Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults.

BACKGROUND: Vitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent. METHODS: In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D3 would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D3 (2000 IU per day), n-3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses. RESULTS: Among 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial. CONCLUSIONS: Vitamin D3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.).

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Effect of Daily Vitamin D Supplementation on Risk of Upper Respiratory Infection in Older Adults: A Randomized Controlled Trial.

BACKGROUND: Among individuals with vitamin D deficiency, daily vitamin D supplementation appears to lower risk of acute respiratory infection. However, recent trials, in different populations and using different regimens, have yielded null results. We investigated the effect of daily vitamin D supplementation (vs placebo) on risk of upper respiratory infection (URI) in older adults. METHODS: The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, double-blind, placebo-controlled trial of supplemental vitamin D and/or omega-3 fatty acids in generally healthy men (age ≥50 years) and women (age ≥55 years). This prespecified analysis focuses on vitamin D3 (2000 IU/day) versus placebo in the 15 804 (61%) participants with baseline serum total 25-hydroxyvitamin D level. The primary outcome was self-report of a recent URI at 1-year follow-up. RESULTS: Participants had a mean age of 68 years and 51% were women; 76% were non-Hispanic White, 16% Black, and 8% other race/ethnicity. The mean 25-hydroxyvitamin D level at baseline was 31 (standard deviation, 10) ng/mL, with <12 ng/mL in 2.4%. The overall effect of vitamin D supplementation on recent URI was nonsignificant (odds ratio [OR], 0.96 [95% confidence interval {CI}, .86-1.06]). In the prespecified subgroup of primary interest (<12 ng/mL and denied taking concurrent vitamin D), which had only 255 participants, vitamin D supplementation was nonsignificant (OR, 0.60 [95% CI, .28-1.30]). Statistical power to assess effect modification in other subgroups was limited. CONCLUSIONS: In older adults not selected for vitamin D deficiency, supplemental vitamin D did not lower URI risk overall. Whether effects differ in subgroups requires further study. Clinical Trials Registration. NCT01169259.

Intake of Blueberries, Anthocyanins, and Risk of Eye Disease in Women.

BACKGROUND: Blueberries and anthocyanins, their key bioactive component, may improve eye health. However, few long-term studies have examined blueberries and anthocyanins with cataract and age-related macular degeneration (AMD). OBJECTIVES: To investigate the prospective association between blueberry and anthocyanin intake with incident cataract, total AMD, and visually significant AMD among middle-aged and older women. METHODS: A total of 36,653 and 35,402 women initially free of AMD and cataract, respectively, aged ≥45 y from the Women's Health Study provided semiquantitative food frequency questionnaire data on blueberry intake categorized as none, 1-3 servings/mo, 1 serving/wk, or ≥2 servings/wk, plus a combined category of ≥1 serving/wk. Total anthocyanin intake and major subclasses were energy-adjusted and categorized into quintiles. Self-reported risk factors of eye disease were adjusted in multivariable hazard ratios (HRs) (95% confidence intervals [CIs]) of confirmed cataract, AMD, and visually significant AMD with mean follow-up of 11 y. RESULTS: Among the participants, 10.5% consumed ≥1 serving/wk of blueberries, with mean total anthocyanin intake of 11.2 mg/d. Compared to no blueberry intake, women consuming 1-3 servings/mo, 1 serving/wk, and ≥2 servings/wk had corresponding multivariable HRs of total AMD of 0.90 (95% CI: 0.73, 1.11), 0.71 (95% CI: 0.50, 1.00), and 0.36 (95% CI: 0.14, 0.93) (Ptrend = 0.011); those consuming ≥1 servings/wk had an HR of 0.68 (95% CI: 0.47, 0.98). A similar magnitude of HRs were found for visually significant AMD (Ptrend = 0.012) but not for cataract. There were no significant associations between increasing total anthocyanin quintiles and total and visually significant AMD, but there was a modest inverse association with cataract (Ptrend = 0.022), driven by a 10% reduction in cataract in the upper 2 quintiles. CONCLUSIONS: Greater blueberry intake significantly reduced total AMD, but not visually significant AMD or cataract. However, the magnitude of effect for visually significant AMD was similar to total AMD. There was a modest but significant inverse association between dietary anthocyanin intake with cataract but not AMD.

