In a recent comprehensive analysis, researchers have revisited the outcomes of the VITAL trial, a randomised study initially focused on the effects of vitamin D and omega-3 fatty acid (n-3 FA) supplementation on incident cancer and cardiovascular disease. This investigation, spearheaded by Karen H. Costenbader, MD, MPH, from Brigham & Women’s Hospital, Boston, Massachusetts, and her team, delved into the extended impacts of these supplements on autoimmune disease risk. The VITAL trial had included 25,871 adults—12,786 men aged 50 years and older and 13,085 women aged 55 and older—who were followed for an average of 5.3 years. All participants were initially monitored for the occurrence of cancer and cardiovascular events[1].
The original VITAL trial on subsequent analysis revealed that a 5-year regimen of vitamin D supplementation resulted in a 22% risk reduction for confirmed autoimmune diseases[2]. Similarly, a 5-year course of n-3 FA supplementation showed an 18% reduction in confirmed and probable incident autoimmune diseases. However, the recent follow-up study sheds light on the longevity of these effects post-supplementation.
This extended study, encompassing an additional 2 years of observation following the cessation of the trial, involved 21,592 VITAL participants[3]. It was found that the protective benefits of daily vitamin D supplementation (2000 IU/d of cholecalciferol) ceased to be statistically significant after discontinuation. In contrast, the advantageous effects of daily marine n-3 FAs (1 g/d as a fish-oil capsule containing 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) persisted for at least 2 years post-supplementation.
Published in Arthritis & Rheumatology on January 25 2024, the findings prompt a reconsideration of vitamin D supplementation strategies for long-term autoimmune disease prevention. The sustained effects of n-3 fatty acids, even after discontinuation, were particularly noteworthy. Costenbader emphasised in subsequent analysis that the rapid diminution of vitamin D’s benefits post-supplementation suggests a need for prolonged or indefinite continuation, beyond the initial 5-year period.
The study also unearthed nuances in the effects of these supplements across different autoimmune diseases. Vitamin D showcased pronounced efficacy against psoriasis, whereas the n-3 fatty acids were particularly effective in reducing the risk of rheumatoid arthritis and inflammatory bowel disease.
In summary, this extended observation underscores the potential of continuous supplementation with vitamin D for robust autoimmune disease prevention and highlights the enduring protective qualities of n-3 fatty acids even after cessation of supplementation.
Further Analysis
Continuing in the same analytical vein, the study’s significance is further accentuated by an editorial in the same journal from rheumatologist Joel M. Kremer, MD, of Albany Medical College and the Corrona Research Foundation, Delray Beach, Florida. Dr. Kremer highlights the pivotal role of the research by Costenbader and colleagues in illuminating the potential of n-3 FA dietary supplements in preventing autoimmune diseases. He emphasises the noteworthy sustained benefits of these supplements, persisting up to two years post-discontinuation. This longevity aligns with the chronic incorporation of FA species in cellular plasma membranes, influencing various crucial metabolic and inflammatory pathways.
VITAL Trial: Design and Ancillary Study Findings
The exploration of vitamin D and n-3 FA supplementation’s preventive potential against autoimmune diseases was an ancillary objective of the VITAL trial, primarily focused on cancer and cardiovascular disease incidence. Employing a 2 × 2 factorial design, the study randomised participants to receive either 2000 IU/d of vitamin D or a placebo, and then further randomised them to either 1 g/d of n-3 FAs or a placebo, across both primary randomisation arms.
Multivariate analyses, adjusted for age, sex, race, and other supplement arms, revealed that vitamin D supplementation alone correlated with a hazard ratio (HR) of 0.68 (P = .02) for incident autoimmune disease. N-3 FAs alone showed a nonsignificant HR of 0.74, while the combination yielded an HR of 0.69 (P = .03). Inclusion of probable incident autoimmune disease cases rendered the effect of n-3 supplementation significant, with an HR of 0.82.
In clinical trials, HR is a key statistic for determining the efficacy of a new treatment or intervention. It helps in understanding whether the new treatment reduces the risk of the event compared to the standard treatment or placebo.
Interpreting the HR Value:
- HR = 1: No difference in risk between the two groups.
- HR > 1: Higher risk of the event in the treatment group compared to the control group. For example, if the HR is 2, the treatment group has twice the risk of the event happening at any given time point compared to the control group.
