Effects of Supplemental Vitamin D3, Omega-3 Fatty Acids on Physical Performance Measures in VITamin D and OmegA-3 TriaL.

CONTEXT: Declining muscle strength and performance in older adults are associated with falls, fractures, and premature death. OBJECTIVE: To determine whether supplementation with vitamin D3 or omega-3 fatty acids vs. placebo for 2 years improves physical performance measures. DESIGN: VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled randomized trial of supplemental vitamin D3 and/or omega-3 fatty acids vs. placebo in the prevention of cancer and cardiovascular disease in 25,871 U.S. adults. This ancillary study was completed in a New England sub-cohort that had in-person evaluations at baseline and 2-year follow-up. SETTING: Center for Clinical Investigations in Boston. PARTICIPANTS: 1,054 participants (men ≥50 and women ≥55 years). INTERVENTIONS: 2x2 factorial design of supplemental vitamin D3 (cholecalciferol, 2000 IU/day) and/or marine omega-3 fatty acids (1 g/day). MAIN OUTCOME MEASURES: 2-year changes in physical performance measures of grip strength, walking speed, standing balance, repeated chair stands, and Timed-up and Go (TUG). RESULTS: At 2 years, all randomized groups showed worsening walking speeds and TUG. There were no differences in changes in grip strength, walking speeds, Short Physical Performance Battery (composite of walking speed, balance, and chair stands), and TUG between the vitamin D3-treated and the placebo-treated groups and between the omega-3-treated and the placebo-treated groups. Effects overall did not vary by sex, age, body mass index, or baseline measures of total or free 25-hydroxyvitamin D (25[OH]D) or plasma n-3 index; TUG slightly worsened with vitamin D supplementation, compared to placebo, in participants with baseline total 25(OH)D levels above the median (p=0.01, p for interaction=0.04). CONCLUSIONS: Neither supplemental vitamin D3 nor marine omega-3 fatty acids for 2 years improved physical performance in this generally healthy adult population.

Joint effects of one year of marine omega-3 fatty acid supplementation and participant dietary fish intake upon circulating lipid mediators of inflammation resolution in a randomized controlled trial.

OBJECTIVES: We assessed the joint effects of omega (n)-3 fatty acid supplementation and dietary fish intake on systemic lipid mediators of inflammation among adults. METHODS: Within VITAL, a double-blind randomized controlled trial, adults were randomized to ω-3 fatty acids (460 mg EPA + 380 mg DHA/d) or placebo. We selected participants who reported low (<1 serving/mo) baseline dietary fish intake and matched them by age, sex, race, and trial arm to participants with self-reported highest fish intake (≥3.9 servings/wk). Baseline and 1-y plasma samples were tested for 9 ω-3 fatty acid-derived lipid mediators. Multivariable linear models assessed lipid mediator changes and joint effects of ω-3 fatty acid supplementation and dietary fish intake. RESULTS: Forty-eight participants with low baseline fish intake were matched to 48 with high fish intake. Mean age was 64.6 (±7.26), 50% were female, and 85% non-Hispanic white. One-year lipid mediator changes in expected directions were observed in those receiving ω-3 fatty acids versus placebo: reductions in proinflammatory mediators, PGD2, 5-HETE, and 12-HETE; increases in proresolving mediators, EPA and DHA. Larger 1-y lipid biomarker changes were seen in those with low baseline fish intake randomized to active ω-3 fatty acids for DHA, EPA, PGD2, Resolvin D1, and Resolvin D4 were observed, although no significant multiplicative interactions were detected. DISCUSSION: Beneficial changes in circulating proresolving and proinflammatory mediators were found with 1-y of ω-3 fatty acid supplementation versus placebo for all participants, with a trend toward larger effects among those with low baseline fish intake, although interactions were not significant.

