今日の臨床サポート

サプリメント(ビタミン)

著者: 大野 智 島根大学医学部附属病院 臨床研究センター

監修: 名郷直樹 武蔵国分寺公園クリニック

著者校正/監修レビュー済:2022/08/03
患者向け説明資料

概要・推奨   

  1. 妊娠前から妊娠前期の妊婦が葉酸を摂取すると、出⽣児の神経管⽋損症が少なくなる可能性があり、4mg/⽇以下の摂取を推奨する(推奨度1)
  1. ビタミンEは⼼⾎管疾患の予防効果は明らかではなく、死亡を増やす懸念があるため、サプリメントとしての摂取を推奨しない(特に慢性疾患を有する患者)(推奨度4)
  1. ビタミンCのかぜの予防効果は明らかではないため推奨しないが、サプリメントとしての摂取は運動選手や患者が希望すれば行ってよい(推奨度3)
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
大野 智 : 特に申告事項無し[2022年]
監修:名郷直樹 : 特に申告事項無し[2022年]

改訂のポイント:
  1. ビタミンDと総死亡について、近年、有効性を示さなかったメタ分析の報告があるため、推奨度を1から3に変更した。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. サプリメントとは、不足する栄養素などを補う目的で利用される栄養補助食品・健康食品のことである。
  1. 健康食品には法律上の定義はなく、広く健康の保持増進に資する食品として販売・利用されるもの全般を指す。そのうち、国が定めた安全性や有効性に関する基準などを満たした「保健機能食品制度」がある。
  1. 健康増進法に基づく保健機能食品には、有効性と安全性が審査された、個別許可制の「特定保健用食品」(1,062品目、令和4年6月24日現在)、特定の成分(脂肪酸1種類、ミネラル6種類、ビタミン13種類)含有を表示できる栄養機能食品、平成27年4月から導入された届出制の機能性表示食品がある(5,628品目、令和4年7月8日現在)。
  1. 保健機能食品以外は「いわゆる健康食品」として一般食品と同じように扱われ、原則として、効能効果を表記することは医薬品医療機器法違反となる。
  1. 健康食品の市場規模は約8,659億円(2020年度推定値)、機能性表示食品は3,044億円(2020年度推定値)と増加傾向にある。市場にはサプリメントも広く流通するが、健康被害の報告も散見される。
  1. 参考:矢野経済研究所 健康食品市場に関する調査
  1. 高齢者では処方薬とサプリメントの併用は高頻度(50~70%)でみられるとの報告があり、注意が必要である。
問診・診察のポイント  
  1. 患者はサプリメントを摂取していることは重要なことではないと思い、医師に自分から伝えないことが多い。このため、服薬歴を尋ねる際にはサプリメントについても積極的に尋ねるように心がける。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
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文献 

Harri Hemilä, Elizabeth Chalker
Vitamin C for preventing and treating the common cold.
Cochrane Database Syst Rev. 2013 Jan 31;1:CD000980. doi: 10.1002/14651858.CD000980.pub4. Epub 2013 Jan 31.
Abstract/Text BACKGROUND: Vitamin C (ascorbic acid) for preventing and treating the common cold has been a subject of controversy for 70 years.
OBJECTIVES: To find out whether vitamin C reduces the incidence, the duration or severity of the common cold when used either as a continuous regular supplementation every day or as a therapy at the onset of cold symptoms.
SEARCH METHODS: We searched CENTRAL 2012, Issue 11, MEDLINE (1966 to November week 3, 2012), EMBASE (1990 to November 2012), CINAHL (January 2010 to November 2012), LILACS (January 2010 to November 2012) and Web of Science (January 2010 to November 2012). We also searched the U.S. National Institutes of Health trials register and WHO ICTRP on 29 November 2012.
SELECTION CRITERIA: We excluded trials which used less than 0.2 g per day of vitamin C and trials without a placebo comparison. We restricted our review to placebo-controlled trials.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We assessed 'incidence' of colds during regular supplementation as the proportion of participants experiencing one or more colds during the study period. 'Duration' was the mean number of days of illness of cold episodes.
MAIN RESULTS: Twenty-nine trial comparisons involving 11,306 participants contributed to the meta-analysis on the risk ratio (RR) of developing a cold whilst taking vitamin C regularly over the study period. In the general community trials involving 10,708 participants, the pooled RR was 0.97 (95% confidence interval (CI) 0.94 to 1.00). Five trials involving a total of 598 marathon runners, skiers and soldiers on subarctic exercises yielded a pooled RR of 0.48 (95% CI 0.35 to 0.64).Thirty-one comparisons examined the effect of regular vitamin C on common cold duration (9745 episodes). In adults the duration of colds was reduced by 8% (3% to 12%) and in children by 14% (7% to 21%). In children, 1 to 2 g/day vitamin C shortened colds by 18%. The severity of colds was also reduced by regular vitamin C administration.Seven comparisons examined the effect of therapeutic vitamin C (3249 episodes). No consistent effect of vitamin C was seen on the duration or severity of colds in the therapeutic trials.The majority of included trials were randomised, double-blind trials. The exclusion of trials that were either not randomised or not double-blind had no effect on the conclusions.
AUTHORS' CONCLUSIONS: The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine vitamin C supplementation is not justified, yet vitamin C may be useful for people exposed to brief periods of severe physical exercise. Regular supplementation trials have shown that vitamin C reduces the duration of colds, but this was not replicated in the few therapeutic trials that have been carried out. Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them. Further therapeutic RCTs are warranted.

PMID 23440782
Carol S Johnston, Gillean M Barkyoumb, Sara S Schumacher
Vitamin C supplementation slightly improves physical activity levels and reduces cold incidence in men with marginal vitamin C status: a randomized controlled trial.
Nutrients. 2014 Jul 9;6(7):2572-83. doi: 10.3390/nu6072572. Epub 2014 Jul 9.
Abstract/Text The early indications of vitamin C deficiency are unremarkable (fatigue, malaise, depression) and may manifest as a reduced desire to be physically active; moreover, hypovitaminosis C may be associated with increased cold duration and severity. This study examined the impact of vitamin C on physical activity and respiratory tract infections during the peak of the cold season. Healthy non-smoking adult men (18-35 years; BMI < 34 kg/m2; plasma vitamin C < 45 µmol/L) received either 1000 mg of vitamin C daily (n = 15) or placebo (n = 13) in a randomized, double-blind, eight-week trial. All participants completed the Wisconsin Upper Respiratory Symptom Survey-21 daily and the Godin Leisure-Time Exercise Questionnaire weekly. In the final two weeks of the trial, the physical activity score rose modestly for the vitamin C group vs. placebo after adjusting for baseline values: +39.6% (95% CI [-4.5,83.7]; p = 0.10). The number of participants reporting cold episodes was 7 and 11 for the vitamin C and placebo groups respectively during the eight-week trial (RR = 0.55; 95% CI [0.33,0.94]; p = 0.04) and cold duration was reduced 59% in the vitamin C versus placebo groups (-3.2 days; 95% CI [-7.0,0.6]; p = 0.06). These data suggest measurable health advantages associated with vitamin C supplementation in a population with adequate-to-low vitamin C status.

PMID 25010554
Rachel S Eidelman, Danielle Hollar, Patricia R Hebert, Gervasio A Lamas, Charles H Hennekens
Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease.
Arch Intern Med. 2004 Jul 26;164(14):1552-6. doi: 10.1001/archinte.164.14.1552.
Abstract/Text BACKGROUND: Observational epidemiological studies consistently show that individuals who choose to take high amounts of vitamin E through diet or supplements experience cardiovascular benefits, for which basic research provides plausible mechanisms. However, because the size of the postulated benefit is small to moderate, the confounding inherent in observational studies is as great as the effect size. Before the availability of randomized evidence, about 1 in 4 adults was taking vitamin E supplements in the United States.
METHODS: We conducted a computerized search of the English-language literature from 1990 to the present and found 7 large-scale randomized trials of the effectiveness vitamin E in the treatment and prevention of cardiovascular disease. Data were available on myocardial infarction, stroke, or cardiovascular death.
RESULTS: Six of the 7 trials showed no significant effect of vitamin E on cardiovascular disease. In an overview, vitamin E had neither a statistically significant nor a clinically important effect on any important cardiovascular event (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.94-1.03) or its components: nonfatal myocardial infarction (OR, 1.00; 95% CI, 0.92-1.09), nonfatal stroke (OR, 1.03; 95% CI, 0.93-1.14), or cardiovascular death (OR, 1.00; 95% CI, 0.94-1.05).
CONCLUSIONS: The ORs and CIs provide strong support for a lack of statistically significant or clinically important effects of vitamin E on cardiovascular disease. The use of agents of proven lack of benefit, especially those easily available over the counter, may contribute to underuse of agents of proven benefit and failure to adopt healthy lifestyles.

PMID 15277288
Eva Lonn, Jackie Bosch, Salim Yusuf, Patrick Sheridan, Janice Pogue, J Malcolm O Arnold, Catherine Ross, Andrew Arnold, Peter Sleight, Jeffrey Probstfield, Gilles R Dagenais, HOPE and HOPE-TOO Trial Investigators
Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial.
JAMA. 2005 Mar 16;293(11):1338-47. doi: 10.1001/jama.293.11.1338.
Abstract/Text CONTEXT: Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration.
OBJECTIVE: To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events.
DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled international trial (the initial Heart Outcomes Prevention Evaluation [HOPE] trial conducted between December 21, 1993, and April 15, 1999) of patients at least 55 years old with vascular disease or diabetes mellitus was extended (HOPE-The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9541 patients, 174 centers participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centers, 916 were deceased at the beginning of the extension, 1382 refused participation, 3994 continued to take the study intervention, and 738 agreed to passive follow-up. Median duration of follow-up was 7.0 years.
INTERVENTION: Daily dose of natural source vitamin E (400 IU) or matching placebo.
MAIN OUTCOME MEASURES: Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations.
RESULTS: Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24); and for major cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P = .34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = .03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P = .045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure.
CONCLUSION: In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.

PMID 15769967
I-Min Lee, Nancy R Cook, J Michael Gaziano, David Gordon, Paul M Ridker, Joann E Manson, Charles H Hennekens, Julie E Buring
Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial.
JAMA. 2005 Jul 6;294(1):56-65. doi: 10.1001/jama.294.1.56.
Abstract/Text CONTEXT: Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons, who self-select for high intakes of vitamin E through diet or supplements, have decreased risks of cardiovascular disease and cancer. Randomized trials do not generally support benefits of vitamin E, but there are few trials of long duration among initially healthy persons.
OBJECTIVE: To test whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women.
DESIGN, SETTING, AND PARTICIPANTS: In the Women's Health Study conducted between 1992 and 2004, 39 876 apparently healthy US women aged at least 45 years were randomly assigned to receive vitamin E or placebo and aspirin or placebo, using a 2 x 2 factorial design, and were followed up for an average of 10.1 years.
INTERVENTION: Administration of 600 IU of natural-source vitamin E on alternate days.
MAIN OUTCOME MEASURES: Primary outcomes were a composite end point of first major cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and total invasive cancer.
RESULTS: During follow-up, there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group, a nonsignificant 7% risk reduction (relative risk [RR], 0.93; 95% confidence interval [CI], 0.82-1.05; P = .26). There were no significant effects on the incidences of myocardial infarction (RR, 1.01; 95% CI, 0.82-1.23; P = .96) or stroke (RR, 0.98; 95% CI, 0.82-1.17; P = .82), as well as ischemic or hemorrhagic stroke. For cardiovascular death, there was a significant 24% reduction (RR, 0.76; 95% CI, 0.59-0.98; P = .03). There was no significant effect on the incidences of total cancer (1437 cases in the vitamin E group and 1428 in the placebo group; RR, 1.01; 95% CI, 0.94-1.08; P = .87) or breast (RR, 1.00; 95% CI, 0.90-1.12; P = .95), lung (RR, 1.09; 95% CI, 0.83-1.44; P = .52), or colon cancers (RR, 1.00; 95% CI, 0.77-1.31; P = .99). Cancer deaths also did not differ significantly between groups. There was no significant effect of vitamin E on total mortality (636 in the vitamin E group and 615 in the placebo group; RR, 1.04; 95% CI, 0.93-1.16; P = .53).
CONCLUSIONS: The data from this large trial indicated that 600 IU of natural-source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, and decreased cardiovascular mortality in healthy women. These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women.

