Diabetics were 4.4 X more likely to die if they had low Vitamin D – July 2018

Vitamin D deficiency, overall and cause-specific mortality: the impact of age

Revue d'Épidémiologie et de Santé Publique. Volume 66, Supplement 5, July 2018, Page S271, https://doi.org/10.1016/j.respe.2018.05.092
T.Waldhoera, G.Endler, .Yang, G.Haidinger, O.Wagner, R.Marculescu

Introduction
Vitamin D deficiency, as reflected by low 25-hydroxyvitamin D blood levels (25D), is a prevalent correctable risk factor for death in most populations around the globe. The evidence ranges from numerous association studies and meta-analyses thereof, over Mendelian randomization studies, to randomized controlled trials (RCTs). However, most studies reported to date were performed in rather older populations and some of the largest association studies may have been confounded by increased vitamin D supplementation at old age, especially in women, and by the use of vitamin D2, which is fully measured by 25D immunoassays but biologically considerably less active. In addition, cause-specific mortalities and the impact of age on the 25D association with the risk of death have not been reported in detail, yet.

Methods
Data of all patients who had a 25D measurement at the Department of Laboratory Medicine, General Hospital of Vienna between 1991 and 2011 were retrieved and matched with the Austrian national register of deaths. First 3 years of mortality since 25D measurement were excluded in the analyses. Fine-Gray regression models adjusting for competing risks were used to estimate the survival time in dependence on 25D, adjusting for sex, age, year and month of blood draw. 25D was represented using a spline with 5 knots placed on the corresponding 1/6th quantiles. Age group (0– < 45, 45– < 60, 60– < 75, 75+ years) specific analyses were conducted owning to a strong interaction between 25D and age, where age was kept as a continuous variable to avoid remaining residual confounding. Using 50 nmol/L as the reference value, we estimated hazard-ratios of chosen serum vitamin D concentration levels (10 and 90 nmol/L). All analyses were conducted in SAS 9.4 (SAS Institute Inc., Cary, NC, US). The significance level was set to 1% in order to adjust for multiple testing.

Results
Data from 78,581 patients (mean age = 51.0 years, men 31.5%) were used for analyses. During 20 years (median = 10.5) of follow-up, 11877 deaths were observed.
Among these patients, 25D ≤ 10 nmol/L had 2-3 fold increased risk of death (

• <45 years old: HR = 2.7, 95% CI:(2.1, 3.4);
• 45- < 60 years old: HR = 2.9, 95% CI:(2.6, 3.4);
• 60– < 75 years old: HR = 2.0, 95% CI:(1.8, 2.3),

Whereas 25D ≥ 90 nmol/L has shown to be associated with up to 40% reduced all-cause mortality (

• < 45 years old: HR = 0.7, 95% CI:(0.6, 0.9);
• 45– < 60 years old: HR = 0.6, 95% CI:(0.5, 0.7);
• 60– < 75 years old: HR = 0.7, 95% CI:(0.7, 0.8).

No associations were observed in the age group 75 years and older (10 nmol/L: HR = 1.1, 95% CI:[1.0, 1.2]; 90 nmol/L: HR = 1.0, 95% CI:[0.9, 1.0]). In terms of cause-specific mortality, we found only a relatively modest relationship for cancer and cardiovascular disease. The strongest association was found for other causes of death with the largest effect size for diabetes HR = 4.4, 95% CI:(3.1,6.3).

Conclusions
Our survival data from a large cohort, covering all age groups, from a population with minimal vitamin D supplementation at old age and negligible intake of vitamin D2, confirm a strong association of vitamin D deficiency (25D < 50 nmol/L) with increased mortality. This association is most pronounced in the younger and middle-aged groups and for causes of deaths other than cancer and cardiovascular disease. Some J-shaped curves were found only for the 25D association with cancer and cardiovascular mortality in certain age groups. Our findings strengthen the rationale for wide spread vitamin D supplementation to prevent premature mortality, emphasize the need for it early in life and mitigate concerns about a possible negative effect at higher 25D levels up to 150 nmol/L. RCTs in younger age groups are needed to confirm these findings.