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Original Investigation
Clinical Trial
October 2016

Dietary Marine ω-3 Fatty Acids and Incident Sight-Threatening Retinopathy in Middle-Aged and Older Individuals With Type 2 Diabetes: Prospective Investigation From the PREDIMED Trial

Author Affiliations
  • 1Lipid Clinic, Endocrinology and Nutrition Service, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
  • 2CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
  • 3Human Nutrition Unit, Biochemistry and Biotechnology Department, Faculty of Medicine and Health Sciences, Institut d’Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain
  • 4Department of Ophthalmology, University of Navarra, Pamplona, Spain
  • 5Department of Nutrition and Food Science, School of Pharmacy, University of Barcelona, Barcelona, Spain
  • 6Cardiovascular Risk and Nutrition Research Group, Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona Biomedical Research Park, Barcelona, Spain
  • 7Department of Preventive Medicine, University of Valencia, Valencia, Spain
  • 8Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
  • 9Department of Preventive Medicine, University of Malaga, Malaga, Spain
  • 10Institute of Health Sciences, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain
  • 11Department of Internal Medicine, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
  • 12Department of Family Medicine, Primary Care Division of Sevilla, San Pablo Health Center, Sevilla, Spain
  • 13Department of Cardiology, University Hospital of Alava, Vitoria, Spain
  • 14Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas, Spain
  • 15Department of Internal Medicine, Bellvitge Biomedical Research Institute–Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, FIPEC (Research Foundation for Cardiovascular Disease Prevention), Barcelona, Spain
JAMA Ophthalmol. 2016;134(10):1142-1149. doi:10.1001/jamaophthalmol.2016.2906
Key Points

Question  Do dietary long-chain ω-3 fatty acids protect against diabetic retinopathy?

Findings  A substudy of the PREDIMED randomized clinical trial analyzed as an observational longitudinal cohort, considering only participants with type 2 diabetes at baseline, showed after median follow-up of 6 years that those reporting intake of at least 500 mg/d of long-chain ω-3 fatty acids at baseline had a 46% decreased risk of sight-threatening diabetic retinopathy compared to those not meeting this target.

Meaning  Results suggest fish-derived long-chain ω-3 fatty acids are a healthy fat in this cohort.


Importance  Diabetic retinopathy (DR) is a devastating complication of individuals with type 2 diabetes mellitus. The retina is rich in long-chain ω-3 polyunsaturated fatty acids (LCω3PUFAs), which are substrate for oxylipins with anti-inflammatory and antiangiogenic properties. Experimental models support dietary LCω3PUFA protection against DR, but clinical data are lacking.

Objective  To determine whether LCω3PUFA intake relates to a decreased incidence of sight-threatening DR in individuals with type 2 diabetes older than 55 years.

Design, Setting, and Participants  In late 2015, we conceived a prospective study within the randomized clinical trial Prevención con Dieta Mediterránea (PREDIMED), testing Mediterranean diets supplemented with extra virgin olive oil or nuts vs a control diet for primary cardiovascular prevention. The trial was conducted in primary health care centers in Spain. From 2003 to 2009, 3614 individuals aged 55 to 80 years with a previous diagnosis of type 2 diabetes were recruited. Full data were available for 3482 participants (48% men; mean age 67 years).

Exposures  Meeting the dietary LCω3PUFA recommendation of at least 500 mg/d for primary cardiovascular prevention, as assessed by a validated food-frequency questionnaire.

Main Outcomes and Measures  The main outcome was incident DR requiring laser photocoagulation, vitrectomy, and/or antiangiogenic therapy confirmed by an external adjudication committee.

Results  Of the 3482 participants, 48% were men and the mean age was 67 years. A total of 2611 participants (75%) met target LCω3PUFA recommendation. During a median follow-up of 6 years, we documented 69 new events. After adjusting for age, sex, intervention group, and lifestyle and clinical variables, participants meeting the LCω3PUFA recommendation at baseline (≥500 mg/d) compared with those not fulfilling this recommendation (<500 mg/d) showed a 48% relatively reduced risk of incident sight-threatening DR, with a hazard ratio of 0.52 (95% CI, 0.31-0.88; P = .001). This association was slightly stronger for yearly updated LCω3PUFA intake (relative risk, 0.48; 95% CI, 0.28-0.82; P = .007).

Conclusions and Relevance  In middle-aged and older individuals with type 2 diabetes, intake of at least 500 mg/d of dietary LCω3PUFA, easily achievable with 2 weekly servings of oily fish, is associated with a decreased risk of sight-threatening DR. Our results concur with findings from experimental models and the current model of DR pathogenesis.

Trial Registration  clinicaltrials.gov Identifier: http://www.controlled-trials.com/ISRCTN35739639