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Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested.We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults.We conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina.During a median follow-up of 3.6 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 (95% CI: 0.66, 1.16) for MI, 0.91 (95% CI: 0.70, 1.17) for stroke, 0.95 (95% CI: 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI: 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). There were no safety concerns.Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events. This trial is registered at www.clinicaltrials.gov as NCT02422745.

Background: To clarify the mechanisms underlying physical activity (PA)-related cardioprotection, we examined the association of PA with plasma bioactive lipids (BALs) and cardiovascular disease (CVD) events. We additionally performed genome-wide associations. Methods: PA-bioactive lipid associations were examined in VITAL (VITamin D and OmegA-3 TriaL)-clinical translational science center (REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01169259; N=1032) and validated in JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)-NC (REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00239681; N=589), using linear models adjusted for age, sex, race, low-density lipoprotein-cholesterol, total-C, and smoking. Significant BALs were carried over to examine associations with incident CVD in 2 nested CVD case-control studies: VITAL-CVD (741 case-control pairs) and JUPITER-CVD (415 case-control pairs; validation). Results: We detected 145 PA-bioactive lipid validated associations (false discovery rate Conclusions: We identified a PA-related bioactive lipidome profile out of which 12 BALs also had opposite associations with incident CVD events.

Although older adults commonly take multivitamin-multimineral (MVM) supplements to promote health, evidence on the use of daily MVMs on invasive cancer is limited.The study objective was to determine if a daily MVM decreases total invasive cancer among older adults.We performed a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of a daily MVM and cocoa extract for prevention of cancer and cardiovascular disease (CVD) among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y) free of major CVD and recently diagnosed cancer. The intervention phase was from June 2015 through December 2020. This article reports on the MVM intervention. Participants were randomly assigned to daily MVM or placebo. The primary outcome was total invasive cancer, excluding nonmelanoma skin cancer. Secondary outcomes included major site-specific cancers, total CVD, all-cause mortality, and total cancer risk among those with a baseline history of cancer.During a median follow-up of 3.6 y, invasive cancer occurred in 518 participants in the MVM group and 535 participants in the placebo group (HR: 0.97; 95% CI: 0.86, 1.09; P = 0.57). We observed no significant effect of a daily MVM on breast cancer (HR: 1.06; 95% CI: 0.79, 1.42) or colorectal cancer (HR: 1.30; 95% CI: 0.80, 2.12). We observed a protective effect of a daily MVM on lung cancer (HR: 0.62; 95% CI: 0.42, 0.92). The composite CVD outcome occurred in 429 participants in the MVM group and 437 participants in the placebo group (HR: 0.98; 95% CI: 0.86, 1.12). MVM use did not significantly affect all-cause mortality (HR: 0.93; 95% CI: 0.81, 1.08). There were no safety concerns.A daily MVM supplement, compared with placebo, did not significantly reduce the incidence of total cancer among older men and women. Future studies are needed to determine the effects of MVMs on other aging-related outcomes among older adults. This trial is registered at www.clinicaltrials.gov as NCT02422745.

Falls and decreased physical function increase markedly with age and result in injury, hospitalization, and premature death. Emerging studies show potential benefits of supplemental cocoa extract on physical performance, including grip strength and walking speed in older adults. However, there are no large, long-term randomized controlled trials of effects of supplemental cocoa extract on falls, muscle performance, and/or fall-related injuries.The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a double-blind, placebo-controlled, 2 × 2 factorial trial investigating effects of supplementation with cocoa extract (500 mg/d, including 80 mg (-)-epicatechin) and/or a multivitamin on prevention of cardiovascular disease and cancer in 21,442 women (≥65 years) and men (≥60 years).Effects on Falls and Physical Performance is an ancillary study to COSMOS that will clarify effects of cocoa extract and/or multivitamin supplementation on falls, physical performance, and incident fracture outcomes in older adults. Injurious fall(s) resulting in healthcare utilization and recurrent falls were regularly assessed by follow-up questionnaires in the overall cohort. Incident fractures were also assessed by annual questionnaires. Circumstances surrounding falls and any fall-related injuries will be confirmed by medical record review. Effects of the interventions on 2-year changes in physical performance measures (grip strength, walking speed, and the Short Physical Performance Battery) will be tested in a clinic sub-cohort (n = 603).Results from this ancillary study will determine whether supplemental cocoa extract slows age-related declines in physical performance and decrease injurious and recurrent falls and fall-related injuries and fractures that are major public health problems in older adults.