Beer taxes associate with lower alcohol and cigarette use; cigarette taxes associate with lower cigarette but higher alcohol use.

Background: There is a yet unmet opportunity to utilize data on taxes and individual behaviors to yield insight for analyzing studies involving alcohol and cigarette use.Objectives: To inform the direction and strength of their mutual associations by leveraging the fact that taxation can affect individual consumption, but individual consumption cannot affect taxation.Methods: We linked state-level data on cigarette and beer taxes in 2009-2020 with individual-level data on self-reported current cigarette and alcohol use from the Behavioral Risk Factor Surveillance System, a telephone survey by the Centers for Disease Control and Prevention that is representative of the population of each state in the United States. We constructed linear and logistic models to examine associations between a $1 increase in cigarette taxes per pack and a $1 increase in beer taxes per gallon and self-reported cigarette use and alcohol consumption (assessed as any current intake, average drinks/day, heavy drinking, and binge drinking), adjusting for survey year and individual characteristics.Results: Among 2,968,839,352 respondents (49% male), a $1 increase in beer taxes was associated with .003 (95% confidence interval [CI] -.013, .008) fewer drinks/day and lower odds of any drinking (odds ratio [OR] = .81 95%CI .80, .83), heavy drinking (OR = .96 95%CI .93, .99), binge drinking (OR = .82 95%CI .80, .83), and smoking (OR = .98 95%CI .96, 1.00). In contrast, a $1 increase in cigarette taxes was associated with lower odds of smoking (OR = .94 95%CI .94, .95) but .007 (95%CI .005, .010) more drinks/day, and higher odds of any drinking (OR = 1.10 95%CI 1.10, 1.11), heavy drinking (OR = 1.02 95%CI 1.01, 1.02), and binge drinking (OR = .82 95%CI .80, .83).Conclusion: Higher beer taxes were associated with lower odds of drinking and smoking, but higher cigarette taxes were associated with lower odds of smoking and higher alcohol consumption. These results suggest that alcohol intake may be a determinant of cigarette use rather than cigarette use as a determinant of alcohol intake.

Accelerometer-measured physical activity and postmenopausal breast cancer incidence in the Women's Health Accelerometry Collaboration.

BACKGROUND: Few studies have examined accelerometer-measured physical activity and incident breast cancer (BC). Thus, this study examined associations between accelerometer-measured vector magnitude counts per 15 seconds (VM/15s) and average daily minutes of light physical activity (LPA), moderate-to-vigorous PA (MVPA), and total PA (TPA) and BC risk among women in the Women's Health Accelerometry Collaboration (WHAC). METHODS: The WHAC comprised 21,089 postmenopausal women (15,375 from the Women's Health Study [WHS]; 5714 from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study [OPACH]). Women wore an ActiGraph GT3X+ on the hip for ≥4 days and were followed for 7.4 average years to identify physician-adjudicated in situ (n = 94) or invasive (n = 546) BCs. Multivariable stratified Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for tertiles of physical activity measures in association with incident BC overall and by cohort. Effect measure modification was examined by age, race/ethnicity, and body mass index (BMI). RESULTS: In covariate-adjusted models, the highest (vs. lowest) tertiles of VM/15s, TPA, LPA, and MVPA were associated with BC HRs of 0.80 (95% CI, 0.64-0.99), 0.84 (95% CI, 0.69-1.02), 0.89 (95% CI, 0.73-1.08), and 0.81 (95% CI, 0.64-1.01), respectively. Further adjustment for BMI or physical function attenuated these associations. Associations were more pronounced among OPACH than WHS women for VM/15s, MVPA, and TPA; younger than older women for MVPA; and women with BMI ≥30 than <30 kg/m2 for LPA. CONCLUSION: Greater levels of accelerometer-assessed PA were associated with lower BC risk. Associations varied by age and obesity and were not independent of BMI or physical function.

Effect of Vitamin D Supplementation on Overactive Bladder and Urinary Incontinence Symptoms in Older Men: Ancillary Findings From a Randomized Trial.

