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Original Investigation | Clinical Trial

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 ONLINE FIRST

Aleix Sala-Vila, DPharm, PhD1,2; Andrés Díaz-López, RD, PhD2,3; Cinta Valls-Pedret, MSc1,2; Montserrat Cofán, DPharm, PhD1,2; Alfredo García-Layana, MD, PhD4; Rosa-María Lamuela-Raventós, DPharm, PhD2,5; Olga Castañer, MD, PhD2,6; Vicente Zanon-Moreno, PhD2,7; Miguel A. Martinez-Gonzalez, MD, PhD2,8; Estefanía Toledo, MD, PhD2,8; Josep Basora, MD, PhD2,3; Jordi Salas-Salvadó, MD, PhD2,3; Dolores Corella, DPharm, PhD2,7; Enrique Gómez-Gracia, MD, PhD2,9; Miquel Fiol, MD, PhD2,10; Ramón Estruch, MD, PhD2,11; José Lapetra, MD, PhD2,12; Montserrat Fitó, MD, PhD2,6; Fernando Arós, MD, PhD2,13; Luis Serra-Majem, MD, PhD2,14; Xavier Pintó, MD, PhD2,15; Emilio Ros, MD, PhD1,2 ; for the Prevención con Dieta Mediterránea (PREDIMED) Investigators
[+] 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. Published online August 18, 2016. doi:10.1001/jamaophthalmol.2016.2906
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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

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Adjusted Hazard Ratios of Sight-Threatening Diabetic Retinopathy by Meeting the International Society for the Study of Fatty Acids and Lipids Recommendation to Consume at Least 500 mg/d of Eicosapentaenoic Acid + Docosahexaenoic Acid at Baseline and PREDIMED Intervention Group

Multivariable Cox regression model stratified by recruitment center. Further information about the adjustment can be found in the text. Values for the “not meeting the recommendation” category are 1 [reference] for the low-fat control diet group; hazard ratio (HR), 0.37 (95% CI, 0.13-1.02) for the Mediterranean diet (MedDiet) supplemented with extra virgin olive oil group; and HR, 0.53 (95% CI, 0.20-1.36) for the MedDiet supplemented with nuts group. Values for the “meeting the recommendation” category are HR, 0.36 (95% CI, 0.17-0.76) for the control diet group; HR, 0.35 (95% CI, 0.17-0.73) for the MedDiet supplemented with extra virgin olive oil group; and HR, 0.32 (95% CI 0.14-0.71) for the MedDiet supplemented with nuts group.

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