ImportanceIn the Vitamin D and Omega-3 Trial (VITAL), the effects of randomized vitamin D supplementation (cholecalciferol), 2000 IU/d, reduced the risk of several health outcomes among participants with normal, but not elevated, body weights. It was unclear whether weight had any association with the outcomes of the supplementation.ObjectiveTo investigate whether baseline body mass index (BMI) modifies vitamin D metabolism and response to supplementation.Design, Setting, and ParticipantsVITAL is a completed randomized, double-blind, placebo-controlled trial for the primary prevention of cancer and cardiovascular disease. In the present cohort study, an analysis was conducted in a subset of VITAL participants who provided a blood sample at baseline and a subset with a repeated sample at 2 years’ follow-up. VITAL was conducted from July 1, 2010, to November 10, 2018; data analysis for the present study was conducted from August 1, 2021, to November 9, 2021.InterventionsTreatment outcomes of vitamin D, 2000 IU/d, supplementation vs placebo associated with clinical and novel vitamin D–related biomarkers by BMI category adjusted for other factors associated with vitamin D status.Main Outcomes and MeasuresMultivariable-adjusted means (SE) or 95% CIs of vitamin D–related serum biomarkers at baseline and follow-up: total 25-hydroxyvitamin D (25-OHD), 25-OHD3, free vitamin D (FVD), bioavailable vitamin D (BioD), vitamin D–binding protein (VDBP), albumin, parathyroid hormone (PTH), and calcium, and log-transformed as needed.ResultsA total of 16 515 participants (mean [SD] age, 67.7 [7.0] years; 8371 women [50.7%]; 12420 non-Hispanic White [76.9%]) were analyzed at baseline, including 2742 with a follow-up blood sample. Before randomization, serum total 25-OHD levels were incrementally lower at higher BMI categories (adjusted mean [SE]: underweight, 32.3 [0.7] ng/mL; normal weight, 32.3 [0.1] ng/mL; overweight, 30.5 [0.1] ng/mL; obesity class I, 29.0 [0.2] ng/mL; and obesity class II, 28.0 [0.2] ng/mL; P P P Conclusions and RelevanceIn this randomized cohort study, vitamin D supplementation increased serum vitamin D–related biomarkers, with a blunted response observed for participants with overweight or obesity at baseline. These longitudinal findings suggest that BMI may be associated with modified response to vitamin D supplementation and may in part explain the observed diminished outcomes of supplementation for various health outcomes among individuals with higher BMI.

Introduction: To better understand the cardioprotective mechanisms of regular physical activity (PA), we examined its association with plasma bioactive lipids (BAL) and prospective cardiovascular disease (CVD) events and evaluated the extent to which BMI might mediate this association. Hypothesis: 1) Higher PA associates with a bioactive lipid profile related to lower CVD risk; 2) BMI mediates the PA-BAL and BAL-CVD associations. Methods: Using linear models (adjusted for age, sex, race, smoking, LDL, and total cholesterol), self-reported PA was examined with BAL assayed by an untargeted metabolomics platform in VITAL (N=1032) with validation in JUPITER (N=589). After performing mediation analysis through BMI (same adjustments), we evaluated both BMI-mediated and non-mediated PA-BAL associations with incident CVD using similarly adjusted conditional logistic regression in two nested CVD case-control studies: VITAL-CVD (770 pairs, followed by mediation analysis) and JUPITER-CVD (415 case-control pairs - validation) Results: We detected 237 significant PA-BAL associations in VITAL with replication in JUPITER (FDRvice-versa . Conclusion: We identified a signature of 22 PA-related BAL, which were also associated with incident CVD in two independent case-control studies. Although BMI-mediated associations were predominant, non-mediated effects were also detected, implying that more than one pathway may play a role in the PA-CVD relationship.