PMID 15998891
Markus Schürks, Robert J Glynn, Pamela M Rist, Christophe Tzourio, Tobias Kurth
Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials.
BMJ. 2010 Nov 4;341:c5702. Epub 2010 Nov 4.
Abstract/Text OBJECTIVE: To evaluate the effect of vitamin E supplementation on incident total, ischaemic, and haemorrhagic stroke.
DESIGN: Systematic review and meta-analysis of randomised, placebo controlled trials published until January 2010.
DATA SOURCES: Electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials) and reference lists of trial reports. Selection criteria Randomised, placebo controlled trials with ≥1 year of follow-up investigating the effect of vitamin E on stroke. Review methods and data extraction Two investigators independently assessed eligibility of identified trials. Disagreements were resolved by consensus. Two different investigators independently extracted data. Risk ratios (and 95% confidence intervals) were calculated for each trial based on the number of cases and non-cases randomised to vitamin E or placebo. Pooled effect estimates were then calculated.
RESULTS: Nine trials investigating the effect of vitamin E on incident stroke were included, totalling 118 765 participants (59 357 randomised to vitamin E and 59 408 to placebo). Among those, seven trials reported data for total stroke and five trials each for haemorrhagic and ischaemic stroke. Vitamin E had no effect on the risk for total stroke (pooled relative risk 0.98 (95% confidence interval 0.91 to 1.05), P=0.53). In contrast, the risk for haemorrhagic stroke was increased (pooled relative risk 1.22 (1.00 to 1.48), P=0.045), while the risk of ischaemic stroke was reduced (pooled relative risk 0.90 (0.82 to 0.99), P=0.02). There was little evidence for heterogeneity among studies. Meta-regression did not identify blinding strategy, vitamin E dose, or morbidity status of participants as sources of heterogeneity. In terms of absolute risk, this translates into one additional haemorrhagic stroke for every 1250 individuals taking vitamin E, in contrast to one ischaemic stroke prevented per 476 individuals taking vitamin E.
CONCLUSION: In this meta-analysis, vitamin E increased the risk for haemorrhagic stroke by 22% and reduced the risk of ischaemic stroke by 10%. This differential risk pattern is obscured when looking at total stroke. Given the relatively small risk reduction of ischaemic stroke and the generally more severe outcome of haemorrhagic stroke, indiscriminate widespread use of vitamin E should be cautioned against.

PMID 21051774
Edgar R Miller, Roberto Pastor-Barriuso, Darshan Dalal, Rudolph A Riemersma, Lawrence J Appel, Eliseo Guallar
Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality.
Ann Intern Med. 2005 Jan 4;142(1):37-46. Epub 2004 Nov 10.
Abstract/Text BACKGROUND: Experimental models and observational studies suggest that vitamin E supplementation may prevent cardiovascular disease and cancer. However, several trials of high-dosage vitamin E supplementation showed non-statistically significant increases in total mortality.
PURPOSE: To perform a meta-analysis of the dose-response relationship between vitamin E supplementation and total mortality by using data from randomized, controlled trials.
PATIENTS: 135,967 participants in 19 clinical trials. Of these trials, 9 tested vitamin E alone and 10 tested vitamin E combined with other vitamins or minerals. The dosages of vitamin E ranged from 16.5 to 2000 IU/d (median, 400 IU/d).
DATA SOURCES: PubMed search from 1966 through August 2004, complemented by a search of the Cochrane Clinical Trials Database and review of citations of published reviews and meta-analyses. No language restrictions were applied.
DATA EXTRACTION: 3 investigators independently abstracted study reports. The investigators of the original publications were contacted if required information was not available.
DATA SYNTHESIS: 9 of 11 trials testing high-dosage vitamin E (> or =400 IU/d) showed increased risk (risk difference > 0) for all-cause mortality in comparisons of vitamin E versus control. The pooled all-cause mortality risk difference in high-dosage vitamin E trials was 39 per 10,000 persons (95% CI, 3 to 74 per 10,000 persons; P = 0.035). For low-dosage vitamin E trials, the risk difference was -16 per 10,000 persons (CI, -41 to 10 per 10,000 persons; P > 0.2). A dose-response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk of dosages greater than 150 IU/d.
LIMITATIONS: High-dosage (> or =400 IU/d) trials were often small and were performed in patients with chronic diseases. The generalizability of the findings to healthy adults is uncertain. Precise estimation of the threshold at which risk increases is difficult.
CONCLUSION: High-dosage (> or =400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.

PMID 15537682
Goran Bjelakovic, Dimitrinka Nikolova, Lise Lotte Gluud, Rosa G Simonetti, Christian Gluud
Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
JAMA. 2007 Feb 28;297(8):842-57. doi: 10.1001/jama.297.8.842.
Abstract/Text CONTEXT: Antioxidant supplements are used for prevention of several diseases.
OBJECTIVE: To assess the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials. DATA SOURCES AND TRIAL SELECTION: We searched electronic databases and bibliographies published by October 2005. All randomized trials involving adults comparing beta carotene, vitamin A, vitamin C (ascorbic acid), vitamin E, and selenium either singly or combined vs placebo or vs no intervention were included in our analysis. Randomization, blinding, and follow-up were considered markers of bias in the included trials. The effect of antioxidant supplements on all-cause mortality was analyzed with random-effects meta-analyses and reported as relative risk (RR) with 95% confidence intervals (CIs). Meta-regression was used to assess the effect of covariates across the trials.
DATA EXTRACTION: We included 68 randomized trials with 232 606 participants (385 publications).
DATA SYNTHESIS: When all low- and high-bias risk trials of antioxidant supplements were pooled together there was no significant effect on mortality (RR, 1.02; 95% CI, 0.98-1.06). Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.04[corrected]-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.
CONCLUSIONS: Treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The potential roles of vitamin C and selenium on mortality need further study.

PMID 17327526
G Bjelakovic, D Nikolova, L L Gluud, R G Simonetti, C Gluud
Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases.
Cochrane Database Syst Rev. 2008 Apr 16;(2):CD007176. doi: 10.1002/14651858.CD007176. Epub 2008 Apr 16.
Abstract/Text BACKGROUND: Animal and physiological research as well as observational studies suggest that antioxidant supplements may improve survival.
OBJECTIVES: To assess the effect of antioxidant supplements on mortality in primary or secondary prevention randomised clinical trials.
SEARCH STRATEGY: We searched The Cochrane Library (Issue 3, 2005), MEDLINE (1966 to October 2005), EMBASE (1985 to October 2005), and the Science Citation Index Expanded (1945 to October 2005). We scanned bibliographies of relevant publications and wrote to pharmaceutical companies for additional trials.
SELECTION CRITERIA: We included all primary and secondary prevention randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. Included participants were either healthy (primary prevention trials) or had any disease (secondary prevention trials).
DATA COLLECTION AND ANALYSIS: Three authors extracted data. Trials with adequate randomisation, blinding, and follow-up were classified as having a low risk of bias. Random-effects and fixed-effect meta-analyses were performed. Random-effects meta-regression analyses were performed to assess sources of intertrial heterogeneity.
MAIN RESULTS: Sixty-seven randomised trials with 232,550 participants were included. Forty-seven trials including 180,938 participants had low risk of bias. Twenty-one trials included 164,439 healthy participants. Forty-six trials included 68111 participants with various diseases (gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, endocrinological, or unspecified). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects meta-analysis (relative risk [RR] 1.02, 95% confidence interval [CI] 0.99 to 1.06), but significantly increased mortality in a fixed-effect model (RR 1.04, 95% CI 1.02 to 1.06). In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. In the trials with a low risk of bias, the antioxidant supplements significantly increased mortality (RR 1.05, 95% CI 1.02 to 1.08). When the different antioxidants were assessed separately, analyses including trials with a low risk of bias and excluding selenium trials found significantly increased mortality by vitamin A (RR 1.16, 95% CI 1.10 to 1.24), beta-carotene (RR 1.07, 95% CI 1.02 to 1.11), and vitamin E (RR 1.04, 95% CI 1.01 to 1.07), but no significant detrimental effect of vitamin C (RR 1.06, 95% CI 0.94 to 1.20). Low-bias risk trials on selenium found no significant effect on mortality (RR 0.91, 95% CI 0.76 to 1.09).
AUTHORS' CONCLUSIONS: We found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamin A, beta-carotene, and vitamin E may increase mortality. Future randomised trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be closely monitored for potential harmful effects. Antioxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.

PMID 18425980
Andrea J Curtis, Michael Bullen, Loretta Piccenna, John J McNeil
Vitamin E supplementation and mortality in healthy people: a meta-analysis of randomised controlled trials.
Cardiovasc Drugs Ther. 2014 Dec;28(6):563-73. doi: 10.1007/s10557-014-6560-7.
Abstract/Text PURPOSE: To evaluate the effect of oral vitamin E supplementation on all-cause mortality in apparently healthy people.
METHODS: A systematic review and meta-analysis was conducted on randomised controlled trials (RCTs) with ≥ 6 months of follow up investigating the effect of vitamin E supplementation on healthy adults in developed countries. Electronic databases (MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials) and reference lists of trial reports were searched for RCTs published between 1966 and June 2012. Three investigators assessed eligibility of identified trials. Disagreements were resolved by consensus. Two investigators independently extracted data according to the criteria.
RESULTS: There were 18 RCTs identified with 142,219 apparently healthy participants (71,116 in vitamin E intervention groups and 71,103 in control groups) that were included in the final analysis. Fixed effect and random effects analysis of the 18 trials revealed that supplementation with vitamin E was not associated with all-cause mortality (relative risk 1.01, 95% confidence interval 0.97 - 1.05, p = 0.65). Subgroup analyses by type of vitamin E (natural or synthetic), dose or duration of exposure, study design or quality, and pre-specified mortality outcome showed no association with all-cause mortality.
CONCLUSIONS: The evidence from pooled analysis of 18 randomised controlled trials undertaken in apparently healthy people shows no effect of vitamin E supplementation at a dose of 23-800 IU/day on all-cause mortality.

PMID 25398301
Dagfinn Aune, NaNa Keum, Edward Giovannucci, Lars T Fadnes, Paolo Boffetta, Darren C Greenwood, Serena Tonstad, Lars J Vatten, Elio Riboli, Teresa Norat
Dietary intake and blood concentrations of antioxidants and the risk of cardiovascular disease, total cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of prospective studies.
Am J Clin Nutr. 2018 Nov 1;108(5):1069-1091. doi: 10.1093/ajcn/nqy097.
Abstract/Text Background: High dietary intake or blood concentrations (as biomarkers of dietary intake) of vitamin C, carotenoids, and vitamin E have been associated with reduced risk of cardiovascular disease, cancer, and mortality, but these associations have not been systematically assessed.
Objective: We conducted a systematic review and meta-analysis of prospective studies of dietary intake and blood concentrations of vitamin C, carotenoids, and vitamin E in relation to these outcomes.
Design: We searched PubMed and Embase up to 14 February 2018. Summary RRs and 95% CIs were calculated with the use of random-effects models.
Results: Sixty-nine prospective studies (99 publications) were included. The summary RR per 100-mg/d increment of dietary vitamin C intake was 0.88 (95% CI: 0.79, 0.98, I2 = 65%, n = 11) for coronary heart disease, 0.92 (95% CI: 0.87, 0.98, I2 = 68%, n = 12) for stroke, 0.89 (95% CI: 0.85, 0.94, I2 = 27%, n = 10) for cardiovascular disease, 0.93 (95% CI: 0.87, 0.99, I2 = 46%, n = 8) for total cancer, and 0.89 (95% CI: 0.85, 0.94, I2 = 80%, n = 14) for all-cause mortality. Corresponding RRs per 50-μmol/L increase in blood concentrations of vitamin C were 0.74 (95% CI: 0.65, 0.83, I2 = 0%, n = 4), 0.70 (95% CI: 0.61, 0.81, I2 = 0%, n = 4), 0.76 (95% CI: 0.65, 0.87, I2 = 56%, n = 6), 0.74 (95% CI: 0.66, 0.82, I2 = 0%, n = 5), and 0.72 (95% CI: 0.66, 0.79, I2 = 0%, n = 8). Dietary intake and/or blood concentrations of carotenoids (total, β-carotene, α-carotene, β-cryptoxanthin, lycopene) and α-tocopherol, but not dietary vitamin E, were similarly inversely associated with coronary heart disease, stroke, cardiovascular disease, cancer, and/or all-cause mortality.
Conclusions: Higher dietary intake and/or blood concentrations of vitamin C, carotenoids, and α-tocopherol (as markers of fruit and vegetable intake) were associated with reduced risk of cardiovascular disease, total cancer, and all-cause mortality. These results support recommendations to increase fruit and vegetable intake, but not antioxidant supplement use, for chronic disease prevention.

PMID 30475962
Luz Maria De-Regil, Juan Pablo Peña-Rosas, Ana C Fernández-Gaxiola, Pura Rayco-Solon
Effects and safety of periconceptional oral folate supplementation for preventing birth defects.
Cochrane Database Syst Rev. 2015 Dec 14;12:CD007950. doi: 10.1002/14651858.CD007950.pub3. Epub 2015 Dec 14.
Abstract/Text BACKGROUND: It has been reported that neural tube defects (NTD) can be prevented with periconceptional folic acid supplementation. The effects of different doses, forms and schemes of folate supplementation for the prevention of other birth defects and maternal and infant outcomes are unclear.
OBJECTIVES: This review aims to examine whether periconceptional folate supplementation reduces the risk of neural tube and other congenital anomalies (including cleft palate) without causing adverse outcomes in mothers or babies. This is an update of a previously published Cochrane review on this topic.
SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2015). Additionally, we searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (31 August 2015) and contacted relevant organisations to identify ongoing and unpublished studies.
SELECTION CRITERIA: We included all randomised or quasi-randomised trials evaluating the effect of periconceptional folate supplementation alone, or in combination with other vitamins and minerals, in women independent of age and parity.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies, checked data entry for accuracy and assessed the risk of bias of the included studies. We assessed the quality of the body of evidence using the GRADE approach.
MAIN RESULTS: Five trials involving 7391 women (2033 with a history of a pregnancy affected by a NTD and 5358 with no history of NTDs) were included. Four comparisons were made: 1) supplementation with any folate versus no intervention, placebo or other micronutrients without folate (five trials); 2) supplementation with folic acid alone versus no treatment or placebo (one trial); 3) supplementation with folate plus other micronutrients versus other micronutrients without folate (four trials); and 4) supplementation with folate plus other micronutrients versus the same other micronutrients without folate (two trials). The risk of bias of the trials was variable. Only one trial was considered to be at low risk of bias. The remaining studies lacked clarity regarding the randomisation method or whether the allocation to the intervention was concealed. All the participants were blinded to the intervention, though blinding was unclear for outcome assessors in the five trials.The results of the first comparison involving 6708 births with information on NTDs and other infant outcomes, show a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.17 to 0.58); five studies; 6708 births; high quality evidence). Only one study assessed the incidence of NTDs and showed no evidence of an effect (RR 0.07, 95% CI 0.00 to 1.32; 4862 births) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence (RR 0.34, 95% CI 0.18 to 0.64); four studies; 1846 births). Subgroup analyses suggest that the positive effect of folic acid on NTD incidence and recurrence is not affected by the explored daily folic acid dosage (400 µg (0.4 mg) or higher) or whether folic acid is given alone or with other vitamins and minerals. These results are consistent across all four review comparisons.There is no evidence of any preventive or negative effects on cleft palate (RR 0.73, 95% CI 0.05 to 10.89; three studies; 5612 births; low quality evidence), cleft lip ((RR 0.79, 95% CI 0.14 to 4.36; three studies; 5612 births; low quality evidence), congenital cardiovascular defects (RR 0.57, 95% CI 0.24 to 1.33; three studies; 5612 births; low quality evidence), miscarriages (RR 1.10, 95% CI 0.94 to 1.28; five studies; 7391 pregnancies; moderate quality evidence) or any other birth defects (RR 0.94, 95% CI 0.53 to 1.66; three studies; 5612 births; low quality evidence). There were no included trials assessing the effects of this intervention on neonatal death, maternal blood folate or anaemia at term.
AUTHORS' CONCLUSIONS: Folic acid, alone or in combination with vitamins and minerals, prevents NTDs, but does not have a clear effect on other birth defects.

