When it comes to managing our patient’s ocular condition, we’re often asked the inevitable question “Is there anything else I can do?” As we’re handing out Amsler grids, AREDS supplements, or prescriptions for Latanoprost, some patients seek additional options to increase their odds of success in preserving their vision. In addition to standard-of-care treatments for glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy, there exist numerous evidenced-based strategies for prescribing nutritional supplements — including fish oil. When done properly, these can help facilitate healing and prevent disease progression.
In the United States, the dietary supplement industry brings in close to $30 billion per year, and offers over 90,000 products.1 Without an in depth understanding of clinical indications, quality and dose, confusion can easily occur between the doctor and the patient.
Arguably, one of the most important nutritional supplements for optimal ocular and systemic health are omega-3 fatty acids, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and alpha-linolenic acid (ALA). EPA and DHA primarily have an anti-inflammatory role within the body, and counter the pro-inflammatory (but still necessary) effects of omega-6 fatty acids – arachidonic acid and linoleic acid. We’ve all seen the literature on omega-3 supplementation for our dry eye patients, but have we overlooked the omega-3 research applicable to the rest of our patient population?
So what kind of omega-3 supplement is best to recommend? While there are several plant-based sources of omega-3s (ie: flaxseed oil, hemp or chia seeds), these primarily consist of ALA only, and are poorly converted to EPA and DHA by the body (5 to 10%). Therefore the most effective form of EPA/DHA to ingest is from cold water fatty fish, such as sardines, salmon or krill (and their associated supplements).
From an evolutionary perspective, our Paleolithic ancestors had an average omega-6/3 ratio ranging from 1:1 to 4:1. In the western world today, the average ratio exceeds 15:1 and is thought to contribute to the explosive growth in chronic disease we now face.2
As we’ll explore in this article, the literature has repeatedly shown the association of EPA/DHA deficiency and the pathogenesis of glaucoma, macular degeneration, type 2 diabetes, and diabetic retinopathy.
Over 50% of the lipid content in retinal photoreceptors is composed of DHA3
Within the retina, DHA plays several key roles, including optimizing mitochondrial activity and inhibition of angiogenesis, inflammation, apoptosis, and oxidative stress.3 DHA is the primary structural fatty acid in our brain, and facilitates learning, memory, and neurogenesis. Optimal levels of EPA and DHA have also been shown to reduce the risk of many of today’s chronic disease, including dementia, cardiovascular disease, cancer, and various autoimmune disease.2
Research also shows an age dependent decrease in EPA/DHA concentration in the neuronal tissues of the brain, which are thought to play a major role in the pathogenesis of neurodegenerative conditions like Alzheimer’s disease.4,5
The NIH recommends a daily intake of omega-3s of 1100mg to 1600mg for healthy adults,31 while the FDA reports that up to 3000mg/day of EPA/DHA can be taken safely.27
Dietary intake of fish has been shown to increase plasma EPA/DHA concentrations more effectively than fish oil supplementation alone.35 Patients can use resources like LabDoor for more information on nutritional supplement testing and ranking by safety, quality, and value. For our vegan/vegetarian patients, we can turn to flax seed, chia seed, or hemp seed as an adequate source of EPA and DHA (although conversion to EPA/DHA is lower when compared to animal-based sources).
Age-related Macular Degeneration
Imbalances in retinal lipid composition have been linked to photoreceptor degradation and abnormal deposition of lipid and lipoprotein debris within the RPE, the hallmark of AMD.6 Over the past decade, we’ve seen significant advancements in the treatment of exudative AMD (leading cause of blindness among older individuals in the U.S.).7 Despite standard-of-care therapy, 5 to 10% of patients will continue to lose 3 or more lines of visual acuity over the course of their lifetime.7 Each year, treatments for advanced AMD place a $10 billion dollar burden on the U.S. healthcare system.7,8 Unfortunately, an increased risk for thromboembolic events, stroke, neuronal toxicity, geographic atrophy and even death has been directly correlated with frequency and duration of anti-VEGF therapy.9-14 As primary eye care providers, any additional treatment strategies we are able to implement to reduce the risk of these poor visual or life-threatening/systemic outcomes is a worthwhile endeavor.
