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.

Cocoa Extract Supplementation and Risk of Type 2 Diabetes: The Cocoa Supplement and Multivitamin Outcomes Study (COSMOS) Randomized Clinical Trial.

OBJECTIVE: Observational studies have indicated that cocoa flavanol supplementation may be a promising strategy for type 2 diabetes (T2D) prevention. We aimed to directly evaluate its clinical efficacy in a large randomized clinical trial (RCT). RESEARCH DESIGN AND METHOD: The Cocoa Supplement and Multivitamin Outcomes Study (COMSOS) was a 2 × 2 factorial RCT performed from June 2015 to December 2020 that tested cocoa extract and a multivitamin for the prevention of cardiovascular disease (CVD) and cancer. A total of 21,442 U.S. adults free of CVD and recent cancer, including 12,666 women aged ≥65 years and 8,776 men aged ≥60 years, were randomly assigned to receive cocoa extract [500 mg/day cocoa flavanols, including 80 mg (-)-epicatechin] or placebo. In this study, we included 18,381 participants without diabetes at enrollment and examined the effect of cocoa extract supplementation on incident self-reported T2D in intention-to-treat analyses. RESULTS: During a median follow-up of 3.5 years, 801 incident T2D cases were reported. Compared with placebo, taking a cocoa extract supplement did not reduce T2D (adjusted hazard ratio 1.04, 95% CI 0.91-1.20, P = 0.58). Stratification analyses showed that the effect of cocoa extract supplementation was not significantly modified by sex, race, BMI, smoking, physical activity, dietary quality, flavanol status at baseline, or randomized multivitamin assignment. CONCLUSIONS: Middle-aged and older adults taking a cocoa extract supplement for a median of 3.5 years did not reduce their risk of incident T2D. Further studies of cocoa extract supplementation beginning earlier in adulthood and in populations with different background diets are warranted.

A randomized clinical trial of omega-3 fatty acid and vitamin D supplementation on electrocardiographic risk profiles.

Beneficial and adverse associations with arrhythmias have been reported for omega-3 fatty acids (omega-3 FA) and Vitamin D. The 12 lead electrocardiogram (ECG) contains quantitative measures reflecting diverse aspects of electrophysiology that might provide insights into mechanisms underlying these associations. In a pre-specified ancillary study of the VITaminD and omegA-3 (VITAL) trial, we examined the effect of 1 g of marine omega-3 FA per day, comprised of 460 mg eicosapentanoic acid and 380 mg of docosahexaenoic acid, and 2000 IU VitaminD3 per day on ECG characteristics associated with atrial and ventricular arrhythmias among individuals age 50 years or greater. A total of 911 study participants underwent ECGs at baseline and again at 2 years after the randomization. Individuals randomized to active omega-3 FA demonstrated significant net increase in PR-interval duration (p = 0.005) and P-wave duration (p = 0.03) as well significant net decrease in P-wave amplitude (p = 0.037) as compared to placebo. RMSSD increased to a greater extent in the omega-3 FA arm compared to placebo (p = 0.040). For Vitamin D3, the Cornell voltage increased to a lesser extent in the participants assigned to active treatment as compared to placebo (p = 0.044). There were no other significant differences in QRS, QTc, Cornell voltage or heart rate. Thus, randomized treatment with omega-3 FA supplements resulted in changes on the ECG that are potentially reflective of heightened vagal tone and/or slowing of intraatrial and AV conduction. Vitamin D3 supplementation resulted in modest reductions in progressive LV voltage suggestive of a potential antihypertrophic effect.Trial registration ClinicalTrials.gov Identifiers: NCT01169259, NCT02178410 (06/26/2010 and 06/30/2014).

Relation of serum BDNF to major depression and exploration of mechanistic roles of serum BDNF in a study of vitamin D3 and omega-3 supplements for late-life depression prevention.

