Vitamin D and Death From Vascular and Non-vascular Causes
Vitamin D and Death From Vascular and Non-vascular Causes
Aims To examine the independent relevance of plasma concentrations of 25-hydroxyvitamin D [25(OH)D] for vascular and non-vascular mortality.
Methods and results We examined associations of plasma concentrations of 25(OH)D and cause-specific mortality in a prospective study of older men living in the UK and included findings in meta-analyses of similar studies identified by a systematic search reporting on vascular and all-cause mortality. In a 13-year follow-up of 5409 men (mean baseline age 77 years), 1358 died from vascular and 1857 from non-vascular causes. Median season-adjusted baseline 25(OH)D concentration was 56 (interquartile range: 45–67) nmol/L. After adjustment for age and seasonality, higher concentrations of 25(OH)D were inversely and approximately linearly (log–log scale) associated with vascular and non-vascular mortality throughout the range 40–90 nmol/L. After additional adjustment for prior disease and cardiovascular risk factors, a doubling in 25(OH)D concentration was associated with 20% [95% confidence interval (CI): 9–30%] lower vascular and 23% (95% CI: 14–31%) lower non-vascular mortality. In meta-analyses of prospective studies, individuals in the top vs. bottom quarter of 25(OH)D concentrations had 21% (95% CI: 13–28%) lower vascular and 28% (95% CI: 24–32%) lower all-cause mortality.
Conclusions Despite strong inverse and apparently independent associations of 25(OH)D with vascular and non-vascular mortality, causality remains uncertain. Large-scale randomized trials, using high doses of vitamin D, are required to assess the clinical relevance of these associations.
Prospective observational studies have reported that low circulating concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with higher risks of cardiovascular disease, cancer, and all-cause mortality. However, as low 25(OH)D concentrations are correlated with several known vascular risk factors, it is possible that any such associations with disease may reflect confounding by these risk factors. Alternatively, these associations with 25(OH)D may be due to reverse causation, as individuals with vascular disease or cancer, who may be frail or unwell, may be more likely to stay indoors, and have low plasma 25(OH)D concentrations due to inadequate sunlight exposure. Previous meta-analyses of prospective studies reported a significant inverse association of 25(OH)D with all-cause mortality, but did not distinguish vascular from non-vascular causes of death.
The relevance of measurements of circulating 25(OH)D levels in the general population, including those with vascular disease, is uncertain. No large randomized trials of vitamin D have yet been completed with vascular disease or cancer as the primary outcome. Previous meta-analyses of randomized trials of vitamin D reported only borderline statistically significant effects of vitamin D treatment on all-cause mortality, but were unable to detect significant effects on vascular outcomes. These trials typically used daily doses of 400–800 IU of vitamin D3, which may not be sufficient to optimize plasma 25(OH)D concentrations throughout the year. If the inverse associations of 25(OH)D with vascular disease and other outcomes are causal and reversible by treatment, then this could have important implications for public health, particularly for countries in the Northern hemisphere where low vitamin D levels are highly prevalent.
We examined the associations of plasma concentrations of 25(OH)D with vascular and non-vascular causes of mortality in a 13-year follow-up of a prospective study of 5409 older men living in the UK in 1997, and compared the results in meta-analyses of similar prospective studies of 25(OH)D and vascular and all-cause mortality. The aims of the present study were: (i) to examine cross-sectional associations of 25(OH)D with other vascular risk factors; (ii) to assess the shape and strength of the associations of plasma 25(OH)D concentrations with vascular and non-vascular causes of death, overall and separately in those with and without any pre-existing disease; and (iii) to compare these results in meta-analyses of prospective studies of 25(OH)D and vascular and all-cause mortality.
Abstract and Introduction
Abstract
Aims To examine the independent relevance of plasma concentrations of 25-hydroxyvitamin D [25(OH)D] for vascular and non-vascular mortality.
Methods and results We examined associations of plasma concentrations of 25(OH)D and cause-specific mortality in a prospective study of older men living in the UK and included findings in meta-analyses of similar studies identified by a systematic search reporting on vascular and all-cause mortality. In a 13-year follow-up of 5409 men (mean baseline age 77 years), 1358 died from vascular and 1857 from non-vascular causes. Median season-adjusted baseline 25(OH)D concentration was 56 (interquartile range: 45–67) nmol/L. After adjustment for age and seasonality, higher concentrations of 25(OH)D were inversely and approximately linearly (log–log scale) associated with vascular and non-vascular mortality throughout the range 40–90 nmol/L. After additional adjustment for prior disease and cardiovascular risk factors, a doubling in 25(OH)D concentration was associated with 20% [95% confidence interval (CI): 9–30%] lower vascular and 23% (95% CI: 14–31%) lower non-vascular mortality. In meta-analyses of prospective studies, individuals in the top vs. bottom quarter of 25(OH)D concentrations had 21% (95% CI: 13–28%) lower vascular and 28% (95% CI: 24–32%) lower all-cause mortality.
Conclusions Despite strong inverse and apparently independent associations of 25(OH)D with vascular and non-vascular mortality, causality remains uncertain. Large-scale randomized trials, using high doses of vitamin D, are required to assess the clinical relevance of these associations.
Introduction
Prospective observational studies have reported that low circulating concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with higher risks of cardiovascular disease, cancer, and all-cause mortality. However, as low 25(OH)D concentrations are correlated with several known vascular risk factors, it is possible that any such associations with disease may reflect confounding by these risk factors. Alternatively, these associations with 25(OH)D may be due to reverse causation, as individuals with vascular disease or cancer, who may be frail or unwell, may be more likely to stay indoors, and have low plasma 25(OH)D concentrations due to inadequate sunlight exposure. Previous meta-analyses of prospective studies reported a significant inverse association of 25(OH)D with all-cause mortality, but did not distinguish vascular from non-vascular causes of death.
The relevance of measurements of circulating 25(OH)D levels in the general population, including those with vascular disease, is uncertain. No large randomized trials of vitamin D have yet been completed with vascular disease or cancer as the primary outcome. Previous meta-analyses of randomized trials of vitamin D reported only borderline statistically significant effects of vitamin D treatment on all-cause mortality, but were unable to detect significant effects on vascular outcomes. These trials typically used daily doses of 400–800 IU of vitamin D3, which may not be sufficient to optimize plasma 25(OH)D concentrations throughout the year. If the inverse associations of 25(OH)D with vascular disease and other outcomes are causal and reversible by treatment, then this could have important implications for public health, particularly for countries in the Northern hemisphere where low vitamin D levels are highly prevalent.
We examined the associations of plasma concentrations of 25(OH)D with vascular and non-vascular causes of mortality in a 13-year follow-up of a prospective study of 5409 older men living in the UK in 1997, and compared the results in meta-analyses of similar prospective studies of 25(OH)D and vascular and all-cause mortality. The aims of the present study were: (i) to examine cross-sectional associations of 25(OH)D with other vascular risk factors; (ii) to assess the shape and strength of the associations of plasma 25(OH)D concentrations with vascular and non-vascular causes of death, overall and separately in those with and without any pre-existing disease; and (iii) to compare these results in meta-analyses of prospective studies of 25(OH)D and vascular and all-cause mortality.