Vitamin D and Marine n-3 Fatty Acids for Autoimmune Disease Prevention: Outcomes Two Years After Completion of a Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: In the 5.3-year randomized, 2 × 2 factorial, double-blind, placebo-controlled Vitamin D and Omega-3 Trial (VITAL), vitamin D supplementation reduced autoimmune disease (AD) incidence (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.61-0.99). Omega-3 (n-3) fatty acid supplementation showed a statistically nonsignificant reduction (HR 0.85, 95% CI 0.67-1.08). We aimed to confirm further AD cases arising during and after randomization and assess sustained effects with two years of postintervention observation. METHODS: Of the 12,786 men aged ≥50 and 13,085 women aged ≥55 initially randomized, we observed surviving and willing participants for two more years. We continued to confirm annual participant-reported new AD by medical record review. Cox models calculated HRs for all confirmed incident AD, (and secondary endpoints, including probable cases, and individual ADs), during the observational and randomized periods. RESULTS: A total of 21,592 participants (83.5%) were observed for two more years; 514 participants developed incident confirmed AD (236 since prior report), of whom 255 had been randomized to vitamin D versus 259 to vitamin D placebo (HR 0.98 [95% CI 0.83-1.17] at 7 years). AD was confirmed in 234 participants initially randomized to n-3 fatty acids versus 280 randomized to its placebo (HR 0.83 [95% CI 0.70-0.99] at 7 years). Of newly confirmed cases, 65 had onset during randomization; their inclusion changed randomized results as follows: HR 0.85 (95% CI 0.70-1.04) for vitamin D and HR 0.87 (95% CI 0.71-1.06) for n-3 fatty acids. CONCLUSION: Two years after trial termination, the protective effects of 2000 IU/day of vitamin D dissipated, but 1,000 mg/day of n-3 fatty acids had a sustained effect in reducing AD incidence.

Over-the-counter fish oil supplementation and pro-resolving and pro-inflammatory lipid mediators in rheumatoid arthritis.

OBJECTIVE: Little is known about the effects of over-the-counter fish oil (FO) supplements on circulating omega-3 polyunsaturated fatty acid (n-3 PUFA)-derived specialized pro-resolving mediators (SPMs), nor about whether having a chronic inflammatory disease such as rheumatoid arthritis (RA) influences SPM levels. We investigated associations between over-the-counter n-3 PUFA FO supplementation and circulating SPMs among patients with vs. without RA. METHODS: We studied 104 participants: 26 with RA taking FO matched by age and sex to 26 with RA not taking FO, 26 without RA taking FO, and 26 without RA not taking FO. Targeted-liquid chromatography-tandem mass spectroscopy was performed on patient plasma to identify and quantify 27 lipid mediators (including eicosanoids and SPMs). We performed t-tests and then multivariable linear regression analyses to assess whether having RA or taking FO supplements was associated with circulating lipid mediator concentrations, adjusting for age, race, sex, smoking, body mass index, and current medication use (statins, prednisone and immunomodulators among RA cases only). We tested for interactions between FO supplementation and RA status. We also conducted Spearman's correlations between EPA, DHA, and ARA and their downstream metabolites. RESULTS: Among patients who were taking FO compared to those who were not, in multivariable- adjusted analyses, SPM substrates EPA and DHA were both elevated as were several of their pro-resolving bioactive products, including 15- and 18-HEPE from EPA, and 14- and 17-HDHA from DHA, which are substrates for specific SPMs. While E-series and D-series resolvins were present and identified, we did not find statistical elevations of other SPMs. Results were similar among patients with RA and patients without RA, taking vs. not taking FO supplementation (no formal statistical interaction observed). There was a strong positive correlation between EPA and DHA and their immediate downstream SPM precursors (18-HEPE and15-HEPE from EPA; 17-HDHA and 14-HDHA from DHA) among all patients. CONCLUSION: Patients taking FO supplements, regardless of RA status, not only had higher blood levels of EPA and DHA, but also of their enzymatic products 18-HEPE (E-series resolvin precursors), 15-HEPE and 17-HDHA (D-series resolvin and protectin precursors). Patients with RA, an inflammatory autoimmune disease, may be able to augment some SPM precursor reserves, similarly to matched controls without RA, by taking oral FO supplements.

Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial.

OBJECTIVE: To investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk. DESIGN: Vitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design. SETTING: Nationwide in the United States. PARTICIPANTS: 25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment. INTERVENTIONS: Vitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence. MAIN OUTCOME MEASURES: The primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others. RESULTS: 25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease. CONCLUSIONS: Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo). STUDY REGISTRATION: ClinicalTrials.gov NCT01351805 and NCT01169259.

Effects of Vitamin D3 Supplementation on Body Composition in the VITamin D and OmegA-3 TriaL (VITAL).