PMID 26662928
Deborah Charles, Andy R Ness, Doris Campbell, George Davey Smith, Marion H Hall
Taking folate in pregnancy and risk of maternal breast cancer.
BMJ. 2004 Dec 11;329(7479):1375-6. doi: 10.1136/bmj.329.7479.1375.
Abstract/Text
PMID 15591563
Meera Viswanathan, Katherine A Treiman, Julia Kish-Doto, Jennifer C Middleton, Emmanuel J L Coker-Schwimmer, Wanda K Nicholson
Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.
JAMA. 2017 Jan 10;317(2):190-203. doi: 10.1001/jama.2016.19193.
Abstract/Text Importance: Neural tube defects are among the most common congenital anomalies in the United States. Periconceptional folic acid supplementation is a primary care-relevant preventive intervention.
Objective: To review the evidence on folic acid supplementation for preventing neural tube defects to inform the US Preventive Services Task Force for an updated Recommendation Statement.
Data Sources: MEDLINE, Cochrane Library, EMBASE, and trial registries through January 28, 2016, with ongoing surveillance through November 11, 2016; references; experts.
Study Selection: English-language studies of folic acid supplementation in women. Excluded were poor-quality studies; studies of prepubertal girls, men, women without the potential for childbearing, and neural tube defect recurrence; and studies conducted in developing countries.
Data Extraction and Synthesis: Two investigators independently reviewed abstracts, full-text articles, and risk of bias of included studies. One investigator extracted data and a second checked accuracy. Because of heterogeneity, data were not pooled.
Main Outcomes and Measures: Neural tube defects, harms of treatment (twinning, respiratory outcomes).
Results: A total of 24 studies (N > 58 860) were included. In 1 randomized clinical trial from Hungary initiated in 1984, incidence of neural tube defects for folic acid supplementation compared with trace element supplementation was 0% vs 0.25% (Peto odds ratio [OR], 0.13 [95% CI, 0.03-0.65]; n = 4862). Odds ratios from cohort studies recruiting participants between 1984 and 1996 demonstrated beneficial associations and ranged from 0.11 to 0.27 (n = 19 982). Three of 4 case-control studies with data from 1976 through 1998 reported ORs ranging from 0.6 to 0.7 (n > 7121). Evidence of benefit led to food fortification in the United States beginning in 1998, after which no new prospective studies have been conducted. More recent case-control studies drawing from data collected after 1998 have not demonstrated a protective association consistently with folic acid supplementation, with ORs ranging from 0.93 to 1.4 and confidence intervals spanning the null (n > 13 990). Regarding harms, 1 trial (OR, 1.40 [95% CI, 0.89-2.21]; n = 4767) and 1 cohort study (OR, 1.04 [95% CI, 0.91-1.18]; n = 2620) found no statistically significant increased risk of twinning. Three systematic reviews found no consistent evidence of increased risk of asthma (OR, 1.06 [95% CI, 0.99-1.14]; n = 14 438), wheezing, or allergy.
Conclusions and Relevance: In studies conducted before the initiation of food fortification in the United States in 1998, folic acid supplementation provided protection against neural tube defects. Newer postfortification studies have not demonstrated a protective association but have the potential for misclassification and recall bias, which can attenuate the measured association of folic acid supplementation with neural tube defects.

PMID 28097361
Goran Bjelakovic, Lise Lotte Gluud, Dimitrinka Nikolova, Kate Whitfield, Jørn Wetterslev, Rosa G Simonetti, Marija Bjelakovic, Christian Gluud
Vitamin D supplementation for prevention of mortality in adults.
Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470. doi: 10.1002/14651858.CD007470.pub3. Epub 2014 Jan 10.
Abstract/Text BACKGROUND: Available evidence on the effects of vitamin D on mortality has been inconclusive. In a recent systematic review, we found evidence that vitamin D3 may decrease mortality in mostly elderly women. The present systematic review updates and reassesses the benefits and harms of vitamin D supplementation used in primary and secondary prophylaxis of mortality.
OBJECTIVES: To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease.
SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index-Expanded and Conference Proceedings Citation Index-Science (all up to February 2012). We checked references of included trials and pharmaceutical companies for unidentified relevant trials.
SELECTION CRITERIA: Randomised trials that compared any type of vitamin D in any dose with any duration and route of administration versus placebo or no intervention in adult participants. Participants could have been recruited from the general population or from patients diagnosed with a disease in a stable phase. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)).
DATA COLLECTION AND ANALYSIS: Six review authors extracted data independently. Random-effects and fixed-effect meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RRs). To account for trials with zero events, we performed meta-analyses of dichotomous data using risk differences (RDs) and empirical continuity corrections. We used published data and data obtained by contacting trial authors.To minimise the risk of systematic error, we assessed the risk of bias of the included trials. Trial sequential analyses controlled the risk of random errors possibly caused by cumulative meta-analyses.
MAIN RESULTS: We identified 159 randomised clinical trials. Ninety-four trials reported no mortality, and nine trials reported mortality but did not report in which intervention group the mortality occurred. Accordingly, 56 randomised trials with 95,286 participants provided usable data on mortality. The age of participants ranged from 18 to 107 years. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. More than half of the trials had a low risk of bias. All trials were conducted in high-income countries. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL).Vitamin D decreased mortality in all 56 trials analysed together (5,920/47,472 (12.5%) vs 6,077/47,814 (12.7%); RR 0.97 (95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I(2) = 0%). More than 8% of participants dropped out. 'Worst-best case' and 'best-worst case' scenario analyses demonstrated that vitamin D could be associated with a dramatic increase or decrease in mortality. When different forms of vitamin D were assessed in separate analyses, only vitamin D3 decreased mortality (4,153/37,817 (11.0%) vs 4,340/38,110 (11.4%); RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I(2) = 0%; 75,927 participants; 38 trials). Vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. A subgroup analysis of trials at high risk of bias suggested that vitamin D2 may even increase mortality, but this finding could be due to random errors. Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. We did not observe any statistically significant differences in the effect of vitamin D on mortality in subgroup analyses of trials at low risk of bias compared with trials at high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 ng/mL at entry compared with trials including participants with vitamin D levels equal to or greater than 20 ng/mL at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of trials using concomitant calcium supplementation compared with trials without calcium; of trials using a dose below 800 IU per day compared with trials using doses above 800 IU per day; and of trials including only women compared with trials including both sexes or only men. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I(2) = 0%; 44,492 participants; 4 trials). Vitamin D3 combined with calcium increased the risk of nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I(2) = 0%; 42,876 participants; 4 trials). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I(2) = 17%; 710 participants; 3 trials).
AUTHORS' CONCLUSIONS: Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium increased nephrolithiasis. Both alfacalcidol and calcitriol increased hypercalcaemia. Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted.

PMID 24414552
Rajiv Chowdhury, Setor Kunutsor, Anna Vitezova, Clare Oliver-Williams, Susmita Chowdhury, Jessica C Kiefte-de-Jong, Hassan Khan, Cristina P Baena, Dorairaj Prabhakaran, Moshe B Hoshen, Becca S Feldman, An Pan, Laura Johnson, Francesca Crowe, Frank B Hu, Oscar H Franco
Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.
BMJ. 2014 Apr 1;348:g1903. Epub 2014 Apr 1.
Abstract/Text OBJECTIVE: To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with mortality from cardiovascular, cancer, or other conditions, under various circumstances.
DESIGN: Systematic review and meta-analysis of observational studies and randomised controlled trials.
DATA SOURCES: Medline, Embase, Cochrane Library, and reference lists of relevant studies to August 2013; correspondance with investigators.
STUDY SELECTION: Observational cohort studies and randomised controlled trials in adults, which reported associations between vitamin D (measured as circulating 25-hydroxyvitamin D concentration or vitamin D supplement given singly) and cause specific mortality outcomes.
DATA EXTRACTION: Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849,412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30,716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics.
RESULTS: In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods.
CONCLUSIONS: Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.

PMID 24690623
Yayuan Zheng, Jianhong Zhu, Manru Zhou, Liao Cui, Weimin Yao, Yuyu Liu
Meta-analysis of long-term vitamin D supplementation on overall mortality.
PLoS One. 2013;8(12):e82109. doi: 10.1371/journal.pone.0082109. Epub 2013 Dec 3.
Abstract/Text INTRODUCTION: It has been suggested that vitamin D is effective to prevent mortality. However, there is no consistent conclusion that the effects of vitamin D supplementation on all-cause mortality are associated with duration of treatment. We conducted a meta-analysis regarding this issue in an effort to provide a more robust answer.
METHODS: A comprehensive search in a number of databases, including MEDLINE, Embase and The Cochrane Central Register of Controlled Trials, was conducted for collecting randomized controlled trials (RCTs) on vitamin D supplementation preventing mortality. Two investigators independently screened the literature according to the inclusive and exclusive criteria and the relative data were extracted. Data analysis was performed by using Review Manager 5.0 software.
RESULTS: Data from forty-two RCT s were included. Vitamin D therapy significantly decreased all-cause mortality with a duration of follow-up longer than 3 years with a RR (95% CI) of 0.94 (0.90-0.98). No benefit was seen in a shorter follow-up periods with a RR (95% CI) of 1.04 (0.97-1.12). Results remain robust after sensitivity analysis. The following subgroups of long-term follow-up had significantly fewer deaths: female only, participants with a mean age younger than 80, daily dose of 800 IU or less, participants with vitamin D insufficiency (baseline 25-hydroxyvitamin D level less than 50 nmol/L) and cholecalciferol therapy. In addition, the combination of vitamin D and calcium significantly reduced mortality and vitamin D alone also had a trend to decrease mortality in a longer time follow up.
CONCLUSIONS: The data suggest that supplementation of vitamin D is effective in preventing overall mortality in a long-term treatment, whereas it is not significantly effective in a treatment duration shorter than 3 years. Future studies are needed to identify the efficacy of vitamin D on specific mortality, such as cancer and cardiovascular disease mortality in a long-term treatment duration.

PMID 24349197
Lars Rejnmark, Alison Avenell, Tahir Masud, Frazer Anderson, Haakon E Meyer, Kerrie M Sanders, Kari Salovaara, Cyrus Cooper, Helen E Smith, Elizabeth T Jacobs, David Torgerson, Rebecca D Jackson, JoAnn E Manson, Kim Brixen, Leif Mosekilde, John A Robbins, Roger M Francis, Bo Abrahamsen
Vitamin D with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials.
J Clin Endocrinol Metab. 2012 Aug;97(8):2670-81. doi: 10.1210/jc.2011-3328. Epub 2012 May 17.
Abstract/Text INTRODUCTION: Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium.
SUBJECTS AND METHODS: Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies.
RESULTS: The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62-77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88-0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84-0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88-0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91-1.06).
CONCLUSION: Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.

PMID 22605432
Philippe Autier, Sara Gandini
Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.
Arch Intern Med. 2007 Sep 10;167(16):1730-7. doi: 10.1001/archinte.167.16.1730.
Abstract/Text BACKGROUND: Ecological and observational studies suggest that low vitamin D status could be associated with higher mortality from life-threatening conditions including cancer, cardiovascular disease, and diabetes mellitus that account for 60% to 70% of total mortality in high-income countries. We examined the risk of dying from any cause in subjects who participated in randomized trials testing the impact of vitamin D supplementation (ergocalciferol [vitamin D(2)] or cholecalciferol [vitamin D(3)]) on any health condition.
METHODS: The literature up to November 2006 was searched without language restriction using the following databases: PubMed, ISI Web of Science (Science Citation Index Expanded), EMBASE, and the Cochrane Library.
RESULTS: We identified 18 independent randomized controlled trials, including 57 311 participants. A total of 4777 deaths from any cause occurred during a trial size-adjusted mean of 5.7 years. Daily doses of vitamin D supplements varied from 300 to 2000 IU. The trial size-adjusted mean daily vitamin D dose was 528 IU. In 9 trials, there was a 1.4- to 5.2-fold difference in serum 25-hydroxyvitamin D between the intervention and control groups. The summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87-0.99). There was neither indication for heterogeneity nor indication for publication biases. The summary relative risk did not change according to the addition of calcium supplements in the intervention.
CONCLUSIONS: Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates. The relationship between baseline vitamin D status, dose of vitamin D supplements, and total mortality rates remains to be investigated. Population-based, placebo-controlled randomized trials with total mortality as the main end point should be organized for confirming these findings.