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.To test the effects of vitamin D3 and omega-3 supplements on change in frailty in older individuals.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.Vitamin D3, 2000 IU/d, and marine omega-3 fatty acids, 1 g/d.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.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.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.ClinicalTrials.gov Identifier: NCT01169259.

Background Cocoa extract and multivitamins have been proposed to reduce the risk of cardiovascular disease (CVD) and cancer, respectively. However, few randomized clinical trials have tested their long-term effects on these outcomes. Methods The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of a cocoa extract supplement and a multivitamin supplement to reduce the risk of CVD and cancer. Here we describe the pragmatic, hybrid design of the trial and baseline characteristics of the trial participants. Results The nationwide study population includes 21,442 U.S. women aged ≥65 years and men aged ≥60 years without baseline myocardial infarction (MI), stroke, or a recent (within the past 2 years) cancer diagnosis. Participants were randomized in a 2 × 2 factorial design to one of four groups: (1) cocoa extract (containing 500 mg/d flavanols, including 80 mg (-)-epicatechin) and a multivitamin (Centrum Silver©); (2) cocoa extract and multivitamin placebo; (3) multivitamin and cocoa extract placebo; or (4) both placebos. Randomization successfully distributed baseline demographic, clinical, behavioral, and dietary characteristics across treatment groups. Baseline biospecimens were collected from 6867 participants, with at least one follow-up biospecimen from 2142 participants. The primary outcome for the cocoa extract intervention is total CVD (a composite of MI, stroke, cardiovascular mortality, coronary revascularization, unstable angina requiring hospitalization, carotid artery surgery, and peripheral artery surgery); the primary outcome for the multivitamin intervention is total invasive cancer. Conclusion COSMOS will provide important information on the health effects of cocoa extract and multivitamin supplementation in older U.S. adults. Clinical Trials Registration: clinicaltrials.gov #NCT02422745.

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.

Introduction: Magnesium (Mg) intake is inversely associated with BP and hypertension risk in observational studies. However, short-term randomized trials on seated BP have been inconsistent, with few studies measuring 24-h ambulatory BP (ABP). In addition, Mg glycinate, a more easily absorbed form of supplemental Mg, has been largely untested in randomized trials and may serve as a first-line approach for BP reduction among those with elevated, untreated, BP. Methods: We conducted a randomized, double-blind, placebo-controlled trial (NCT03688503) testing 480 mg/d of elemental Mg glycinate versus placebo for 12 weeks among 59 otherwise healthy participants aged 30-74 y with elevated seated BP (systolic BP (SBP) 120-149 mmHg and/or diastolic BP (DBP) 80-94 mmHg) and no history of anti-hypertensive medication use. At baseline, 6 weeks, and 12 weeks, we measured seated BP, monitored 24-h ABP, and collected blood samples. Our primary aim tested Mg glycinate on 12-week changes in seated BP and 24-h ABP, and subgroup analyses considered if sex, age, or baseline BP modified the effect of Mg on BP. Results: Baseline characteristics were equally distributed at randomization (mean age, 57.2 y; 58% men) with mean seated BP of 133.4/82.6 mmHg. Compliance was high (Mg, 87%; placebo, 96%). After 12 weeks, there was no significant effect of Mg glycinate versus placebo on seated SBP (-4.5 vs -1.6 mmHg from baseline; p=0.38) and DBP (-1.9 vs -0.9 mmHg from baseline; p=0.64), nor was there any significant effect on overall, daytime, or nighttime 24-h ambulatory SBP and DBP (all p>0.05). In subgroup analyses, the effect of Mg glycinate on seated SBP was suggestively, but non-significantly, stronger among those with baseline seated SBP ≥130 mmHg (-9.3 vs -2.7 mmHg; p=0.12; p, interaction=0.24) and among women (-9.7 vs -3.1 mmHg; p=0.26; p, interaction=0.29). Age, seated DBP, and mean 24-h ambulatory SBP and DBP did not modify the effects of Mg supplementation. Conclusions: A Mg glycinate supplement did not significantly reduce seated or 24-h BP in adults with elevated, untreated BP. Forthcoming analyses will expand on the role of serum and dietary Mg levels. Larger trials are warranted to elucidate possible effects of Mg glycinate on seated SBP among those with elevated BP and among women.

