Vitamin D supplementation
Multiple studies were done to evaluate the effect of Vitamin D supplementation on cardiovascular disease and mortality. In a randomized clinical trial of 5108 community-residents adults aged 50–84 year, monthly high-dose vitamin D supplementation (100,000 IU) did not prevent cardiovascular disease compared with placebo [
102]. Furthermore, the EVITA (Effect of Vitamin D on All-cause Mortality in Heart Failure) randomized trial, did not show a reduction of mortality in patients with advanced heart failure received a daily vitamin D of 4000 IU compared with placebo [
103]. Also, in a systematic review and meta-analysis of 18 trials and 13 observational studies, there were uncertain associations between vitamin D status and cardiometabolic outcomes [
104]. In addition, another meta-analysis by Wang et al. showed a linear inverse association between 25(OH)D and risk of CVD [
105]. While Ford et al.’s meta-analysis showed some benefits of vitamin D supplementation on cardiac failure, it did not show benefits on myocardial infarction/stroke [
106].
With the proven association between vitamin D and hypertension, several studies were conducted to see whether vitamin D supplementation would help in treating hypertension. However, these studies resulted in different outcomes and recommendations. Some studies have shown some beneficial outcomes with vitamin D supplementation in reducing blood pressure in patients with low baseline vitamin D levels [
39,
106‐
109]. In a study of 112 patients conducted in Denmark, a 20 weeks’ supply of 3000 IU cholecalciferol in winter resulted in a nonsignificant reduction of 3/1 mmHg (P 0.26/0.18), however, significant results were obtained in patients with low baseline 25(OH)D (< 32 ng/ml) of 4/3 mmHg (P 0.05/0.01) [
108]. Another study targeted females over 69 years old showed the benefit of 8 weeks’ supplementation of vitamin D3 (800 IU) and calcium (1200 mg) on systolic blood pressure by a 5 mmHg or more decrease in SBP in 60 subjects (81%) (
P = 0.04) [
107]. In a randomized controlled trial of 283 African Americans between 2008 and 2010 showed for each 1 ng/ml increase in 25(OH)D there was a 0.2 mmHg reduction in SBP (
P = 0.02) after 3 months’ supplementation of (doses 1000, 2000 or 4000 IU) cholecalciferol [
106]. On the other hand, some studies did not show any reduction in blood pressure with vitamin D supplementation [
110‐
112]. As we see in a randomized controlled trial of 161 predominately white individuals, large doses of vitamin D3 (200,000 for 2 months then 100,000 monthly) up to 18 months showed no effect on BP [
111]. Also, the DAYLIGHT randomized controlled trial showed no benefit of vitamin D supplementation on BP [
112]. A similar result was found in Austria in the Styrian Vitamin D Hypertension Trial (2011–2014) of 200 participants after 8 weeks of vitamin D3 2800 IU [
110].
Therefore, multiple meta-analyses were conducted to study the benefit of replacing vitamin D in hypertensive patients. But again, these meta-analyses also had mixed results. Beveridge et al. did a meta-analysis of 46 trials and concluded there was no effect of vitamin D supplementation on blood pressure [
113]. A meta-analysis done by Wu et al. of 8 randomized controlled trials studying the effect of calcium and vitamin D supplementation on blood pressure showed no meaningful effect on daytime office BP [
114]. Furthermore, two systemic reviews and meta-analyses attributed the inconsistency in evidence regarding vitamin D supplementation’s effect on blood pressure to the heterogeneity in study design [
115,
116]. However, in a mendelian randomization study, Vimaleswaran et al. have found a genetic evidence that increased vitamin D concentrations are causally associated with reduced blood pressure and the risk of hypertension [
117].
With regards to the efficacy of vitamin D supplementation on reducing CVA, available evidence are conflicting [
118]. However, in a recent small scale randomized clinical trial, a single dose of 6 lac IU of Cholecalciferol Intramuscular (IM) injection was associated with a significant improvement in the stroke outcome after three months [
119]. We hope that the ongoing Vitamin D and Omega-3 Trial (VITAL) would shed some light on the role of vitamin D supplementation in reducing cardiovascular events, including CVA [
120,
121].
With the above mentioned evidence, the inconsistencies between those studies could be due to the differences in vitamin D preparations, follow-up length, patient compliance with the medications, differences in study populations’ baseline characteristics, sample size and the metabolic heterogeneity among the included patients [
122]. So, there is a worldwide call for a larger randomized control trial [
12,
123‐
136].