PMID 17846391
Judith Hsia, Gerardo Heiss, Hong Ren, Matthew Allison, Nancy C Dolan, Philip Greenland, Susan R Heckbert, Karen C Johnson, JoAnn E Manson, Stephen Sidney, Maurizio Trevisan, Women's Health Initiative Investigators
Calcium/vitamin D supplementation and cardiovascular events.
Circulation. 2007 Feb 20;115(7):846-54. doi: 10.1161/CIRCULATIONAHA.106.673491.
Abstract/Text BACKGROUND: Individuals with vascular or valvular calcification are at increased risk for coronary events, but the relationship between calcium consumption and cardiovascular events is uncertain. We evaluated the risk of coronary and cerebrovascular events in the Women's Health Initiative randomized trial of calcium plus vitamin D supplementation.
METHODS AND RESULTS: We randomized 36,282 postmenopausal women 50 to 79 years of age at 40 clinical sites to calcium carbonate 500 mg with vitamin D 200 IU twice daily or to placebo. Cardiovascular disease was a prespecified secondary efficacy outcome. During 7 years of follow-up, myocardial infarction or coronary heart disease death was confirmed for 499 women assigned to calcium/vitamin D and 475 women assigned to placebo (hazard ratio, 1.04; 95% confidence interval, 0.92 to 1.18). Stroke was confirmed among 362 women assigned to calcium/vitamin D and 377 assigned to placebo (hazard ratio, 0.95; 95% confidence interval, 0.82 to 1.10). In subgroup analyses, women with higher total calcium intake (diet plus supplements) at baseline were not at higher risk for coronary events (P=0.91 for interaction) or stroke (P=0.14 for interaction) if assigned to active calcium/vitamin D.
CONCLUSIONS: Calcium/vitamin D supplementation neither increased nor decreased coronary or cerebrovascular risk in generally healthy postmenopausal women over a 7-year use period.

PMID 17309935
Alison Avenell, Graeme S MacLennan, David J Jenkinson, Gladys C McPherson, Alison M McDonald, Puspa R Pant, Adrian M Grant, Marion K Campbell, Frazer H Anderson, Cyrus Cooper, Roger M Francis, William J Gillespie, C Michael Robinson, David J Torgerson, W Angus Wallace, RECORD Trial Group
Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial).
J Clin Endocrinol Metab. 2012 Feb;97(2):614-22. doi: 10.1210/jc.2011-1309. Epub 2011 Nov 23.
Abstract/Text CONTEXT: Vitamin D or calcium supplementation may have effects on vascular disease and cancer.
OBJECTIVE: Our objective was to investigate whether vitamin D or calcium supplementation affects mortality, vascular disease, and cancer in older people.
DESIGN AND SETTING: The study included long-term follow-up of participants in a two by two factorial, randomized controlled trial from 21 orthopedic centers in the United Kingdom.
PARTICIPANTS: Participants were 5292 people (85% women) aged at least 70 yr with previous low-trauma fracture.
INTERVENTIONS: Participants were randomly allocated to daily vitamin D(3) (800 IU), calcium (1000 mg), both, or placebo for 24-62 months, with a follow-up of 3 yr after intervention.
MAIN OUTCOME MEASURES: All-cause mortality, vascular disease mortality, cancer mortality, and cancer incidence were evaluated.
RESULTS: In intention-to-treat analyses, mortality [hazard ratio (HR) = 0.93; 95% confidence interval (CI) = 0.85-1.02], vascular disease mortality (HR = 0.91; 95% CI = 0.79-1.05), cancer mortality (HR = 0.85; 95% CI = 0.68-1.06), and cancer incidence (HR = 1.07; 95% CI = 0.92-1.25) did not differ significantly between participants allocated vitamin D and those not. All-cause mortality (HR = 1.03; 95% CI = 0.94-1.13), vascular disease mortality (HR = 1.07; 95% CI = 0.92-1.24), cancer mortality (HR = 1.13; 95% CI = 0.91-1.40), and cancer incidence (HR = 1.06; 95% CI = 0.91-1.23) also did not differ significantly between participants allocated calcium and those not. In a post hoc statistical analysis adjusting for compliance, thus with fewer participants, trends for reduced mortality with vitamin D and increased mortality with calcium were accentuated, although all results remain nonsignificant.
CONCLUSIONS: Daily vitamin D or calcium supplementation did not affect mortality, vascular disease, cancer mortality, or cancer incidence.

PMID 22112804
Lukas Schwingshackl, Heiner Boeing, Marta Stelmach-Mardas, Marion Gottschald, Stefan Dietrich, Georg Hoffmann, Anna Chaimani
Dietary Supplements and Risk of Cause-Specific Death, Cardiovascular Disease, and Cancer: A Systematic Review and Meta-Analysis of Primary Prevention Trials.
Adv Nutr. 2017 Jan;8(1):27-39. doi: 10.3945/an.116.013516. Epub 2017 Jan 17.
Abstract/Text Our aim was to assess the efficacy of dietary supplements in the primary prevention of cause-specific death, cardiovascular disease (CVD), and cancer by using meta-analytical approaches. Electronic and hand searches were performed until August 2016. Inclusion criteria were as follows: 1) minimum intervention period of 12 mo; 2) primary prevention trials; 3) mean age ≥18 y; 4) interventions included vitamins, fatty acids, minerals, supplements containing combinations of vitamins and minerals, protein, fiber, prebiotics, and probiotics; and 5) primary outcome of all-cause mortality and secondary outcomes of mortality or incidence from CVD or cancer. Pooled effects across studies were estimated by using random-effects meta-analysis. Overall, 49 trials (69 reports) including 287,304 participants met the inclusion criteria. Thirty-two trials were judged as low risk-, 15 trials as moderate risk-, and 2 trials as high risk-of-bias studies. Supplements containing vitamin E (RR: 0.88; 95% CI: 0.80, 0.96) significantly reduced cardiovascular mortality risk, whereas supplements with folic acid reduced the risk of CVD (RR: 0.81; 95% CI: 0.70, 0.94). Vitamins D, C, and K; selenium; zinc; magnesium; and eicosapentaenoic acid showed no significant risk reduction for any of the outcomes. On the contrary, vitamin A was linked to an increased cancer risk (RR: 1.16; 95% CI: 1.00, 1.35). Supplements with β-carotene showed no significant effect; however, in the subgroup with β-carotene given singly, an increased risk of all-cause mortality by 6% (RR: 1.06; 95% CI: 1.02, 1.10) was observed. Taken together, we found insufficient evidence to support the use of dietary supplements in the primary prevention of cause-specific death, incidence of CVD, and incidence of cancer. The application of some supplements generated small beneficial effects; however, the heterogeneous types and doses of supplements limit the generalizability to the overall population.

© 2017 American Society for Nutrition.
PMID 28096125
David J A Jenkins, J David Spence, Edward L Giovannucci, Young-In Kim, Robert Josse, Reinhold Vieth, Sonia Blanco Mejia, Effie Viguiliouk, Stephanie Nishi, Sandhya Sahye-Pudaruth, Melanie Paquette, Darshna Patel, Sandy Mitchell, Meaghan Kavanagh, Tom Tsirakis, Lina Bachiri, Atherai Maran, Narmada Umatheva, Taylor McKay, Gelaine Trinidad, Daniel Bernstein, Awad Chowdhury, Julieta Correa-Betanzo, Gabriella Del Principe, Anisa Hajizadeh, Rohit Jayaraman, Amy Jenkins, Wendy Jenkins, Ruben Kalaichandran, Geithayini Kirupaharan, Preveena Manisekaran, Tina Qutta, Ramsha Shahid, Alexis Silver, Cleo Villegas, Jessica White, Cyril W C Kendall, Sathish C Pichika, John L Sievenpiper
Supplemental Vitamins and Minerals for CVD Prevention and Treatment.
J Am Coll Cardiol. 2018 Jun 5;71(22):2570-2584. doi: 10.1016/j.jacc.2018.04.020.
Abstract/Text The authors identified individual randomized controlled trials from previous meta-analyses and additional searches, and then performed meta-analyses on cardiovascular disease outcomes and all-cause mortality. The authors assessed publications from 2012, both before and including the U.S. Preventive Service Task Force review. Their systematic reviews and meta-analyses showed generally moderate- or low-quality evidence for preventive benefits (folic acid for total cardiovascular disease, folic acid and B-vitamins for stroke), no effect (multivitamins, vitamins C, D, β-carotene, calcium, and selenium), or increased risk (antioxidant mixtures and niacin [with a statin] for all-cause mortality). Conclusive evidence for the benefit of any supplement across all dietary backgrounds (including deficiency and sufficiency) was not demonstrated; therefore, any benefits seen must be balanced against possible risks.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
PMID 29852980
Yu Zhang, Fang Fang, Jingjing Tang, Lu Jia, Yuning Feng, Ping Xu, Andrew Faramand
Association between vitamin D supplementation and mortality: systematic review and meta-analysis.
BMJ. 2019 Aug 12;366:l4673. doi: 10.1136/bmj.l4673. Epub 2019 Aug 12.
Abstract/Text OBJECTIVE: To investigate whether vitamin D supplementation is associated with lower mortality in adults.
DESIGN: Systematic review and meta-analysis of randomised controlled trials.
DATA SOURCES: Medline, Embase, and the Cochrane Central Register from their inception to 26 December 2018.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing vitamin D supplementation with a placebo or no treatment for mortality were included. Independent data extraction was conducted and study quality assessed. A meta-analysis was carried out by using fixed effects and random effects models to calculate risk ratio of death in the group receiving vitamin D supplementation and the control group.
MAIN OUTCOME MEASURES: All cause mortality.
RESULTS: 52 trials with a total of 75 454 participants were identified. Vitamin D supplementation was not associated with all cause mortality (risk ratio 0.98, 95% confidence interval 0.95 to 1.02, I2=0%), cardiovascular mortality (0.98, 0.88 to 1.08, 0%), or non-cancer, non-cardiovascular mortality (1.05, 0.93 to 1.18, 0%). Vitamin D supplementation statistically significantly reduced the risk of cancer death (0.84, 0.74 to 0.95, 0%). In subgroup analyses, all cause mortality was significantly lower in trials with vitamin D3 supplementation than in trials with vitamin D2 supplementation (P for interaction=0.04); neither vitamin D3 nor vitamin D2 was associated with a statistically significant reduction in all cause mortality.
CONCLUSIONS: Vitamin D supplementation alone was not associated with all cause mortality in adults compared with placebo or no treatment. Vitamin D supplementation reduced the risk of cancer death by 16%. Additional large clinical studies are needed to determine whether vitamin D3 supplementation is associated with lower all cause mortality.
STUDY REGISTRATION: PROSPERO registration number CRD42018117823.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
PMID 31405892
Rachel E Neale, Catherine Baxter, Briony Duarte Romero, Donald S A McLeod, Dallas R English, Bruce K Armstrong, Peter R Ebeling, Gunter Hartel, Michael G Kimlin, Rachel O'Connell, Jolieke C van der Pols, Alison J Venn, Penelope M Webb, David C Whiteman, Mary Waterhouse
The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality.
Lancet Diabetes Endocrinol. 2022 Feb;10(2):120-128. doi: 10.1016/S2213-8587(21)00345-4. Epub 2022 Jan 10.
Abstract/Text BACKGROUND: The effect of supplementing unscreened adults with vitamin D3 on mortality is unclear. We aimed to determine whether monthly doses of vitamin D3 influenced mortality in older Australians.
METHODS: We did a randomised, double-blind, placebo-controlled trial of oral vitamin D3 supplementation (60 000 IU per month) in Australians 60 years or older who were recruited across the country via the Commonwealth electoral roll. Participants were randomly assigned (1:1), using automated computer-generated permuted block randomisation, to receive one oral gel capsule of either 60 000 IU vitamin D3 or placebo once a month for 5 years. Participants, staff, and investigators were blinded to study group allocation. The primary endpoint was all-cause mortality assessed in all participants who were randomly assigned. We also analysed mortality from cancer, cardiovascular disease, and other causes. Hazard ratios (HRs) and 95% CIs were generated using flexible parametric survival models. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763.
FINDINGS: Between Feb 14, 2014, and June 17, 2015, we randomly assigned 21 315 participants, including 10 662 to the vitamin D group and 10 653 to the placebo group. In 4441 blood samples collected from randomly sampled participants (N=3943) during follow-up, mean serum 25-hydroxy-vitamin D concentrations were 77 (SD 25) in the placebo group and 115 (SD 30) nmol/L in the vitamin D group. Following 5 years of intervention (median follow-up 5·7 years [IQR 5·4-6·7]), 1100 deaths were recorded (placebo 538 [5·1%]; vitamin D 562 [5·3%]). 10 661 participants in the vitamin D group and 10 649 participants in the placebo group were included in the primary analysis. Five participants (one in the vitamin D group and four in the placebo group) were not included as they requested to be withdrawn and their data to be destroyed. The HR of vitamin D3 effect on all-cause mortality was 1.04 [95% CI 0·93 to 1·18]; p=0·47)and the HR of vitamin D3 effect on cardiovascular disease mortality was 0·96 (95% CI 0·72 to 1·28; p=0·77). The HR for cancer mortality was 1·15 (95% CI 0·96 to 1·39; p=0·13) and for mortality from other causes it was 0·83 (95% CI 0·65 to 1·07; p=0·15). The odds ratio for the per-protocol analysis was OR 1·18 (95% CI 1·00 to 1·40; p=0·06). In exploratory analyses excluding the first 2 years of follow-up, those randomly assigned to receive vitamin D had a numerically higher hazard of cancer mortality than those in the placebo group (HR 1·24 [95% CI 1·01-1·54]; p=0·05).
INTERPRETATION: Administering vitamin D3 monthly to unscreened older people did not reduce all-cause mortality. Point estimates and exploratory analyses excluding the early follow-up period were consistent with an increased risk of death from cancer. Pending further evidence, the precautionary principle would suggest that this dosing regimen might not be appropriate in people who are vitamin D-replete.
FUNDING: The D-Health Trial is funded by National Health and Medical Research Council.

