Vitamin D And Omega-3 Trial Research Articles

Abstract 12860: Effects of Marine Omega-3 and Vitamin D Supplementation on Circulating Biomarkers of Glucose-Insulin Homeostasis and Incident Cardiovascular Disease in the Vitamin D and Omega-3 Trial (VITAL)

Introduction: Dysglycemia and insulin resistance increase cardiovascular disease (CVD) risk. Associations between specific glucose-insulin biomarkers and CVD have been inconsistent. Hypothesis: We hypothesized that higher insulin, C-peptide, insulin resistance score (IRS), and HbA1c are associated with incident CVD and coronary heart disease (CHD) events and that both vitamin D and omega-3 fatty acids (n-3 FA) would improve these biomarkers and attenuate their risks with CVD. Methods: VITAL (NCT01169259) was a 2x2 factorial design RCT testing vitamin D (cholecalciferol, 2000 IU/d) and n-3 FA (EPA+DHA, 1 g/d) for the primary prevention of CVD. Incident CVD cases [non-fatal myocardial infarction (MI), non-fatal stroke, or CV death] were matched 1:1 on age and sex to healthy controls (n=715 CVD pairs including 423 CHD [MI, revascularization, CHD death] pairs). Conditional logistic regression adjusting for demographics, CV risk factors, and randomized treatment was used to assess the adjusted odds ratio (aOR) and 95% CI between baseline levels of insulin, C-peptide, IRS (Insulinх0.0265+C-peptideх0.00511+Creatinineх-3.2641), and HbA1c with risk of CVD and CHD events. In control participants, we examined the randomized effects of vitamin D or n-3 FA on changes in these biomarkers at 1- or 2-years follow-up. Results: Mean age of participants was 71 years, approximately 42% were female, and 12% were African American. Baseline insulin, C-peptide, and IRS were not associated with CVD ( Figure 1 ). HbA1c was associated with CVD risk, aOR (95% CI) per SD increment, 1.17 (1.01, 1.38). Of the 4 biomarkers, only IRS was associated with CHD risk, aOR (95% CI): 1.22 (1.01, 1.46). Randomization to vitamin D or n-3 FA did not modify levels of these biomarkers or their associations. Conclusions: HbA1c was significantly associated with CVD risk, whereas IRS was associated with CHD risk. Neither vitamin D nor n-3 FA appreciably modified these biomarker levels or their risk associations.

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

ContextAlthough observational studies show inverse associations between vitamin D status and body weight/adiposity, there are few large randomized controlled trials (RCTs) investigating this relationship.ObjectiveTo determine whether vitamin D3 supplementation lowers weight or improves body composition.DesignThe 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).SettingHarvard Clinical and Translational Science Center in Boston.Participants771 participants (men ≥ 50 and women ≥ 55 years).Interventions2 × 2 factorial design of supplemental vitamin D3 (2000 IU/day) and/or omega-3 fatty acids (1 g/day).Main Outcome MeasuresEndpoints 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.ResultsThere 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).ConclusionsDaily 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.

Effect of Vitamin D and/or Marine n-3 Fatty Acid Supplementation on Changes in Migraine Frequency and Severity

BackgroundThere is interest in whether supplements, including vitamin D and marine omega-3 (n-3) fatty acids, may be effective migraine prophylaxis. However, few studies have evaluated whether vitamin D or n-3 fatty acid supplementation may reduce migraine frequency or severity. MethodsParticipants in the VITamin D and OmegA-3 TriaL (VITAL) were assigned to vitamin D3 (2000 IU/d) or marine n-3 fatty acid (1 g/d) supplementation in a 2-by-2 factorial design. Lifetime history of migraine was assessed a median of 4.6 years after the start of the trial. Individuals were asked to self-report changes in migraine frequency (no change, more frequent, or less frequent) and severity (no change, more severe, less severe) in the past 5 years. We used χ2 tests to compare proportions of individuals reporting changes in migraine frequency and severity between active and placebo groups. ResultsAmong the 25,871 participants in VITAL, 1032 participants had a history of probable migraine and provided information on changes in migraine frequency and severity. The percentage of individuals reporting decreases in migraine frequency did not differ between active (69.0%) and placebo vitamin D (68.4%) (P value = 0.54) or between active (67.8%) and placebo n-3 fatty acid (69.6%) (P value = 0.82). Similarly, the percentage of individuals reporting decreases in migraine severity did not differ between active (64.1%) and placebo vitamin D (65.0%) (P value = 0.86) or between active (64.5%) and placebo n-3 fatty acid (64.5%) (P value = 0.96). ConclusionsNeither vitamin D nor marine n-3 fatty acid supplementation, compared to placebo, affected migraine frequency or severity among middle-aged or older adults.

