**12. Future directions**

**9. Diabetes**

diabetes by 41% [66].

**10. Endothelial dysfunction**

12 A Critical Evaluation of Vitamin D - Clinical Overview

inflammatory markers was observed [33].

gamma), and CXCL‐10 [68].

ml) [69].

blood pressure [70].

A meta‐analysis of 11 prospective studies involving 3612 cases and 55,713 non‐case partici‐ pants suggested a strong inverse association between serum 25(OH)D concentration and incidence of type 2 diabetes. Results suggested that optimal levels may reduce the risk of future

Other contrasting meta‐analysis of 15 trials did not find sufficient evidence to recommend vitamin D supplementation for improving glycemia or insulin resistance in obese patients with

Vitamin D deficiency has been associated with endothelial dysfunction as measured by flow‐ mediated dilation (FMD) and reactive hyperemia peripheral arterial tonometry (RH‐PAT) [68].

A small study involving 23 asymptomatic subjects demonstrated that subjects with significant vitamin D deficiency had impaired brachial artery FMD, which improved after vitamin D replacement therapy. Recently, a stepwise change in FMD according to vitamin D status was demonstrated and an inverse association between serum 25(OH)D levels and vascular

A prospective placebo‐controlled pilot study evaluated the effects of vitamin D repletion on endothelial function and inflammation in subjects with both vitamin D deficiency and CAD. The study was conducted over a 12‐week period in 90 subjects. RH‐PAT was used to estimate endothelial function. No significant differences between groups were found in reactive hyperemia index, blood pressure, and levels of hs‐CRP, IL‐6, IL‐12, interferon‐gamma (INF‐

Similar results were obtained on a larger scale, the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), that studied 852 men and found no significant relationship between vitamin D levels and endothelium‐dependent vasodilation, flow‐mediated vasodilation, and reflectance index. However, serum 25(OH)D level showed a negative correlation with SYNTAX score (angiographic grading tool to determine severity of coronary disease) and high‐sensi‐ tivity C‐reactive protein (hsCRP) level. Logistic regression analysis identified 25(OH)D as an independent factor related to high SYNTAX scores. Patients whose vitamin D levels were in the lowest 25(OH)D category (<20 ng/ml) were more often in the high SYNTAX scores group, with their incidence about twofold higher than those in the highest 25(OH)D category (>30 ng/

In cross‐sectional analyses, low 25(OH)D (<20 ng/ml) was not associated with stiffer arteries after adjustment for cardiovascular disease risk factors (*P* > 0.4). PTH >65 pg/ml was associated with stiffer arteries after adjustment for cardiovascular disease risk factors, other than systolic

diabetes, normal fasting glucose levels, or impaired glucose tolerance [67].

Several large‐scale randomized trials of moderate‐to‐high dose vitamin D supplementation for cardiovascular disease prevention are currently being conducted. The Vitamin D and OmegA‐3 TriaL (VITAL) is a randomized, double‐blind, placebo‐controlled clinical trial among more than 20,000 US men and women above age 50, testing 2000 IU/day of oral vitamin D3 and omega 3 fatty acid supplements in a 2 × 2 factorial design, with cardiovascular disease and cancer as primary prespecified outcomes. Results are expected in 2017 [13]. Another large randomized trial of CVD prevention, the VIDA trial, is evaluating a higher dose of vitamin D (100,000 IU a month) over 3.3 years and expects results in late 2016 [14].

Evaluating whether common polymorphisms in the VDR receptor modifies the association between 25(OH)D concentrations and individual CVD risk has been proposed. A recent trial evaluating two previously studied VDR polymorphisms failed to reveal a significant role to this end; however, further study may be warranted [73].