IMPORTANCE: Low levels of 25-hydroxyvitamin D have been associated with higher risk for depression later in life, but there have been few long-term, high-dose large-scale trials. OBJECTIVE: To test the effects of vitamin D(3) supplementation on late-life depression risk and mood scores. DESIGN, SETTING, AND PARTICIPANTS: There were 18 353 men and women aged 50 years or older in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among 25 871 adults in the US. There were 16 657 at risk for incident depression (ie, no depression history) and 1696 at risk for recurrent depression (ie, depression history but no treatment for depression within the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017, and this was the final date of follow-up. INTERVENTION: Randomized assignment in a 2 × 2 factorial design to vitamin D(3) (2000 IU/d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D(3) and 9172 were randomized to matching placebo. MAIN OUTCOMES AND MEASURES: The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]; the minimal clinically important difference for change in scores was 0.5 points). RESULTS: Among the 18 353 randomized participants (mean age, 67.5 [SD, 7.1] years; 49.2% women), the median treatment duration was 5.3 years and 90.5% completed the trial (93.5% among those alive at the end of the trial). Risk of depression or clinically relevant depressive symptoms was not significantly different between the vitamin D(3) group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years) (hazard ratio, 0.97 [95% CI, 0.87 to 1.09]; P = .62); there were no significant differences between groups in depression incidence or recurrence. No significant differences were observed between treatment groups for change in mood scores over time; mean change in PHQ-8 score was not significantly different from zero (mean difference for change in mood scores, 0.01 points [95% CI, −0.04 to 0.05 points]). CONCLUSIONS AND RELEVANCE: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D(3) compared with placebo did not result in a statistically significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D(3) in adults to prevent depression. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01169259 and NCT01696435

We investigated the association of clinical variables with TBS at baseline in the bone health sub-cohort of the VITamin D and OmegA-3 TriaL (VITAL). Lower TBS was associated with female sex, aging, BMI ≥ 25 kg/m2, SSRI use, high alcohol intake, and presence of diabetes; there was a trend towards significance between lower TBS and history of fragility fractures. We investigated whether TBS differs by sex, race, body mass index (BMI), and other clinical variables. The VITamin D and OmegA-3 TriaL (VITAL) is determining effects of vitamin D3 and/or omega-3 fatty acid (FA) supplements in reducing risks of cancer and cardiovascular disease. In the VITAL: Effects on Bone Structure/Architecture ancillary study, effects of these interventions on bone will be investigated. Here, we examine the associations of clinical risk factors with TBS assessments at baseline in the bone health sub-cohort, comprised of 672 participants (369 men and 303 women), mean (± SD) age 63.5 ± 6.0 years; BMI ≤ 37 kg/m2, no bisphosphonates within 2 years or other bone active medications within 1 year. TBS was greater in men than women (1.311 vs. 1.278, P

Rationale Depression is a leading cause of disease burden and disability for older adults; thus, prevention is a priority. Biologic and observational data support potential mental health benefits of vitamin D and omega-3 fatty acids; however, it is unclear whether these supplements can prevent late-life depression. Design We describe the novel methodology of a large-scale study: VITAL-DEP (VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention), an ancillary to the VITAL trial. Primary Aims of VITAL-DEP are to determine effects on prevention of depression and on trajectory of mood symptoms of long-term (mean = 5 years) supplementation with vitamin D (vitamin D3 [cholecalciferol], 2000 IU/day) and marine omega-3 fatty-acids (eicosapentaenoic acid + docosahexaenoic acid, 1 g/day), in a 2 × 2 factorial design, among 25,874 older adults. Secondary Aims will evaluate: vitamin D's effects among African-Americans (an at-risk group for vitamin D deficiency); both agents' effects among those with high-risk factors or sub-syndromal depression in a sub-set of ~1000 participants with detailed examinations at baseline and 2-year follow-up; whether baseline nutrient levels influence depression risk and/or modify agents' effects. Additional planned analyses will use pre-randomization blood samples available in ~17,000 participants to address whether key biomarkers and factors influence long-term mood and depression risk and/or the agents' effects. Conclusion VITAL-DEP applies all modalities of state-of-the-art prevention research – universal, selective and indicated. VITAL-DEP will clarify effects of supplemental vitamin D and/or omega-3 on mood, and inform clinical care and public health guidelines on the use of these agents for prevention of depression in mid-life and older adults.