The VITamin D and OmegA-3 TriaL (VITAL): Do Results Differ by Sex or Race/Ethnicity?

Whether vitamin D or marine omega-3 (n-3) fatty acid supplementation reduces risk of cancer or cardiovascular disease (CVD) in general populations at usual risk for these outcomes is relatively unexplored in randomized trials. The primary goal of the VITamin D and OmegA-3 TriaL (VITAL), a nationwide, randomized, placebo-controlled, 2 × 2 factorial trial of vitamin D3 (2000 IU/day) and marine n-3 fatty acids (1 g/day) in the primary prevention of cancer and CVD among 25 871 US men aged ≥50 years and women aged ≥55 years, was to fill these knowledge gaps. Studying the influence of sex and race/ethnicity on treatment-related outcomes was a prespecified goal; such analyses help ensure that important effects are not missed and contribute to the foundation for developing targeted recommendations for supplement use. To enable investigation of potential sex- and race-specific treatment effects, trial investigators enrolled an even balance of men (n = 12 786) and women (n = 13 085) and oversampled African Americans (n = 5106). Significant or suggestive variation in intervention effects according to sex, race/ethnicity, and other participant characteristics was observed for some, though not all, outcomes. Additional research is needed to determine which individuals may be most likely to derive a net benefit from vitamin D or n-3 fatty acid supplementation. (VITAL clinicaltrials.gov identifier: NCT01169259).

Effect of vitamin D and/or omega-3 fatty acid supplementation on stroke outcomes: A randomized trial.

Among stroke patients, low serum 25-hydroxyvitamin D predicts poor outcomes. In mice, higher omega-3 (n-3) fatty acid intake diminishes brain damage after stroke. In this study, we tested whether vitamin D or n-3 fatty acids supplementation prior to stroke reduces the risk of functional limitations and physical disability after stroke. We used data from VITAL (the VITamin D and OmegA-3 TriaL) which randomized middle-aged and older men and women without cardiovascular disease to vitamin D3 (2000IU/day) and/or marine n-3 fatty acids (1g/day) and followed them for incident stroke events. Individuals experiencing a non-fatal stroke were mailed questionnaires assessing functional limitations (the physical performance scale adapted from Nagi) and physical disability (the modified Katz Activities of Daily Living and Rosow-Breslau Functional Health scales). We used logistic regression to analyze associations between randomized treatment and limitations on each scale. A total of 290 individuals experienced their first stroke during the trial, of whom 197 stroke survivors completed the stroke outcomes questionnaire a median of 1.4years after diagnosis. We observed no associations between randomized treatment to vitamin D and functional limitations (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.52, 1.97) or physical disability (Rosow-Breslau scale: OR 0.92, 95% CI 0.50, 1.67; Katz scale: OR 1.03, 95% CI 0.31, 3.42). Those randomized to n-3 fatty acids had a non-significantly lower risk of functional limitations (OR 0.55, 95% CI 0.28, 1.09) and physical disability (Rosow-Breslau scale: OR0.56, 95% CI 0.31, 1.02; Katz sclae: OR0.32, 95% CI 0.50, 1.67). Vitamin D or omega-3 fatty acid supplementation prior to stroke did not result in significantly improved post-stroke outcomes.