This study: 1) examined cross-sectional and longitudinal relations of serum brain-derived neurotrophic factor (BDNF) to late-life depression (LLD); 2) tested effects of vitamin D3 and omega-3s on change in BDNF; 3) explored modifying or mediating roles of BDNF on effects of vitamin D3 and omega-3s for LLD. We selected 400 adults from a completed trial of vitamin D3 and omega-3 supplements for LLD prevention. BDNF was measured using an enzyme-linked immunosorbent assay. We administered semi-structured diagnostic interviews and Patient Health Questionnaire [PHQ]-9 to ascertain outcomes at baseline (depression caseness vs. non-caseness; PHQ-9) and at 2-year follow-up among baseline non-depressed individuals (incident vs. no incident MDD; change in PHQ-9). At baseline, while there were no significant differences in mean serum BDNF comparing depression cases and non-cases, being in the lowest vs. highest serum BDNF quartile was significantly associated with worse depressive symptoms. There were no significant longitudinal associations between serum BDNF and LLD. Neither supplement significantly affected change in BDNF; serum BDNF did not appear to modify or mediate treatment effects on LLD. In conclusion, we observed significant cross-sectional but not longitudinal associations between serum BDNF levels and LLD. Vitamin D3 or omega-3s did not alter serum BDNF over 2 years.

Effects of Vitamin D3 and Marine Omega-3 Fatty Acids Supplementation on Indicated and Selective Prevention of Depression in Older Adults: Results From the Clinical Center Sub-Cohort of the VITamin D and OmegA-3 TriaL (VITAL).

Objective: To test vitamin D3 and omega-3 fatty acids (omega-3s) for late-life depression prevention under the National Academy of Medicine framework for indicated (targeting subthreshold depression) and selective (targeting presence of high-risk factors) prevention.Methods: The VITamin D and OmegA-3 TriaL (VITAL) is a 2 × 2 factorial trial of vitamin D3 (2,000 IU/d) and/or omega-3s (1 g/d) for cardiovascular and cancer prevention (enrollment: November 2011-March 2014; end date: December 31, 2017). In this targeted prevention study, we included 720 VITAL clinical sub-cohort participants who completed neurobehavioral assessments at baseline and 2 years (91.9% retention). High-risk factors were subthreshold or clinical anxiety, impaired activities of daily living, physical/functional limitation, medical comorbidity, cognitive impairment, caregiving burden, problem drinking, and low psychosocial support. Coprimary outcomes were incident major depressive disorder (MDD), adjudicated using DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), and change in mood (Patient Health Questionnaire-9 [PHQ-9]). We used exact tests to determine treatment effects on MDD incidence and repeated-measures models to determine treatment effects on PHQ-9.Results: A total of 11.1% had subthreshold depression, 60.8% had ≥ 1 high-risk factor, MDD incidence was 4.7% (5.1% among completers), and mean PHQ-9 score change was 0.02 points. Among those with subthreshold depression, the MDD risk ratio (95% confidence interval) was 0.36 (0.06 to 1.28) for vitamin D3 and 0.85 (0.25 to 2.92) for omega-3s, compared to placebo; results were also null among those with ≥ 1 high-risk factor (vitamin D3 vs placebo: 0.63 [0.25 to 1.53]; omega-3s vs placebo: 1.08 [0.46 to 2.71]). There were no significant differences in PHQ-9 score change comparing either supplement with placebo.Conclusions: Neither vitamin D3 nor omega-3s showed benefits for indicated and selective prevention of late-life depression; statistical power was limited.Trial Registration: ClinicalTrials.gov identifier: NCT01696435.

Dietary flavanols restore hippocampal-dependent memory in older adults with lower diet quality and lower habitual flavanol consumption.

