Effect of Vitamin D and ω-3 Fatty Acid Supplementation on Risk of Age-Related Macular Degeneration: An Ancillary Study of the VITAL Randomized Clinical Trial

William G Christen; Nancy R Cook; JoAnn E Manson; Julie E Buring; Daniel I Chasman; I-Min Lee; Vadim Bubes; Chunying Li; Margarette Haubourg; Debra A Schaumberg

doi:10.1001/jamaophthalmol.2020.4409

. 2020 Oct 29;138(12):1280–1289. doi: 10.1001/jamaophthalmol.2020.4409

Effect of Vitamin D and ω-3 Fatty Acid Supplementation on Risk of Age-Related Macular Degeneration

An Ancillary Study of the VITAL Randomized Clinical Trial

William G Christen ^1,^✉, Nancy R Cook ^1,², JoAnn E Manson ^1,², Julie E Buring ^1,², Daniel I Chasman ^1,², I-Min Lee ², Vadim Bubes ¹, Chunying Li ¹, Margarette Haubourg ¹, Debra A Schaumberg ¹, for the VITAL Research Group

¹Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

²Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts

Group Information: The VITAL Research Group members appear at the end of the article.

Accepted for Publication: September 9, 2020.

Published Online: October 29, 2020. doi:10.1001/jamaophthalmol.2020.4409

^✉

Corresponding Author: William G. Christen, ScD, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue E, Boston, MA 02215-1204 (wchristen@rics.bwh.harvard.edu).

Author Contributions: Drs Christen and Manson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Christen, Manson, Schaumberg.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Christen, Li.

Critical revision of the manuscript for important intellectual content: Cook, Manson, Buring, Chasman, Lee, Bubes, Haubourg, Schaumberg.

Statistical analysis: Cook, Bubes, Li.

Obtained funding: Christen, Manson, Chasman, Schaumberg.

Administrative, technical, or material support: Christen, Manson, Lee, Bubes, Haubourg.

Supervision: Christen, Manson, Lee, Schaumberg.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by grants from the National Eye Institute (R01 EY021900), the National Cancer Institute (U01 CA138962 and R01 CA138962), the National Heart, Lung, and Blood Institute, the Office of Dietary Supplements, the National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health. Pharmavite donated vitamin D, and Pronova BioPharma and BASF donated the ω-3 fatty acids (Omacor); the companies also donated matching placebos and packaging in the form of calendar packs. Quest Diagnostics measured the serum 25-hydroxyvitamin D levels and plasma ω-3 index at no cost to the trial.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Members of the VITAL Research Group: VITAL Steering Committee: JoAnn E. Manson, MD, DrPH (Chair), Julie E. Buring, ScD (Chair), Nancy R. Cook, ScD, I-Min Lee, MBBs, ScD, William G. Christen, ScD, Shari S. Bassuk, ScD, Samia Mora, MD, MHS, Heike Gibson, PhD, David Gordon, MAT, Trisha Copeland, MS, RD, Denise D’Agostino, BS, Georgina Friedenberg, MPH, Claire Ridge, MPH, Vadim Bubes, PhD, Edward L. Giovannucci, MD, ScD, Walter C. Willett, MD, DrPH (all at Brigham and Women’s Hospital, Harvard Medical School, Boston; Drs Manson, Buring, Cook, Lee, Giovannucci, and Willett are also at the Harvard T.H. Chan School of Public Health). Scientific Consultants: John Baron, MD, MS, MSc (University of North Carolina, Chapel Hill), Michael Holick, MD, PhD (Boston Medical Center), Bruce Hollis, PhD (University of South Carolina). Other Members of the VITAL Research Group: (Brigham and Women’s Hospital): Christine M. Albert, MD, MPH, Diane Gold, MD, MPH, Meryl LeBoff, MD, Olivia Okereke, MD, MS, Aruna Pradhan, MD, MPH, MSc, Howard Sesso, ScD, MPH, Wendy Chen, MD, MPH, Paulette Chandler, MD, MPH, J. Michael Gaziano, MD, MPH, Olga Demler, PhD, Kathryn Rexrode, MD, MPH, Karen Costenbader, MD, MPH, John Forman, MD, Erik Alexander, MD, Sonia Friedman, MD, Jeffrey Katz, MD, MS, Shumin Zhang, MS, ScD, Jennifer Lin, PhD, Joseph Walter, BS, Julie Duszlak, BS, Kate Kalan, BS, Jean MacFadyen, BA, Natalya Gomelskaya, MD, David Bates, BS, Ara Sarkissian, MS, Mary Breen, Yeulolani Andrade, Manickavasagar Vinayagamoorthy, PhD, Chunying Li, BM, PhD, Eunjung Kim, MS, Franco Giulianini, BS, MS, PhD, Gregory Kotler, PhD, Marty Van Denburgh, BA, Rimma Dushkes, MS, Yanyan Liu, MS, PhD, Eduardo Pereira, MS, Lisa Fields-Johnson, BS, George Menjin, AA, Lucy Liu, BA, Lauren Girard, BS, Scott Zeller, MA, PA, Naomi Riches, BA, MPH, Katelyn Hasson, BS, Ellen Bhang, BA, MSW, Maria Revilla, BS, Elena McCarthy, BS, Alex Moran, BS, Kristen Haise, Leah Arsenault, BA, Philomena Quinn, Sancia Grimes, Ivan Fitchorov, MS, PhD, Kurt Schwerin, BA, Shamikhah Curry, Annie Murray, Angela Zhang, Diana Walrond-Williams, Alison Weinberg, MA, Chris Pfeffer, BS, Margarette Haubourg, Viviane Nguyen, BS, Henry Ouellette, Rolando Rodriguez, Tony Montgomery, Keith Morse, Vincent Guzman, Megan Perry, BA, Sandra Weekes, Doug Smith, BS, Allison Clar, BS, Sara Curran, BS, Yaneve Fonge, BSc, David Hibbert, BA, Louisa Paine, BA, Kelly Royce, BS, Courtney Splaine, BA, Jennifer McMahon, David Eldridge, BA, Laura Hand, BA, Kay Inandan, BS, Meghan RieuWerden, BS, Harriet Samuelson, MA, Andrea Hrbek, Megan Mele, BS, Eileen Bowes, Mary Anne Ryan, BA (Massachusetts General Hospital, Boston): Carlos Camargo, MD, DrPH, Jacqueline Danik, MD, DrPH, Ravi Thadhani, MD, MPH (Vanderbilt University, Nashville): Thomas Wang, MD (Rush University Medical Center, Chicago): Raj C. Shah, MD (University of California, San Francisco): Michelle A.