Copyright © 2022 Elsevier Ltd. All rights reserved.
PMID 35026158
Heike A Bischoff-Ferrari, Bess Dawson-Hughes, Walter C Willett, Hannes B Staehelin, Marlet G Bazemore, Robert Y Zee, John B Wong
Effect of Vitamin D on falls: a meta-analysis.
JAMA. 2004 Apr 28;291(16):1999-2006. doi: 10.1001/jama.291.16.1999.
Abstract/Text CONTEXT: Falls among elderly individuals occur frequently, increase with age, and lead to substantial morbidity and mortality. The role of vitamin D in preventing falls among elderly people has not been well established.
OBJECTIVE: To assess the effectiveness of vitamin D in preventing an older person from falling.
DATA SOURCES: MEDLINE and the Cochrane Controlled Trials Register from January 1960 to February 2004, EMBASE from January 1991 to February 2004, clinical experts, bibliographies, and abstracts. Search terms included trial terms: randomized-controlled trial or controlled-clinical trial or random-allocation or double-blind method, or single-blind method or uncontrolled-trials with vitamin D terms: cholecalciferol or hydroxycholecalciferols or calcifediol or dihydroxycholecalciferols or calcitriol or vitamin D/aa[analogs & derivates] or ergocalciferol or vitamin D/bl[blood]; and with accidental falls or falls, and humans.
STUDY SELECTION: We included only double-blind randomized, controlled trials (RCTs) of vitamin D in elderly populations (mean age, 60 years) that examined falls resulting from low trauma for which the method of fall ascertainment and definition of falls were defined explicitly. Studies including patients in unstable health states were excluded. Five of 38 identified studies were included in the primary analysis and 5 other studies were included in a sensitivity analysis.
DATA EXTRACTION: Independent extraction by 3 authors using predefined data fields including study quality indicators.
DATA SYNTHESIS: Based on 5 RCTs involving 1237 participants, vitamin D reduced the corrected odds ratio (OR) of falling by 22% (corrected OR, 0.78; 95% confidence interval [CI], 0.64-0.92) compared with patients receiving calcium or placebo. From the pooled risk difference, the number needed to treat (NNT) was 15 (95% CI, 8-53), or equivalently 15 patients would need to be treated with vitamin D to prevent 1 person from falling. The inclusion of 5 additional studies, involving 10 001 participants, in a sensitivity analysis resulted in a smaller but still significant effect size (corrected RR, 0.87; 95% CI, 0.80-0.96). Subgroup analyses suggested that the effect size was independent of calcium supplementation, type of vitamin D, duration of therapy, and sex, but reduced sample sizes made the results statistically nonsignificant for calcium supplementation, cholecalciferol, and among men.
CONCLUSIONS: Vitamin D supplementation appears to reduce the risk of falls among ambulatory or institutionalized older individuals with stable health by more than 20%. Further studies examining the effect of alternative types of vitamin D and their doses, the role of calcium supplementation, and effects in men should be considered.

PMID 15113819
H A Bischoff-Ferrari, B Dawson-Hughes, H B Staehelin, J E Orav, A E Stuck, R Theiler, J B Wong, A Egli, D P Kiel, J Henschkowski
Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials.
BMJ. 2009 Oct 1;339:b3692. Epub 2009 Oct 1.
Abstract/Text OBJECTIVE: To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals.
DATA SOURCES: We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol)) or an active form of vitamin D (1alpha-hydroxyvitamin D(3) (1alpha-hydroxycalciferol) or 1,25-dihydroxyvitamin D(3) (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion.
RESULTS: Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D(3) concentration (25(OH)D concentration: <60 nmol/l v >or=60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94).
CONCLUSIONS: Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.

PMID 19797342
Kerrie M Sanders, Amanda L Stuart, Elizabeth J Williamson, Julie A Simpson, Mark A Kotowicz, Doris Young, Geoffrey C Nicholson
Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.
JAMA. 2010 May 12;303(18):1815-22. doi: 10.1001/jama.2010.594.
Abstract/Text CONTEXT: Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.
OBJECTIVE: To determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.
DESIGN, SETTING, AND PARTICIPANTS: A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.
INTERVENTION: 500,000 IU of cholecalciferol or placebo.
MAIN OUTCOME MEASURES: Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.
RESULTS: Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.
CONCLUSION: Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.
TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.

PMID 20460620
Mohammad Hassan Murad, Khalid B Elamin, Nisrin O Abu Elnour, Mohamed B Elamin, Aziz A Alkatib, Mitra M Fatourechi, Jaime P Almandoz, Rebecca J Mullan, Melanie A Lane, Hau Liu, Patricia J Erwin, Donald D Hensrud, Victor M Montori
Clinical review: The effect of vitamin D on falls: a systematic review and meta-analysis.
J Clin Endocrinol Metab. 2011 Oct;96(10):2997-3006. doi: 10.1210/jc.2011-1193. Epub 2011 Jul 27.
Abstract/Text CONTEXT: Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly.
OBJECTIVE: The aim of this systematic review is to summarize the existing evidence on vitamin D use and the risk of falls.
DATA SOURCES: We searched electronic databases from inception through August 2010.
STUDY SELECTION: Eligible studies were randomized controlled trials in which the intervention was vitamin D and the incidence of falls was reported.
DATA EXTRACTION: Reviewers working in duplicate and independently extracted study characteristics, quality, and outcomes data.
DATA SYNTHESIS: Odds ratio and associated 95% confidence interval were estimated from each study and pooled using the random effects model.
RESULTS: We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96). This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. The quality of evidence was low to moderate because of heterogeneity and publication bias.
CONCLUSIONS: Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women.

PMID 21795448
Lesley D Gillespie, M Clare Robertson, William J Gillespie, Catherine Sherrington, Simon Gates, Lindy M Clemson, Sarah E Lamb
Interventions for preventing falls in older people living in the community.
Cochrane Database Syst Rev. 2012 Sep 12;9:CD007146. doi: 10.1002/14651858.CD007146.pub3. Epub 2012 Sep 12.
Abstract/Text BACKGROUND: Approximately 30% of people over 65 years of age living in the community fall each year. This is an update of a Cochrane review first published in 2009.
OBJECTIVES: To assess the effects of interventions designed to reduce the incidence of falls in older people living in the community.
SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (February 2012), CENTRAL (The Cochrane Library 2012, Issue 3), MEDLINE (1946 to March 2012), EMBASE (1947 to March 2012), CINAHL (1982 to February 2012), and online trial registers.
SELECTION CRITERIA: Randomised trials of interventions to reduce falls in community-dwelling older people.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data. We used a rate ratio (RaR) and 95% confidence interval (CI) to compare the rate of falls (e.g. falls per person year) between intervention and control groups. For risk of falling, we used a risk ratio (RR) and 95% CI based on the number of people falling (fallers) in each group. We pooled data where appropriate.
MAIN RESULTS: We included 159 trials with 79,193 participants. Most trials compared a fall prevention intervention with no intervention or an intervention not expected to reduce falls. The most common interventions tested were exercise as a single intervention (59 trials) and multifactorial programmes (40 trials). Sixty-two per cent (99/159) of trials were at low risk of bias for sequence generation, 60% for attrition bias for falls (66/110), 73% for attrition bias for fallers (96/131), and only 38% (60/159) for allocation concealment.Multiple-component group exercise significantly reduced rate of falls (RaR 0.71, 95% CI 0.63 to 0.82; 16 trials; 3622 participants) and risk of falling (RR 0.85, 95% CI 0.76 to 0.96; 22 trials; 5333 participants), as did multiple-component home-based exercise (RaR 0.68, 95% CI 0.58 to 0.80; seven trials; 951 participants and RR 0.78, 95% CI 0.64 to 0.94; six trials; 714 participants). For Tai Chi, the reduction in rate of falls bordered on statistical significance (RaR 0.72, 95% CI 0.52 to 1.00; five trials; 1563 participants) but Tai Chi did significantly reduce risk of falling (RR 0.71, 95% CI 0.57 to 0.87; six trials; 1625 participants).Multifactorial interventions, which include individual risk assessment, reduced rate of falls (RaR 0.76, 95% CI 0.67 to 0.86; 19 trials; 9503 participants), but not risk of falling (RR 0.93, 95% CI 0.86 to 1.02; 34 trials; 13,617 participants).Overall, vitamin D did not reduce rate of falls (RaR 1.00, 95% CI 0.90 to 1.11; seven trials; 9324 participants) or risk of falling (RR 0.96, 95% CI 0.89 to 1.03; 13 trials; 26,747 participants), but may do so in people with lower vitamin D levels before treatment.Home safety assessment and modification interventions were effective in reducing rate of falls (RR 0.81, 95% CI 0.68 to 0.97; six trials; 4208 participants) and risk of falling (RR 0.88, 95% CI 0.80 to 0.96; seven trials; 4051 participants). These interventions were more effective in people at higher risk of falling, including those with severe visual impairment. Home safety interventions appear to be more effective when delivered by an occupational therapist.An intervention to treat vision problems (616 participants) resulted in a significant increase in the rate of falls (RaR 1.57, 95% CI 1.19 to 2.06) and risk of falling (RR 1.54, 95% CI 1.24 to 1.91). When regular wearers of multifocal glasses (597 participants) were given single lens glasses, all falls and outside falls were significantly reduced in the subgroup that regularly took part in outside activities. Conversely, there was a significant increase in outside falls in intervention group participants who took part in little outside activity.Pacemakers reduced rate of falls in people with carotid sinus hypersensitivity (RaR 0.73, 95% CI 0.57 to 0.93; three trials; 349 participants) but not risk of falling. First eye cataract surgery in women reduced rate of falls (RaR 0.66, 95% CI 0.45 to 0.95; one trial; 306 participants), but second eye cataract surgery did not.Gradual withdrawal of psychotropic medication reduced rate of falls (RaR 0.34, 95% CI 0.16 to 0.73; one trial; 93 participants), but not risk of falling. A prescribing modification programme for primary care physicians significantly reduced risk of falling (RR 0.61, 95% CI 0.41 to 0.91; one trial; 659 participants).An anti-slip shoe device reduced rate of falls in icy conditions (RaR 0.42, 95% CI 0.22 to 0.78; one trial; 109 participants). One trial (305 participants) comparing multifaceted podiatry including foot and ankle exercises with standard podiatry in people with disabling foot pain significantly reduced the rate of falls (RaR 0.64, 95% CI 0.45 to 0.91) but not the risk of falling.There is no evidence of effect for cognitive behavioural interventions on rate of falls (RaR 1.00, 95% CI 0.37 to 2.72; one trial; 120 participants) or risk of falling (RR 1.11, 95% CI 0.80 to 1.54; two trials; 350 participants).Trials testing interventions to increase knowledge/educate about fall prevention alone did not significantly reduce the rate of falls (RaR 0.33, 95% CI 0.09 to 1.20; one trial; 45 participants) or risk of falling (RR 0.88, 95% CI 0.75 to 1.03; four trials; 2555 participants).No conclusions can be drawn from the 47 trials reporting fall-related fractures.Thirteen trials provided a comprehensive economic evaluation. Three of these indicated cost savings for their interventions during the trial period: home-based exercise in over 80-year-olds, home safety assessment and modification in those with a previous fall, and one multifactorial programme targeting eight specific risk factors.
AUTHORS' CONCLUSIONS: Group and home-based exercise programmes, and home safety interventions reduce rate of falls and risk of falling.Multifactorial assessment and intervention programmes reduce rate of falls but not risk of falling; Tai Chi reduces risk of falling.Overall, vitamin D supplementation does not appear to reduce falls but may be effective in people who have lower vitamin D levels before treatment.