A 2014 study looked at the effect of 1000mg/day of EPA/DHA supplementation on vitreal VEGF concentration in wet AMD patients who were already undergoing treatment with intravitreal injection.7 The results showed over a 75% additional reduction in vitreal VEGF concentration when compared to the control group. This suggests that fish oil could be considered an adjunct treatment to patients with exudative AMD receiving intravitreal anti-VEGF treatments. Cold-water fatty fish consumption (2 to 3 servings per week) has also been shown to reduce the risk in developing exudative AMD by up 50%.15-19 So we may even want to suggest this to patients with the first signs of drusen to help preserve their vision.
Since we are limited in our ability to naturally biosynthesize these, dietary intake is essential, primarily through consumption of cold-water fatty fish (wild caught). Also commonly found in fish oil supplements, EPA and DHA are available in several different formulations, including ethyl ester (EE) and triglyceride (TG) forms. The EE form of EPA/DHA was used in the AREDS 2 study,20 and may explain the unremarkable outcome on dry AMD progression as some studies have shown the EE form to be less bioavailable.21
Recommendations for EPA/DHA supplementation can also be applicable for our patients with diabetes, prediabetes, obesity, and metabolic syndrome. There is evidence that shows regular EPA and DHA consumption improves beta cell function in the pancreas and increases insulin sensitivity.22 A 2014 study from Finland showed that regular consumption of EPA/DHA, between 500-1000mg/day, was able to lower the risk of developing type 2 diabetes by over 30% over 19 years.22
DHA and EPA play a role in regulating capillary permeability and inflammation within the retina.6 Recent studies have shown that omega 3 supplementation can lower the risk of developing sight-threatening diabetic retinopathy by as much as 50%,32 while also improving visual outcomes in patients with diabetic macular edema.33 Therefore, omega-3 supplementation could play a significant role in prevention for our at-risk patients, while also providing adjunct therapy for diabetic retinopathy.
Research has also demonstrated a correlation between EPA/DHA deficiency, excess omega-6 intake, and the severity of primary open angle glaucoma.34 In animal studies, EPA/DHA supplementation has been shown to lower intraocular pressure,23 while in human studies to improve visual field indices.24
It is believed that the fatty acid composition on the red blood cell plays an important role in autoregulation and vasodilation of eye’s microcirculation.24-26 EPA and DHA help to improve ocular blood flow and perfusion in this way, and should be considered an adjunct therapy for our glaucoma patients.
Sure, some doctors may think it’s unrealistic or even fringe to view nutritional supplements as a potential game-changer. As healthcare providers, it’s always beneficial to have more tools in the toolbox. The ability to educate our patients on current evidence-based therapy is increasingly important as we strive to provide the best care, while also reducing the burden on our healthcare system.
When it comes to the management of diabetic retinopathy, glaucoma, or macular degeneration, recommending omega-3 supplementation can serve as an excellent adjunct therapy for our motivated patients.
Action-List for ODs:
Start appropriate patients on 2-3 servings of low mercury, cold water fatty fish per week:
- Sockeye Salmon
- Anchovies, Mackerel
- Wild Trout
- Fish/krill oil supplements (ie Nordic Naturals) 1000-1500mg/day
Caution patients on blood thinners and consult PCP, due to increased risk of bleeding:
- Clopidogrel bisulfate (Plavix)
- Warfarin (Coumadin)
Reduce omega-6 fatty acid consumption:
- Industrial seed oils28,29
- Excessive nuts/grains
- Processed foods
- Farm-raised fish30
Optimize omega-6/omega-3 ratio – Direct-to-consumer lab services offer at-home testing:
- Manson, J E, and S S Bassuk. “Vitamin and Mineral Supplements: What Clinicians Need to Know.” JAMA, U.S. National Library of Medicine, 6 Mar. 2018.
- Simopoulos, A P. “The Importance of the Omega-6/Omega-3 Fatty Acid Ratio in Cardiovascular Disease and Other Chronic Diseases.” Experimental Biology and Medicine (Maywood, N.J.)., U.S. National Library of Medicine, June 2008.
- Souied, Eric H., et al. “Oral Docosahexaenoic Acid in the Prevention of Exudative Age-Related Macular Degeneration: The Nutritional AMD Treatment 2 Study.” Ophthalmology, Elsevier, 8 Feb. 2013.