Effect of Vitamin D3 Supplements on Development of Advanced Cancer

Epidemiologic and trial data suggest that vitamin D supplementation may reduce metastatic cancer and cancer mortality, reflecting shared biological pathways. To follow up on the possible reduction in cancer death in the Vitamin D and Omega-3 Trial (VITAL) with an evaluation of whether vitamin D reduces the incidence of advanced (metastatic or fatal) cancer and an examination possible effect modification by body mass index. VITAL is a randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial of vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d). This multicenter clinical trial was conducted in the United States; participants included men aged 50 years or older and women aged 55 years or older who were free of cancer and cardiovascular disease at baseline. Randomization took place from November 2011 through March 2014, and study medication ended on December 31, 2017. Data for this secondary analysis were analyzed from November 1, 2011, to December 31, 2017. Vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d) supplements. For the present analysis, the primary outcome was a composite incidence of metastatic and fatal invasive total cancer, because the main VITAL study showed a possible reduction in fatal cancer with vitamin D supplementation and effect modification by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) for total cancer incidence reduction for individuals with normal BMI, but not for individuals with overweight or obesity. Secondary analyses included examination of BMI (<25, 25 to < 30, and ≥30) as effect modifiers of the observed associations. Among 25 871 randomized VITAL participants (51% female; mean [SD] age, 67.1 [7.1] years), 1617 were diagnosed with invasive cancer over a median intervention period of 5.3 years (range, 3.8-6.1 years). As previously reported, no significant differences for cancer incidence by treatment arm were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D compared with placebo (226 of 12 927 assigned to vitamin D [1.7%] and 274 of 12 944 assigned to placebo [2.1%]; HR, 0.83 [95% CI, 0.69-0.99]; P = .04). When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI<25: HR, 0.62 [95% CI, 0.45-0.86]) but not among those with overweight or obesity (BMI 25-<30: HR, 0.89 [95% CI, 0.68-1.17]; BMI≥30: HR, 1.05 [95% CI, 0.74-1.49]) (P = .03 for interaction by BMI). In this randomized clinical trial, supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with the strongest risk reduction seen in individuals with normal weight. ClinicalTrials.gov Identifier: NCT01169259.

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

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. To evaluate whether daily supplementation with vitamin D3, marine ω-3 fatty acids, or both prevents the development or progression of AMD. 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. Vitamin D3 (cholecalciferol), 2000 IU per day, and marine ω-3 fatty acids, 1 g per day. 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. 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. Neither vitamin D3 nor marine ω-3 fatty acid supplementation had a significant overall effect on AMD incidence or progression. ClinicalTrials.gov Identifier: NCT01782352.

One-Year Effects of Omega-3 Treatment on Fatty Acids, Oxylipins, and Related Bioactive Lipids and Their Associations with Clinical Lipid and Inflammatory Biomarkers: Findings from a Substudy of the Vitamin D and Omega-3 Trial (VITAL).

Omega-3 (n-3) treatment may lower cardiovascular risk, yet its effects on the circulating lipidome and relation to cardiovascular risk biomarkers are unclear. We hypothesized that n-3 treatment is associated with favorable changes in downstream fatty acids (FAs), oxylipins, bioactive lipids, clinical lipid and inflammatory biomarkers. We examined these VITAL200, a nested substudy of 200 subjects balanced on demographics and treatment and randomly selected from the Vitamin D and Omega-3 Trial (VITAL). VITAL is a randomized double-blind trial of 840 mg/d eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) vs. placebo among 25,871 individuals. Small polar bioactive lipid features, oxylipins and FAs from plasma and red blood cells were measured using three independent assaying techniques at baseline and one year. The Women’s Health Study (WHS) was used for replication with dietary n-3 intake. Randomized n-3 treatment led to changes in 143 FAs, oxylipins and bioactive lipids (False Discovery Rate (FDR) < 0.05 in VITAL200, validated (p-values < 0.05)) in WHS with increases in 95 including EPA, DHA, n-3 docosapentaenoic acid (DPA-n3), and decreases in 48 including DPA-n6, dihomo gamma linolenic (DGLA), adrenic and arachidonic acids. N-3 related changes in the bioactive lipidome were heterogeneously associated with changes in clinical lipid and inflammatory biomarkers. N-3 treatment significantly modulates the bioactive lipidome, which may contribute to its clinical benefits.

The Effects of Vitamin D and Marine Omega-3 Fatty Acid Supplementation on Chronic Knee Pain in Older US Adults: Results From a Randomized Trial.

