Effect of Vitamin D3 and Omega-3 Fatty Acid Supplementation on Risk of Frailty: An Ancillary Study of a Randomized Clinical Trial

Abstract

Importance: Preventive strategies for frailty are needed. Whether supplements with anti-inflammatory properties, such as vitamin D3 or marine omega-3 fatty acids, are useful for frailty prevention is unknown.

Objective: To test the effects of vitamin D3 and omega-3 supplements on change in frailty in older individuals.

Design, setting, and participants: This study was conducted in 2021, as a prespecified ancillary to the Vitamin D and Omega-3 (VITAL) trial, a 2 × 2 factorial randomized clinical trial. A total of 25 871 individuals (men aged ≥50 years and women aged ≥55 years), without cancer or cardiovascular disease and with data on frailty, were recruited across all 50 US states from November 2011 to March 2014 and followed up through December 31, 2017. Data analysis for the ancillary study was conducted from December 1, 2019, to March 30, 2022.

Interventions: Vitamin D3, 2000 IU/d, and marine omega-3 fatty acids, 1 g/d.

Main outcomes and measures: Frailty was measured using a validated 36-item frailty index that includes measures of function, cognition, mood, and comorbidities from annual questionnaires. Change in frailty score from baseline to year 5, according to randomization, using an intention-to-treat protocol, was assessed using repeated measures. Cox proportional hazards regression models assessed incident frailty. In subgroup analysis, an alternative frailty definition, the physical phenotype, was used as a sensitivity analysis.

Results: Of 25 871 VITAL trial participants randomized, 25 057 had sufficient data to calculate a frailty index. Baseline mean (SD) age was 67.2 (7.0) years, and 12 698 (50.7.%) were women. Mean (SD) frailty score was 0.109 (0.090) (range, 0.00-0.685), and 3174 individuals (12.7%) were frail. During a median 5-year follow-up, mean (SD) frailty scores increased to 0.121 (0.099) (range, 0.00-0.792). Neither vitamin D3 nor omega-3 fatty acid supplementation affected mean frailty scores over time (mean difference at year 5: vitamin D3, -0.0002; P = .85; omega-3 fatty acid, -0.0001; P = .90) or rate of change in mean frailty score (interaction with time: vitamin D3; P = .98; omega-3 fatty acid; P = .13) Incident frailty remained similar over time (interaction with time: vitamin D3, P = .90; omega-3 fatty acid; P = .32). Results were unchanged using the frailty physical phenotype.

Conclusions and relevance: In this ancillary study of the VITAL randomized clinical trial, treatment with vitamin D3 or omega-3 fatty acid supplementation, compared with placebo, did not affect the rate of frailty change or incidence over time. These results do not support routine use of either vitamin D3 or omega-3 fatty acid supplementation for frailty prevention in generally healthy community-dwelling older adults not selected for vitamin D3 deficiency.

Trial registration: ClinicalTrials.gov Identifier: NCT01169259.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Buring reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study and that her spouse was a member of the Pharmavite Scientific Advisory Board when the trial began. Dr Lee reported receiving grants from the NIH during the conduct of the study. Dr Okereke reported receiving royalties from Springer Publishing for a book on late-life depression prevention outside the submitted work. Dr Manson reported receiving grants from the NIH during the conduct of the study and grants from the NIH and Mars Edge outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Participant Flow Diagram

EPA-DHA indicates eicosapentaenoic acid and docosahexaenoic acid.

Figure 2.. Change in Mean Frailty Levels During the Study

A, Change in mean frailty levels in vitamin D group compared with placebo. B, Change in mean frailty levels in omega-3 fatty acids group compared with placebo. Error bars indicate 95% CI.

Figure 3.. Mean Change in Frailty Score at Each Year Since Randomization According to Vitamin D3 and Placebo Groups by Baseline Subgroups

BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared; 25(OH)D, 25-hydroxyvitamin D. aSelf-reported Asian/Pacific Islander, Native American/Alaskan Native, non-Black Hispanic, and unknown race and ethnicity.

Figure 4.. Mean Change in Frailty Score at Each Year Since Randomization According to Omega-3 Fatty Acid and Placebo Groups by Baseline Subgroups

aSelf-reported Asian/Pacific Islander, Native American/Alaskan Native, non-Black Hispanic, and unknown race and ethnicity.