- HR < 1: Lower risk in the treatment group. For example, an HR of 0.5 suggests that the treatment group has half the risk compared to the control group.
VITAL Study: Extended Observational Analysis
In this subsequent phase, Costenbader and team analysed observational data from 21,592 VITAL participants, representing a significant portion of the original cohort. Annual questionnaires were used to track new cases of autoimmune diseases, including rheumatoid arthritis, polymyalgia rheumatica, psoriasis, autoimmune thyroid disease, and inflammatory bowel disease, along with other newly diagnosed autoimmune conditions.
The study documented 236 new confirmed autoimmune cases since the initial results, 65 probable cases during the median 5.3 years of the randomised phase, and 42 probable cases in the 2-year observational period. Post-observation, the occurrence of autoimmune diseases in the vitamin D group was similar to that in the placebo group, yielding a nonsignificant HR of 0.98. Including probable, cases slightly altered this figure to an adjusted HR of 0.95, still nonsignificant.
Conversely, the n-3 group demonstrated a significant reduction in autoimmune disease incidence, with an HR of 0.83 compared to the placebo group.
The researchers acknowledged certain limitations, such as the doses used, primarily intended for cancer and cardiovascular disease prevention. They speculated that higher doses, particularly for high-risk or nutritionally deficient groups, might demonstrate more pronounced effects. Additionally, the challenge of precisely identifying the onset of incident diseases and the limited number of cases during the observational period restricted detailed analyses of individual autoimmune diseases.
In conclusion, this extended analysis of the VITAL trial offers valuable insights into the long-term impacts of vitamin D and n-3 FA supplementation on autoimmune disease prevention, underscoring the need for continuous research and potential dose optimisation in future studies.
Research has consistently shown that the intake of Omega-3 fatty acids is beneficial in enhancing lipid profiles, mitigating the severity of fatty liver disease, reducing obesity, improving cognitive function, and alleviating cardiovascular complications[4]. The critical role of chronic inflammation in the pathogenesis and persistence of a wide array of diseases – including degenerative, autoimmune, and infectious diseases – is increasingly recognised as an important modifiable risk factor in the scientific community.
Individuals who are genetically predisposed and exposed to certain environmental triggers may exhibit a dysfunctional hyperinflammatory and hyperimmune response. This predisposition plays a significant role in increasing their susceptibility to complications, as well as in the onset and progression of autoimmune diseases.
A significant area of current research focuses on endogenous lipid mediators that positively influence the resolution of inflammation. Among these, Omega-3 metabolites, particularly resolvins, have garnered considerable scientific interest. These compounds are being intensively investigated for their potential therapeutic effects in modulating inflammatory responses and contributing to the resolution of chronic inflammatory states. Resolvins act by interacting with specific receptors on the surface of cells involved in the inflammatory response, such as immune cells. By binding to these receptors, resolvins can inhibit the production and migration of inflammatory cells and substances. This helps to reduce swelling, pain, and other symptoms of inflammation[5].
Derived from fish oils, regular consumption of oily fish or carefully extracted supplements of stabilised fish oils, in conjunction with vitamin D, are safe interventional and preventative strategies.
References
[1] Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, Zaharris E, Macfadyen JG, Danielson E, Lin J, Zhang SM, Buring JE. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012 Jan;33(1):159-71.
[2] Hahn J, Cook NR, Alexander EK, Friedman S, Walter J, Bubes V, Kotler G, Lee IM, Manson JE, Costenbader KH. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ. 2022 Jan 26;376:e066452.
[3] Costenbader KH, Cook NR, Lee IM, Hahn J, Walter J, Bubes V, Kotler G, Yang N, Friedman S, Alexander EK, Manson JE. Vitamin D and Marine n-3 Fatty Acids for Autoimmune Disease Prevention: Outcomes at Two Years after VITAL Trial Completion. Arthritis Rheumatol. 2024 Jan 25.
[4] Poggioli R, Hirani K, Jogani VG, Ricordi C. Modulation of inflammation and immunity by omega-3 fatty acids: a possible role for prevention and to halt disease progression in autoimmune, viral, and age-related disorders. Eur Rev Med Pharmacol Sci. 2023 Aug;27(15):7380-7400.
[5] Zhang X, Zhang H. Pro-resolving and anti-inflammatory effects of resolvins and protectins in rheumatoid arthritis. Inflammopharmacology. 2023 Dec;31(6):2995-3004. doi: 10.1007/s10787-023-01343-5.