PMID 22972103
Saran Thanapluetiwong, Api Chewcharat, Kullaya Takkavatakarn, Kearkiat Praditpornsilpa, Somchai Eiam-Ong, Paweena Susantitaphong
Vitamin D supplement on prevention of fall and fracture: A Meta-analysis of Randomized Controlled Trials.
Medicine (Baltimore). 2020 Aug 21;99(34):e21506. doi: 10.1097/MD.0000000000021506.
Abstract/Text BACKGROUND: Vitamin D supplement is one of the current possible interventions to reduce fall and fracture. Despite having several studies on vitamin D supplement and fall and fracture reductions, the results are still inconclusive. We conducted a meta-analysis to examine the effect of vitamin D supplement in different forms and patient settings on fall and fracture.
METHODS: A systematic literature research was conducted in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials to identify randomized controlled trials (RCTs) to compare the effects of vitamin D supplements on fall and fracture outcomes. Random-effect models were used to compute the weighted mean difference for continuous variables and the risk ratio for binary variables.
RESULTS: Forty-seven RCTs with 58,424 participants were identified reporting on fall outcome. Twenty-four of 47 studies with 40,102 subjects also reported fracture outcome. Major populations were elderly women with age less than 80 years. Overall, vitamin D supplement demonstrated a significant effect on fall reduction, RR = 0.948 (95% CI 0.914-0.984; P = .004, I = 41.52). By subgroup analyses, only vitamin D with calcium supplement significantly reduce fall incidence, RR = 0.881 (95% CI 0.821-0.945; P < .001, I = 49.19). Vitamin D3 supplement decreased incidence of fall but this occurred only when vitamin D3 was supplemented with calcium. Regarding fracture outcome, vitamin D supplement failed to show fracture lowering benefit, RR = 0.949 (95% CI 0.846-1.064; P = .37, I = 37.92). Vitamin D along with calcium supplement could significantly lower fracture rates, RR = 0.859 (95% CI 0.741-0.996; P = .045, I = 25.48).
CONCLUSIONS: The use of vitamin D supplement, especially vitamin D3 could reduce incidence of fall. Only vitamin D with calcium supplement showed benefit in fracture reduction.

PMID 32846760
Adrian R Martineau, David A Jolliffe, Richard L Hooper, Lauren Greenberg, John F Aloia, Peter Bergman, Gal Dubnov-Raz, Susanna Esposito, Davaasambuu Ganmaa, Adit A Ginde, Emma C Goodall, Cameron C Grant, Christopher J Griffiths, Wim Janssens, Ilkka Laaksi, Semira Manaseki-Holland, David Mauger, David R Murdoch, Rachel Neale, Judy R Rees, Steve Simpson, Iwona Stelmach, Geeta Trilok Kumar, Mitsuyoshi Urashima, Carlos A Camargo
Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.
BMJ. 2017 Feb 15;356:i6583. Epub 2017 Feb 15.
Abstract/Text Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.

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PMID 28202713
Mitsuyoshi Urashima, Hidetoshi Mezawa, Miki Noya, Carlos A Camargo
Effects of vitamin D supplements on influenza A illness during the 2009 H1N1 pandemic: a randomized controlled trial.
Food Funct. 2014 Sep;5(9):2365-70. doi: 10.1039/c4fo00371c.
Abstract/Text In a prior randomized trial, we found that the incidence of influenza A was less in the vitamin D3 group than among those on placebo, but the total incidence of either influenza A or B did not differ between groups. In this trial, the incidence of influenza A or B was less in the vitamin D3 group than in the placebo group only during the first half of the study. To elucidate whether vitamin D3 has preventive actions against influenza A, we conducted another trial during the 2009 pandemic of the H1N1 subtype of influenza A. Students (n = 247) of a Japanese high school were randomly assigned to receive vitamin D3 supplements (n = 148; 2000 IU per day) or a placebo (n = 99) in a double-blind study for 2 months. The primary outcome was incidence of influenza A diagnosed by a rapid influenza diagnostic test by medical doctors. Influenza A was equally likely in the vitamin D3 group (20/148: 13.5%) compared with the placebo group (12/99: 12.1%). By post hoc analysis, influenza A occurred significantly less in the vitamin D3 group (2/148: 1.4%) compared with the placebo group (8/99: 8.1%) (risk ratio, 0.17; 95% confidence interval, 0.04 to 0.77; P = 0.009) in the first month. However, during the second month, the vitamin D3 group experienced more events and effectively caught up with the placebo group. Vitamin D3 supplementation did not lower the overall incidence of influenza A during the 2009 H1N1 pandemic. A post hoc analysis suggests that the initial benefit during the first month of treatment was lost during the second month.

PMID 25088394
Loren C Denlinger, Tonya S King, Juan Carlos Cardet, Timothy Craig, Fernando Holguin, Daniel J Jackson, Monica Kraft, Stephen P Peters, Kristie Ross, Kaharu Sumino, Homer A Boushey, Nizar N Jarjour, Michael E Wechsler, Sally E Wenzel, Mario Castro, Pedro C Avila, NHLBI AsthmaNet Investigators
Vitamin D Supplementation and the Risk of Colds in Patients with Asthma.
Am J Respir Crit Care Med. 2016 Mar 15;193(6):634-41. doi: 10.1164/rccm.201506-1169OC.
Abstract/Text RATIONALE: Restoration of vitamin D sufficiency may reduce asthma exacerbations, events that are often associated with respiratory tract infections and cold symptoms.
OBJECTIVES: To determine whether vitamin D supplementation reduces cold symptom occurrence and severity in adults with mild to moderate asthma and vitamin D insufficiency.
METHODS: Colds were assessed in the AsthmaNet VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness) trial, in which 408 adult patients were randomized to receive placebo or cholecalciferol (100,000 IU load plus 4,000 IU/d) for 28 weeks as add-on therapy. The primary outcome was cold symptom severity, which was assessed using daily scores on the 21-item Wisconsin Upper Respiratory Symptom Survey.
MEASUREMENTS AND MAIN RESULTS: A total of 203 participants experienced at least one cold. Despite achieving 25-hydroxyvitamin D levels of 41.9 ng/ml (95% confidence interval [CI], 40.1-43.7 ng/ml) by 12 weeks, vitamin D supplementation had no effect on the primary outcome: the average peak WURSS-21 scores (62.0 [95% CI, 55.1-68.9; placebo] and 58.7 [95% CI, 52.4-65.0; vitamin D]; P = 0.39). The rate of colds did not differ between groups (rate ratio [RR], 1.2; 95% CI, 0.9-1.5); however, among African Americans, those receiving vitamin D versus placebo had an increased rate of colds (RR, 1.7; 95% CI, 1.1-2.7; P = 0.02). This was also observed in a responder analysis of all subjects achieving vitamin D sufficiency, regardless of treatment assignment (RR, 1.4; 95% CI, 1.1-1.7; P = 0.009).
CONCLUSIONS: Our findings in patients with mild to moderate asthma undergoing an inhaled corticosteroid dose reduction do not support the use of vitamin D supplementation for the purpose of reducing cold severity or frequency.

PMID 26540136
Mario Castro, Tonya S King, Susan J Kunselman, Michael D Cabana, Loren Denlinger, Fernando Holguin, Shamsah D Kazani, Wendy C Moore, James Moy, Christine A Sorkness, Pedro Avila, Leonard B Bacharier, Eugene Bleecker, Homer A Boushey, James Chmiel, Anne M Fitzpatrick, Deborah Gentile, Mandeep Hundal, Elliot Israel, Monica Kraft, Jerry A Krishnan, Craig LaForce, Stephen C Lazarus, Robert Lemanske, Njira Lugogo, Richard J Martin, David T Mauger, Edward Naureckas, Stephen P Peters, Wanda Phipatanakul, Loretta G Que, Ajay Sheshadri, Lewis Smith, Julian Solway, Lisa Sullivan-Vedder, Kaharu Sumino, Michael E Wechsler, Sally Wenzel, Steven R White, E Rand Sutherland, National Heart, Lung, and Blood Institute’s AsthmaNet
Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.
JAMA. 2014 May;311(20):2083-91. doi: 10.1001/jama.2014.5052.
Abstract/Text IMPORTANCE: In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency.
OBJECTIVE: To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels.
DESIGN, SETTING, AND PARTICIPANTS: The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized.
INTERVENTIONS: Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained.
MAIN OUTCOMES AND MEASURES: The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care).
RESULTS: Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]).
CONCLUSIONS AND RELEVANCE: Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01248065.

PMID 24838406
David A Jolliffe, Carlos A Camargo, John D Sluyter, Mary Aglipay, John F Aloia, Davaasambuu Ganmaa, Peter Bergman, Heike A Bischoff-Ferrari, Arturo Borzutzky, Camilla T Damsgaard, Gal Dubnov-Raz, Susanna Esposito, Clare Gilham, Adit A Ginde, Inbal Golan-Tripto, Emma C Goodall, Cameron C Grant, Christopher J Griffiths, Anna Maria Hibbs, Wim Janssens, Anuradha Vaman Khadilkar, Ilkka Laaksi, Margaret T Lee, Mark Loeb, Jonathon L Maguire, Paweł Majak, David T Mauger, Semira Manaseki-Holland, David R Murdoch, Akio Nakashima, Rachel E Neale, Hai Pham, Christine Rake, Judy R Rees, Jenni Rosendahl, Robert Scragg, Dheeraj Shah, Yoshiki Shimizu, Steve Simpson-Yap, Geeta Trilok-Kumar, Mitsuyoshi Urashima, Adrian R Martineau
Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials.
Lancet Diabetes Endocrinol. 2021 May;9(5):276-292. doi: 10.1016/S2213-8587(21)00051-6. Epub 2021 Mar 30.
Abstract/Text BACKGROUND: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis.
METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D3, vitamin D2, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units [IU] vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633.
FINDINGS: We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I2=35·6%, pheterogeneity=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65-0·94]; 19 studies; I2=53·5%, pheterogeneity=0·003), at daily dose equivalents of 400-1000 IU (0·70 [0·55-0·89]; ten studies; I2=31·2%, pheterogeneity=0·16), for a duration of 12 months or less (0·82 [0·72-0·93]; 29 studies; I2=38·1%, pheterogeneity=0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 [0·57-0·90]; 15 studies; I2=46·0%, pheterogeneity=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86-1·07]; 36 studies; I2=0·0%, pheterogeneity=0·99). Risk of bias within individual studies was assessed as being low for all but three trials.
INTERPRETATION: Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation.
FUNDING: None.

Copyright © 2021 Elsevier Ltd. All rights reserved.
PMID 33798465
Cynthia D Ang, Maria Jenelyn M Alviar, Antonio L Dans, Gwyneth Giselle P Bautista-Velez, Maria Vanessa C Villaruz-Sulit, Jennifer J Tan, Homer U Co, Maria Rhida M Bautista, Artemio A Roxas
Vitamin B for treating peripheral neuropathy.
Cochrane Database Syst Rev. 2008 Jul 16;(3):CD004573. doi: 10.1002/14651858.CD004573.pub3. Epub 2008 Jul 16.
Abstract/Text BACKGROUND: Vitamin B is frequently used for treating peripheral neuropathy but its efficacy is not clear.
OBJECTIVES: The objective of this review was to assess the effects of vitamin B for treating generalised peripheral neuropathy.
SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (searched August 2005), MEDLINE (January 1966 to September 2005), EMBASE (January 1980 to September 2005), Philippine databases (searched September 2005) and reference lists of articles. We also contacted manufacturers and researchers in the field.
SELECTION CRITERIA: Randomised and quasi-randomised trials where vitamin B was compared with placebo or another treatment in generalised peripheral neuropathy.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information.
MAIN RESULTS: Thirteen studies involving 741 participants with alcoholic or diabetic neuropathy were included. In the comparison of vitamin B with placebo, two small trials showed no significant short-term benefit in pain intensity while one of the trials showed a small significant benefit in vibration detection from oral benfotiamine, a derivative of thiamine. In the larger of two trials comparing different doses of vitamin B complex, there was some evidence that higher doses resulted in a significant short-term reduction in pain and improvement in paraesthesiae, in a composite outcome combining pain, temperature and vibration, and in a composite outcome combining pain, numbness and paraesthesiae. There was some evidence that vitamin B is less efficacious than alpha-lipoic acid, cilostazol or cytidine triphosphate in the short-term improvement of clinical and nerve conduction study outcomes but the trials were small. There were few minor adverse effects reported.
AUTHORS' CONCLUSIONS: There are only limited data in randomised trials testing the efficacy of vitamin B for treating peripheral neuropathy and the evidence is insufficient to determine whether vitamin B is beneficial or harmful. One small trial in alcoholic peripheral neuropathy reported slightly greater improvement in vibration perception threshold with oral benfotiamine for eight weeks than placebo. In another small study, a higher dose of oral vitamin B complex for four weeks was more efficacious than a lower dose in reducing symptoms and signs. Vitamin B administered by various routes for two to eight weeks was less efficacious than alpha-lipoic acid, cilostazol or cytidine triphosphate in short-term improvement of clinical and nerve conduction study outcomes. Vitamin B is generally well-tolerated.