PURPOSE: Our goal was to evaluate vitamin D supplementation for preventing or treating overactive bladder and urinary incontinence in men. MATERIALS AND METHODS: Ancillary study of men aged ≥55 years in VITAL (VITamin D and OmegA-3 TriaL). Randomized treatments included: vitamin D3 (cholecalciferol), marine omega-3 fatty acids, or matching placebo. Structured urinary incontinence questions measured the prevalence of overactive bladder at year 5 and urinary incontinence at years 2 and 5, along with incidence and progression of urinary incontinence from years 2 to 5. Prespecified subgroup analyses examined men with low baseline serum 25-hydroxyvitamin D (<20 ng/mL). RESULTS: Among the 11,486 men who provided data at year 2 and 10,474 at year 5, mean age was 68 years at year 2, with 23% racial/ethnic minorities. In primary analyses, vitamin D supplementation compared to placebo did not lower odds of overactive bladder at year 5 (OR 0.97, 95% CI 0.87-1.08) or weekly urinary incontinence at year 2 (OR 0.94, 95% CI 0.83-1.05) or year 5 (OR 0.98, 95% CI 0.88-1.09). We found interactions of baseline serum 25-hydroxyvitamin D level with vitamin D supplementation for overactive bladder (P value for interaction = .001), and secondarily, for any urinary incontinence at year 2 (P value for interaction = .05). Men with baseline 25-hydroxyvitamin D <20 ng/mL, who were assigned to vitamin D supplements, had lower odds of overactive bladder (OR 0.51, 95% CI 0.35-0.76) compared to placebo, yet higher odds of any urinary incontinence (OR 1.24, 95% CI 0.93-1.64). CONCLUSIONS: Overall, vitamin D supplementation did not improve overactive bladder or urinary incontinence compared to placebo. However, specific use of vitamin D in men with lower 25-hydroxyvitamin D levels had inconsistent findings.

Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts.

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100- < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

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 .).

Statin-associated muscle symptoms in the VITamin D and OmegA-3 TriaL (VITAL).

Statins are highly effective medications that reduce risk of atherosclerotic cardiovascular disease, but are very commonly discontinued by patients because of muscle symptoms. The risk factors for statin-associated muscle symptoms (SAMS) are not well understood, so in this study we examined the predictors of SAMS in a well-studied cohort of patients in the VITAL trial. We found that female sex and younger age (50-64 years) were significant, independent predictors of higher rates of SAMS.

Association of Modifiable Lifestyle Factors with Plasma Branched-Chain Amino Acid Metabolites in Women.

BACKGROUND: Circulating branched-chain amino acids (BCAAs-isoleucine, leucine, and valine) are strongly associated with higher risk of incident type 2 diabetes (T2D); however, determinants of elevated fasting BCAA concentrations are largely unknown. OBJECTIVES: We aimed to characterize the modifiable lifestyle factors related to plasma BCAAs. METHODS: We performed a cross-sectional analysis among n = 18,897 women (mean ± SD age: 54.9 ± 7.2 y) in the Women's Health Study, free of T2D and cardiovascular disease at baseline blood draw. Lifestyle factors, weight, and height were self-reported via questionnaire, including smoking status, alcohol, leisure-time physical activity (LTPA), diet quality scores [2010 Alternative Healthy Eating Index (without alcohol) (aHEI); alternate Mediterranean Diet (aMED)], and dietary sources of BCAAs. Plasma BCAAs were quantified via NMR spectroscopy. We calculated multivariable-adjusted percentage mean differences (95% CIs) and P values for linear trend of BCAAs stratified by categoric lifestyle factors. We estimated R2 from univariate cubic spline regression models to estimate the variability in BCAAs explained. RESULTS: Compared with women with BMI (in kg/m2) <25.0, BCAAs were 8.6% (95% CI: 8.0%, 9.3%), 15.3% (95% CI: 14.4%, 16.3%), and 21.0% (95% CI: 18.2%, 23.9%) higher for the BMI strata 25.0-29.9, 30.0-39.9, and ≥40.0, respectively (P-trend < 0.0001). Women with higher LTPA and higher alcohol intake compared with lower had modestly (∼1%) lower plasma BCAAs (P-trend = 0.014 and 0.0003, respectively). Differences in smoking status, aHEI, and aMED score were not related to plasma BCAAs. Women with higher dietary BCAAs had dose-response higher plasma BCAA concentrations, 3.4% (95% CI: 2.5%, 4.4%) higher when comparing the highest with the lowest quintile (P-trend < 0.0001). BMI explained 11.6% of the variability of BCAAs, whereas other factors explained between 0.1% and 1%. CONCLUSIONS: Our findings among a large cohort of US women indicate that BMI, but less so diet, physical activity, and other lifestyle factors, is related to plasma BCAAs.This trial was registered at clinicaltrials.gov as NCT00000479.