- Denis, I., Potier, B., Heberden, C., & Vancassel, S. (2015). “Omega-3 polyunsaturated fatty acids and brain aging.” Current Opinion in Clinical Nutrition and Metabolic Care, 18(2), 139-146. doi:10.1097/mco.0000000000000141
- Song, C., Shieh, C., Wu, Y., Kalueff, A., Gaikwad, S., & Su, K. (2016). “The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer’s disease: Acting separately or synergistically?” Progress in Lipid Research, 62, 41-54. doi:10.1016/j.plipres.2015.12.003
- SanGiovanni, J P, and E Y Chew. “The Role of Omega-3 Long-Chain Polyunsaturated Fatty Acids in Health and Disease of the Retina.” Progress in Retinal and Eye Research., U.S. National Library of Medicine, Jan. 2005.
- REZENDE, F. A., LAPALME, E., QIAN, C. X., SMITH, L. E., SANGIOVANNI, J. P., & SAPIEHA, P. (2014). “Omega-3 Supplementation Combined With Anti–Vascular Endothelial Growth Factor Lowers Vitreal Levels of Vascular Endothelial Growth Factor in Wet Age-Related Macular Degeneration.” American Journal of Ophthalmology, 158(5), 1071–1078.
- Rein DB, Zhang P, Wirth KE, Lee PP, Hoerger TJ, McCall N, Klein R, Tielsch JM, Vijan S, Saaddine J. “The Economic Burden of Major Adult Visual Disorders in the United States.” Arch Ophthalmol. 2006;124(12):1754–1760. doi:10.1001/archopht.124.12.1754
- Danis, R. P., Lavine, J. A., & Domalpally, A. (2015). “Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects.” Clinical Ophthalmology (Auckland, N.Z.), 9, 2159–2174.
- Stewart, M. W. (2012). “The Expanding Role of Vascular Endothelial Growth Factor Inhibitors in Ophthalmology.” Mayo Clinic Proceedings, 87(1), 77–88.
- Robinson, G S, et al. “Nonvascular Role for VEGF: VEGFR-1, 2 Activity Is Critical for Neural Retinal Development.” FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology., U.S. National Library of Medicine, May 2001.
- Grunwald, J. E., Daniel, E., Huang, J., Ying, G., Maguire, M. G., Toth, C. A., Martin, D. F. (2014). “Risk of Geographic Atrophy in the Comparison of Age-related Macular Degeneration Treatments Trials.” Ophthalmology, 121(1), 150–161.
- Avery RL, Gordon GM. “Systemic Safety of Prolonged Monthly Anti–Vascular Endothelial Growth Factor Therapy for Diabetic Macular EdemaA Systematic Review and Meta-analysis.” JAMA Ophthalmol. 2016;134(1):21–29. doi:10.1001/jamaophthalmol.2015.4070
- Thulliez M, Angoulvant D, Pisella P, Bejan-Angoulvant T. “Overview of Systematic Reviews and Meta-analyses on Systemic Adverse Events Associated With Intravitreal Anti–Vascular Endothelial Growth Factor Medication Use.” JAMA Ophthalmol. Published online March 22, 2018. doi:10.1001/jamaophthalmol.2018.0002
- Querques, Giuseppe, and Eric H. Souied. “The Role of Omega-3 and Micronutrients in Age-Related Macular Degeneration.” Survey of Ophthalmology, Elsevier, 27 Jan. 2014.
- Tan, J S, et al. “Dietary Fatty Acids and the 10-Year Incidence of Age-Related Macular Degeneration: the Blue Mountains Eye Study.” Archives of Ophthalmology (Chicago, Ill. : 1960)., U.S. National Library of Medicine, May 2009.
- Cho, E, et al. “Prospective Study of Dietary Fat and the Risk of Age-Related Macular Degeneration.” The American Journal of Clinical Nutrition., U.S. National Library of Medicine, Feb. 2001.
- Chong EW, Kreis AJ, Wong TY, Simpson JA, Guymer RH. Dietary ω-3 Fatty Acid and Fish Intake in the Primary Prevention of Age-Related Macular DegenerationA Systematic Review and Meta-analysis. Arch Ophthalmol. 2008;126(6):826–833. doi:10.1001/archopht.126.6.826
- Augood, C, et al. “Oily Fish Consumption, Dietary Docosahexaenoic Acid and Eicosapentaenoic Acid Intakes, and Associations with Neovascular Age-Related Macular Degeneration.” The American Journal of Clinical Nutrition., U.S. National Library of Medicine, Aug. 2008.