Albert, MD, MPH.

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC7596682 PMID: 33119047

Key Points

Question

Can daily supplementation with vitamin D₃ and marine ω-3 fatty acids prevent the development or progression of age-related macular degeneration (AMD)?

Findings

In this randomized clinical trial of 25 871 adult US men and women, daily supplementation with vitamin D₃, 2000 IU, and marine ω-3 fatty acids, 1 g, for a median of 5.3 years had no overall effect on the primary vision end point of total AMD events, a composite of incident AMD and progression to advanced AMD.

Meaning

Neither vitamin D₃ nor marine ω-3 fatty acid supplementation had a significant overall effect on AMD incidence or progression.

Abstract

Importance

Observational studies suggest that higher intake or blood levels of vitamin D and marine ω-3 fatty acids may be associated with lower risks of age-related macular degeneration (AMD). However, evidence from randomized trials is limited.

Objective

To evaluate whether daily supplementation with vitamin D₃, marine ω-3 fatty acids, or both prevents the development or progression of AMD.

Design, Setting, and Participants

This was a prespecified ancillary study of the Vitamin D and Omega-3 Trial (VITAL), a nationwide, placebo-controlled, 2 × 2 factorial design randomized clinical trial of supplementation with vitamin D and marine ω-3 fatty acids for the primary prevention of cancer and cardiovascular disease. Participants included 25 871 men and women in the US. Randomization was from November 2011 to March 2014, and study pill-taking ended as planned on December 31, 2017.

Interventions

Vitamin D₃ (cholecalciferol), 2000 IU per day, and marine ω-3 fatty acids, 1 g per day.

Main Outcomes and Measures

The primary end point was total AMD events, a composite of incident cases of AMD plus cases of progression to advanced AMD among participants with AMD at baseline, based on self-report confirmed by medical record review. Analyses were conducted using the intention-to-treat population.

Results

In total, 25 871 participants with a mean (SD) age of 67.1 (7.0) years were included in the trial. Of them, 50.6% were women, 71.3% were self-declared non-Hispanic White participants, and 20.2% were Black participants. During a median (range) of 5.3 (3.8-6.1) years of treatment and follow-up, 324 participants experienced an AMD event (285 incident AMD and 39 progression to advanced AMD). For vitamin D₃, there were 163 events in the treated group and 161 in the placebo group (hazard ratio [HR], 1.02; 95% CI, 0.82-1.27). For ω-3 fatty acids, there were 157 events in the treated group and 167 in the placebo group (HR, 0.94; 95% CI, 0.76-1.17). In analyses of individual components for the primary end point, HRs comparing vitamin D₃ groups were 1.09 (95% CI, 0.86-1.37) for incident AMD and 0.63 (95% CI, 0.33-1.21) for AMD progression. For ω-3 fatty acids, HRs were 0.93 (95% CI, 0.73-1.17) for incident AMD and 1.05 (95% CI, 0.56-1.97) for AMD progression.

Conclusion and Relevance

Neither vitamin D₃ nor marine ω-3 fatty acid supplementation had a significant overall effect on AMD incidence or progression.

Trial Registration

ClinicalTrials.gov Identifier: NCT01782352

This prespecified ancillary analysis of the VITAL (Vitamin D and Omega-3 Trial) nationwide randomized clinical trial assesses whether daily supplementation for approximately 4 to 6 years with vitamin D₃, marine ω-3 fatty acids, or both vs placebo prevents the development or progression of age-related macular degeneration in initially healthy US adults.

