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Meta-Analysis
. 2024 Sep 27;9(9):CD013284.
doi: 10.1002/14651858.CD013284.pub2.

Vitamin D for the management of chronic obstructive pulmonary disease

Anne Williamson  1 , Adrian R Martineau  1   2 , David Jolliffe  1 , Aziz Sheikh  3 , Wim Janssens  4 , John Sluyter  5 , Rachida Rafiq  6 , Renate de Jongh  7   8 , Chris J Griffiths  9
Affiliations
Meta-Analysis

Vitamin D for the management of chronic obstructive pulmonary disease

Anne Williamson et al. Cochrane Database Syst Rev. .

Abstract

Background: COPD is a common, preventable and treatable airway disease, and is currently the third leading cause of death worldwide. About one billion people worldwide are estimated to have vitamin D deficiency or insufficiency. Vitamin D deficiency is common among people with COPD, and has been reported to be associated with reduced lung function and increased risk of acute exacerbations of COPD. Several clinical trials of vitamin D to prevent acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and improve COPD control have been conducted, but an up-to-date meta-analysis of all double-blind, randomised, placebo-controlled trials of this intervention is lacking.

Objectives: To assess the effects of vitamin D for the management of acute exacerbations and symptoms for people with COPD.

Search methods: We searched the Cochrane Airways Trials Register and reference lists of articles. We also searched trial registries directly, and contacted the authors of studies in order to identify additional trials. The date of the last search was 24 August 2022.

Selection criteria: We included double-blind, randomised, placebo-controlled trials of vitamin D or its hydroxylated metabolites, for adults with a clinical diagnosis of chronic obstructive pulmonary disease based on the presence of characteristic symptoms and irreversible airflow obstruction. We did not impose restrictions regarding disease severity or baseline vitamin D status, in order to maximise generalisability.

Data collection and analysis: We used standard Cochrane methods. The primary outcome was the rate of moderate or severe exacerbations (requiring systemic corticosteroids, antibiotics or both). We also performed subgroup analyses to determine whether the effect of vitamin D on the rate of moderate or severe exacerbations was modified by baseline vitamin D status, COPD severity or regular inhaled corticosteroid use. The main secondary outcomes of interest were the proportion of participants experiencing one or more exacerbations (moderate or severe), the change in forced expiratory volume in one second (FEV1, % predicted) and the proportion of participants with one or more serious adverse events of any cause, mortality (all-cause) and quality of life. We used GRADE to assess the certainty of evidence for each outcome.

Main results: We included 10 double-blind, randomised, placebo-controlled trials in this review, involving a total of 1372 adults. Five studies contributed to the primary outcome analysis of the rate of moderate or severe exacerbations requiring systemic corticosteroids, antibiotics or both. The duration of studies ranged from six weeks to 40 months, and all investigated the effects of administering cholecalciferol (vitamin D3). One study included two intervention arms, one where vitamin D3 was given and one where calcitriol (1,25-dihydroxyvitamin D) was given. The majority of participants had mild to moderate COPD, and profound vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25 nmol/L) at baseline was rare (123 participants contributing data to subgroup analysis). Administration of vitamin D or its hydroxylated metabolites results in little to no change in the overall rate of exacerbations requiring systemic corticosteroids, antibiotics or both (rate ratio (RR) 0.98, 95% CI 0.86 to 1.11; 5 studies, 980 participants; high-certainty evidence). Vitamin D supplementation did not influence any meta-analysed secondary outcomes. These were all based on moderate- or high-certainty evidence aside from adverse events and quality of life, which were based on low-certainty evidence. We observed little to no change in the proportion of participants experiencing one or more moderate or severe exacerbations (odds ratio (OR) 0.94, 95% CI 0.72 to 1.24; 5 studies, 980 participants; high-certainty evidence). Additionally, vitamin D probably results in little to no difference in the inter-arm mean change in FEV1 (% predicted) (mean difference 2.82 higher in intervention arm, 95% CI -2.42 to 8.06; 7 studies, 1063 participants; moderate-certainty evidence). There was also probably no effect of vitamin D on the incidence of serious adverse events due to any cause; although we identified an anticipated absolute effect of 36 additional adverse events per 1000 people, the confidence interval included the null hypothesis of no effect (OR 1.19, 95% CI 0.82 to 1.71; 5 studies, 663 participants; moderate-certainty evidence). Vitamin D may have little to no effect on mortality (OR 1.13, 95% CI 0.57 to 2.21; 6 studies, 1019 participants; low-certainty evidence). It also may have little to no effect on quality of life as measured by validated instruments (narrative findings; 5 studies, 663 participants; low-certainty evidence). We assessed one study as being at high risk of bias in at least one domain; this did not contribute data to the meta-analysis of the primary outcome reported above. Sensitivity analysis that excluded this study from the meta-analysed outcome to which it contributed, the inter-arm mean change in FEV1, did not change the findings.