CONTEXT: Although observational studies show inverse associations between vitamin D status and body weight/adiposity, there are few large randomized controlled trials (RCTs) investigating this relationship. OBJECTIVE: To determine whether vitamin D3 supplementation lowers weight or improves body composition. DESIGN: The VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled RCT including 25 871 US adults. This ancillary study was completed in a sub-cohort that underwent body composition assessments at baseline and 2-year follow-up (89% retention). SETTING: Harvard Clinical and Translational Science Center in Boston. PARTICIPANTS: 771 participants (men ≥ 50 and women ≥ 55 years). INTERVENTIONS: 2 × 2 factorial design of supplemental vitamin D3 (2000 IU/day) and/or omega-3 fatty acids (1 g/day). MAIN OUTCOME MEASURES: Endpoints were 2-year changes in weight, body mass index (BMI), waist circumference, and total and/or regional fat and lean tissue measures determined by dual-energy X-ray absorptiometry. Effect modification by clinical variables and total and free 25-hydroxyvitamin D (25[OH]D) levels was explored. RESULTS: There were no effects of supplemental vitamin D3vs placebo on weight, BMI, or measures of adiposity and lean tissue. Effects did not vary by sex, race/ethnicity, fat mass index, or baseline total or free 25(OH)D levels. Vitamin D3 supplementation did slightly improve body fat percentage in participants with normal BMI at baseline, but not in the overweight or obese (P for interaction = 0.04). CONCLUSIONS: Daily vitamin D3 supplementation vs placebo in the general older population did not improve weight or body composition. Whether supplemental vitamin D3 may benefit individuals with normal BMI warrants further study.

Is competitive atrial pacing a possible trigger for atrial fibrillation? Observations from the RATE registry.

BACKGROUND: A high incidence of asymptomatic atrial tachycardia and atrial fibrillation (AT/AF) has been recognized in patients with cardiac implantable devices (CIED). The clinical significance of these AT/AF episodes remains unclear. Some "device-detected AT/AF" was previously shown to be triggered by competitive atrial pacing (CAP). OBJECTIVE: To investigate and characterize a potential association between CAP and AT/AF in the largest series of observations to date. METHODS: RATE, a multicenter registry, included 5379 patients with CIEDs followed for approximately 2 years. Electrograms (EGMs) from 1352 patients with AT/AF, CAP, or both were analyzed by experienced adjudicators to assess a causal relationship between AT/AF and CAP onset, duration, and morphology. RESULTS: In 225 patients, 1394 episodes of both AT/AF and CAP were present in the same tracing. CAP and AT/AF were strongly associated (P ≤ .02). AT/AF occurred during the course of the study in 71% of patients with CAP. In 62% of the episodes, expert adjudication concluded that CAP triggered AT/AF. The duration and morphology of triggered and spontaneous AT/AF episodes differed. Spontaneous AT/AF episodes were associated with constant EGM morphology, and were either long or extremely short. CAP-triggered AT/AF more often had variable and shorter cycle length EGMs. The incidence of short AT/AF events was higher among triggered episodes (25% vs 12.8%, P < .002). CONCLUSION: Device-triggered AT/AF due to CAP is likely more common than previously recognized. This AT/AF entity differs from spontaneous AT/AF in duration and morphology. Clinical implications of spontaneous and device-triggered AT/AF may be different.

VITamin D and OmegA-3 TriaL (VITAL): Effects of Vitamin D Supplements on Risk of Falls in the US Population.

CONTEXT: It is unclear whether vitamin D supplementation reduces risk of falls, and results from randomized controlled trials (RCTs) are conflicting. OBJECTIVE: The objective of this work is to determine whether 2000 IU/day of supplemental vitamin D3 decreases fall risk. DESIGN: VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT including 25 871 adults, randomly assigned November 2011 to March 2014 and treated for 5.3 years (median). SETTING: This is a nationwide study. PARTICIPANTS: Men 50 years or older and women 55 years or older (mean age, 67.1 years) without cancer or cardiovascular disease at baseline participated in this study. INTERVENTIONS: Interventions included vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (1 g/day) or respective placebos in a 2 × 2 factorial design. MAIN OUTCOME MEASURES: Main outcome measures include 2 or more falls and falls resulting in a doctor or hospital visit. RESULTS: Baseline serum total 25-hydroxyvitamin D (25[OH]D) level was 77 nmol/L; characteristics were well-balanced between groups. Numbers of participants with 2 or more falls were similar between active and placebo groups (9.8% vs 9.4%). Over 5 years, there were no differences in the proportion having 2 or more falls (odds ratio [OR] = 0.97; 95% CI, 0.90-1.05, P = .50), falls resulting in a doctor visit (OR = 1.03; 95% CI, 0.94-1.13, P = .46), or resulting in a hospital visit (OR = 1.04; 95% CI, 0.90-1.19, P = .61) between groups. Results did not differ between those with baseline 25(OH)D less than 50 vs 50 nmol/L or greater or other cut points. CONCLUSION: Daily supplemental vitamin D3 vs placebo did not decrease fall risk in generally healthy adults not selected for vitamin D insufficiency. This large RCT does not indicate that supplemental vitamin D should be used for primary prevention of falls in the US population.

