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Putting the “D” in Death

A reverse J-shaped association between serum 25- hydroxyvitamin D and cardiovascular disease mortality – the CopD-study

Study under review: A reverse J-shaped association between serum 25- hydroxyvitamin D and cardiovascular disease mortality – the CopD-study

Introduction

The recommended daily allowances for vitamins and minerals were first established by the Institute of Medicine (IOM) in 1943. Since then, small revisions have been made periodically to incorporate new scientific knowledge. Perhaps the largest change came in the 1990s, when new findings linking diet, health, and chronic disease challenged the status quo. In response, the IOM embarked on an initiative to develop a new, broader set of dietary reference values, known as the Dietary Reference Intakes (DRIs).

Since the publication of the DRIs between 1997 and 2005, the only vitamin to be revisited is vitamin D. In their 2010 report, the IOM tripled their recommendation from 200 IU to 600 IU daily for all people ages 1-70 years old, as a response to the vastly larger base of higher-quality studies published since 1997, when the recommendation was first established. Yet, this updated recommendation continues to come under fire from researchers across the world.

Recent evidence[1] suggests vitamin D is implicated in numerous chronic diseases and adverse health conditions outside of its primary role in skeletal health. However, the optimal blood level of vitamin D measured as 25(OH)D is a matter of considerable debate. Vitamin D deficiency and insufficiency have been defined by the Endocrine Society as a 25-hydroxyvitamin D 25(OH)D <20 ng/mL and 21-29 ng/mL respectively, with optimal levels for health considered to be 30-40 ng/mL.

Of great concern, however, is the notion put out by the IOM that the mortality curve for blood levels of 25(OH)D is U-shaped, indicating an increased risk of death associated with both too low and too high 25(OH)D levels . This was supported by research showing 25(OH)D blood levels of 20-25 ng/mL are associated with the lowest mortality risk in a cohort of nearly 250,000 Denmark citizens. However, two recent systematic reviews and meta-analyses challenge this view.

The first, published in April 2014, was a systematic review and meta-analysis of 73 observational and 22 randomized controlled trials (RCTs) with 849,412 and 30,716 participants, respectively. Analysis of the observational studies showed that the risk of death from any cause was increased by 16% for each 10 ng/mL reduction of 25(OH)D level below 30 ng/mL, while analysis of the RCTs revealed that vitamin D3 supplementation (10-6000 IU/day) compared to placebo or no treatment reduced the risk of death by 11%. To put this into perspective, using the population prevalence estimates of vitamin D deficiency from this study, 9.4% of all deaths in Europe and 12.8% of those in the United States could be attributed to vitamin D deficiency.

The second, published in August 2014, reviewed 32 observational studies from 1966 to 2013 with more than 500,000 participants. In 25 of the 32 studies, there was a significant association between reduced all-cause mortality and higher 25(OH)D concentrations, which was confirmed by the meta-analysis showing that, in general, blood 25(OH)D levels ≤30 ng/mL were associated with a significantly increased risk of death compared to ≥30 ng/mL. Specifically, the point at which the risk of death stopped declining significantly was 36 ng/mL, although there was a trend for further reduction with 25(OH)D levels of 40-49 ng/mL. Importantly, there was no increased risk of death with increased 25(OH)D concentrations.

This matters because an estimated one billion people worldwide are vitamin D deficient or insufficient, and analysis of the NHANES 2005-2006 data suggests that 41.6%[2] of Americans are deficient. Yet, death from any cause is a broad umbrella under which some health outcomes may hold more weight than others, and thus unfairly influence the relationship between 25(OH)D and mortality. This is why researchers look into more specific relationships, such as that between vitamin D and the number one global killer – cardiovascular disease (CVD).

Unfortunately, the results are not clear-cut. According to the study under review, there have been no less than 24 published studies estimating the association between 25(OH)D levels and CVD mortality. Some of the studies did find an association between low 25(OH)D levels and increased CVD mortality, but others did not, and some even found an inverse association only among those with low 25(OH)D levels. These discrepancies may be due to different study populations and follow-up procedures. Thus, the current study sought to evaluate the association between CVD and 25(OH)D concentrations of a Denmark-based cohort of 243,672 men and women.

Serum 25(OH)D concentrations appear to be protective against death from any cause when between 30-40 ng/mL, with no apparent risk as concentrations increase further. However, data specifically looking at cardiovascular disease is conflicting.

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