Effect of vitamin D supplementation on urinary incontinence in older women: ancillary findings from a randomized trial.

BACKGROUND: Observational studies among older women have associated vitamin D insufficiency with a greater prevalence and incidence of urinary incontinence. However, little is known about the effect of vitamin D supplementation in reducing urinary incontinence. OBJECTIVE: This study aimed to evaluate the effects of vitamin D supplementation in reducing the frequency of urinary incontinence in older women. STUDY DESIGN: We conducted an ancillary study of women aged ≥55 years in the Vitamin D and Omega-3 Trial, a randomized trial with a 2×2 factorial design. Recruitment of participants started from 2011 to 2014 across 50 US states, and the follow-up of participants ended in January 2018. Randomized treatments in the parent study included (1) vitamin D3 (cholecalciferol) at a dosage of 2000 IU/d, (2) marine omega-3 fatty acids at a dosage of 1 g/d, and (3) matching placebo. Here, we analyzed women according to their randomization to vitamin D supplementation or placebo, regardless of treatment with omega-3 fatty acid supplementation. Validated frequency of urinary incontinence questions were added in year 2 of the study and were used again in year 5 at the end of trial. Prespecified ancillary outcomes included the prevalence of urinary incontinence at years 2 and 5, along with incident incontinence and progression of incontinence (from lower to higher frequency) from year 2 to year 5. Preplanned subgroup analyses examined the following outcomes: prerandomization of low serum levels of vitamin D (serum 25-hydroxyvitamin D<20 ng/mL), incontinence types, weight categories, and African American race. RESULTS: Among the randomized women who provided urinary incontinence data, 11,646 women at year 2 and 10,527 women at year 5, the mean age was 70 years at year 2, with 29% racial and ethnic minorities. The prevalence of urinary incontinence that occurred at least weekly was 29% at year 2 and increased to 37% at year 5. Vitamin D supplementation compared to with placebo was not associated with lower odds of urinary incontinence occurring at least weekly at year 2 (odds ratio, 1.08; 95% confidence interval, 0.99-1.19) or year 5 (odds ratio, 1.04; 95% confidence interval, 0.94-1.15). Vitamin D supplementation compared to placebo was not associated with lower incidence or progression of urinary incontinence from year 2 to year 5: incidence (odds ratio, 1.06; 95% confidence interval, 0.83-1.35) or progression (odds ratio, 0.94; 95% confidence interval, 0.82-1.08). Women with prerandomization of low serum levels of vitamin D (n=836) did not have lower odds of the prevalence, incidence, or progression of urinary incontinence. The findings were null in subgroups according to incontinence type, women with obesity, and African American women. Only women with healthy weight randomized to vitamin D had lower odds of progression of urinary incontinence (odds ratio, 0.78; 95% confidence interval, 0.63-0.95; P=.01). CONCLUSION: Vitamin D supplementation compared to placebo for 2 to 5 years was not associated with differences in the prevalence, incidence, or progression of urinary incontinence in older women with and without adequate serum vitamin D levels, with inconsistent differences among subgroups. The findings showed that the broad use of moderate doses of vitamin D supplementation did not reduce urinary incontinence in older women.

Vitamin D, Marine n-3 Fatty Acids, and Primary Prevention of Cardiovascular Disease Current Evidence.