Knee pain from osteoarthritis is frequent in the adult population. Prior trials have had conflicting results concerning the therapeutic effects of vitamin D on knee pain, and few trials have investigated marine Omega-3 fatty acids (n-3 FA). In the double-blind, placebo-controlled Vitamin D and Omega-3 Trial (VITAL), 25,871 US adults were randomized in a 2-by-2 factorial design to receive vitamin D or n-3 FA. We identified a subgroup with chronic knee pain prior to randomization and assessed knee pain at baseline and annually during follow-up using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (graded on a 0-100 scale, where 100 indicates worst symptoms). Repeated measures modeling was used to test the effect of randomized treatment on WOMAC pain scores over follow-up after adjustment for age and sex. Analyses were repeated for WOMAC function and stiffness. This study included 1,398 participants who returned at least one knee pain questionnaire. The mean age was 67.7 years, 66% were women, and the mean ± SD WOMAC pain score was 37 ± 19. The mean ± SD follow-up time was 5.3 ± 0.7 years. WOMAC pain did not differ between the active vitamin D group and the vitamin D placebo group or between the active n-3 FA group and the n-3 FA placebo group at any time point during follow-up. Linear time-by-treatment interactions were not significant for either treatment (vitamin D, P = 0.41; n-3 FA, P = 0.77). Vitamin D and n-3 FA supplementation did not significantly affect WOMAC function or stiffness scores over time. Our findings indicate that vitamin D and n-3 FA supplementation for a mean of 5.3 years does not reduce knee pain or improve function or stiffness in a large sample of US adults with chronic knee pain.

Hype um die Vitamin-D-Substitution: Was bleibt?

Der „Hype um Vitamin D“ ist neben der Bedeutung für die Knochengesundheit auch auf die ubiquitäre Präsenz des Vitamin-D-Rezeptors in vielen Organsystemen zurückzuführen. Große Beobachtungsstudien lieferten Hinweise, dass ein Vitamin-D-Mangel Risiken altersassoziierte chronische Erkrankungen, wie Krebs- und kardiovaskuläre Erkrankungen, begünstigt. In der vorliegenden Übersicht werden neueste Informationen, einerseits zur Knochengesundheit bei erwachsenen Menschen sowie andererseits zu Krebs- und kardiovaskulären Erkrankungen, anhand der aktuellen Resultate des großen Vitamin D and Omega‑3 Trial (VITAL) eingeordnet.