Introduction

Age-related macular degeneration (AMD) is a chronic, progressive disease of the central retina and the leading cause of severe, irreversible vision loss in US adults.¹ Most cases of severe vision loss are due to the advanced form of the disease, either neovascular AMD or geographic atrophy.² For persons with early AMD, there is usually little associated vision loss,^2,3,4 but they are at elevated risk of progression to advanced AMD.^5,6,7,8 Treatment is available in the form of anti–vascular endothelial growth factor therapy for patients with neovascular AMD,^9,10,11 and supplements of antioxidants plus zinc for people with intermediate to advanced AMD.^12,13 New therapeutic strategies are being explored in numerous ongoing trials, but most target the advanced forms of disease.^14,15 Consequently, for the large majority of people with early or no AMD, there is no effective intervention other than lifestyle modifications, such as avoidance of cigarette smoking.^16,17,18

Accumulating observational evidence suggests that individuals with higher dietary intake or blood levels of vitamin D or marine ω-3 fatty acids (docosahexanoic acid [DHA] and eicosapentaenoic acid [EPA]) may have lower rates of AMD.^19,20,21,22 However, randomized trial data to evaluate the efficacy of supplemental use of these nutrients in AMD prevention are limited. The Age-Related Eye Disease Study 2 (AREDS2)¹³ showed that the addition of marine ω-3 fatty acids (DHA plus EPA) to the original AREDS formulation of high-dose antioxidants and zinc did not further reduce the risk of progression to advanced AMD. For vitamin D supplementation, randomized trial data in AMD prevention are not yet available.

In this report, we present the findings for AMD from the Vitamin D and Omega-3 Trial (VITAL), a double-blind, placebo-controlled randomized clinical trial designed to test vitamin D and marine ω-3 fatty acids in the primary prevention of cancer and cardiovascular disease among US men and women. To our knowledge, these data represent the first randomized trial data to examine vitamin D in AMD prevention.

Methods

Study Design

The present VITAL-AMD study is a prespecified ancillary study of VITAL, which is a nationwide, double-blind, placebo-controlled, 2 × 2 factorial design randomized clinical trial of supplementation with vitamin D₃ (cholecalciferol), 2000 IU daily, and marine ω-3 fatty acids (Omacor fish oil; a capsule containing EPA and DHA in a ratio of approximately 1.2:1), 1 g daily, in the primary prevention of cancer and cardiovascular disease among 25 871 men aged 50 years or older and women aged 55 years or older, including 5106 African American participants. Details of this study are described elsewhere.^23,24 In brief, eligible participants had no history of cancer (except nonmelanoma skin cancer), myocardial infarction, stroke, transient ischemic attack, or coronary revascularization at study entry. They were required to agree to limit nonstudy intake of supplemental vitamin D and calcium to 800 IU/d or lower and 1200 mg/d or lower, respectively, and to forgo use of fish oil supplements. Randomization took place from November 2011 to March 2014 and was computer generated within sex, race (African American vs not), and 5-year age groups (Figure 1). Study pill-taking ended as planned on December 31, 2017, yielding a median (range) treatment of 5.3 (3.8-6.1) years. The full trial protocol for the present study is provided in Supplement 1. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials. The trial was approved by the institutional review board of Brigham and Women’s Hospital, Boston, Massachusetts, and was monitored by an external data and safety monitoring board. All participants provided written informed consent before enrollment in the trial. They were not offered any compensation or incentives for participation.

Figure 1. — The primary comparisons are shown in gray for any ω-3 vs no ω-3 and in orange for any vitamin D vs no vitamin D.

Baseline questionnaires requested information on clinical and lifestyle risk factors and included a food frequency questionnaire. Annual questionnaires assessed compliance with randomized treatments, use of nonstudy vitamin D or fish oil supplements, development of major illnesses, including AMD, and potential adverse effects of the study agents.

Baseline blood samples were collected before randomization from all willing individuals, including 16 956 randomized participants (65.5%). Samples were assayed for plasma ω-3 index (EPA plus DHA as a percentage of total fatty acids²⁵) and serum 25-hydroxyvitamin D using liquid chromatography–tandem mass spectrometry by Quest Diagnostics.

Ascertainment and Definition of End Points

At baseline, participants were asked “Have you EVER had macular degeneration?” On annual questionnaires, participants were asked about new diagnoses in the past year, including “macular degeneration.” Participants who responded affirmatively were asked to provide the date of diagnosis and written consent to review medical records pertaining to the diagnosis. Ophthalmologists and optometrists were contacted by mail and asked to complete an AMD questionnaire that requested information on the date of initial diagnosis, best-corrected visual acuity at the time of diagnosis, and date when best-corrected visual acuity reached 20/30 or worse. The questionnaire also asked about signs of AMD observed (drusen, retinal pigment epithelium [RPE] hypopigmentation or hyperpigmentation, geographic atrophy, RPE detachment, subretinal neovascular membrane, or disciform scar) when visual acuity was first noted to be 20/30 or worse, and date when exudative neovascular disease, if present, was first noted (defined by presence of RPE detachment, subretinal neovascular membrane, or disciform scar). If other ocular abnormalities were present, physicians were asked to indicate whether AMD, by itself, was sufficient to reduce best-corrected visual acuity to 20/30 or worse. Ophthalmologists and optometrists could also provide the requested information by supplying copies of relevant medical records. Medical record data were obtained for 94.9% of participants providing consent to review medical records.

Study end points were defined a priori. The primary end point was total AMD events, a composite of incident cases of AMD plus cases of progression to advanced AMD among participants with AMD at baseline. Secondary end points were (1) individual components of the primary end point; (2) incident cases of visually significant AMD (20/30 or worse) among those without AMD at baseline; and (3) incident cases of advanced AMD (neovascular AMD and central geographic atrophy) among those without AMD at baseline.

