry eye patient who comes into ophthalmologists’ offices.
“They have already tried tears, maybe some other things, and they are still unhappy,” Dr. Asbell said. “It’s the kind of person who comes into the office and says, ‘What else can you do for me? I’m still symptomatic; my dry eye still bothers me.’”
Dr. Sheppard acknowledged the subset analysis performed by the study authors but wanted a deeper analysis of previous dietary intake in each group and their dry eye severity. He also raised questions about the olive oil placebo and the need for “a true placebo control.”
“In our trial we used an inert solid, and it was difficult to get that preparation,” Dr. Sheppard said about his previous dry eye supplement research.2
“With the refined low phenolic content olive oil five pills a day control group, I have some reservations that there might have been a positive therapeutic effect,” Dr. Sheppard said. Refined olive oil contains palmitoleic3 and oleic4 acids, both of which possess anti-inflammatory properties.
Dr. Asbell noted that her study shared the common characteristic of previous dry eye research, in which all participants—both active and placebo groups—obtained improved outcomes. In addition, she noted that in the DREAM study, placebo patients only received one teaspoon of refined olive oil per day, not extra virgin olive oil that is high in the polyphenols thought to provide much of the anti-inflammatory effect associated with olive oil. Further, red blood cell analysis showed no change in oleic acid, the major constituent of olive oil. “There is no evidence that the small amount of olive oil had any biological effect on subjects,” she said.
“Both groups got better but were not significantly different,” Dr. Asbell continued. “It’s hard to recommend anything from this trial because they both got better with no significant difference in many measures of signs and symptoms.”

Clinical impacts

Despite the significance of the results, it is not clear how much they will affect ophthalmologists’ clinical practice.
Dr. Matossian said the “less-than-ideally controlled arms of the DREAM study” meant it would not impact her clinical approach, which includes a “starter triad” of preservative-free artificial tears, re-esterified oral omega-3s,5 and a microwaveable heated mask. After that, Dr. Matossian moves to prescription medication eye drops and an in-office vectored thermal pulsation procedure.
Similarly, Dr. Sheppard did not see the DREAM study impacting his dry eye approach, which includes the use of a black currant seed oil supplement, a source of gamma-linolenic acid (GLA). His research on GLA with other polyunsaturated fatty acid (PUFA) supplements found significantly improved dry eye signs and symptoms among post-menopausal female patients.2
“Many of us in the field have a concern that the placebo effect will cause some practitioners to refrain from using all forms of PUFAs, including the GLA, that do benefit patients with dry eye,” Dr. Sheppard said.
Even Dr. Galor doubted much clinical impact from the research because she views omega-3s as part of a holistic approach to dry eye.
“I talk to patients about dietary factors and the importance of a healthy diet, not just with omega-3s but with vegetables, fish, and foods with high antioxidant qualities,” Dr. Galor said. “I mention that supplements have been shown to improve dry eye symptoms and signs in smaller studies, and I don’t think we should discard the results of those studies.”


1. Asbell PA, et al. n-3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378:1681–1690.
2. Sheppard JD Jr, et al. Long-term supplementation with n-6 and n-3 PUFAs improves moderate-to-severe keratoconjunctivitis sicca: A randomized double-blind clinical trial. Cornea. 2013;32:1297–304.
3. Kimura Y, et al. Restoration of tear secretion in a murine dry eye model by oral administration of palmitoleic acid. Nutrients. 2017;9.
4. Basu A, et al. Dietary factors that promote or retard inflammation. Arterioscler Thromb Vasc Biol. 2006;26:995–1001.
5. Epitropoulos AT, et al. Effect of oral re-esterified omega-3 nutritional supplementation on dry eyes. Cornea. 2016;35:1185–91.

Editors’ note: Dr. Matossian has financial interests with Allergan (Dublin, Ireland), Bruder Healthcare Company (Alpharetta, Georgia), Johnson & Johnson Vision (Santa Ana, California), Physician Recommended Nutriceuticals (Blue Bell, Pennsylvania), Shire (Lexington, Massachusetts), Sun Pharmaceuticals (Mumbai, India), and TearLab (San Diego). Dr. Galor has financial interests with Shire and Allergan. Dr. Sheppard has financial interests with TearLab, Quidel (San Diego), Allergan, Bausch + Lomb (Bridgewater, New Jersey), Topcon (Oakland, New Jersey), and Novartis (Basel, Switzerland). Dr. Asbell has financial interests with Santen Pharmaceutical (Osaka, Japan), Shire, Novartis (Basel, Switzerland), MC2 Therapeutics (Copenhagen, Denmark), Valeant Pharmaceuticals (Laval, Canada), Allergan, Oculus (Wetzlar, Germany), CLAO (St. Paul, Minnesota), and Vindico (Thorofare, New Jersey).

Contact information

Asbell: penny.asbell@mssm.edu
Galor: agalor@med.miami.edu
Matossian: cmatossian@matossianeye.com
Sheppard: docshep@hotmail.com

Study shows little effect from omega-3 fatty acids Study shows little effect from omega-3 fatty acids
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