Vitamin D3 Found Ineffective at Preventing Depression

Back to table of contents Previous article Next article Clinical & ResearchFull AccessVitamin D3 Found Ineffective at Preventing DepressionNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:15 Sep 2020https://doi.org/10.1176/appi.pn.2020.9a25AbstractThe trial involved over 18,000 middle-aged and older adults from across the country who took a high dose of vitamin D supplements or placebo daily for over five years.iStock/Helin Loik-TomsonHigh-dose vitamin D3 supplements do not appear to be effective at preventing depression in older adults, according to a large, placebo-controlled study published August 4 in JAMA.Observational studies have suggested that people with lower blood levels of vitamin D are at higher risk of late-life depression, while other research has found that vitamin D deficiency may be involved in seasonal depressive disorder. But to date prospective studies of people taking vitamin D supplements have yielded little evidence that adding vitamin D protects against depression.It is possible that previous supplement studies examined vitamin D doses that were too low and/or the studies were too short in duration. This new study addressed previous shortcomings by evaluating over 18,000 older adults across the United States for over five years.The adults were participants in the Vitamin D and Omega-3 Trial (VITAL), a randomized study examining the effects of daily vitamin D3 and/or fish oil supplements on the prevention of cancer and cardiovascular disease. As an ancillary part of the study (VITAL-DEP), participants were also given the eight-item Patient Health Questionnaire (PHQ-8) during their periodic assessments to screen for depressive symptoms. Participants who were currently receiving treatment for depression or had another psychiatric or neurological condition were excluded from this ancillary analysis.The final sample included 9,181 adults who took 2,000 IU/d of vitamin D3 daily for an average of 5.3 years and 9,172 adults who took placebo for the same average time. By the end of the study, 609 adults taking vitamin D3 and 625 taking placebo received a diagnosis of depression or developed clinically relevant depressive symptoms (a PHQ-8 score of ≥10)—which the authors noted was not a significant difference between the groups.There was also no significant difference between the two groups in overall mood over time; average PHQ-8 scores rose by 0.20 points in the vitamin D3 group and 0.16 points in the placebo group.“By no means is this study a verdict on vitamin D as a supplement in general,” said study author Olivia Okereke, M.D., the director of geriatric psychiatry at Massachusetts General Hospital and an associate professor of psychiatry and epidemiology at Harvard Medical School. “This vitamin is important for bone health and immune health and potentially other conditions.”She continued, “The findings indicate that for an average adult, taking vitamin D3 supplements for the purpose of improving mood will provide no benefit.”Okereke and colleagues also looked at data on various subgroups in the study to see whether there might be a population that experienced a positive effect from vitamin D3. However, vitamin D3 did not appear to prevent depression in any of the tested subgroups, including grouping by sex, ethnicity, age group, and depression history.“Now, there was one interesting signal that showed adults with normal body weight [body mass index score of 25 or less] might be gaining some protection from depression,” Okereke noted. This signal mirrored some data seen in the main VITAL study, which was published last year in the New England Journal of Medicine. This study found that while vitamin D3 supplements did not prevent cancer or major cardiovascular events in the general population, the supplements did appear to reduce the risk of cancer in adults with low body mass index.Okereke cautioned that the findings on obesity are still preliminary, but if there was one variable worth pursuing with further research, that would be it.The VITAL-DEP researchers are reviewing data related to fish oil and depression and hope to release those findings soon.VITAL-DEP was supported by a grant from the National Institute of Mental Health. The main VITAL study was supported by grants from the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Institute of Neurological Disorders and Stroke; the National Center for Complementary and Integrative Health; and the Office of Dietary Supplements. Pharmavite LLC and Pronova BioPharma/ BASF donated the vitamin D3 and fish oil for the study, respectively. ■“Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial” is posted here.The parent VITAL study, “Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease” is posted here. ISSUES NewArchived

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

ContextIt is unclear whether vitamin D supplementation reduces risk of falls, and results from randomized controlled trials (RCTs) are conflicting.ObjectiveThe objective of this work is to determine whether 2000 IU/day of supplemental vitamin D3 decreases fall risk.DesignVITamin 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).SettingThis is a nationwide study.ParticipantsMen 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.InterventionsInterventions 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 MeasuresMain outcome measures include 2 or more falls and falls resulting in a doctor or hospital visit.ResultsBaseline 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.ConclusionDaily 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.

Effect of Vitamin D3 (Cholecalciferol) Supplementation on Serum Vitamin D3 and 25-hydroxyvitamin D (25(OH)D) Concentrations Among Participants in the VITAL-DKD Study

Abstract Objectives To compare the serum vitamin D3 and 25(OH)D responses to vitamin D3 supplementation in the VITAL-DKD study. Methods The Vitamin D and OmegA-3 TriaL (VITAL)-DKD was a 2 × 2 factorial, randomized, placebo-controlled trial of vitamin D3 (2000 IU/day) and omega-3 fatty acids (1 g/day) for prevention of chronic kidney disease among adults with type 2 diabetes. For the first 200 enrolled participants, we measured baseline and year 2 serum vitamin D3 concentration with a new validated liquid chromatography-tandem mass spectrometry method. Linear regression was used to test the effects of D3 treatment on changes in serum D3 and 25(OH)D concentrations and to examine possible effect modification by relevant clinical characteristics. Results Participants were 70 ± 6 years of age, 64% male, 70% non-Hispanic white, and 15% black. At baseline and year 2, serum D3 concentration and 25(OH)D3 concentration were positively related, with a threshold effect at a 25(OH)D3 concentration of 50 nmol/L. Below this threshold, serum D3 concentration rarely exceeded 5 nmol/L. Above it, serum D3 concentration was much more variable. Supplementation increased mean serum D3 concentration from 12 nmol/L at baseline to 41 nmol/L at year 2 (difference compared with placebo 30 nmol/L; 95% CI 25 to 35 nmol/L) and increased mean serum 25(OH)D concentration from 76 nmol/L to 102 nmol/L (difference compared with placebo 33 nmol/L; 95% CI 26 to 40 nmol/L). The effect of treatment on change in serum 25(OH)D was modified by body weight (−0.48 nmol/L per kg of weight; P &amp;lt; 0.01), baseline 25(OH)D concentration (−0.30 nmol/L per nmol/L of baseline 25(OH)D; P &amp;lt; 0.01), baseline D3 concentration (−5 nmol/L per 100% increase in baseline D3; P = 0.04), and non-study vitamin D supplement use (smaller effect as dose of non-study supplement increased). The effect of treatment on change in serum D3 concentration was modified only by body weight (−0.33 nmol/L per kg of weight; P = 0.01). Conclusions Among older adults, 2 years of 2000 IU/day vitamin D3 led to similar mean increases in serum D3 and 25(OH)D. Unlike the serum 25(OH)D response, the serum D3 response to supplementation did not depend on baseline vitamin D status. The serum vitamin D concentration may be an additional, valuable marker of exposure to vitamin D during supplementation. Funding Sources NIDDK NIH ODS NHLBI.