Statistical Analysis

The estimated power of the trial was based on annual event rates for AMD observed in previous trials of men and women by members of our team^{26,27,28,29,30,31,32} and an anticipated mean follow-up of 6 years. We expected the study to have adequate power (80%) to detect a 20% reduction in the primary end point of total AMD events. All analyses were conducted using the intention-to-treat population. The distributions of baseline characteristics in the treated and placebo groups were compared using 2-sample t tests, χ² tests for proportions, and tests of trend for ordinal categories. Cox proportional hazards models were used to estimate the hazard ratio (HR) of AMD among those in the treated group compared with placebo after adjustment for age (years) at baseline, sex, and randomized assignment to the other agent. Models were also fit separately within 3 baseline age groups (50-64, 65-74, and ≥75 years). Tests of trend for the effect of age on the association between the study agent and AMD were calculated by including a term for the interaction of the agent and age (with values 1 to 3 corresponding to the 3 age groups) in the Cox model. The proportionality assumption was tested by including an interaction term of the study agent with the logarithm of time in Cox models. For both agents, the proportionality assumption was not violated for the primary combined end point, its individual components, or any prespecified secondary end point (all P > .20). Because it is possible that some AMD cases diagnosed during the treatment period may have been prevalent at baseline, and to explore possible latent treatment effects, we conducted sensitivity analyses excluding participants with AMD diagnosed during the first year and during the first 2 years of the trial. The 95% CIs and 2-sided P values were calculated, and P < .05 was considered statistically significant. There was no control for multiple hypothesis testing, and no formal adjustment was made for the P values or 95% CIs. Thus, the results regarding secondary end points and subgroups should be interpreted with caution.

Results

Study Participants

In total, 25 871 participants were randomized into the trial, with a mean (SD) age of 67.1 (7.0) years, and 50.6% of participants were women. The cohort was racially diverse and included 71.3% self-declared non-Hispanic White participants and 20.2% Black participants. Baseline characteristics of study participants were distributed equally between active and placebo treatment groups (Table 1).

Table 1. Baseline Characteristics of VITAL Participants, by Randomized Vitamin D₃ and ω-3 Fatty Acid Assignment^a.

Baseline characteristic	No. (%) of participants
	Total cohort	Vitamin D₃		ω-3 Fatty acids
	Total cohort	Active	Placebo	Active	Placebo
No.	25 871	12 927	12 944	12 933	12 938
Female sex	13 085 (50.6)	6547 (50.6)	6538 (50.5)	6547 (50.6)	6538 (50.5)
Age, mean (SD), y	67.1 (7.0)	67.1 (7.0)	67.1 (7.1)	67.1 (7.0)	67.1 (7.0)
Age group, y
50-64	9848 (38.1)	4920 (38.1)	4928 (38.1)	4919 (38.0)	4929 (38.1)
65-74	12 705 (49.1)	6349 (49.1)	6356 (49.1)	6352 (49.1)	6353 (49.1)
≥75	3318 (12.8)	1658 (12.8)	1660 (12.8)	1662 (12.9)	1656 (12.8)
Race/ethnicity
Non-Hispanic White	18 046 (71.3)	9013 (71.3)	9033 (71.4)	9044 (71.5)	9002 (71.2)
Black	5106 (20.2)	2553 (20.2)	2553 (20.2)	2549 (20.1)	2557 (20.2)
Hispanic (not African American)	1013 (4.0)	516 (4.1)	497 (3.9)	491 (3.9)	522 (4.1)
Asian/Pacific Islander	388 (1.5)	188 (1.5)	200 (1.6)	200 (1.6)	188 (1.5)
American Indian/Alaskan Native	228 (0.9)	118 (0.9)	110 (0.9)	120 (0.9)	108 (0.9)
Other/unknown	523 (2.1)	259 (2.0)	264 (2.1)	249 (2.0)	274 (2.2)
BMI, mean (SD)	28.1 (5.7)	28.1 (5.7)	28.1 (5.8)	28.1 (5.7)	28.1 (5.8)
Hypertension	13 343 (51.9)	6625 (51.6)	6718 (52.1)	6624 (51.5)	6719 (52.2)
Cholesterol-lowering medication	9524 (37.5)	4822 (38.0)	4702 (36.9)	4788 (37.7)	4736 (37.2)
Diabetes	3549 (13.7)	1812 (14.0)	1737 (13.4)	1799 (13.9)	1750 (13.6)
Current smoking	1836 (7.2)	921 (7.2)	915 (7.2)	920 (7.2)	916 (7.2)
Any alcohol use^b	17 443 (68.6)	8726 (68.7)	8717 (68.5)	8759 (68.8)	8684 (68.3)
Current regular aspirin use	11 570 (45.4)	5756 (45.2)	5814 (45.6)	5771 (45.3)	5799 (45.5)
Current postmenopausal hormone use (women only)	1483 (11.6)	717 (11.2)	766 (12.0)	735 (11.5)	748 (11.7)
Current use of multivitamins	11 406 (44.8)	5750 (45.2)	5656 (44.4)	5661 (44.5)	5745 (45.2)
Current use of supplemental vitamin D (≤800 IU/d)^c	11 030 (42.6)	5497 (42.5)	5533 (42.8)	5498 (42.5)	5532 (42.8)
Current use of supplemental calcium (≤1200 mg/d)^d	5166 (20.0)	2627 (20.3)	2539 (19.6)	2550 (19.7)	2616 (20.2)
Intake of foods related to vitamin D, mean (SD)
Milk, servings/d	0.7 (0.9)	0.7 (0.9)	0.7 (0.9)	0.7 (0.9)	0.7 (0.9)
Other vitamin D–fortified foods, servings/d	0.6 (0.8)	0.6 (0.8)	0.6 (0.8)	0.6 (0.8)	0.6 (0.8)
Intake of foods related to ω-3 fatty acids, mean (SD)
Dark-meat fish, servings/wk	1.0 (1.8)	1.0 (1.9)	1.0 (1.7)	1.0 (1.9)	1.0 (1.8)
Other fish and seafood, servings/wk	1.1 (2.3)	1.1 (2.4)	1.1 (2.2)	1.1 (2.4)	1.1 (2.3)
Baseline biomarker levels
25(OH)D, ng/mL, mean (SD)^e	30.8 (10.0)	30.9 (10.0)	30.8 (10.0)	30.9 (10.0)	30.8 (10.0)
Plasma, median (IQR), %^f
EPA	0.5 (0.4-0.7)	0.5 (0.4-0.7)	0.5 (0.4-0.7)	0.5 (0.4-0.7)	0.5 (0.4-0.7)
DHA	1.9 (1.5-2.4)	1.9 (1.5-2.4)	1.9 (1.5-2.4)	1.9 (1.5-2.4)	1.9 (1.5-2.4)