Authors' conclusions: We found that administration of vitamin D results in little to no effect on the rate of moderate or severe exacerbations requiring systemic corticosteroids, antibiotics or both or the proportion of participants experiencing one or more exacerbations (moderate or severe) (both high-certainty evidence). Further, vitamin D probably has no effect on the inter-arm difference in change in lung volumes and the proportion of participants with one or more serious adverse event of any cause (both moderate-certainty evidence), and may make little to no difference to mortality or quality of life (both low-certainty evidence). We recommend further research on the balance of benefits and harms of vitamin D supplements in COPD for those with very low or very high starting vitamin D levels, because we assessed the available evidence as low-certainty for these groups.

Trial registration: ClinicalTrials.gov NCT03679325 NCT03781895.

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Conflict of interest statement

AW: works as a junior doctor at Guy's and St Thomas' Foundation Trust.

ARM declares speaker fees from Linus Pauling Institute (personal payment); consulting fees from DSM Nutritional Products (personal payment); grants from Cytoplan, DSM Nutritional Products Ltd, Hyphens Pharma Ltd, Pharma Nord Ltd, Synergy Biologics and Thornton & Ross Ltd (all paid to institution); and travel expenses from Abiogen Pharma Ltd and Pharma Nord Ltd (both paid to institution). ARM also declares participation on the Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, NCT01784029), London School of Hygiene and Tropical Medicine, and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID‐19 Patients in India (NCT04641195), Harvard School of Public Health (both paid to institution). ARM also declares unpaid work as a Programme Committee member for the Vitamin D Workshop. ARM declares that he has given opinions on the topic in multiple interviews in printed and broadcast media. Lastly, ARM declares being involved in two studies eligible for inclusion in the review. The first, Martineau 2015, was funded by NIHR and sponsored by Queen Mary University of London*. This study was assessed by AW and JS for eligibility, data extraction and risk of bias, and by AW and AS for certainty of evidence**. The second, Camargo 2021, was funded by the Health Research Council of New Zealand* and assessed by AW and CJG for inclusion, data extraction and risk of bias, and by AW and AS for certainty of evidence**.

DJ: investigator on a study included in the review (Martineau 2015); the study was funded by the NIHR and sponsored by Queen Mary University of London*. This study was assessed by AW and JS for eligibility, data extraction and risk of bias, and by AW and AS for certainty of evidence**.

AS: works as a Consultant in Paediatric Allergy.

WJ works as a health professional at KU Leuven. WJ declares having received grants, consultancy fees and payments for advisory board activities from Astra Zeneca, Chiesi and Boehringer Ingelheim (none of whom manufacture or distribute vitamin D), all paid to his institution (KU Leuven). WJ declares that he was involved in a study eligible for inclusion in the review (Lehouck 2012); the study was funded by FWO Vlaanderen*, paid to KU Leuven. This study was assessed by AW and ARM for inclusion, data extraction, risk of bias and certainty of evidence**.

JS: declares that he was involved in the analysis and publication of the ViDA study (Camargo 2021), which is included in the review; the study was funded by the Health Research Council of New Zealand*. This study was assessed by AW and CJS for inclusion, data extraction, risk of bias and certainty of evidence**.