Vitamin D supplements and marine omega-3 fatty acids and development of advanced cancer.

1510 Background: Epidemiologic data suggest that vitamin D supplementation may reduce cancer mortality. We tested whether vitamin D and/or omega-3 supplementation reduces the incidence of advanced stage cancer at diagnosis or lethal cancer, and whether body mass index (BMI) modifies these associations. Methods: The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, placebo-controlled, 2x2 factorial trial of vitamin D3 (cholecalciferol, 2000 IU/day) and marine omega-3 fatty acids (1 g/day) that enrolled men aged ≥50 years and women aged ≥55 years free of cancer and cardiovascular disease at baseline. For this particular analysis, the primary outcome is a composite of metastatic and fatal invasive total cancer. Secondary analyses included examination of BMI (&lt;25, 25-&lt;30, and &gt;= 30 kg/m2) as effect modifiers of the observed associations. Results: VITAL randomized 25,871 participants, among whom 1,617 were diagnosed with invasive cancer over a median 5.3 year intervention period. No significant differences by treatment arm (vitamin D vs placebo: hazard ratio [HR]=0.96; 95% confidence interval, 0.88-1.06; p=0.47; omega-3 vs placebo; HR 1.03 [0.93-1.13]; p=0.56) were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D, compared to placebo (226 assigned to vitamin D and 274 to placebo; HR 0.83 [0.69-0.99]; p=0.036). There was no difference by omega-3 assignment (246 assigned to omega-3 and 254 to placebo: HR 0.97 [0.81-1.15], p=0.72). When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI&lt;25: HR 0.62 [0.45-0.86], but not among those who were overweight or obese (BMI 25-&lt;30: HR 0.89 [0.68-1.17]; BMI &gt;=30: HR 1.05 [0.74-1.49]); p for interaction by BMI =0.03. There was no effect modification by BMI noted for the omega 3 arm. Conclusions: In a randomized clinical trial, supplementation with vitamin D, but not omega-3s, reduced incidence of advanced (metastatic or fatal) cancer in the overall cohort, with strongest risk reduction in normal weight individuals. Further research is needed to understand these findings. Clinical trial information: NCT01169259.

Optimal Dose of n-3 Polyunsaturated Fatty Acids for Cardiovascular Event Prevention.

Background: The n-3 polyunsaturated fatty acids (PUFA), represented by eicosapentaenoic acid (EPA) and docosahexaenoic acid, have anti-atherogenic effects (e.g., neutral fat-lowering effects) and other beneficial effects such as antiplatelet, anti-inflammatory, plaque stabilizing, vascular endothelial function ameliorative, antihypertensive, and anti-arrhythmic effects. Epidemiological studies and clinical trials have assessed the inhibitory effects of n-3 PUFA on cardiovascular events.Methods and Results: Studies that reported positive outcomes, such as the Japan EPA Lipid intervention Study (JELIS) and the Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia (REDUCE-IT), noted a tendency toward the use of high-dose n-3 PUFA (1.8–4 g/day). The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Prevenzione (GISSI-Prevenzione) trial and the JELIS had high EPA/arachidonic acid (AA) baseline ratios. In contrast, negative outcome studies, such as the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, Risk and Prevention study, A Study of Cardiovascular Events in Diabetes (ASCEND), and the Vitamin D and Omega-3 Trial (VITAL) had participants who tended to use low-dose n-3 PUFA (0.84–1 g/day) and to have low baseline EPA/AA.Conclusions: Differences in baseline EPA/AA ratio and the EPA/AA ratio threshold for the prevention of cardiovascular events seem to contribute to the different outcomes, together with the dose of n-3 PUFA.