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Abbreviations: 25(OH)D, 25-dihydroxyvitamin D; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IQR, interquartile range; VITAL, Vitamin D and Omega-3 Trial.

SI conversion factor: To convert 25(OH)D to nmol/L, multiply by 2.496.

^{^a}

Values are expressed as No. (%) unless otherwise indicated. Percentages are based on participants with data available.

^{^b}

At least monthly.

^{^c}

From all supplemental sources of vitamin D combined (individual vitamin D supplements, calcium plus vitamin D supplements, medications with vitamin D, and multivitamins).

^{^d}

From all supplemental sources of calcium combined.

^{^e}

For 15 787 with measured values.

^{^f}

For 15 527 with measured values for EPA and 15 534 for DHA.

The mean rate of response to questionnaires was 93.1%. The mean rate of adherence to the trial regimen that was reported by the participants (percentage of participants who took at least two-thirds of the trial capsules) was 82.0% in the vitamin D group and 80.3% in the placebo group, during 5 years of follow-up. For ω-3, the mean rates of adherence to the trial regimen were 81.6% in the treated group and 81.5% in the placebo group during this time.

Of randomized participants, 15 787 (61%) provided a baseline blood sample that could be analyzed for 25-hydroxyvitamin D. Among these participants, the mean (SD) serum total 25-hydroxyvitamin D level was 30.8 (10.0) ng/mL (to convert to nmol/L, multiply by 2.496). In a subgroup of 1644 participants with repeated measurements after 1 year, the mean (SD) 25-hydroxyvitamin D levels increased from 29.8 (10.4) ng/mL at baseline to 41.8 (10.0) ng/mL at 1 year (40% increase) in the vitamin D₃ group and changed minimally (mean [SD], −0.7 [6.9] ng/mL) in the placebo group.

Slightly fewer randomized participants (15 535 [60%]) provided a baseline blood sample that could be analyzed for the ω-3 index. Among these participants, the mean (SD) plasma ω-3 index was 2.7% (0.9%) in each group. Among 1583 of these participants who also provided a blood sample at 1 year that could be analyzed, the mean (SD) ω-3 index increased to 4.1% (1.2%), an increase of 54.7%, in the ω-3 group and changed by less than 2% in the placebo group.

During a median (range) of 5.3 (3.8-6.1) years of treatment and follow-up, 324 participants experienced a confirmed AMD event, the primary study end point. These included 285 cases of incident AMD and 39 cases of AMD progression.

Vitamin D₃

There was no difference in the primary combined end point by vitamin D₃ assignment (324 AMD events, 163 in the treated group and 161 in the placebo group; hazard ratio [HR], 1.02; 95% CI, 0.82-1.27) (Table 2). Individual components of the primary end point also did not vary significantly between groups, although there was some suggestion of a benefit for vitamin D₃ in reducing AMD progression (285 incident AMD events: HR, 1.09; 95% CI, 0.86-1.37; 39 AMD progression events: HR, 0.63; 95% CI, 0.33-1.21) (Table 2). In analyses of prespecified secondary end points, no significant differences were observed between groups for visually significant AMD (134 visually significant AMD events: HR, 1.21; 95% CI, 0.86-1.70) or incident advanced AMD (93 advanced AMD events: HR, 1.23; 95% CI, 0.81-1.84) (Table 2).

Table 2. Primary and Secondary Outcomes by Randomized Treatment Assignment.

Outcome	Vitamin D₃				ω-3 Fatty acids
Outcome	Active, No. (n = 12 927)	Placebo, No. (n = 12 944)	HR (95% CI)	P value	Active, No. (n = 12 933)	Placebo, No. (n = 12 938)	HR (95% CI)	P value
Total AMD events^a	163	161	1.02 (0.82-1.27)	.86	157	167	0.94 (0.76-1.17)	.57
Incident AMD	148	137	1.09 (0.86-1.37)	.48	137	148	0.93 (0.73-1.17)	.52
AMD progression	15	24	0.63 (0.33-1.21)	.17	20	19	1.05 (0.56-1.97)	.88
Secondary end points
Incident visually significant AMD	73	61	1.21 (0.86-1.70)	.27	61	73	0.84 (0.59-1.17)	.30
Incident advanced AMD	51	42	1.23 (0.81-1.84)	.33	39	54	0.72 (0.48-1.09)	.12

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Abbreviations: AMD, age-related macular degeneration; HR, hazard ratio.