PMID 18646107
Vivian A Fonseca, Lawrence A Lavery, Tina K Thethi, Yahya Daoud, Cyrus DeSouza, Fernando Ovalle, Douglas S Denham, Teodoro Bottiglieri, Peter Sheehan, Julio Rosenstock
Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial.
Am J Med. 2013 Feb;126(2):141-9. doi: 10.1016/j.amjmed.2012.06.022. Epub 2012 Dec 5.
Abstract/Text PURPOSE: To determine whether a combination of L-methylfolate, methylcobalamin, and pyridoxal-5'-phosphate (LMF-MC-PLP [Metanx; Pamlab LLC, Covington, La]) improves sensory neuropathy.
RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled trial involved 214 patients with type 2 diabetes and neuropathy (baseline vibration perception threshold [VPT]: 25-45 volts), who were randomly assigned to 24 weeks of treatment with either L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg or placebo. The primary end point was effect on VPT. Secondary end points included Neuropathy Total Symptom Score (NTSS-6) and Short Form 36 (SF-36), as well as plasma levels of folate, vitamins B(6) and B(12), methylmalonic acid (MMA), and homocysteine.
RESULTS: There was no significant effect on VPT. However, patients receiving LMF-MC-PLP consistently reported symptomatic relief, with clinically significant improvement in NTSS-6 scores at week 16 (P=.013 vs placebo) and week 24 (P=.033). Improvement in NTSS scores was related to baseline MMA and inversely related to baseline PLP and metformin use. Quality-of-life measures also improved. Homocysteine decreased by 2.7±3.0 μmol/L with LMF-MC-PLP versus an increase of 0.5±2.4 μmol/L with placebo (P=.0001). Adverse events were infrequent, with no single event occurring in ≥2% of subjects.
CONCLUSIONS: LMF-MC-PLP appears to be a safe and effective therapy for alleviation of peripheral neuropathy symptoms, at least in the short term. Additional long-term studies should be conducted, as the trial duration may have been too short to show an effect on VPT. In addition, further research on the effects in patients with cobalamin deficiency would be useful.

Copyright © 2013 Elsevier Inc. All rights reserved.
PMID 23218892
Bhavani Jayabalan, Lian Leng Low
Vitamin B supplementation for diabetic peripheral neuropathy.
Singapore Med J. 2016 Feb;57(2):55-9. doi: 10.11622/smedj.2016027.
Abstract/Text Vitamin B12 deficiency has been associated with significant neurological pathology, especially peripheral neuropathy. This review aims to examine the existing evidence on the effectiveness of vitamin B12 supplementation for the treatment of diabetic peripheral neuropathy. A search of PubMed and the Cochrane Central Register of Controlled Trials for all relevant randomised controlled trials was conducted in December 2014. Any type of therapy using vitamin B12 or its coenzyme forms was assessed for efficacy and safety in diabetics with peripheral neuropathy. Changes in vibration perception thresholds, neuropathic symptoms and nerve conduction velocities, as well as the adverse effects of vitamin B12 therapy, were assessed. Four studies comprising 363 patients met the inclusion criteria. This review found no evidence that the use of oral vitamin B12 supplements is associated with improvement in the clinical symptoms of diabetic neuropathy. Furthermore, the majority of studies reported no improvement in the electrophysiological markers of nerve conduction.

Copyright © Singapore Medical Association.
PMID 26892473
Stephanie Farah, Kaissar Yammine
A systematic review on the efficacy of vitamin B supplementation on diabetic peripheral neuropathy.
Nutr Rev. 2022 Apr 8;80(5):1340-1355. doi: 10.1093/nutrit/nuab116.
Abstract/Text CONTEXT: Diabetic peripheral neuropathy (DPN) is a common complication.
OBJECTIVE: To re-evaluate the role of vitamin B supplementation on reducing the signs and symptoms of DPN.
DATA SOURCES: Electronic databases such as PubMed, Cochrane Library, and Medline.
DATA EXTRACTION: An Excel spreadsheet was used to report the extracted relevant data.
DATA ANALYSIS: Fourteen randomized controlled trials were selected, comprising a pooled sample of 997 study subjects. The pooled odds ratio values were 3.1 (95%CI, 1.197-8.089) and 3.04 (95%CI, 1.556-5.937) for pain and dysesthesia outcomes, respectively. For the amplitude change in electromyography of the sensory sural nerve, the weighted difference from 2 studies was 0.37 (95%CI, 0.034-0.709) in favor of intervention. Peak latency changes were in favor of the intervention group. Two studies yielded a weighted difference of 0.571 (95%CI, 0.310-0.831) for the velocity outcome in favor of intervention. Unlike the fibular nerve, the electromyographic motor outcomes of the tibial nerve were in favor of vitamin B supplementation.
CONCLUSION: Vitamin B supplementation could improve many symptoms and signs of DPN.

© The Author(s) 2022. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PMID 34990506
Simone J Eussen, Lisette C de Groot, Liesbeth W Joosten, Rubia J Bloo, Robert Clarke, Per M Ueland, Jörn Schneede, Henk J Blom, Willibrord H Hoefnagels, Wija A van Staveren
Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial.
Am J Clin Nutr. 2006 Aug;84(2):361-70.
Abstract/Text BACKGROUND: Vitamin B-12 deficiency is associated with cognitive impairment in older people. However, evidence from randomized trials of the effects of vitamin B-12 supplementation on cognitive function is limited and inconclusive.
OBJECTIVE: The objective was to investigate whether daily supplementation with high doses of oral vitamin B-12 alone or in combination with folic acid has any beneficial effects on cognitive function in persons aged >/=70 y with mild vitamin B-12 deficiency.
DESIGN: In a double-blind, placebo-controlled trial, 195 subjects were randomly assigned to receive 1000 microg vitamin B-12, 1000 microg vitamin B-12 + 400 microg folic acid, or placebo for 24 wk. Vitamin B-12 status was assessed on the basis of methylmalonic acid, total homocysteine (tHcy), and holotranscobalamin (holoTC) concentrations before and after 12 and 24 wk of treatment. Cognitive function was assessed before and after 24 wk of treatment with the use of an extensive neuropsychologic test battery that included the domains of attention, construction, sensomotor speed, memory, and executive function.
RESULTS: Vitamin B-12 status did not change significantly after treatment in the placebo group; however, oral vitamin B-12 supplementation corrected mild vitamin B-12 deficiency. Vitamin B-12 + folic acid supplementation increased red blood cell folate concentrations and decreased tHcy concentrations by 36%. Improvement in memory function was greater in the placebo group than in the group who received vitamin B-12 alone (P = 0.0036). Neither supplementation with vitamin B-12 alone nor that in combination with folic acid was accompanied by any improvement in other cognitive domains.
CONCLUSION: Oral supplementation with vitamin B-12 alone or in combination with folic acid for 24 wk does not improve cognitive function.

PMID 16895884
Christopher H van Dyck, Jeffrey M Lyness, Robert M Rohrbaugh, Alan P Siegal
Cognitive and psychiatric effects of vitamin B12 replacement in dementia with low serum B12 levels: a nursing home study.
Int Psychogeriatr. 2009 Feb;21(1):138-47. doi: 10.1017/S1041610208007904. Epub 2008 Oct 17.
Abstract/Text BACKGROUND: The aim of this study is to determine whether B12 replacement would ameliorate cognitive and psychiatric symptoms in elderly subjects with dementia and low serum B12 levels.
METHODS: A test group (n = 28) of nursing home residents with low serum B12 levels (<250 pg/mL) and a matched comparison group (n = 28) with normal serum B12 levels (>300 pg/mL) were evaluated by blinded raters while the test group received intramuscular (IM) B12 replacement therapy. All subjects were assessed at baseline, 8 weeks, and 16 weeks with the Dementia Rating Scale, Brief Psychiatric Rating Scale, and Geriatric Depression Scale.
RESULTS: Although B12 replacement produced significant improvement in hematologic and metabolic parameters, it yielded no significant effect on cognitive or psychiatric variables. A few subjects evidenced notable individual treatment responses; however, these were not statistically more frequent than in the normal B12 group.
CONCLUSIONS: These results suggest that B12 replacement is unlikely to benefit cognitive or psychiatric symptoms in the vast majority of elderly dementia patients with low serum B12 levels.

PMID 18925978
Dong-Mei Zhang, Jian-Xin Ye, Jun-Shan Mu, Xiao-Ping Cui
Efficacy of Vitamin B Supplementation on Cognition in Elderly Patients With Cognitive-Related Diseases.
J Geriatr Psychiatry Neurol. 2017 Jan;30(1):50-59. doi: 10.1177/0891988716673466. Epub 2016 Oct 17.
Abstract/Text Increase in serum homocysteine is shown to be a potential risk factor for cognitive impairment. Evidence suggests that vitamin B supplementation may reduce cognitive decline by lowering the homocysteine levels. The current meta-analysis evaluated the efficacy of folic acid along with vitamin B12 and/or B6 in lowering homocysteine, thereby attenuating cognitive decline in elderly patients with Alzheimer disease or dementia. Randomized controlled trials (RCTs) comparing the efficacy of folate and B vitamin supplementation in patients with cognitive decline secondary to Alzheimer disease or dementia were identified using the keywords, "homocysteine, hyper-homocysteinemia, B vitamin, vitamin B6, B12, folic acid, cognitive, Alzheimer's disease, and dementia." The outcome measures analyzed were the Mini-Mental State Examination (MMSE) score and serum homocysteine. Of the 77 studies identified, 4 RCTs were included in the current meta-analysis. The baseline characteristics, age, and gender distribution of patients among the 2 groups (supplement vs placebo) were comparable. The results reveal that the intervention group achieved significantly greater reduction in homocysteine levels than the control (pooled difference in means = -3.625, 95% confidence interval [CI] = -5.642 to -1.608, P < .001). However, no significant difference in MMSE (pooled difference in means = 0.027, 95% CI = -0.518 to 0.573, P = 0.921) was observed between the groups. Taken together, vitamin B supplementation was effective in reducing serum homocysteine levels. However, it did not translate into cognitive improvement, indicating that the existing data on vitamin B-induced improvement in cognition by lowering homocysteine levels are conflicting.

PMID 28248558
Jenny McCleery, Rajesh P Abraham, David A Denton, Anne Ws Rutjes, Lee-Yee Chong, Aalya S Al-Assaf, Daniel J Griffith, Shireen Rafeeq, Hakan Yaman, Muzaffar A Malik, Marcello Di Nisio, Gabriel Martínez, Robin Wm Vernooij, Naji Tabet
Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment.
Cochrane Database Syst Rev. 2018 Nov 1;11:CD011905. doi: 10.1002/14651858.CD011905.pub2. Epub 2018 Nov 1.
Abstract/Text BACKGROUND: Vitamins and minerals have many functions in the nervous system which are important for brain health. It has been suggested that various different vitamin and mineral supplements might be useful in maintaining cognitive function and delaying the onset of dementia. In this review, we sought to examine the evidence for this in people who already had mild cognitive impairment (MCI).
OBJECTIVES: To evaluate the effects of vitamin and mineral supplementation on cognitive function and the incidence of dementia in people with mild cognitive impairment.
SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CENTRAL, CINAHL, LILACs, Web of Science Core Collection, ClinicalTrials.gov, and the WHO Portal/ICTRP, from inception to 25 January 2018.
SELECTION CRITERIA: We included randomised or quasi-randomised, placebo-controlled trials which evaluated orally administered vitamin or mineral supplements in participants with a diagnosis of mild cognitive impairment and which assessed the incidence of dementia or cognitive outcomes, or both. We were interested in studies applicable to the general population of older people and therefore excluded studies in which participants had severe vitamin or mineral deficiencies.
DATA COLLECTION AND ANALYSIS: We sought data on our primary outcomes of dementia incidence and overall cognitive function and on secondary outcomes of episodic memory, executive function, speed of processing, quality of life, functional performance, clinical global impression, adverse events, and mortality. We conducted data collection and analysis according to standard Cochrane systematic review methods. We assessed the risk of bias of included studies using the Cochrane 'Risk of bias' assessment tool. We grouped vitamins and minerals according to their putative mechanism of action and, where we considered it to be clinically appropriate, we pooled data using random-effects methods. We used GRADE methods to assess the overall quality of evidence for each comparison and outcome.
MAIN RESULTS: We included five trials with 879 participants which investigated B vitamin supplements. In four trials, the intervention was a combination of vitamins B6, B12, and folic acid; in one, it was folic acid only. Doses varied. We considered there to be some risks of performance and attrition bias and of selective outcome reporting among these trials. Our primary efficacy outcomes were the incidence of dementia and scores on measures of overall cognitive function. None of the trials reported the incidence of dementia and the evidence on overall cognitive function was of very low-quality. There was probably little or no effect of B vitamins taken for six to 24 months on episodic memory, executive function, speed of processing, or quality of life. The evidence on our other secondary clinical outcomes, including harms, was very sparse or very low-quality. There was evidence from one study that there may be a slower rate of brain atrophy over two years in participants taking B vitamins. The same study reported subgroup analyses based on the level of serum homocysteine (tHcy) at baseline and found evidence that B vitamins may improve episodic memory in those with tHcy above the median at baseline.We included one trial (n = 516) of vitamin E supplementation. Vitamin E was given as 1000 IU of alpha-tocopherol twice daily. We considered this trial to be at risk of attrition and selective reporting bias. There was probably no effect of vitamin E on the probability of progression from MCI to Alzheimer's dementia over three years (HR 1.02; 95% CI 0.74 to 1.41; n = 516; 1 study, moderate-quality evidence). There was also no evidence of an effect at intermediate time points. The available data did not allow us to conduct analyses, but the authors reported no significant effect of three years of supplementation with vitamin E on overall cognitive function, episodic memory, speed of processing, clinical global impression, functional performance, adverse events, or mortality (five deaths in each group). We considered this to be low-quality evidence.We included one trial (n = 256) of combined vitamin E and vitamin C supplementation and one trial (n = 26) of supplementation with chromium picolinate. In both cases, there was a single eligible cognitive outcome, but we considered the evidence to be very low-quality and so could not be sure of any effects.
AUTHORS' CONCLUSIONS: The evidence on vitamin and mineral supplements as treatments for MCI is very limited. Three years of treatment with high-dose vitamin E probably does not reduce the risk of progression to dementia, but we have no data on this outcome for other supplements. Only B vitamins have been assessed in more than one RCT. There is no evidence for beneficial effects on cognition of supplementation with B vitamins for six to 24 months. Evidence from a single study of a reduced rate of brain atrophy in participants taking vitamin B and a beneficial effect of vitamin B on episodic memory in those with higher tHcy at baseline warrants attempted replication.

