Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies

Abstract

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.

Fig 1 Association of circulating 25-hydroxyvitamin D concentrations with cause specific mortality in observational cohort studies. *Pooled estimates are based on random effects meta-analysis. Using fixed effects models, for primary prevention cohorts, secondary prevention cohorts, and all cohorts, the estimates were 1.40 (1.32 to 1.47), 1.50 (1.35 to 1.66), and 1.42 (1.35 to 1.49) for cardiovascular deaths; 1.10 (1.02 to 1.17), 1.45 (1.28 to 1.65), and 1.16 (1.10 to 1.24) for cancer deaths; 1.28 (1.12 to 1.47), 1.38 (1.09 to 1.75), and 1.30 (1.16 to 1.47) for non-vascular, non-cancer deaths; and 1.45 (1.41 to 1.49), 1.49 (1.42 to 1.56), and 1.44 (1.40 to 1.47) for all cause deaths. Size of data marker is proportional to inverse of variance of relative risk; horizontal line represents 95% CI. Corresponding forest plots and I² (95% CI) estimates are provided in supplementary material

Fig 2 Association of circulating 25-hydroxyvitamin D concentrations with all cause mortality, based on primary prevention cohorts. *Indirect comparisons based on available studies with relevant information in each category; summary estimates presented were calculated using random effects models. Using fixed effects models, the estimates were 1.09 (1.06 to 1.11) for clinical cut-off of 21-29 v ≥30, 1.20 (1.15 to 1.26) for 10-20 v ≥30, 1.23 (1.20 to 1.26) for <10 v ≥30, and 1.19 (1.18 to 1.21) per 10 ng/mL decrease

Fig 3 Association of circulating 25-hydroxyvitamin D concentration and risk of cardiovascular disease mortality in primary prevention cohorts, according to various characteristics. Based on available studies with relevant subgroup information. CPBA=competitive binding protein assay; +=relative risks adjusted for established cardiovascular risk factors such as age, sex, smoking status, lipids, hypertension, history of cardiometabolic disease; ++=adjusted for other potential risk factors such as physical activity, body mass index, social status; +++=adjusted for other additional variables such as bone minerals. *P<0.05 from meta-regression analyses. †Based on available studies with relevant subgroup information. ‡Based on Newcastle-Ottawa scale.

Fig 4 Association of circulating 25-hydroxyvitamin D concentration and risk of cancer mortality in primary prevention cohorts, according to various characteristics. Based on available studies with relevant subgroup information. CPBA=competitive binding protein assay; +=relative risks adjusted for established cardiovascular risk factors such as age, sex, smoking status, lipids, hypertension, history of cardiometabolic disease; ++=adjusted for other potential risk factors such as physical activity, body mass index, social status; +++=adjusted for other additional variables such as bone minerals. *P<0.05 from meta-regression analyses. †Based on available studies with relevant subgroup information. ‡Based on Newcastle-Ottawa scale.

Fig 5 Association of circulating 25-hydroxyvitamin D concentration and risk of all cause mortality in primary prevention cohorts, according to various characteristics. Based on available studies with relevant subgroup information. CPBA=competitive binding protein assay; +=relative risks adjusted for established cardiovascular risk factors such as age, sex, smoking status, lipids, hypertension, history of cardiometabolic disease; ++=adjusted for other potential risk factors such as physical activity, body mass index, social status; +++=adjusted for other additional variables such as bone minerals. *P<0.05 from meta-regression analyses. †Based on available studies with relevant subgroup information. ‡Based on Newcastle-Ottawa scale.

Fig 6 Effects of vitamin D supplementation on all cause mortality when given alone, derived from available randomised control trials. *Pooled estimates are based on random effects meta-analysis. Using fixed effects models, for community dwelling, hospital based, and overall population, the estimates were 0.91 (0.81 to 1.01), 0.88 (0.77 to 1.01), and 0.90 (0.82 to 0.98) for vitamin D₃ trials and 1.05 (0.94 to 1.17), 1.15 (0.63 to 2.11), and 1.03 (0.97 to 1.09) for vitamin D₂ trials. Overall fixed effect estimate for all trials was 0.98 (0.94 to 1.03). Size of data marker is proportional to inverse of variance of relative risk; horizontal line represents 95% CI. Corresponding forest plots and I² (95% CI) estimates are provided in supplementary material

Fig 7 Effects of vitamin D supplementation on all cause mortality, derived from available randomised controlled trials and according to various characteristics. Based on available studies with relevant subgroup information; P values are from meta-regression analyses. *Low risk and high risk categories are defined by studies that met ≥5 criteria versus those that met <5 criteria in Cochrane Collaboration’s tool, respectively