^{^a}

Primary outcome; a composite end point comprising incident AMD plus cases of progression to advanced AMD among participants with AMD at baseline.

Cumulative incidence curves for total AMD did not vary significantly between the vitamin D₃ and placebo groups at any year of follow-up (Figure 2A). Although these data are not included in the figure, excluding the first year or excluding the first 1 and 2 years of follow-up had no material influence on the HR estimate (excluding first year [251 AMD events]: HR, 0.98; 95% CI, 0.77-1.26; excluding first 2 years [175 AMD events]: HR, 0.93; 95% CI, 0.69-1.25). For AMD progression (35 events), the HR was 0.53 (95% CI, 0.26-1.07) when we excluded the first 2 years of follow-up, but this difference remained statistically nonsignificant.

ω-3 Fatty Acids

There was no difference in total AMD events by randomized ω-3 fatty acid assignment (157 events in the treated group, 167 in the placebo group; HR, 0.94; 95% CI, 0.76-1.17). The HRs for the individual components of the primary end point were 0.93 (95% CI, 0.73-1.17) for incident AMD and 1.05 (95% CI, 0.56-1.97) for AMD progression. With respect to secondary end points, those assigned ω-3 fatty acids had lower rates of visually significant AMD (HR, 0.84; 95% CI, 0.59-1.17) and incident advanced AMD (HR, 0.72; 95% CI, 0.48-1.09), although the differences were not statistically significant.

The cumulative incidence curves for total AMD did not differ significantly between trial groups at any year of follow-up (Figure 2B). Although the data are not included in the figure, the results were not materially different when we excluded the first year (251 AMD events: HR, 0.92; 95% CI, 0.72-1.17) or the first 2 years (175 AMD events: HR, 0.90; 95% CI, 0.67-1.21) of follow-up. The HRs for the individual components of the primary end point (incident AMD and AMD progression) also varied little when we excluded early events. For secondary end points, excluding the first 2 years of follow-up reduced the HR for visually significant AMD (68 events) to 0.70 (95% CI, 0.43-1.13) and incident advanced AMD (44 events) to 0.52 (95% CI, 0.28-0.96), which was statistically significant.

Subgroup Analyses

There was no evidence for any modification of the lack of effect of vitamin D₃ or ω-3 fatty acids (Table 3) on the primary end point of total AMD events by baseline categories of possible risk factors for AMD. The lack of effect of vitamin D₃ did not vary by baseline serum 25-hydroxyvitamin D level or by outside use of vitamin D supplements, and the lack of effect of ω-3 fatty acids did not vary by baseline plasma ω-3 level.

Table 3. Total AMD Events Comparing Vitamin D₃ and Placebo Groups and Comparing ω-3 Fatty Acids and Placebo Groups, According to Baseline Characteristics in VITAL Participants.

Subgroup	Total No.	No. of AMD events		HR (95% CI)	P value	P value for interaction
Subgroup	Total No.	Treated group	Placebo group	HR (95% CI)	P value	P value for interaction
Vitamin D₃ group vs placebo group
Sex
Female	13 085	99	109	0.91 (0.69-1.20)	.50	.18
Male	12 786	64	52	1.25 (0.87-1.80)	.23	.18
Age, y
50-64	9848	22	20	1.10 (0.60-2.02)	.75	.90
65-74	12 705	82	86	0.96 (0.71-1.29)	.77
≥75	3318	59	55	1.07 (0.74-1.55)	.70
Race/ethnicity
Non-Hispanic White	18 046	138	135	1.03 (0.81-1.30)	.83	.99
Black	5106	7	4	1.75 (0.51-5.97)	.37
Other	2152	15	12	1.28 (0.60-2.74)	.52
BMI
<25	7843	53	59	0.95 (0.66-1.38)	.79	.21
25 to <30	10 122	63	66	0.93 (0.66-1.32)	.69
≥30	7289	46	31	1.44 (0.91-2.27)	.12
Baseline serum 25-hydroxyvitamin D category
<Median of 30.8 ng/mL	7824	41	38	1.12 (0.72-1.74)	.63	.93
≥Median of 30.8 ng/mL	7980	78	67	1.14 (0.82-1.58)	.44	.93
Baseline serum 25-hydroxyvitamin D
<20 ng/mL	2003	5	5	1.08 (0.31-3.74)	.90	.99
≥20 ng/mL	13 801	114	100	1.13 (0.86-1.48)	.38	.99
Any outside use of vitamin D supplements
No	14 841	58	67	0.89 (0.62-1.26)	.50	.33
Yes	11 030	105	94	1.11 (0.84-1.46)	.48	.33
Multivitamin use
No	14 033	64	73	0.89 (0.64-1.25)	.51	.31
Yes	11 406	96	85	1.12 (0.84-1.50)	.45	.31
Randomized ω-3 fatty acids
Active	12 933	89	68	1.32 (0.96-1.81)	.08	.02
Placebo	12 938	74	93	0.80 (0.59-1.09)	.15	.02
ω-3 Fatty acids group vs placebo group
Sex
Female	13 085	102	106	0.96 (0.73-1.26)	.79	.76
Male	12 786	55	61	0.90 (0.62-1.29)	.56	.76
Age, y
50-64	9848	21	21	1.00 (0.55-1.84)	.99	.42
65-74	12 705	85	83	1.02 (0.76-1.38)	.89
≥75	3318	51	63	0.81 (0.56-1.18)	.27
Race/ethnicity
Non-Hispanic White	18 046	129	144	0.89 (0.70-1.13)	.34	.45
Black	5106	8	3	2.66 (0.71-10.02)	.15
Other	2152	13	14	0.99 (0.47-2.12)	.99
BMI
<25	7843	55	57	1.00 (0.69-1.45)	.99	.79
25 to <30	10 122	59	70	0.83 (0.59-1.17)	.28
≥30	7289	41	36	1.12 (0.72-1.75)	.62
Baseline plasma ω-3 level
<Median of 2.7%	6938	49	45	1.12 (0.75-1.68)	.59	.31
≥Median of 2.7%	8599	58	67	0.85 (0.60-1.20)	.35	.31
Fish consumption
<Median of 1.5 servings/wk	12 298	89	82	1.10 (0.81-1.48)	.54	.08
≥Median of 1.5 servings/wk	13 137	61	82	0.73 (0.53-1.02)	.07	.08
Multivitamin use
No	14 033	75	62	1.20 (0.86-1.68)	.29	.08
Yes	11 406	80	101	0.80 (0.60-1.07)	.14	.08
Randomized vitamin D₃
Active	12 927	89	74	1.20 (0.88-1.64)	.24	.02
Placebo	12 944	68	93	0.73 (0.53-1.00)	.047	.02