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 .

IMPORTANCE: Marine omega-3 fatty acid (omega-3) supplements have been used to treat depression but their ability to prevent depression in the general adult population is unknown. OBJECTIVE: To test effects of omega-3 supplementation on late-life depression risk and mood scores. DESIGN, SETTING, AND PARTICIPANTS: A total of 18 353 adults participated in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized trial of cardiovascular disease and cancer prevention among 25 871 US adults. There were 16 657 at risk of incident depression (no previous depression) and 1696 at risk of recurrent depression (previous depression, but not for the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017. INTERVENTIONS: Randomized 2 × 2 factorial assignment to vitamin D(3) (2000 IU/d), marine omega-3 fatty acids (1 g/d of fish oil, including 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid) or placebo; 9171 were randomized to omega-3 and 9182 were randomized to matching placebo. MAIN OUTCOMES AND MEASURES: Prespecified coprimary outcomes were risk of depression or clinically relevant depressive symptoms (total of incident + recurrent cases); mean difference in mood score (8-item Patient Health Questionnaire [PHQ-8] depression scale). RESULTS: Among 18 353 participants who were randomized (mean age, 67.5 [SD, 7.1] years; 49.2% women), 90.3% completed the trial (93.5% among those alive at the end of the trial); the median treatment duration was 5.3 years. The test for interaction between the omega-3 and the vitamin D agents was not significant (P for interaction = .14). Depression risk was significantly higher comparing omega-3 (651 events, 13.9 per 1000 person-years) with placebo (583 events, 12.3 per 1000 person-years; hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P = .03). No significant differences were observed comparing omega-3 with placebo groups in longitudinal mood scores: the mean difference in change in PHQ-8 score was 0.03 points (95% CI, −0.01 to 0.07; P = .19). Regarding serious and common adverse events, the respective prevalence values in omega-3 vs placebo groups were major cardiovascular events (2.7% vs 2.9%), all-cause mortality (3.3% vs 3.1%), suicide (0.02% vs 0.01%), gastrointestinal bleeding (2.6% vs 2.7%), easy bruising (24.8% vs 25.1%), and stomach upset or pain (35.2% vs 35.1%). CONCLUSIONS AND RELEVANCE: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with omega-3 supplements compared with placebo yielded mixed results, with a small but statistically significant increase in risk of depression or clinically relevant depressive symptoms but no difference in mood scores, over a median follow-up of 5.3 years. These findings do not support the use of omega-3 supplements in adults to prevent depression. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01696435 and NCT01169259

BACKGROUND: Whether vitamin D supplementation reduces cancer or cardiovascular disease remains unclear, and randomized trial evidence is limited. METHODS: The VITamin D and OmegA-3 TriaL (VITAL) was a nationwide, randomized, placebo-controlled, 2X2 factorial trial of vitamin D(3) (cholecalciferol, 2000 IU/day) and marine omega-3 fatty acids (1 g/day) for the prevention of cancer and cardiovascular disease. There were 25,871 U.S. men aged ≥50 and women aged ≥55, including 5,106 African Americans, who participated. Primary endpoints were total invasive cancer and major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular mortality). Secondary endpoints included site-specific cancers, cancer mortality, and additional cardiovascular events. RESULTS: Vitamin D supplementation did not reduce either of the primary endpoints. During a median 5.3 year intervention, 1,617 participants were diagnosed with cancer (793 assigned to vitamin D and 824 assigned placebo; hazard ratio [HR]=0.96; 95% confidence interval, 0.88–1.06; p-value=0.47); and 805 experienced a major cardiovascular event (396 assigned to vitamin D and 409 assigned to placebo; HR=0.97 [0.85–1.12]; p-value=0.69). For secondary endpoints, the hazard ratios and 95% confidence intervals comparing Vitamin D to placebo were: cancer deaths (n=341, HR 0.83 (0.67–1.02); breast cancer (1.02; 0.79–1.31); prostate cancer 0.88 (0.72–1.07); colorectal cancer 1.09 (0.73–1.62); expanded cardiovascular disease events 0.96 (0.86–1.08); myocardial infarction 0.96 (0.78–1.19); stroke 0.95 (0.76–1.20); and cardiovascular mortality 1.11 (0.88–1.40). The HR for all-cause deaths (n=978) was 0.99 (0.87–1.12). No excess risks of hypercalcemia or other adverse events were identified. CONCLUSION: Vitamin D supplementation did not reduce invasive cancer incidence or cardiovascular events.