Whether marine omega-3 fatty acid (n-3 FA) or vitamin D supplementation can prevent cardiovascular disease (CVD) in general populations at usual risk for this outcome is unknown. A major goal of VITAL (Vitamin D and Omega-3 Trial) was to fill this knowledge gap. In this article, we review the results of VITAL, discuss relevant mechanistic studies regarding n-3 FAs, vitamin D, and vascular disease, and summarize recent meta-analyses of the randomized trial evidence on these agents. VITAL was a nationwide, randomized, placebo-controlled, 2×2 factorial trial of marine n-3 FAs (1 g/d) and vitamin D3 (2000 IU/d) in the primary prevention of CVD and cancer among 25 871 US men aged ≥50 and women aged ≥55 years, including 5106 blacks. Median treatment duration was 5.3 years. Supplemental n-3 FAs did not significantly reduce the primary cardiovascular end point of major CVD events (composite of myocardial infarction, stroke, and CVD mortality; hazard ratio [HR], 0.92 [95% CI, 0.80-1.06]) but were associated with significant reductions in total myocardial infarction (HR, 0.72 [95% CI, 0.59-0.90]), percutaneous coronary intervention (HR, 0.78 [95% CI, 0.63-0.95]), and fatal myocardial infarction (HR, 0.50 [95% CI, 0.26-0.97]) but not stroke or other cardiovascular end points. For major CVD events, a treatment benefit was seen in those with dietary fish intake below the cohort median of 1.5 servings/wk (HR, 0.81 [95% CI, 0.67-0.98]) but not in those above (P interaction=0.045). For myocardial infarction, the greatest risk reductions were in blacks (HR, 0.23 [95% CI, 0.11-0.47]; P interaction by race, 0.001). Vitamin D supplementation did not reduce major CVD events (HR, 0.97 [95% CI, 0.85-1.12]) or other cardiovascular end points. Updated meta-analyses that include VITAL and other recent trials document coronary risk reduction from supplemental marine n-3 FAs but no clear CVD risk reduction from supplemental vitamin D. Additional research is needed to determine which individuals may be most likely to derive net benefit from supplementation. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01169259.

Association between white matter hyperintensity volume and social functioning limitations among stroke survivors.

OBJECTIVE: Existing literature on white matter hyperintensity volume (WMHV) in stroke patients has rarely focused on post-stroke outcomes related to social functioning limitations, such as transportation, social interaction, food preparation, grocery shopping, and housekeeping. Using prospective data from the VITamin D and OmegA-3 TriaL (VITAL) study, we evaluated the association between WMHV and social functioning limitations among 151 ischemic stroke patients. MATERIALS AND METHODS: WMHV was ascertained from magnetic resonance imaging (MRI) collected at the time of the stroke event using a validated semiautomated method, and social functioning limitations were assessed using a stroke outcomes questionnaire administered a median of 1.25 years after the date of the MRI scan. Logistic regression was used to explore the association between WMHV and social functioning limitations. RESULTS: After adjusting for age and sex, a statistically significant association was found between WMHV and limitations in social interaction (OR=2.82; 95% CI: 1.21-7.55). Increased risks were seen for limitations related to food preparation (OR=2.06; 95% CI: 0.99-4.54), transportation (OR=1.39; 95% CI: 0.85-2.27), and housekeeping (OR=1.37; 95% CI: 0.91-2.11); however, the associations did not reach statistical significance. We observed no association between WMHV and limitations in grocery shopping (OR=1.08; 95% CI: 0.61-1.89). CONCLUSIONS: Future studies are needed to further explore the biological mechanisms underlying the relationship with limitations in social interaction and to replicate our findings using a larger and more diverse study sample.

Effects of long-term vitamin D and n-3 fatty acid supplementation on inflammatory and cardiac biomarkers in patients with type 2 diabetes: secondary analyses from a randomised controlled trial.

AIMS/HYPOTHESIS: Interventions that reduce inflammation may delay progression of microvascular and macrovascular complications in diabetes. We examined the effects of vitamin D3 and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes. METHODS: This study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1312 US adults with type 2 diabetes and without known cardiovascular disease, malignancy, or end-stage kidney disease were randomised using computer-generated random numbers in blocks of eight to vitamin D3 (2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years. RESULTS: A total of 333 participants were randomised to vitamin D3 and placebo n-3 fatty acids, 289 to n-3 fatty acids and placebo vitamin D3, 370 to vitamin D3 and n-3 fatty acids, and 320 to 2 placebos; 989 (75%) and 934 (71%) participants returned blood samples at 2 and 5 years, respectively. Participants had a mean age of 67.6 years (46% women). Overall, baseline geometric means of IL-6, hsCRP and NT-proBNP were 1.2 pg/ml, 1.9 mg/l and 262 ng/l, respectively. After 5 years, mean IL-6 and hsCRP remained within 6% of their baseline values while mean NT-proBNP increased by 55% overall. Compared with placebo, participants assigned to vitamin D3 had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index. CONCLUSIONS/INTERPRETATION: Among adults with type 2 diabetes, supplementation with vitamin D3 or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01684722 FUNDING: The study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases. Graphical abstract.