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Abbreviations: AMD, age-related macular degeneration; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HR, hazard ratio; VITAL, Vitamin D and Omega-3 Trial.

SI conversion factor: To convert serum 25-hydroxyvitamin D to nmol/L, multiply by 2.496.

However, the effect of the interventions on total AMD did appear to be modified by the other treatment assignment. Compared with participants assigned vitamin D₃ placebo and ω-3 fatty acid placebo, HRs were 0.80 (95% CI, 0.59-1.09) in the vitamin D₃ alone group, 0.73 (95% CI, 0.53-1.00) in the ω-3 fatty acid alone group, and 0.96 (95% CI, 0.72-1.29) in the combined group (P = .02 for interaction) (Figure 2C).

Discussion

In this large randomized trial of initially healthy men and women, daily supplementation with vitamin D₃ (2000 IU/d) and marine ω-3 fatty acids (1 g/d) for a median of 5.3 years had no overall effect on the primary vision end point of total AMD events (a composite of incident AMD and progression to advanced AMD). Exclusion of events confirmed early in follow-up had no material influence on effect estimates. For each intervention, the apparent lack of effect on total AMD did not vary by baseline categories of possible AMD risk factors but did appear to vary according to the other treatment assignment. Findings for secondary end points representing more advanced stages of the disease were in the direction of benefit for ω-3 fatty acids and included a significant reduction in incident advanced AMD when early follow-up was excluded. These findings for secondary end points and subgroups need to be interpreted with caution because of multiple hypothesis testing.

To our knowledge, these are the first randomized trial data to evaluate vitamin D₃ in AMD prevention. Prior findings from numerous cross-sectional and case-control studies,^19,20 and limited prospective studies,^33,34,35 generally support an inverse relationship between vitamin D intake or blood levels and risk of AMD. However, the potential for residual or unmeasured confounding in these observational studies remains an important limitation.

In our trial, we found no overall benefit of vitamin D₃ supplementation on total AMD, nor did we observe any material effect of the intervention on the secondary end points of visually significant AMD or incident advanced AMD. Age-related macular degeneration progression, a component of the primary end point, was less common in the vitamin D₃ group, but the difference was not statistically significant, perhaps owing to the small number (39) of cases of AMD progression.

A systematic review and meta-analysis of observational studies found that older adults with circulating 25-hydroxyvitamin D concentrations below 20 ng/mL were at higher risk of AMD, in particular advanced AMD.²⁰ In the present analysis of VITAL, only 12.7% of participants had levels below 20 ng/mL, raising the possibility that vitamin D requirements for AMD prevention may have already been met for most participants. Moreover, we found no evidence that the null findings for vitamin D₃ varied between those with 25-hydroxyvitamin D concentrations above or below 20 ng/mL, or above or below the median concentration of 30.8 ng/mL.

With respect to ω-3 fatty acids, data are available from 2 prior trials of AMD prevention. A single-center investigation of 263 adults with early AMD in the study eye and neovascular AMD in the fellow eye reported no effect of 3 years of treatment with high-dose EPA (270 mg/d) plus DHA (840 mg/d) on risk of progression to advanced AMD.³⁶ However, interpretation of those findings is complicated by the small sample size, short duration of the trial, and poor compliance with study treatment. The second trial was the landmark AREDS2,¹³ which showed that the addition of marine ω-3 fatty acids (DHA, 350 mg, plus EPA, 650 mg) to the original AREDS formulation of high-dose antioxidants and zinc did not further reduce the risk of progression to advanced AMD among participants with intermediate AMD at study entry. However, AREDS2 had insufficient information to evaluate the effect of ω-3 fatty acids in participants with early or no AMD at baseline. In addition, because nearly all AREDS2 participants with intermediate AMD took AREDS supplements daily (either the original commercial AREDS formulation or a modified version) as recommended by study directors, there was no true placebo group against which to evaluate the efficacy of ω-3 fatty acid supplementation.