Dietary flavanols are food constituents found in certain fruits and vegetables that have been linked to cognitive aging. Previous studies suggested that consumption of dietary flavanols might specifically be associated with the hippocampal-dependent memory component of cognitive aging and that memory benefits of a flavanol intervention might depend on habitual diet quality. Here, we tested these hypotheses in the context of a large-scale study of 3,562 older adults, who were randomly assigned to a 3-y intervention of cocoa extract (500 mg of cocoa flavanols per day) or a placebo [(COcoa Supplement and Multivitamin Outcomes Study) COSMOS-Web, NCT04582617]. Using the alternative Healthy Eating Index in all participants and a urine-based biomarker of flavanol intake in a subset of participants [n = 1,361], we show that habitual flavanol consumption and diet quality at baseline are positively and selectively correlated with hippocampal-dependent memory. While the prespecified primary end point testing for an intervention-related improvement in memory in all participants after 1 y was not statistically significant, the flavanol intervention restored memory among participants in lower tertiles of habitual diet quality or habitual flavanol consumption. Increases in the flavanol biomarker over the course of the trial were associated with improving memory. Collectively, our results allow dietary flavanols to be considered in the context of a depletion-repletion paradigm and suggest that low flavanol consumption can act as a driver of the hippocampal-dependent component of cognitive aging.

Multivitamin Supplementation Improves Memory in Older Adults: A Randomized Clinical Trial.

BACKGROUND: Maintenance of cognitive abilities is of critical importance to older adults, yet few effective strategies to slow cognitive decline currently exist. Multivitamin supplementation is used to promote general health; it is unclear whether it favorably affects cognition in older age. OBJECTIVES: To examine the effect of daily multivitamin/multimineral supplementation on memory in older adults. METHODS: The COcoa Supplement and Multivitamin Outcomes Study Web (COSMOS-Web) ancillary study (NCT04582617) included 3562 older adults. Participants were randomly assigned to a daily multivitamin supplement (Centrum Silver) or placebo and evaluated annually with an Internet-based battery of neuropsychological tests for 3 y. The prespecified primary outcome measure was change in episodic memory, operationally defined as immediate recall performance on the ModRey test, after 1 y of intervention. Secondary outcome measures included changes in episodic memory over 3 y of follow-up and changes in performance on neuropsychological tasks of novel object recognition and executive function over 3 y. RESULTS: Compared with placebo, participants randomly assigned to multivitamin supplementation had significantly better ModRey immediate recall at 1 y, the primary endpoint (t(5889) = 2.25, P = 0.025), as well as across the 3 y of follow-up on average (t(5889) = 2.54, P = 0.011). Multivitamin supplementation had no significant effects on secondary outcomes. Based on cross-sectional analysis of the association between age and performance on the ModRey, we estimated that the effect of the multivitamin intervention improved memory performance above placebo by the equivalent of 3.1 y of age-related memory change. CONCLUSIONS: Daily multivitamin supplementation, compared with placebo, improves memory in older adults. Multivitamin supplementation holds promise as a safe and accessible approach to maintaining cognitive health in older age. This trial was registered at clinicaltrials.gov as NCT04582617.

Rationale and design of an ancillary study evaluating the effects of the cocoa flavanol and/or multivitamin interventions on falls and physical performance outcomes in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS).

BACKGROUND: 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. METHODS: 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). COSMOS: 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). CONCLUSION: 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.

Association of Body Weight With Response to Vitamin D Supplementation and Metabolism.

Importance: In 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. Objective: To investigate whether baseline body mass index (BMI) modifies vitamin D metabolism and response to supplementation. Design, Setting, and Participants: VITAL 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. Interventions: Treatment 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 Measures: Multivariable-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. Results: A 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 < .001 for linear trend). Similarly, baseline 25-OHD3, FVD, BioD, VDBP, albumin, and calcium levels were lower with higher BMI, while PTH level was higher (all P < .001 for linear trend). Compared with placebo, randomization to vitamin D supplementation was associated with an increase in total 25-OHD, 25-OHD3, FVD, and BioD levels compared with placebo at 2 years' follow-up, but increases were significantly lower at higher BMI categories (all treatment effect interactions P < .001). Supplementation did not substantially change VDBP, albumin, PTH, or calcium levels. Conclusions and Relevance: In 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.

Effects of Vitamin D3 and Marine Omega-3 Fatty Acids Supplementation on Biomarkers of Systemic Inflammation: 4-Year Findings from the VITAL Randomized Trial.