No Association Between Vitamin D Supplementation and Risk of Colorectal Adenomas or Serrated Polyps in a Randomized Trial.

BACKGROUND & AIMS: The effects of vitamin D on risk of colorectal cancer precursors are not clear. We examined the influence of vitamin D supplementation on risk of colorectal adenomas and serrated polyps in a prespecified ancillary study of a large-scale prevention trial (the vitamin D and omegA-3 trial, VITAL) of individuals who were free of cancer and cardiovascular disease at enrollment. METHODS: In VITAL trial, 25,871 adults with no history of cancer or cardiovascular disease (12,786 men 50 years or older and 13,085 women 55 years or older) were randomly assigned to groups given daily dietary supplements (2000 IU vitamin D3 and 1 g marine n-3 fatty acid) or placebo. Patients were assigned to groups from November 2011 through March 2014 and the study ended on December 31, 2017. We confirmed conventional adenomas and serrated polyps by reviewing histopathology reports from participants who had reported a diagnosis of polyps and were asked by their doctors to return for a repeat colonoscopy or sigmoidoscopy in 5 years or less. We calculated the odds ratios (ORs) and 95% CIs by logistic regression, after adjusting for age, sex, n-3 treatment assignment, and history of endoscopy at time of randomization. RESULTS: During a median follow-up of 5.3 years, we documented 308 cases of conventional adenomas in 12,927 participants in the vitamin D group and 287 cases in 12,944 participants in the placebo group (OR for the association of vitamin D supplementation with adenoma, 1.08; 95% CI, 0.92-1.27). There were 172 cases of serrated polyps in the vitamin D group and 169 cases in the placebo group (OR for the association of vitamin D supplementation with serrated polyp, 1.02; 95% CI, 0.82-1.26). Supplementation was not associated with polyp size, location, multiplicity, or histologic features. We found evidence for an interaction between vitamin D supplementation and serum level of 25-hydroxyvitamin D, measured in 15,787 participants at randomization. Among individuals with serum levels of 25-hydroxyvitamin D below 30 ng/mL, the OR associated with supplementation for conventional adenoma was 0.82 (95% CI, 0.60-1.13), whereas among individuals with serum levels of 25-hydroxyvitamin D above 30 ng/mL, the OR for conventional adenoma was 1.20 (95% CI, 0.92-1.55) (P for interaction = .07). There was a significant interaction between vitamin D supplementation and serum level of 25-hydroxyvitamin D in their association with advanced adenoma (P for interaction = .04). CONCLUSIONS: Based on an ancillary study of data from the VITAL trial, daily vitamin D supplementation (2000 IU) was not associated with risk of colorectal cancer precursors in average-risk adults not selected for vitamin D insufficiency. A potential benefit for individuals with low baseline level of vitamin D requires further investigation. ClinicalTrials.gov number: NCT01169259.

Associations Between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Liver Cancer Among Postmenopausal Women.

BACKGROUND AND AIMS: In almost all countries, incidence rates of liver cancer (LC) are 100%-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of LC cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with LC risk, overall and by histology, by leveraging resources from five prospective cohorts. APPROACH AND RESULTS: Seven sex steroid hormones and SHBG were quantitated using gas chromatography/tandem mass spectrometry and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 postmenopausal female LC cases (HCC, n = 83; ICC, n = 56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log2 hormone value (approximate doubling of circulating concentration) and LC were calculated using multivariable-adjusted conditional logistic regression. A doubling in the concentration of 4-androstenedione (4-dione) was associated with a 50% decreased LC risk (OR = 0.50; 95% CI = 0.30-0.82), whereas SHBG was associated with a 31% increased risk (OR = 1.31; 95% CI = 1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR = 1.40; 95% CI = 1.05-1.89), but not HCC (OR = 1.12; 95% CI = 0.81-1.54). CONCLUSIONS: This study provides evidence that higher levels of 4-dione may be associated with lower, and SHBG with higher, LC risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease LC risk. Indeed, estradiol may be associated with an increased ICC risk.