The present trial tested ω-3 fatty acid supplements against a true placebo group in a usual risk population, most of whom (97.3%) did not report a prior diagnosis of AMD at baseline. Therefore, direct comparison of our findings with those of AREDS2 is not possible. Nonetheless, our findings of no overall protective effect of ω-3 fatty acids on AMD incidence and no beneficial effect on AMD progression among those with early AMD at baseline appear broadly consistent with the null findings for persons with intermediate AMD reported in AREDS2.¹³ The observations in our study of nonsignificant reductions in the secondary end points of visually significant AMD and incident advanced AMD events (among those without AMD at baseline), together with a significant reduction in incident advanced AMD events after exclusion of early follow-up, were suggestive, but study power for these analyses was limited.

Our finding of a possible interaction between study agents was unexpected and could be due to chance in view of the multiple comparisons. A treatment interaction has not been found for any other end point in VITAL, and a blood substudy of VITAL participants indicated no interaction between vitamin D and ω-3 fatty acid treatment on biomarker concentrations for these nutrients.³⁷ Vitamin D and ω-3 fatty acids are hypothesized to lower risks of AMD through antioxidative, immunomodulatory, anti-inflammatory, and antiangiogenic mechanisms,^38,39 and there is developing interest in examining possible complementary benefits of cosupplementation with these nutrients in patients with cancer,^40,41 gestational diabetes,⁴² or multiple sclerosis.⁴³ However, information regarding possible interference between ω-3 fatty acids and vitamin D in a subadditive interaction is scarce.⁴⁴

Strengths and Limitations

Our study had a number of strengths, including the randomized trial design, a large general population sample with racial, ethnic group, and geographic diversities, a high rate of response to study questionnaires, which averaged 93.1% during the course of the trial, and high follow-up rates. Adherence to the pill regimen was high, with more than 80% of participants in the active and placebo groups for both interventions reporting taking at least two-thirds of the trial capsules during 5 years of follow-up, consistent with changes in blood biomarkers for these nutrients.

Our trial also had several limitations. The median duration of the trial intervention was 5.3 years, and detection of supplement-related benefits, if present, may require longer follow-up. No adjustment was made for multiple comparisons, and some subgroup analyses were based on small numbers of events. The subadditive interaction we observed, if real, may have influenced power of our primary analyses, which did not take this interaction into account. Finally, the AMD end point was based on participant reports followed by medical record review. Consequently, some underascertainment of AMD is likely.^45,46 Such underascertainment would likely reduce study power but is not associated with bias in randomized comparisons.

Conclusions

In conclusion, in this large randomized trial of initially healthy men and women, supplementation with vitamin D₃ and marine ω-3 fatty acids for a median of 5.3 years had no significant overall effect on AMD incidence or progression.

Supplement 1.

Trial Protocol

Click here for additional data file.^{(181.3KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(19.4KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

Click here for additional data file.^{(181.3KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(19.4KB, pdf)}

[eoi200081r1] 1.Congdon N, O’Colmain B, Klaver CC, et al. ; Eye Diseases Prevalence Research Group . Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122(4):477-485. doi: 10.1001/archopht.122.4.477 [DOI] [PubMed] [Google Scholar]

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PERMALINK

Effect of Vitamin D and ω-3 Fatty Acid Supplementation on Risk of Age-Related Macular Degeneration

William G Christen, ScD

Nancy R Cook, ScD

JoAnn E Manson, MD, DrPH

Julie E Buring, ScD

Daniel I Chasman, PhD

I-Min Lee, MBBS, ScD

Vadim Bubes, PhD

Chunying Li, PhD

Margarette Haubourg

Debra A Schaumberg, ScD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusion and Relevance

Trial Registration

Introduction

Methods

Study Design

Figure 1. Flowchart of Randomization and Follow-up for the Age-Related Macular Degeneration (AMD) Trial.

Ascertainment and Definition of End Points

Statistical Analysis

Results

Study Participants

Table 1. Baseline Characteristics of VITAL Participants, by Randomized Vitamin D3 and ω-3 Fatty Acid Assignmenta.

Vitamin D3

Table 2. Primary and Secondary Outcomes by Randomized Treatment Assignment.

Figure 2. Cumulative Incidence Rates of Age-Related Macular Degeneration Events by Treatment Group.

ω-3 Fatty Acids

Subgroup Analyses

Table 3. Total AMD Events Comparing Vitamin D3 and Placebo Groups and Comparing ω-3 Fatty Acids and Placebo Groups, According to Baseline Characteristics in VITAL Participants.

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Table 1. Baseline Characteristics of VITAL Participants, by Randomized Vitamin D₃ and ω-3 Fatty Acid Assignment^a.

Vitamin D₃

Table 3. Total AMD Events Comparing Vitamin D₃ and Placebo Groups and Comparing ω-3 Fatty Acids and Placebo Groups, According to Baseline Characteristics in VITAL Participants.