Background: The VITAL study was a nationwide, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of vitamin D3 (2000 IU/day) and marine n-3 FAs (1 g/day) supplements. We recently reported that vitamin D supplementation with or without omega 3 fatty acids reduced autoimmune disease by 22% in the VITAL study. Objective: To investigate the effects of vitamin D3 and/or n-3 FAs on changes in systemic inflammatory biomarkers including pro- and anti-inflammatory cytokines over a 4-year period in the VITAL sub-cohort with in-person evaluations at the Center for Clinical Investigations (CCI) in Boston. Design: Serum levels of four inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6, interleukin-10, and tumor necrosis factor-α) were measured in a total of 2713 samples from those 1054 VITAL/CCI participants (aged 64.9 ± 6.5 years, 49% female, 84% white, and 9% black) at baseline, year 2, and year 4 follow-up visits. Results: In multiple-adjusted models, vitamin D3 supplementation decreased serum hs-CRP levels by 19% at 2-year follow-up (nominal p = 0.007; p-value after multiple comparison adjustment = 0.028), but not at 4-year follow-up (nominal and adjusted p-values > 0.05). The effects of vitamin D3 on other inflammatory markers were not statistically significant either at year 2 or year 4 (all adjusted p-values > 0.05). Marine n-3 FAs were not significantly associated with changes of all the above inflammatory markers either at years 2 and 4, after multiple comparison adjustment (all p-values > 0.05). Conclusions: Vitamin D3 supplementation with or without n-3 FAs decreased hs-CRP by 19% at year 2, but not other inflammatory biomarkers at year 2 or year 4, while n-3 FAs with or without vitamin D3 did not significantly affect these biomarkers at either time point. Our findings support a potential role of vitamin D supplementation in modulating the chronic inflammatory process, systemic inflammation, and possibly autoimmune disease progression.

Effect of Vitamin D3 and Omega-3 Fatty Acid Supplementation on Risk of Frailty: An Ancillary Study of a Randomized Clinical Trial.

Importance: 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. Objective: To test the effects of vitamin D3 and omega-3 supplements on change in frailty in older individuals. Design, Setting, and Participants: 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. Interventions: Vitamin D3, 2000 IU/d, and marine omega-3 fatty acids, 1 g/d. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01169259.

Association of Physical Activity With Bioactive Lipids and Cardiovascular Events.

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 <0.1). Annotations were found for 6 of these BALs: 12,13-diHOME, 9,10-diHOME, lysoPC(15:0), oxymorphone-3b-D-glucuronide, cortisone, and oleoyl-glycerol. Genetic analysis within JUPITER-NC showed associations of 32 PA-related BALs with 22 single-nucleotide polymorphisms. From PA-related BALs, 12 are associated with CVD. CONCLUSIONS: We identified a PA-related bioactive lipidome profile out of which 12 BALs also had opposite associations with incident CVD events.

Design and baseline characteristics of participants in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS).

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.

Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial.

BACKGROUND: 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. OBJECTIVES: We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Multivitamins in the prevention of cancer and cardiovascular disease: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial.

BACKGROUND: Although older adults commonly take multivitamin-multimineral (MVM) supplements to promote health, evidence on the use of daily MVMs on invasive cancer is limited. OBJECTIVES: The study objective was to determine if a daily MVM decreases total invasive cancer among older adults. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial.

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 D3 (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.

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.

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.

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 D3 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 D3 (2000 IU/d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D3 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 D3 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 D3 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 D3 in adults to prevent depression. Trial Registration: ClinicalTrials.gov Identifiers: NCT01169259 and NCT01696435.

Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease.

BACKGROUND: It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited. METHODS: We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (cholecalciferol) at a dose of 2000 IU per day and marine n-3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo. RESULTS: A total of 25,871 participants, including 5106 black participants, underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified. CONCLUSIONS: Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .).

Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer.

BACKGROUND: Higher intake of marine n-3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation with n-3 fatty acids has such effects in general populations at usual risk for these end points is unclear. METHODS: We conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n-3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n-3 fatty acids with placebo. RESULTS: A total of 25,871 participants, including 5106 black participants, underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n-3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n-3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed. CONCLUSIONS: Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .).