Hahn J, Cook NR, Alexander EK, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ. 2022;376:e066452.
To investigate the effect of vitamin D and fish oil supplementation, alone and in combination, on the 5-year incidence of new-onset autoimmune disease in an older population
Randomized, double-blind, placebo-controlled trial with a 2-by-2 factorial design
This study included 25,871 participants, of whom 12,786 were men aged ≥50 years (51%) and 13,085 were women aged ≥55 years. The mean age was 67.1 years. Those with a previous diagnosis of renal failure or dialysis, cirrhosis, hypercalcemia, cancer (except non-melanoma skin cancer), cardiovascular disease, or other serious illness were excluded. Of the 25,871 participants, 5,106 were Black, and 2,152 belonged to other non-White racial and ethnic groups.
Participants were randomized to 1 of 4 groups:
- Omega-3 fatty acid (1,000 mg/day; 460 mg eicosapentaenoic acid and 380 mg docosahexaenoic acid) and vitamin D supplementation (2,000 IU/day)
- Omega-3 fatty acid (1,000 mg/day) and placebo
- Vitamin D supplementation (2,000 IU/day) and placebo
Participants self-reported many health outcomes yearly for 5 years, and extensive medical review confirmed reported diseases.
Study Parameters Assessed
Participants completed baseline questionnaires regarding lifestyle factors and were queried regarding vitamin D supplementation and fish and dairy intake. Blood samples were obtained from 16,956 participants and assayed for 25-hydroxyvitamin D and plasma omega-3 index. Participants completed repeat questionnaires at 6 months and 1 year after randomization, then annually for 5 years. Participants were specifically asked about new-onset clinically diagnosed rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and inflammatory bowel disease, and they were also given a blank space to write in any new autoimmune diagnosis.
In older adults, supplementing with daily vitamin D (2,000 IU) for 5 years decreased the incidence of autoimmune disease by 22%. Omega-3 fatty acid supplementation alone decreased incidence of autoimmune disease by 15% but was not statistically significant. The combination of vitamin D and omega-3 did not appear to have significant added benefit. Omega-3 supplementation alone did appear to be more beneficial for prevention of autoimmune disease onset in those with a positive family history and also appeared to have more impact in the later years of the study.
The National Institutes of Health funded this study, and each author declared they had no affiliation with entities that may derive monetary benefit from the study.
The VITAL study was a large randomized, controlled, and double-blinded study that ran from 2011 to 2017. The primary outcomes of this large endeavor were:
- Number of participants with invasive cancer of any type, and
- Number of participants with a major cardiovascular event (composite end point of myocardial infarction, stroke, and death from cardiovascular causes).
Results from this trial have spurred 25 publications to date, and researchers continue to mine the data for new information regarding issues such as urinary incontinence, metabolic health, and bone density.1 The primary targets of this study had disappointing results, with no change in cancer or cardiovascular risk with either vitamin D or omega-3 fatty acid supplementation.2,3
Autoimmune diseases are common, and they appear to be increasing in frequency.4 While the impact on quality of life, morbidity, mortality, and cost vary significantly depending on the specific diagnosis, autoimmune disease as a whole is a major contributing factor to overall human suffering, as well as healthcare costs. These costs are rising, as new medications such as biologics become the standard of care. For example, rheumatoid arthritis (RA) costs approximately $29,000 a year to treat, which is typical for a severe autoimmune disease.5 Moreover, experiencing an autoimmune disease can have a tremendous impact on quality of life and the ability of the individual to engage with the activities that bring them joy. This study is most welcome, as large-scale studies that evaluate the prevention of autoimmune diseases have been scarce.
Perhaps the omega-3 outcome was not statistically significant because the duration of the trial was not adequate to fully show its benefit.
We do have growing evidence that a low-omega 3 index is a major risk factor for developing autoimmune disorders such as rheumatoid arthritis.6 There is also evidence that treating new-onset RA patients with high-dose (5.5 g), but not low-dose (0.4 g), omega-3 fatty acids can decrease disease activity scores and decrease medication escalation.7
One might argue that this study failed to show benefits from the omega-3 fatty acid supplementation due to inadequate dose. This may be a potential bias on the part of the integrative community to expect positive outcomes from a study such as this. The authors did well in providing biological evidence that, in fact, the omega-3 was adequately dosed. Indeed, the omega-3 fatty acid index (Quest Diagnostics) increased 54.7% over the first year of the study to a mean of 4.1%, which is in optimal range. Perhaps the omega-3 outcome was not statistically significant because the duration of the trial was not adequate to fully show its benefit. Interestingly, the researchers found that the omega-3 effect was more pronounced toward the end of the study and reached statistical significance, with an 18% decrease in incidence, if “probable autoimmune disease” was included.
The VITAL study was a well-designed and expansive study, inclusive of a diverse population, that aimed to evaluate the impact of vitamin D supplementation, with or without omega-3 supplementation, on the incidence of cancer and cardiovascular disease. Although there were disappointing results for these outcomes, as well as multiple other secondary outcomes, it does appear that vitamin D supplementation, with or without omega-3 supplementation, decreases the incidence of new-onset autoimmune disease in people aged more than 55 years. The study did an excellent job ensuring regimen adherence with the use of biomarkers.
There are 3 major challenges. First, many autoimmune diseases onset at younger ages than are captured in this study. Second, many common autoimmune diseases like Hashimoto’s thyroiditis can be present for many years before onset of major clinical symptoms, making it difficult to distinguish new-onset disease. Third, despite the large size of the study, with more than 25,000 participants, there were few new diagnoses of autoimmune disease. For instance, in the vitamin D arm, only 123 participants had onset of autoimmune disease compared to 155 in the placebo group. This highlights how statements such as “vitamin D supplementation reduces incidence of autoimmune disease by 22%” can seem like a bigger impact than they are.
This study did not include a cost analysis—meaning, from a public health perspective, does it save money to prevent 32 new-onset autoimmune diseases in a population of 25,000 through vitamin D supplementation? These types of studies would be particularly helpful for nutritional supplements, which are not typically covered by insurance. Despite these challenges, this study improves our understanding of factors that increase the risk of autoimmune disease.