PMID 30383288
Andrew H Ford, Osvaldo P Almeida
Effect of Vitamin B Supplementation on Cognitive Function in the Elderly: A Systematic Review and Meta-Analysis.
Drugs Aging. 2019 May;36(5):419-434. doi: 10.1007/s40266-019-00649-w.
Abstract/Text BACKGROUND: Vitamin B deficiency and elevated total plasma homocysteine have been associated with cognitive impairment and dementia in later life, although it is unknown if treatment with these vitamins improves cognitive outcomes.
OBJECTIVES: The objectives of this study were to examine the efficacy of treatment with vitamin B12, vitamin B6, or folic acid in slowing cognitive decline amongst older adults with and without cognitive impairment.
METHODS: We summarized findings from previous systematic reviews of clinical trials and performed a new systematic review and meta-analysis of 31 English-language, randomized placebo-controlled trials of B-vitamin supplementation of individuals with and without existing cognitive impairment.
RESULTS: Previous reviews have generally reported no effect of B vitamins on cognitive function in older adults with or without cognitive impairment at study entry, although these vitamins effectively lowered total plasma homocysteine levels in participants. Ten randomized placebo-controlled trials of 1925 participants with pre-existing cognitive impairment and 21 trials of 15,104 participants without cognitive impairment have been completed to date but these generally confirmed findings from previous reviews with the exception of two trials that showed a modest but clinically uncertain benefit for vitamins in people with elevated plasma homocysteine. B-vitamin supplementation did not show an improvement in Mini-Mental State Examination scores for individuals with (mean difference 0.16, 95% confidence interval - 0.18 to 0.51) and without (mean difference 0.04, 95% confidence interval - 0.10 to 0.18) cognitive impairment compared to placebo.
CONCLUSIONS: Raised total plasma homocysteine is associated with an increased risk of cognitive impairment and dementia, although available evidence from randomized controlled trials shows no obvious cognitive benefit of lowering homocysteine using B vitamins. Existing trials vary greatly in the type of supplementation, population sampled, study quality, and duration of treatment, thereby making it difficult to draw firm conclusions from existing data. Findings should therefore be viewed in the context of the limitations of the available data and the lack of evidence of effect should not necessarily be interpreted as evidence of no effect.

PMID 30949983
Jasleen K Duggal, Mukesh Singh, Navneet Attri, Param P Singh, Neyaz Ahmed, Suneet Pahwa, Janos Molnar, Sarabjeet Singh, Sandeep Khosla, Rohit Arora
Effect of niacin therapy on cardiovascular outcomes in patients with coronary artery disease.
J Cardiovasc Pharmacol Ther. 2010 Jun;15(2):158-66. doi: 10.1177/1074248410361337. Epub 2010 Mar 5.
Abstract/Text BACKGROUND: Niacin or nicotinic acid (vitamin B3) raises the levels of high-density lipoprotein cholesterol (HDL) by about 30% to 35%. In patients with prior coronary disease, 7 trials have been published on clinical cardiovascular disease outcomes and the results, not surprisingly, are inconsistent. Hence, we performed this meta-analysis of randomized placebo-controlled trials (RCTs) to evaluate the effect of niacin on cardiovascular outcomes in patients with coronary artery disease.
METHODS: A systematic search using PubMed, EMBASE, and Cochrane library databases was performed. Seven studies with a total of 5137 patients met our inclusion criteria. Heterogeneity of the studies was analyzed by the Cochran Q statistics. The significance of common treatment effect was assessed by computing the combined relative risks using the Mantel-Haenszel fixed-effect model. A 2-sided alpha error of less than .05 was considered statistically significant (P < .05).
RESULTS: Compared to placebo group, niacin therapy significantly reduced coronary artery revascularization (RR [relative risk]: 0.307 with 95% CI: 0.150-0.628; P = .001), nonfatal myocardial infarction ([MI]; RR: 0.719; 95% CI: 0.603-0.856; P = .000), stroke, and TIA ([transient ischemic attack] RR: 0.759; 95%CI: 0.613-0.940; P = .012), as well as a possible but nonsignificant decrease in cardiac mortality (RR: 0.883: 95% CI: 0.773-1.008; p= 0.066).
CONCLUSIONS: In a meta-analysis of seven trials of secondary prevention, niacin was associated with a significant reduction in cardiovascular events and possible small but non-significant decreases in coronary and cardiovascular mortality.

PMID 20208032
Abstract/Text OBJECTIVE: To investigate the effects on cardiovascular outcomes of drug interventions that increase high density lipoprotein levels.
DESIGN: Meta-analysis.
STUDIES REVIEWED: Therapeutic benefit of niacin, fibrates, and cholesteryl ester transfer protein (CETP) inhibitors on cardiovascular events (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarction, and stroke).
RESULTS: 117,411 patients were randomised in a total of 39 trials. All interventions increased the levels of high density lipoprotein cholesterol. No significant effect was seen on all cause mortality for niacin (odds ratio 1.03, 95% confidence interval 0.92 to 1.15, P=0.59), fibrates (0.98, 0.89 to 1.08, P=0.66), or CETP inhibitors (1.16, 0.93 to 1.44, P=0.19); on coronary heart disease mortality for niacin (0.93, 0.76 to 1.12, P=0.44), fibrates (0.92, 0.81 to 1.04, P=0.19), or CETP inhibitors (1.00, 0.80 to 1.24, P=0.99); or on stroke outcomes for niacin (0.96, 0.75 to 1.22, P=0.72), fibrates (1.01, 0.90 to 1.13, P=0.84), or CETP inhibitors (1.14, 0.90 to 1.45, P=0.29). In studies with patients not receiving statins (before the statin era), niacin was associated with a significant reduction in non-fatal myocardial infarction (0.69, 0.56 to 0.85, P=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect (0.96, 0.85 to 1.09, P=0.52). A significant difference was seen between these subgroups (P=0.007). A similar trend relating to non-fatal myocardial infarction was seen with fibrates: without statin treatment (0.78, 0.71 to 0.86, P<0.001) and with all or some patients taking statins (0.83, 0.69 to 1.01, P=0.07); P=0.58 for difference.
CONCLUSIONS: Neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.

© Keene et al 2014.
PMID 25038074
Stefan Schandelmaier, Matthias Briel, Ramon Saccilotto, Kelechi K Olu, Armon Arpagaus, Lars G Hemkens, Alain J Nordmann
Niacin for primary and secondary prevention of cardiovascular events.
Cochrane Database Syst Rev. 2017 Jun 14;6:CD009744. doi: 10.1002/14651858.CD009744.pub2. Epub 2017 Jun 14.
Abstract/Text BACKGROUND: Nicotinic acid (niacin) is known to decrease LDL-cholesterol, and triglycerides, and increase HDL-cholesterol levels. The evidence of benefits with niacin monotherapy or add-on to statin-based therapy is controversial.
OBJECTIVES: To assess the effectiveness of niacin therapy versus placebo, administered as monotherapy or add-on to statin-based therapy in people with or at risk of cardiovascular disease (CVD) in terms of mortality, CVD events, and side effects.
SEARCH METHODS: Two reviewers independently and in duplicate screened records and potentially eligible full texts identified through electronic searches of CENTRAL, MEDLINE, Embase, Web of Science, two trial registries, and reference lists of relevant articles (latest search in August 2016).
SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that either compared niacin monotherapy to placebo/usual care or niacin in combination with other component versus other component alone. We considered RCTs that administered niacin for at least six months, reported a clinical outcome, and included adults with or without established CVD.
DATA COLLECTION AND ANALYSIS: Two reviewers used pre-piloted forms to independently and in duplicate extract trials characteristics, risk of bias items, and outcomes data. Disagreements were resolved by consensus or third party arbitration. We conducted random-effects meta-analyses, sensitivity analyses based on risk of bias and different assumptions for missing data, and used meta-regression analyses to investigate potential relationships between treatment effects and duration of treatment, proportion of participants with established coronary heart disease and proportion of participants receiving background statin therapy. We used GRADE to assess the quality of evidence.
MAIN RESULTS: We included 23 RCTs that were published between 1968 and 2015 and included 39,195 participants in total. The mean age ranged from 33 to 71 years. The median duration of treatment was 11.5 months, and the median dose of niacin was 2 g/day. The proportion of participants with prior myocardial infarction ranged from 0% (4 trials) to 100% (2 trials, median proportion 48%); the proportion of participants taking statin ranged from 0% (4 trials) to 100% (12 trials, median proportion 100%).Using available cases, niacin did not reduce overall mortality (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.97 to 1.12; participants = 35,543; studies = 12; I(2) = 0%; high-quality evidence), cardiovascular mortality (RR 1.02, 95% CI 0.93 to 1.12; participants = 32,966; studies = 5; I(2) = 0%; moderate-quality evidence), non-cardiovascular mortality (RR 1.12, 95% CI 0.98 to 1.28; participants = 32,966; studies = 5; I(2) = 0%; high-quality evidence), the number of fatal or non-fatal myocardial infarctions (RR 0.93, 95% CI 0.87 to 1.00; participants = 34,829; studies = 9; I(2) = 0%; moderate-quality evidence), nor the number of fatal or non-fatal strokes (RR 0.95, 95% CI 0.74 to 1.22; participants = 33,661; studies = 7; I(2) = 42%; low-quality evidence). Participants randomised to niacin were more likely to discontinue treatment due to side effects than participants randomised to control group (RR 2.17, 95% CI 1.70 to 2.77; participants = 33,539; studies = 17; I(2) = 77%; moderate-quality evidence). The results were robust to sensitivity analyses using different assumptions for missing data.
AUTHORS' CONCLUSIONS: Moderate- to high-quality evidence suggests that niacin does not reduce mortality, cardiovascular mortality, non-cardiovascular mortality, the number of fatal or non-fatal myocardial infarctions, nor the number of fatal or non-fatal strokes but is associated with side effects. Benefits from niacin therapy in the prevention of cardiovascular disease events are unlikely.

PMID 28616955
Aakash Garg, Abhishek Sharma, Parasuram Krishnamoorthy, Jalaj Garg, Deepti Virmani, Toishi Sharma, Giulio Stefanini, John B Kostis, Debabrata Mukherjee, Ekaterina Sikorskaya
Role of Niacin in Current Clinical Practice: A Systematic Review.
Am J Med. 2017 Feb;130(2):173-187. doi: 10.1016/j.amjmed.2016.07.038. Epub 2016 Oct 26.
Abstract/Text BACKGROUND: Niacin, a potent high-density lipoprotein cholesterol-raising drug, seems an attractive approach to reduce cardiac events in patients with or at risk of atherosclerotic cardiovascular disease. However, previous evidence for niacin has been challenged recently by negative outcomes in 2 large, randomized, controlled trials comparing niacin to placebo with background statin therapy. We studied the currently available evidence for the role of niacin treatment for reducing the risk of cardiovascular events in current practice.
METHODS: A systematic review of randomized controlled trials in the MEDLINE, EMBASE, CINAHL, and Cochrane databases comparing niacin alone or combined with statin therapy was performed. We extracted trial level data, including basic characteristics and number of patients enrolled, duration of follow up, occurrence of adverse events, and cardiovascular-related outcomes. Random effects meta-analysis was conducted to estimate the risk ratio (RR) for individual trial endpoints.
RESULTS: Thirteen trials (N = 35,206) were selected for final analysis. The mean follow-up duration was 32.8 months. Overall, niacin led to significant increases in serum high-density lipoprotein cholesterol levels from baseline trial enrolment by 21.4%, 9.31 (95% confidence interval [CI] 5.11-13.51) mg/dL. However, we did not observe any differences in all-cause mortality rates (RR 0.99; 95% CI 0.88-1.12) between niacin and control arms. Further, niacin treatment was associated with a trend toward lower risk of cardiovascular mortality (RR 0.91; 95% CI 0.81-1.02), coronary death (RR 0.93; 95% CI 0.78-1.10), nonfatal myocardial infarction (RR 0.85; 95% CI 0.73-1.0), revascularization (coronary and noncoronary) (RR 0.83; 95% CI 0.65-1.06), and stroke (RR 0.89; 95% CI 0.72-1.10), compared with control.
CONCLUSION: Niacin therapy does not lead to significant reductions in total or cause-specific mortality or recurrent cardiovascular events among persons with or at risk of atherosclerotic cardiovascular disease.

Copyright © 2016 Elsevier Inc. All rights reserved.
PMID 27793642
Scott M Grundy, Neil J Stone, Alison L Bailey, Craig Beam, Kim K Birtcher, Roger S Blumenthal, Lynne T Braun, Sarah de Ferranti, Joseph Faiella-Tommasino, Daniel E Forman, Ronald Goldberg, Paul A Heidenreich, Mark A Hlatky, Daniel W Jones, Donald Lloyd-Jones, Nuria Lopez-Pajares, Chiadi E Ndumele, Carl E Orringer, Carmen A Peralta, Joseph J Saseen, Sidney C Smith, Laurence Sperling, Salim S Virani, Joseph Yeboah
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
J Am Coll Cardiol. 2019 Jun 25;73(24):e285-e350. doi: 10.1016/j.jacc.2018.11.003. Epub 2018 Nov 10.
Abstract/Text
PMID 30423393

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