RR: declares that she was involved in the Rafiq 2017 study included in the review, which had no specific funding sources. She was also involved in the Rafiq 2022 study included in the review; this study was funded by a grant from the Lung Foundation, Netherlands (project number 5.1.13.033) and an unrestricted grant from Almirall (who do not manufacture vitamin D)*. These two studies were assessed by AW and ARM for inclusion, data extraction, risk of bias and certainty of evidence**.

RdJ: declares speaker fees from Amgen (personal payment) and a grant from Takeda Pharmaceutical Company (paid to institution; however, she has control over the funds) for a pharmacy‐initiated study (SHP634‐401) on which she is principal investigator; neither of these companies manufacture or distribute vitamin D. RdJ also declares writing assistance from Faes Farma SA, who produce calcifediol (paid to institution). Further, RdJ declares that she was the principal investigator on two RCTs included in this Cochrane review. The first, Rafiq 2017, had no specific funding sources. The second, Rafiq 2022, was funded by a grant from the Lung Foundation, Netherlands (project number 5113033) and an unrestricted grant from Almirall (who do not manufacture vitamin D)*. These two studies were assessed by AW and ARM for inclusion, data extraction, risk of bias and certainty of evidence**.

CJG: is supported by the National Institute for Health Research ARC North Thames; the views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. CJG is a collaborator on the Genes & Health study, which is funded by Alnylam Pharmaceuticals, Genomics PLC; and a Life Sciences Industry Consortium of AstraZeneca, Bristol‐Myers Squibb, GlaxoSmithKline, Maze Therapeutics, Merck Sharp and Dohme, Novo Nordisk, Pfizer and Takeda Development Center Americas Inc (none of whom produce or distribute vitamin D or cholecalciferol), all paid to institution. CJG received funds to enable his institution to host an academic conference on the clinical aspects of vitamin D. CJG declares that he was a trialist on a study eligible for inclusion in the review (Martineau 2015); the study was funded by NIHR*. This study was assessed by AW and JS for eligibility, data extraction and risk of bias, and by AW and AS for certainty of evidence**.

*For each study with declared funders, the funders played no role in the design, conduct or publication of the research.

**To minimise the risk of bias, authors who were investigators on any study to be included in the review were not involved in the decision about eligibility, nor did they extract data, or assess the risk of bias for that study or GRADE the overall certainty of outcomes to which the study contributed. These tasks were performed by two independent review authors.

Figures

1
1
PRISMA Study Flow Diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 1: Rate of moderate or severe exacerbations
1.2
1.2. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 2: Rate of moderate or severe exacerbations (stratified by baseline 25(OH)D)
1.3
1.3. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 3: Rate of moderate or severe exacerbations (stratified by baseline FEV1, % predicted)
1.4
1.4. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 4: Rate of moderate or severe exacerbations (stratified by baseline corticosteroid use)
1.5
1.5. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 5: Proportion of participants experiencing one or more exacerbations (moderate or severe)
1.6
1.6. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 6: Time to first exacerbation
1.7
1.7. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 7: Rate of severe exacerbation, requiring ED attendance or hospitalisation
1.8
1.8. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 8: Rate of moderate exacerbation
1.9
1.9. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 9: Incidence of study defined exacerbation
1.10
1.10. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 10: Inter‐arm difference in mean change in FEV1 (% predicted)
1.11
1.11. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 11: Inter‐arm difference in mean change in FVC (% predicted)
1.12
1.12. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 12: Proportion of participants with one or more serious adverse event of any cause
1.13
1.13. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 13: Mortality (all‐cause)
1.14
1.14. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 14: Mortality (all‐cause), risk difference
1.15
1.15. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 15: Mortality (respiratory)
1.16
1.16. Analysis
Comparison 1: Vitamin D versus placebo, Outcome 16: Mortality (respiratory), risk difference
2.1
2.1. Analysis
Comparison 2: Sensitivity analyses, Outcome 1: Inter‐arm difference in mean change in FEV1 (% predicted), excluding studies at high risk of bias
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013284

References

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