Olive oil had no therapeutic effect in DREAM study

Issue: September 2018

To the Editor:

We were pleased to see the coverage in Primary Care Optometry News of the results from the Dry Eye Assessment and Management study (“DREAM study: Omega-3 no better than olive oil for dry eye,” May 2018, pages 1 and 16), because the results are important to the members of the optometric community who care for patients with dry eye disease.

In both the editorial from PCON Editor Dr. Michael DePaolis and the commentary by Dr. Stuart Richer there are comments that the olive oil placebo used in DREAM was an effective treatment for the symptoms and signs of dry eye disease. Because these comments may influence patient care, we believe they deserve further scrutiny.

Indeed, patients in DREAM improved between baseline and 3 months both in the group receiving omega-3 supplements and in the group receiving placebo supplement. The magnitude of improvement in the 100-point Ocular Surface Disease Index was substantial, a mean of approximately 13 points in each group.

However, improvement of symptoms and signs in the placebo group has been observed in most previous randomized clinical trials of treatments for dry eye disease regardless of whether the placebo has been vehicle eye drops or a variety of oils in low oral doses (safflower oil [omega-6], corn oil [omega-6 and omega-9], sunflower oil [omega-6] and olive oil [omega-9]). Specific examples of improvement in the placebo group include a mean decrease of 30 points on the 100-point Eye Dryness Scale in the group of 356 patients receiving placebo drops in the OPUS-3 clinical trial of lifitegrast (Holland et al.) and a change from symptomatic to asymptomatic in 33% of 254 patients receiving corn oil oral supplements in a clinical trial of omega-3 supplementation (Bhargava et al.).

Thus, improvement over time in clinical signs and symptoms by itself cannot be interpreted as treatment efficacy in dry eye patients.

The commentaries noted that olive oil has anti-inflammatory effects and is part of the Mediterranean diet that has been associated with beneficial effects on cardiovascular and other systemic diseases. We note that the anti-inflammatory effects associated with olive oil have been attributed mainly to the polyphenols that are abundant in extra virgin olive oil, but not found in the refined olive oil used in DREAM (Gorzynik-Debicka et al.). There are other key components in addition to olive oil in the Mediterranean diet, including nuts, fresh fruits, vegetables and fish (Estruch et al.).

In addition, the dose of olive oil in DREAM was 1 teaspoon (5 g) daily, while the Mediterranean diet daily intake is at least 4 tablespoons (60 g) of olive oil (Estruch et al.). The intake of olive oil from the DREAM placebos had a very low impact or no impact on systemic levels of oleic acid, the predominant component of olive oil. There was only a negligible (1%) mean decrease from baseline in the placebo group when the level of oleic acid was measured in red blood cell membranes. This is in stark contrast to the mean increase of approximately 400% for eicosapentaenoic acid (EPA) and 40% for docosahexaenoic acid (DHA) in the group assigned to omega-3 supplements.

Based on these facts, we do not believe that a therapeutic effect on dry eye disease from 1 teaspoon of refined olive oil daily is plausible.

References:
Bhargava R, et al. Int J Ophthalmol. 2013;doi:10.3980/j.issn.2222-3959.2013.06.13.
The Dry Eye Assessment and Management Study Research Group. NEngl J Med. 2018;doi:10.1056/NEJMoa1709691.
Estruch R, et al. N Engl J Med. 2018;doi: 10.1056/NEJMoa1800389.
Gorzynik-Debicka M, et al. Int J Mol Sci. 2018;doi:10.3390/ijms19030686.
Holland EJ, et al. Ophthalmology. 2017;doi:10.1016/j.ophtha.2016.09.025.

Meng C. Lin, OD, PhD
Maureen G. Maguire, PhD
Penny Asbell, MD, MBA
DREAM Research Group

Disclosures: All authors were supported by grants from the National Eye Institute. Asbell reports receiving personal fees and nonfinancial support from Santen and Shire; grants and personal fees from MC2 Therapeutics, Miotech, Novartis and Rtech; personal fees from Allergan, Medscape Oculus and ScientiaCME; and grants, personal fees and nonfinancial support from Valeant/Bausch + Lomb. Lin reports receiving personal fees from Shire and Essilor USA. Maguire reports no relevant financial disclosures.

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Dr. Richer responds:

Thank you for your letter and for extending our knowledge concerning important scientific issues, including the possibility for strong placebo effects in clinical medical research and medicine itself. However, the anomalous results of the DREAM Study are biologically implausible and contradict the preponderance of both empirical and published epidemiological clinical evidence with respect to the benefit of omega-3 essential fatty acids in patients suffering with dry eye.

I agree that olive oil contains abundant oleic acid, the oil’s major health-promoting mono-unsaturated fatty acid. But olive oil also contains the phenolic antioxidant hydroxytyrosine, squalene and an unknown concentration of gamma linoleic acid (GLA). The latter ingredient, perhaps the most important in olive oil, is found in many commercial dry eye formulations.

Omega-3 and omega-6 oils were discovered to be essential for life by Burr and Burr in 1929. Not all omega-6 fatty acids are pro-inflammatory. GLA is known as the most powerful health-promoting omega-6 and is found in borage seed oil, black currant seed oil, evening primrose oil, hemp oil and, yes, olive oil.