Triglycerides and residual risk.

To review the recent evidence from observational/genetic/interventional studies addressing triglycerides and residual cardiovascular risk (CVRisk). Large population-based and secondary prevention studies consistently show an association of higher triglycerides with increased CVRisk. This is compounded by genetic studies demonstrating an independent relationship between triglyceride raising or lowering genetic variants affecting triglyceride-rich lipoproteins (TRL) metabolism and CVRisk. Mendelian randomization analysis suggests the benefit of genetic lowering of triglycerides and LDL-cholesterol is similar per unit change in apolipoprotein-B. Among cholesterol-lowering trials, more intensive statin therapy produced greater CVRisk reductions in patients with higher TRL-cholesterol or triglycerides; proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition led to similar triglycerides reduction but greater non-HDL-C or apolipoprotein-B reductions than fibrates or fish oils. Regarding n-3 fatty acids, A Study of Cardiovascular Events in Diabetes (ASCEND) and Vitamin D and Omega-3 Trial (VITAL) primary prevention trials with eicosapentaenoic acid (EPA) and docosahexaenoic acid failed to demonstrate cardiovascular benefits, Conversely, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) using high-dose icosapent-ethyl (purified EPA) in primary (diabetes) and secondary prevention with hypertriglyceridemia showed significant cardiovascular events reductions (greater than expected by the observed triglycerides or apolipoprotein-B reductions, suggesting potential benefits through non-lipid pathways). Evidence suggests higher triglycerides are a marker of CVRisk and may help identify patients who benefit from intensification of therapy. Moreover, genetic studies support a causal link between TRL/triglycerides and cardiovascular disease. Treatment with high-dose EPA may be of benefit in high-risk patients with hypertriglyceridemia to reduce CVRisk.

Association of Race and Ethnicity With Late-Life Depression Severity, Symptom Burden, and Care

Knowledge gaps persist regarding racial and ethnic variation in late-life depression, including differences in specific depressive symptoms and disparities in care. To examine racial/ethnic differences in depression severity, symptom burden, and care. This cross-sectional study included 25 503 of 25 871 community-dwelling older adults who participated in the Vitamin D and Omega-3 Trial (VITAL), a randomized trial of cancer and cardiovascular disease prevention conducted from November 2011 to December 2017. Data analysis was conducted from June to September 2018. Racial/ethnic group (ie, non-Hispanic white; black; Hispanic; Asian; and other, multiple, or unspecified race). Depressive symptoms, assessed using the Patient Health Questionnaire-8 (PHQ-8); participant-reported diagnosis, medication, and/or counseling for depression. Differences across racial/ethnic groups were evaluated using multivariable zero-inflated negative binomial regression to compare PHQ-8 scores and multivariable logistic regression to estimate odds of item-level symptom burden and odds of depression treatment among those with diagnosed depression. There were 25 503 VITAL participants with adequate depression data (mean [SD] age, 67.1 [7.1] years) including 12 888 [50.5%] women, 17 828 [69.9%] non-Hispanic white participants, 5004 [19.6%] black participants, 1001 [3.9%] Hispanic participants, 377 [1.5%] Asian participants, and 1293 participants [5.1%] who were categorized in the other, multiple, or unspecified race group. After adjustment for sociodemographic, lifestyle, and health confounders, black participants had a 10% higher severity level of PHQ-8 scores compared with non-Hispanic white participants (rate ratio [RR], 1.10; 95% CI, 1.04-1.17; P < .001); Hispanic participants had a 23% higher severity level of PHQ-8 scores compared with non-Hispanic white participants (RR, 1.23; 95% CI, 1.10-1.38; P < .001); and participants in the other, multiple, or unspecified group had a 14% higher severity level of PHQ-8 scores compared with non-Hispanic white participants (RR, 1.14; 95% CI, 1.04-1.25; P = .007). Compared with non-Hispanic white participants, participants belonging to minority groups had 1.5-fold to 2-fold significantly higher fully adjusted odds of anhedonia (among black participants: odds ratio [OR], 1.76; 95% CI, 1.47-2.11; among Hispanic participants: OR, 1.96; 95% CI, 1.43-2.69), sadness (among black participants: OR, 1.31; 95% CI, 1.07-1.60; among Hispanic participants: OR, 2.09; 95% CI, 1.51-2.88), and psychomotor symptoms (among black participants: OR, 1.77; 95% CI, 1.31-2.39; among Hispanic participants: OR, 2.12; 95% CI, 1.28-3.50); multivariable-adjusted odds of sleep problems and guilt appeared higher among Hispanic vs non-Hispanic white participants (sleep: OR, 1.24; 95% CI, 1.01-1.52; guilt: 1.84; 95% CI, 1.31-2.59). Among those with clinically significant depressive symptoms (ie, PHQ-8 score ≥10) and/or those with diagnosed depression, black participants were 61% less likely to report any treatment (ie, medications and/or counseling) than non-Hispanic white participants after adjusting for confounders (adjusted OR, 0.39; 95% CI, 0.27-0.56). In this cross-sectional study, significant racial and ethnic differences in late-life depression severity, item-level symptom burden, and depression care were observed after adjustment for numerous confounders. These findings suggest a need for further examination of novel patient-level and clinician-level factors underlying these associations.

