**7. Randomized controlled trials**

Many randomized interventional studies have focused on improving surrogate endpoints rather than hard CV outcomes. Those focusing primarily on CV outcomes are sparse. Most of the available studies have varied methodologically in defining baseline vitamin D status, dose used, and definition and ascertainment of outcomes.

These flaws are seen in studies that evaluate all‐cause mortality and those evaluating CVD outcomes.

A meta‐analysis of randomized placebo control trials with varying levels of vitamin D using mortality as a secondary endpoint found a significant 8% reduction in mortality in individuals receiving vitamin D. This study was limited by the inability to evaluate cause-specific mortality [56].

In another meta-analysis, individuals who took vitamin D at daily doses ranging from 300 to 2000 IU (average dose 528 IU) for an average of 5.7 years had a 7% lower risk of death (from all causes) than those who did not.

The relatively low dose of vitamin D and the short treatment period may have led to an underestimation of its effect. It was noted that the clinical evolution of chronic conditions may take longer to be influenced by vitamin D supplementation; hence, very long-term follow-up would be required to observe the full effect [57].

In the CVD arena, a double-blinded, placebo-controlled, randomized trial in the United Kingdom, including 2686 patients between the ages of 65 and 85, showed no benefits on CVD outcomes in the group that received 100,000 IU of supplemental vitamin D3 every 4 months (833 IU daily) for 5 years [58]. A systematic review of 14 prospective studies and 18 randomized trials examining supplementation with vitamin D, calcium, or both and subsequent cardiovascular events concluded that vitamin D supplementation might reduce the risk of CVD. Separate analysis of the eight randomized trials found a non-significant reduction in CVD risk with vitamin D supplementation [30].

Results from the Women's Health Initiative (WHI) suggests that postmenopausal women receiving 400 IU/day of oral vitamin D3 combined with calcium 1000 mg/day had no reduction in their risk of CHD events or stroke. In a subanalysis of the WHI, calcium and vitamin D3 supplementations were not found to improve blood pressure or coronary artery calcium score. Furthermore, after 7 years of follow-up, there was no decrease in incident hypertension or prevention of the metabolic syndrome, diabetes, or decreases in cerebrovascular risk [59].