Laboratory and observational research studies suggest that vitamin D and marine omega-3 fatty acids may reduce risk for pneumonia, acute exacerbations of respiratory diseases including chronic obstructive lung disease (COPD) or asthma, and decline of lung function, but prevention trials with adequate dosing, adequate power, and adequate time to follow-up are lacking. The ongoing Lung VITAL study is taking advantage of a large clinical trial-the VITamin D and OmegA-3 TriaL (VITAL)--to conduct the first major evaluation of the influences of vitamin D and marine omega-3 fatty acid supplementation on pneumonia risk, respiratory exacerbation episodes, asthma control and lung function in adults. VITAL is a 5-year U.S.-wide randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of supplementation with vitamin D3 ([cholecalciferol], 2000 IU/day) and marine omega-3 FA (Omacor® fish oil, eicosapentaenoic acid [EPA]+docosahexaenoic acid [DHA], 1g/day) for primary prevention of CVD and cancer among men and women, at baseline aged ≥50 and ≥55, respectively, with 5107 African Americans. In a subset of 1973 participants from 11 urban U.S. centers, lung function is measured before and two years after randomization. Yearly follow-up questionnaires assess incident pneumonia in the entire randomized population, and exacerbations of respiratory disease, asthma control and dyspnea in a subpopulation of 4314 randomized participants enriched, as shown in presentation of baseline characteristics, for respiratory disease, respiratory symptoms, and history of cigarette smoking. Self-reported pneumonia hospitalization will be confirmed by medical record review, and exacerbations will be confirmed by Center for Medicare and Medicaid Services data review.

Although vitamin D is widely used to promote skeletal health, definitive data on benefits and risks of supplemental vitamin D alone on bone are lacking. Results from large, randomized controlled trials in the general population are sparse. Data on the effects of supplemental omega-3 fatty acids (FAs) on bone are also limited.The VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled trial assessing the role of vitamin D3 (2000 IU/d) and omega-3 FA (1g/d) supplements in reducing risks of cancer and cardiovascular disease among U.S. men aged ≥50 and women aged ≥55. To comprehensively test effects of supplemental vitamin D and/or omega-3 FAs on skeletal health, the VITAL: Effects on Fractures ancillary study is determining the effects of these supplements on incident fractures among 25,875 participants enrolled in the parent trial. Study investigators adjudicate fractures through a detailed review of medical records and radiological images (hip and femur). In a complementary ancillary, VITAL: Effects on Structure and Architecture is determining the effects of supplemental vitamin D and/or omega-3 FAs on bone with detailed phenotyping during in-person visits. Comprehensive assessments of bone density, turnover, structure/architecture, body composition, and physical performance are being performed at baseline and 2 years post-randomization.Results from these studies will clarify the relationship between supplemental vitamin D and/or omega-3 FAs on bone health outcomes, and inform clinical care and public health guidelines on the use of supplemental vitamin D for the primary prevention of fractures in women and men.