Abstract TP433: Effect of Vitamin D and Marine Omega-3 Fatty Acid Supplements on Stroke Outcomes

Introduction: Low serum 25-hydroxyvitamin D (25(OH)D) and low marine omega-3 fatty acid (n-3) intake are associated with increased stroke risk in observational studies. Among stroke patients, low serum 25(OH)D at admission predicts poor outcomes and animal studies suggest that higher n-3 intake may diminish brain damage in ischemic stroke. However, few studies have examined effects of vitamin D or n-3 supplements on stroke outcomes. Hypothesis: We hypothesized that vitamin D (cholecalciferol, 2,000 IU/day) or n-3 (840 mg/day of EPA/DHA [ratio of 1.3:1]) supplementation initiated prior to stroke would reduce risk of functional limitations or physical disability after stroke compared to placebo. Methods: We used data from the completed VITamin D and OmegA-3 TriaL (VITAL) which randomized 25,871 men aged ≥50 years and women aged ≥55 years without cardiovascular disease or cancer at baseline and followed them for incident events over 5.3 years. Individuals experiencing a stroke were mailed a questionnaire to assess functional limitations (with the physical performance scale adapted from Nagi) and physical disability (with the modified Katz Activities of Daily Living and Rosow-Breslau Functional Health scales). We used logistic regression to analyze associations between randomized treatment assignments and limitations on each scale. Results: 290 individuals experienced their first stroke during the trial (including 42 fatal strokes). 197 stroke survivors completed the stroke outcomes questionnaire a mean of 1.6 years after diagnosis. We observed no associations between randomized treatment to vitamin D and functional limitations (odds ratio (OR)=1.01, 95% confidence interval (CI): 0.52, 1.97) or physical disability on the Rosow-Breslau (OR=1.03, 95% CI: 0.31, 3.42) or Katz (OR=0.92, 95% CI: 0.50, 1.67) scales. Although not statistically significant, those randomized to n-3 had lower risk of functional limitations (OR=0.55, 95% CI: 0.28, 1.09) and physical disability on the Katz scale (OR=0.32, 95% CI: 0.50, 1.67) but not on the Rosow-Breslau scale (OR=1.03, 95% CI: 0.31, 3.42). Conclusion: Supplementation with vitamin D or omega-3 fatty acids prior to stroke did not result in significantly improved outcomes after stroke among older individuals.

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

ABSTRACTAlthough 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.

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. 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. 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]. 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. NCT01169259; NCT01351805.