- “Fish Oil: EE vs. TG Omega-3s — Which Is Better?”
- Dyerberg J, et al. “Bioavailability of n-3 fatty acids.” In n-3 Fatty Acids: Prevention and Treatment in Vascular Disease, SD Kristensen, EB Schmidt, R DeCaterina and S Endres, eds. Bi and Gi Publishers, Verona—Springer Verlag, London pp. 217-26, 1995.
- Virtanen, J. K., Mursu, J., Voutilainen, S., Uusitupa, M., & Tuomainen, T. (2013). Serum Omega-3 Polyunsaturated Fatty Acids and Risk of Incident Type 2 Diabetes in Men: The Kuopio Ischemic Heart Disease Risk Factor Study. Diabetes Care Dia Care, 37(1), 189-196. doi:10.2337/dc13-1504
- Nguyen, C. T., B. V. Bui, and A. J. Sinclair. “Dietary Omega 3 Fatty Acids Decrease Intraocular Pressure with Age by Increasing Aqueous Outflow.” Investigative Ophthalmology and Vision Science (2007): n. pag.
- Cellini, M., N. Caramazza, P. Mangiafico, G. L. Possati, and R. Caramazza. “Fatty Acid Use in Glaucomatous Optic Neuropathy Treatment.” Acta Ophthalmologica Scandinavica 76.S227 (1998): 41-42.
- Acar, Niyazi, Olivier Berdeaux, Pierre Juaneda, Stéphane Grégoire, Stéphanie Cabaret, Corinne Joffre, Catherine P. Creuzot-Garcher, Lionel Bretillon, and Alain M. Bron. “Red Blood Cell Plasmalogens and Docosahexaenoic Acid Are Independently Reduced in Primary Open-angle Glaucoma.” Experimental Eye Research 89.6 (2009): 840-53.
- Ren, Hongmei, Nwabueze Magulike, Kebreab Ghebremeskel, and Et Al. “Primary Open-angle Glaucoma Patients Have Reduced Levels of Blood Docosahexaenoic and Eicosapentaenoic Acids.” National Center for Biotechnology Information. U.S. National Library of Medicine, 4 Nov. 2005.
- “CFR – Code of Federal Regulations Title 21.” Substances Affirmed as Generally Recognized as Safe, Accessdata.fda.gov.
- Ramsden, Christopher E, et al. “The Sydney Diet Heart Study: a Randomised Controlled Trial of Linoleic Acid for Secondary Prevention of Coronary Heart Disease and Death.” Federation of American Societies for Experimental Biology, 1 Apr. 2013.
- Pearce, Morton Lee, and Seymour Dayton. “INCIDENCE OF CANCER IN MEN ON A DIET HIGH IN POLYUNSATURATED FAT.” The Lancet, 6 Mar. 1971.
- Sprague, M., Dick, J. R., & Tocher, D. R. (2016). Impact of sustainable feeds on omega-3 long-chain fatty acid levels in farmed Atlantic salmon, 2006–2015. Scientific Reports, 6, 21892.
- “Office of Dietary Supplements – Omega-3 Fatty Acids.” NIH Office of Dietary Supplements, U.S. Department of Health and Human Services,
- Chew EY. Dietary Intake of Omega-3 Fatty Acids From Fish and Risk of Diabetic Retinopathy. JAMA. 2017;317(21):2226–2227. doi:10.1001/jama.2017.1926
- Lafuente, María, et al. “COMBINED INTRAVITREAL RANIBIZUMAB AND ORAL SUPPLEMENTATION WITH DOCOSAHEXAENOIC ACID AND ANTIOXIDANTS FOR DIABETIC MACULAR EDEMA: Two-Year Randomized Single-Blind Controlled Trial Results: RETINA.” The Journal of Retina and Vitrous Diseases, July 2017.
- Yu M, Chen B, Gong B, Shuai P, Wu Z-Z, Lin W. Association of n3 and n6 polyunsaturated fatty acids in red blood cell membrane and plasma with severity of normal tension glaucoma. International Journal of Ophthalmology. 2015;8(3):476-483. doi:10.3980/j.issn.2222-3959.2015.03.08
- Visioli, F, et al. “Dietary Intake of Fish vs. Formulations Leads to Higher Plasma Concentrations of n-3 Fatty Acids.” Lipids., U.S. National Library of Medicine, Apr. 2003.