Omega-6 GLA is essential for the outer lipid tear layer. Signs of essential omega-6 GLA deficiency are not limited to the eyes and induce additional symptoms of systemic dryness: dry hair (dandruff), dry skin (rough elbows) and cracked, brittle nails. As clinicians we should be alert to these accompanying systemic signs and symptoms of dry eyes, especially in females. The fatty acid profile of borage oil is unique in that it contains 20% to 24% GLA, black currant oil contains 15% to 17% and evening primrose oil contains 8% to 10%.

It is more difficult to discern the actual concentration and amount of GLA in olive oil, as there are few published studies. Nonetheless, while 75% of olive oil is oleic acid with some saturated fatty acids, we know that olive oil also contains approximately 10% polyunsaturated fatty acids (Conscious Life).

Of those polyunsaturated fatty acids (approximately 500 mg within the DREAM Study placebo capsule), the overall ratio of omega-6 to omega-3 is approximately 13:1. Therefore, one can assume that at least 450 mg/d of omega-6 as arachidonic, dihomo-gamma-linolenic acid and GLA were provided in the 5,000-mg/d placebo. Determining the actual GLA molar fraction constituents (and other actives) in the DREAM Study placebo is important, as GLA converts into anti-inflammatory PGE1 prostaglandins, beneficial against both inflammatory dry eye and Sjögren’s syndrome.

In summary, five large capsules per day of olive oil is not inert. GLA and the other biologic actives in olive oil used in the DREAM Study placebo might be a strong confounder and account for the negative omega-3 results, until proven otherwise. It would be helpful to follow up the meticulous work of the DREAM Study team with complementary basic science tissue and cellular studies using identical treatment and placebo arm ingredients at the same concentration. Perhaps this would also help us understand the confounding negative results found in the Alienor age-related macular degeneration study (Delcourt et al.), where olive oil was also chosen as the placebo.

References:
Brosche T, et al. Arch Gerontol Geriatr. 2000;30(2):139-150.
Caramia G. Minerva Pediatr. 2008;60(2):219-233.
The Conscious Life. Fat composition of olive oil. https://theconsciouslife.com/foods/olive-oil-04053.htm. Accessed August 23, 2018.
de la Puerta R, et al. Z Naturforsch C. 2000;55(9-10):814-819.
Delcourt C, et al. J Nutr Health Aging. 2010;14(10):854-861.
Poteet J. Review of Optometry. Posted May 15, 2017. Accessed August 23, 2018. https://www.reviewofoptometry.com/article/from-alpha-to-omega-how-fatty-acids-fight-dry-eye.
Visioli F, et al. Crit Rev Food Sci Nutr. 2002;doi:10.1080/10408690290825529.
Waterman E, et al. Altern Med Rev. 2007;12(4):331-342.

Stuart Richer, OD, PhD, FAAO
Director, ocular preventive medicine, James Lovell Federal Health Care Facility, Chicago
Associate professor, family and preventive medicine, Chicago Medical School
Assistant clinical professor, department of ophthalmology and visual science, University of Illinois at Chicago
Member, Primary Care Optometry News Editorial Board

Disclosures: Richer reports he is global scientific director of the Zeaxanthin Trade Association and president of the Ocular Wellness and Nutrition Society. He receives research funding from ZeaVision and consults for Bausch + Lomb, Douglas Labs, Eyecheck and Stereo Optical.

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Dr. DePaolis responds:

Thank you for your letter regarding our recent coverage of the DREAM Study. Again, I applaud your collective efforts in bringing the study to fruition — no small undertaking, for certain, and a tremendous effort to shed more light on a very complex entity. While I understand the composition of and rationale for selecting olive oil as a control, one nagging question remains. Is olive oil truly of no benefit to those with dry eye?

As a clinician toiling in the dry eye trenches daily, I’ve come to appreciate its complexities. Frequent symptom-sign disparities, lack of definitive markers and variable responses to a plethora of treatments are a constant reminder of how little we really know about this condition. Despite these uncertainties, it is universally accepted that we make every effort to curtail inflammation in dry eye. Until a definitive biomarker emerges, we rely on patient signs (staining and tear break-up time) and symptoms (Ocular Surface Disease Index) for managing inflammation. I was pleased to see an improvement in signs and symptoms for both arms of the DREAM study.

I concur that a placebo effect likely played a role in DREAM control arm symptoms but wonder whether this is the only plausible explanation. Or, is it conceivable that other anti-inflammatory aspects – beyond oleic acid – are responsible for patient gains? Olive oil might well derive its anti-inflammatory abilities from constituents other than oleic acid.

Certainly, the DREAM Study has provided greater clarity on the role of omega-3s — and, perhaps, olive oil — in dry eye management. As in any study, however, we must exercise caution in extrapolating results. In short, should we stop counseling dry eye patients on the potential benefits of omega-3s? Given their successful therapeutic track record, I’d say not just yet.

Michael D. DePaolis, OD, FAAO
Editor, Primary Care Optometry News

Disclosure: DePaolis reports no relevant financial disclosures