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

BACKGROUND AND PURPOSE: Among stroke patients, low serum 25-hydroxyvitamin D predicts poor outcomes. In mice, higher omega-3 (n-3) fatty acid intake diminishes brain damage after stroke. In this study, we tested whether vitamin D or n-3 fatty acids supplementation prior to stroke reduces the risk of functional limitations and physical disability after stroke. METHODS: We used data from VITAL (the VITamin D and OmegA-3 TriaL) which randomized middle-aged and older men and women without cardiovascular disease to vitamin D3 (2000 IU/day) and/or marine n-3 fatty acids (1 g/day) and followed them for incident stroke events. Individuals experiencing a non-fatal stroke were mailed questionnaires assessing functional limitations (the physical performance scale adapted from Nagi) and physical disability (the modified Katz Activities of Daily Living and Rosow-Breslau Functional Health scales). We used logistic regression to analyze associations between randomized treatment and limitations on each scale. RESULTS: A total of 290 individuals experienced their first stroke during the trial, of whom 197 stroke survivors completed the stroke outcomes questionnaire a median of 1.4 years after diagnosis. We observed no associations between randomized treatment to vitamin D and functional limitations (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.52, 1.97) or physical disability (Rosow-Breslau scale: OR 0.92, 95% CI 0.50, 1.67; Katz scale: OR 1.03, 95% CI 0.31, 3.42). Those randomized to n-3 fatty acids had a non-significantly lower risk of functional limitations (OR 0.55, 95% CI 0.28, 1.09) and physical disability (Rosow-Breslau scale: OR 0.56, 95% CI 0.31, 1.02; Katz sclae: OR 0.32, 95% CI 0.50, 1.67). CONCLUSION: Vitamin D or omega-3 fatty acid supplementation prior to stroke did not result in significantly improved post-stroke outcomes.

Revisiting the association of sedentary behavior and physical activity with all-cause mortality using a compositional approach: the Women's Health Study.

BACKGROUND: While physical activity has consistently been associated with decreased mortality rates, it remains unknown if there is a single "ideal" combination of time in physical activities of different intensities and sedentary behavior (SB) associated with the lowest rate. This study examined the associations of combinations of time in moderate-to-vigorous intensity (MVPA), higher-light intensity (HLPA), lower-light intensity activities (LLPA), and SB with mortality rates in older women. METHODS: This prospective cohort study included 16,676 older women from throughout the United States enrolled in the Women's Health Study. Women wore accelerometers on their hip from 2011 to 2015 and were followed through 2017 (mean (SD) of 4.3 (1.1) years). Deaths were confirmed with medical records, death certificates, or the National Death Index. Compositional Cox regression models were used. RESULTS: The mean (SD) age was 72 (5.7) years at accelerometer wear; 503 women died. Compared to the least active women (mean, 3 min/day MVPA, 27 min/day HLPA, 162 min/day LLPA, and 701 min/day SB): compositional models showed an inverse L-shaped dose-response association of MVPA replacing other behaviors with mortality rates mortality rates (P = .02); SB relative to LLPA, HLPA, and MVPA was directly associated with mortality rates in a curvilinear dose-response manner (P < .001); replacing 10 min of SB for MVPA (HR (95% CI) = .86 (.73-.98)) or for HLPA (HR (95% CI.94 (.88-1.00)) associated with 14 and 6% lower mortality rates, respectively; a 47% risk reduction (HR [95% CI] = .53 [.42-.64]) was observed among women meeting physical activity guidelines (mean, 36 min/day MVPA, 79 min/day HLPA, 227 min/day LLPA and 549 min/day SB); and similar mortality rate reductions of 43% (HR (95% CI) = .57 (.41-.73)) were observed with increases in HLPA and LLPA without increasing MVPA, e.g., reallocating SB to 90 min/day of HLPA plus 120 min/day of LLPA. CONCLUSIONS: There was no "ideal" combination of physical activities of different intensities and SB associated with the lowest mortality rates. Of particular relevance to older women, replacing SB with light intensity activity was associated with lower mortality rates, and "mixing and matching" times in different intensities yielded equivalent mortality risk reductions.