Evidence for a role of supplemental vitamin D and marine omega-3 fatty acids in preventing cancer and cardiovascular disease (CVD) remains inconclusive and insufficient to inform nutritional recommendations for primary prevention. The VITamin D and Omega-A 3 TriaL (VITAL) is an ongoing nationwide, randomized, double-blind, placebo-controlled clinical trial designed to fill this knowledge gap. The study population consists of 25,874 U.S. adults without cancer or CVD at baseline, who were selected only on age (men aged ≥50 and women aged ≥55), with an oversampling of African Americans (n=5,107). In a 2 × 2 factorial design, participants were randomized to one of four supplement groups: [1] active vitamin D3 (cholecalciferol; 2000 IU/d) and active marine omega-3 fatty acids (Omacor® fish oil, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA], 1g/d); [2] active vitamin D and omega-3 placebo; [3] vitamin D placebo and active marine omega-3 fatty acids; or [4] vitamin D placebo and omega-3 placebo. The mean length of the randomized treatment period will be 5 years. The randomization was successful, as evidenced by similar distributions of baseline demographic, health, and behavioral characteristics across treatment groups. The similar distribution of known potential confounders across treatment groups strongly suggests that unmeasured or unknown potential confounders are also equally distributed. VITAL is expected to provide important information on the benefit-risk balance of vitamin D and omega-3 fatty acid supplementation when taken for the primary prevention of cancer and CVD.

Obesity, overweight, and a sedentary lifestyle-all common conditions in breast cancer patients-are likely to be associated with poor survival and poor quality of life in women with breast cancer. Diet-related factors are thought to account for about 30% of cancers in developed countries. Most studies of diet and healthcare have focused on the role of single nutrients, foods, or food groups in disease prevention or promotion. Recent cancer guidelines on nutrition and physical activity emphasize diets that promote maintenance of a healthy body weight and a prudent dietary pattern that is low in red and processed meats and high in a variety of vegetables, fruits, and whole grains. Except for dietary fat, few nutritional factors in adult life have been associated with breast cancer. Extensive data from animal model research, international correlations linking fat intake and breast cancer rates, and case-control studies support the hypothesis that a high-fat diet is conducive to the development of breast cancer in postmenopausal women. Conflicting findings from cohort studies, however, have created uncertainty over the role of dietary fat in breast cancer growth and recurrence. Results from large-scale nutritional intervention trials are expected to resolve such issues. As new and improved data on dietary factors and patterns accumulate, dietary guidelines for cancer risk reduction will become more focused.

Reliable dietary intake data are essential for determining outcomes in nutrition-related clinical trials. Nevertheless, systems for quality assurance of dietary intake data are often slighted in the design of such trials and not incorporated or monitored as the trials continue. The Women's Intervention Nutrition Study (WINS), a multicenter clinical trial investigating the effect of reduction of dietary fat intake together with adjuvant systemic therapy on recurrence rates in and survival of postmenopausal women with early stage, surgically treated, breast cancer, has developed a quality assurance system to minimize errors and to produce data that are complete and reliable. The system involves development of standardized procedures for data collection, a quality control program to evaluate the data collected, and continual monitoring and reevaluation. The WINS system is offered as a model for studies collecting dietary intake data, no matter how simple or complex the trial design. J Am Diet Assoc. 2000; 100:1186-1190 .

The Women’s Intervention Nutrition Study is a randomized clinical trial designed to evaluate if a lifestyle intervention targeting fat intake reduction influences breast cancer recurrence in women with early stage, resected disease receiving conventional cancer management. This report details the concept, content, and implementation of the low-fat eating plan used in the dietary intervention group of this trial. Intervention group participants were given a daily fat gram goal. The intervention was delivered by centrally trained, registered dietitians who applied behavioral, cognitive, and motivational counseling techniques. The low-fat eating plan was implemented in an intensive phase with eight biweekly (up to Month 4), individual counseling sessions followed by a maintenance phase (Month 5 up to and including Year 5) with registered dietitian visits every 3 months and optional monthly group sessions. Self-monitoring (daily fat gram counting and recording), goal setting, and motivational interviewing strategies were key components. Dietary fat intake was equivalent at baseline and consistently lower in the intervention compared with the control group at all time points (percent eneregy from fat at 60 months 23.2% ± 8.4% vs 31.2% ± 8.9%, respectively, P< 0.0001) and was associated with mean 6.1 lb mean weight difference between groups (P = 0.005) at 5 years (baseline and 5 years, respectively: control 160.0 ± 35.0 and 161.7 ± 32.8 lb; intervention 160.2 ± 35.1 and 155.6 ± 32.1 lb). Together with previously reported efficacy results, this information suggests that a lifestyle intervention that reduces dietary fat intake and is associated with modest weight loss may favorably influence breast cancer recurrence. The Women’s Intervention Nutrition Study low-fat eating plan can serve as a model for implementing such a long-term dietary intervention in clinical practice.

Importance Foods that have similar carbohydrate content can differ in the amount they raise blood glucose. The effects of this property, called the glycemic index, on risk factors for cardiovascular disease and diabetes are not well understood. Objective To determine the effect of glycemic index and amount of total dietary carbohydrate on risk factors for cardiovascular disease and diabetes. Design, Setting, and Participants Randomized crossover-controlled feeding trial conducted in research units in academic medical centers, in which 163 overweight adults (systolic blood pressure, 120-159 mm Hg) were given 4 complete diets that contained all of their meals, snacks, and calorie-containing beverages, each for 5 weeks, and completed at least 2 study diets. The first participant was enrolled April 1, 2008; the last participant finished December 22, 2010. For any pair of the 4 diets, there were 135 to 150 participants contributing at least 1 primary outcome measure. Interventions (1) A high–glycemic index (65% on the glucose scale), high-carbohydrate diet (58% energy); (2) a low–glycemic index (40%), high-carbohydrate diet; (3) a high–glycemic index, low-carbohydrate diet (40% energy); and (4) a low–glycemic index, low-carbohydrate diet. Each diet was based on a healthful DASH-type diet. Main Outcomes and Measures The 5 primary outcomes were insulin sensitivity, determined from the areas under the curves of glucose and insulin levels during an oral glucose tolerance test; levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides; and systolic blood pressure. Results At high dietary carbohydrate content, the low– compared with high–glycemic index level decreased insulin sensitivity from 8.9 to 7.1 units (−20%, P = .002); increased LDL cholesterol from 139 to 147 mg/dL (6%, P ≤ .001); and did not affect levels of HDL cholesterol, triglycerides, or blood pressure. At low carbohydrate content, the low– compared with high–glycemic index level did not affect the outcomes except for decreasing triglycerides from 91 to 86 mg/dL (−5%, P = .02). In the primary diet contrast, the low–glycemic index, low-carbohydrate diet, compared with the high–glycemic index, high-carbohydrate diet, did not affect insulin sensitivity, systolic blood pressure, LDL cholesterol, or HDL cholesterol but did lower triglycerides from 111 to 86 mg/dL (−23%, P ≤ .001). Conclusions and Relevance In this 5-week controlled feeding study, diets with low glycemic index of dietary carbohydrate, compared with high glycemic index of dietary carbohydrate, did not result in improvements in insulin sensitivity, lipid levels, or systolic blood pressure. In the context of an overall DASH-type diet, using glycemic index to select specific foods may not improve cardiovascular risk factors or insulin resistance. Trial Registration clinicaltrials.gov Identifier:NCT00608049

LEARNING OUTCOME: To comprehend the logistics and success of nutrition intervention in a large, multi-centered clinical trial. WINS is a NCI sponsored multi-center randomized trial testing the hypothesis that dietary fat intake reduction as a component of standard adjuvant breast cancer therapy (tamoxifen + defined Chemo Rx) will reduce recurrence and increase survival for women with localized breast cancer. Currently over 1,000 women of a target of 2,500 (≥48 to ≤ 78 years), from 34 participating clinics have been randomized to either the intervention group (IIG) (target of 15% energy from fat) or the non-intervention group (NIG). The intervention is initially provided in a series of eight one on one counseling sessions with a Registered Dietitian over a four month period. Social and behavioral theories are incorporated to promote dietary change and long-term adherence through individualized intervention and goal setting. IIG counseling also includes individual "booster" visits every 3 months and monthly group nutrition and support sessions. Dietary data is collected annually via unannounced 24-hour telephone recalls using the Nutrition Data System. Data from the interim analysis (n=293) shows significant dietary change is achieved hi the IIG from baseline to 12 months [% energy from fat (25.9% to 17.2%, median)] with no significant change in NIG participants. This represents a total reduction of fat intake of 39.1% in the IIG. WINS has designed a successful intervention for reducing dietary fat intake in a one on one and group counseling format, thus allowing for definitive evaluation of the effect of dietary fat intake reduction on breast cancer outcome.