Effects of Supplemental Vitamin D on Bone Health Outcomes in Women and Men in the VITamin D and OmegA-3 TriaL (VITAL).

Although supplemental vitamin D is used to promote bone health in the general population, data from randomized controlled trials (RCTs) have been inconsistent. We determined whether daily, vitamin D3 supplementation improves bone mineral density (BMD) and/or structure. VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT of supplemental vitamin D3 (2000 IU/d) and/or omega-3 fatty acids (1 g/d) in 25,871 adults nationwide. This ancillary study included a subcohort of 771 participants (men ≥50 and women ≥55 years; not taking bone active medications) evaluated at baseline and at 2-year follow-up (89% retention). Total 25(OH)D levels were measured by liquid chromatography tandem mass spectrometry (Quest Diagnostics, San Juan Capistrano, CA, USA). Free 25(OH)D (FVD) levels were measured using the ELISA assay by Future Diagnostics Solutions BV (Wijchen, Netherlands). Primary endpoints were 2-year changes in areal (a) BMD at the spine, hip, and whole body determined by dual-energy X-ray absorptiometry (DXA). Secondary endpoints were 2-year changes in volumetric (v) BMD and cortical thickness at the radius and tibia assessed by peripheral quantitative computed tomography. Supplemental vitamin D3 versus placebo had no effect on 2-year changes in aBMD at the spine (0.33% versus 0.17%; p = 0.55), femoral neck (-0.27% versus -0.68%; p = 0.16), total hip (-0.76% versus -0.95%; p = 0.23), or whole body (-0.22% versus -0.15%; p = 0.60), or on measures of bone structure. Effects did not vary by sex, race/ethnicity, body mass index, or 25(OH)D levels. Among participants with baseline FVD levels below the median (<14.2 pmol/L), there was a slight increase in spine aBMD (0.75% versus 0%; p = 0.043) and attenuation in loss of total hip aBMD (-0.42% versus -0.98%; p = 0.044) with vitamin D3 . Whether baseline FVD levels help to identify those more likely to benefit from supplementation warrants further study. Supplemental vitamin D3 versus placebo for 2 years in general healthy adults not selected for vitamin D insufficiency did not improve BMD or structure. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Effects of One Year of Vitamin D and Marine Omega-3 Fatty Acid Supplementation on Biomarkers of Systemic Inflammation in Older US Adults.

BACKGROUND: Observational studies suggest vitamin D and marine ω-3 fatty acid (n-3 FA) supplements are associated with lower systemic inflammation. However, past trials have been inconsistent. METHODS: The randomized, double-blind, placebo-controlled VITamin D and OmegA-3 TriaL (VITAL) tested vitamin D (2000 IU/day) and/or n-3 FA (1 g/day) supplementation in a 2 × 2 factorial design among women ≥55 and men ≥50 years of age. We assessed changes in interleukin (IL)-6, tumor necrosis factor receptor 2 (TNFR2), and high-sensitivity C-reactive protein (hsCRP) concentrations from baseline to 1 year among participants randomized to vitamin D + n-3 FA (392), vitamin D (392), n-3 FA (392), or placebo only (385). Geometric means and percent changes were compared, adjusting for baseline factors. RESULTS: Baseline characteristics were well balanced. In the active arms, 25-OH vitamin D rose 39% and n-3 FA rose 55% vs minimal change in placebo arms. Neither supplement reduced biomarkers at 1 year. Vitamin D resulted in 8.2% higher IL-6 (95% CI, 1.5%-15.3%; adjusted P = 0.02), but TNFR2 and hsCRP did not. Among 784 receiving vitamin D, hsCRP increased 35.7% (7.8%-70.9%) in those with low (<20 ng/mL) but not with higher baseline serum 25(OH) vitamin D [0.45% (-8.9% to 10.8%); P interaction = 0.02]. Among 777 randomized to n-3 FA, hsCRP declined [-10.5% (-20.4% to 0.8%)] in those with baseline low (<1.5 servings/week), but not with higher fish intake [6.4% (95% CI, -7.11% to 21.8%); P interaction = 0.06]. CONCLUSIONS: In this large sample from a population-based randomized controlled trial, neither vitamin D nor n-3 FA supplementation over 1 year decreased these biomarkers of inflammation. CLINICALTRIALSGOV IDENTIFIER: NCT01169259; NCT01351805.

Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL): Effects on Bone Structure and Architecture.

Vitamin D supplements are often used to benefit skeletal health, although data on effects of daily high-dose vitamin D alone on bone density and structure are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, randomized, placebo-controlled trial testing effects of high-dose supplemental vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (FAs; 1 g/day) for the primary prevention of cancer and cardiovascular disease. The study has a mean treatment period of 5 years among 25,874 U.S. men ≥50 years and women ≥55 years old from all 50 states. The ancillary study, VITAL: Effects on Bone Structure and Architecture, is testing effects of vitamin D3 and/or omega-3 FAs on musculoskeletal outcomes and body composition in a subcohort of 771 participants. At in-person visits at the Harvard Catalyst Clinical and Translational Science Center (CTSC), participants completed bone density/architecture, body composition, and physical performance assessments at baseline and two-year follow-up. Baseline characteristics were evenly distributed among treatment groups, suggesting that any uninvestigated confounders will be evenly distributed; sex differences were also analyzed. Future analyses of the two-year follow-up visits will elucidate whether daily high-dose, supplemental vitamin D3 and/or omega-3 FAs improve musculoskeletal outcomes, helping to advance clinical and public health recommendations. CLINICAL TRIAL REGISTRATION NUMBER: NCT01747447.

Effect of Baseline Nutritional Status on Long-term Multivitamin Use and Cardiovascular Disease Risk: A Secondary Analysis of the Physicians' Health Study II Randomized Clinical Trial.

Importance: Long-term multivitamin use had no effect on risk of cardiovascular disease (CVD) in the Physicians' Health Study II. Baseline nutritional status may have modified the lack of effect. Objective: To investigate effect modification by various baseline dietary factors on CVD risk in the Physicians' Health Study II. Design, Setting, and Participants: The Physicians' Health Study II was a randomized, double-blind, placebo-controlled trial testing multivitamin use (multivitamin [Centrum Silver] or placebo daily) among US male physicians. The Physicians' Health Study II included 14 641 male physicians 50 years or older, 13 316 of whom (91.0%) completed a baseline 116-item semiquantitative food frequency questionnaire and were included in the analyses. This study examined effect modification by baseline intake of key foods, individual nutrients, dietary patterns (Alternate Healthy Eating Index and Alternate Mediterranean Diet Score), and dietary supplement use. The study began in 1997, with continued treatment and follow-up through June 1, 2011. Interventions: Multivitamin or placebo daily. Main Outcomes and Measures: Major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, and CVD mortality. Secondary outcomes included myocardial infarction, total stroke, CVD mortality, and total mortality individually. Results: In total, 13 316 male physicians (mean [SD] age at randomization, 64.0 [9.0] years in those receiving the active multivitamin and 64.0 [9.1] years in those receiving the placebo) were observed for a mean (SD) follow-up of 11.4 (2.3) years. There was no consistent evidence of effect modification by various foods, nutrients, dietary patterns, or baseline supplement use on the effect of multivitamin use on CVD end points. Statistically significant interaction effects were observed between multivitamin use and vitamin B6 intake on myocardial infarction, between multivitamin use and vitamin D intake on CVD mortality, and between multivitamin use and vitamin B12 intake on CVD mortality and total mortality. However, there were inconsistent patterns in hazard ratios across tertiles of each dietary factor that are likely explained by multiple testing. Conclusions and Relevance: The results suggest that baseline nutritional status does not influence the effect of randomized long-term multivitamin use on major CVD events. Future studies are needed to investigate the role of baseline nutritional biomarkers on the effect of multivitamin use on CVD and other outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT00270647.