The supplementation with vitamin D does not lower blood pressure in the general population.
Emerging evidence suggests that vitamin D deficiency is a widespread global problem . According to the Institute of Medicine (IOM), vitamin D deficiency is defined as circulating 25-hydroxyvitamin D (25[OH]D) level <50 nmol/L based on the optimal concentration for skeletal health . Interest has increased concerning the potential health consequences of vitamin D deficiency, such as increased risk of cardiovascular diseases, cancers, and Alzheimer’s disease (3–5). Although observational data have demonstrated that poor vitamin D status is associated with increased risk of hypertension (6–9), randomized controlled trials (RCTs) have provided little support for the beneficial effect of vitamin D supplementation on blood pressure). Considering the potential residual confounding, inferring causality or reversibility of this relationship and reaching consensus from these findings is difficult. Several meta-analyses of observational studies and RCTs have been published, but results are conflicting (14–17). Golzarand et al evaluated 30 RCTs with 4,744 participants and concluded that vitamin D has a beneficial effect in subgroups of daily doses >800 IU/d, a duration less than 6 months, or older subjects. Kunutsor et al suggested that supplementation with vitamin D significantly reduced diastolic blood pressure (DBP) by 1.31 mm Hg in participants with preexisting cardiometabolic conditions . However, another meta-analysis performed by incorporating individual data supported that vitamin D supplementation is ineffective in lowering blood pressure .
Taken together, it may be hypothesized that the increased blood pressure or risk of hypertension is partly explained by individuals’ baseline vitamin D status, the sample size, the intervention dose, and the follow-up duration. Meanwhile, considering that pre-existing conditions such as diabetes, cardiovascular disease, and kidney disease may influence the physiologic mechanism of vitamin D on blood pressure, considerable variability may exist between individual patients and the general population. Therefore, restricting the participants to the general population may help to explore the true association hidden by the confounders. Analyzing the population as a whole rather than restricting analyses to certain population subgroups may help us to explore the true association hidden by confounders. In addition, results from at least 10 more studies including 1,716 participants have been published on this topic since the latest meta-analysis in 2015 .
We aimed to provide a comprehensive and quantitative meta-analysis from the published cohort studies and RCTs on the effect of vitamin D involving hypertension risk and blood pressure levels in the general population.
This meta-analysis of cohort studies suggested an inverse association between 25(OH)D levels and incident hypertension, with hypertension risk reduced by 7% per 25 nmol/L increment in 25(OH)D levels. Meanwhile, summary data of RCTs indicated no evidence of blood pressure reduction by supplementation with vitamin D, a finding consistent with subgroup analyses based on baseline overweight/obese status, baseline 25(OH)D level, follow-up duration, and intervention dose.
The findings from numerous observational studies have shown that sufficient vitamin D status is a protective factor for hypertension. Analysis of Mendelian randomization also provided the causal evidence for the effect of increased circulating 25(OH)D levels on reduced blood pressure levels and risk of hypertension . However, our subgroup analyses of the cohort studies produced inconsistent results, which indicated that the quantitative data failed to provide convincing evidence of the protective effect of vitamin D on hypertension. Meanwhile, most of the interventional studies did not provide consistent evidence of blood pressure benefit from supplementing with vitamin D. Given these findings, we speculate that the beneficial effect observed in cohort studies may be partly explained by the tendency that sufficient vitamin D levels are closely related to healthy lifestyle or study participants being young. It may be also in part because of the hypothesis that low 25(OH)D levels could be the result of sub-health status rather than a precursor of diseases. Furthermore, differences exist among the various methods used (ie, liquid chromatography-mass spectrometry; high-performance liquid chromatography; and enzymoimmunoassay, radioimmunoassay, and chemiluminescence immunoassays) and in the laboratories that measured 25(OH)D levels, which would also influence the accuracy of the study results.
Similar with previous meta-analyses also showed no overall lowering effect of vitamin D supplementation on blood pressure . However, they suggested that vitamin D may show a beneficial effect on blood pressure in specific subgroups, such as older people, people whose dosage of vitamin D was high (>800 IU/d), short-term interventions (<6 months), or individuals with pre-existing cardiometabolic disease. A possible reason for this discrepancy is that the recruited populations of included studies had high heterogeneity. Therefore, we restricted this meta-analysis to analyses of apparently healthy individuals. We excluded trials that have targeted patients with hypertension, diabetes, cardiovascular disease, or other diseases, because the known or unknown interaction between vitamin D and antihypertensive or cardiovascular medications may mask or attenuate the small effects of blood pressure reduction.
Complicated factors such as baseline vitamin D status, intervention design, or adiposity may modify or blunt the beneficial effect on blood pressure of improving vitamin D levels. An increasing body of evidence supports the presence of thresholds in vitamin D status. Similarly, the approximately L-shaped relationship between 25(OH)D levels and hypertension risk in our meta-analysis showed that hypertension risk increased substantially below 75 nmol/L but remained marginally significant above 75 nmol/L, which suggests that subjects with vitamin D insufficiency or deficiency show higher response to supplementation. In addition, evidence showed a therapeutic effect of cholecalciferol only in vitamin D–depleted participants by decreasing their 24-hour blood pressure by 3–4 mm Hg . Therefore, we speculated that the protective effect would only appear in subjects with low vitamin D levels. Indeed, we classified the studies according to their baseline vitamin D status, but the results indicated that vitamin D supplementation had no apparent effect on blood pressure, regardless of its baseline status. This finding is in accord with a recent meta-analysis that used individual patient data . However, considering that the number of people with low vitamin D levels may be insufficient in our study, further trials are needed to verify this finding.
Individuals who are taking vitamin D supplements should do so for at least 6 months to reach the maximum attained 25(OH)D level . It is reasonable to assume that the effect of vitamin D is time-dependent. However, our findings from subgroup analyses of RCTs suggested that response of blood pressure to vitamin D is independent of interventional duration (<6 months and ≥6 months). Similar findings have been reported (16,61). Considering these findings, we still cannot rule out that the duration of vitamin D intervention is insufficient to detect any slight but significant reduction in blood pressures, especially in the apparently healthy subjects whose normal values are less likely to be further improved. It is worth noting that until June 2019 only one RCT lasting up to 2 years was included in our study; therefore, a protective effect of longer intervention could not be studied adequately. Future RCTs with longer follow‐up duration are needed to provide in-depth insight into the long‐term benefits of vitamin D supplementation.
The optimal dose for vitamin D supplementation would influence the effect on blood pressure. A 4-arm trial conducted in African Americans reported dose-dependent reductions in SBP after 3 months of cholecalciferol supplementation with 1,000 IU, 2,000 IU, and 4,000 IU per day (0.66 mm Hg, 3.4 mm Hg, and 4.0 mm Hg, respectively) (34). In addition, a meta-analysis synthesizing the results of 30 RCTs suggested that vitamin D supplementation at a dose of >800 IU/d reduced blood pressures significantly. Contrary to these results, we did not find the dose–response relationship for vitamin D on blood pressure. We should consider the possibility that the supplementary doses in most included trials may be larger or smaller to observe a beneficial effect. Further studies are needed to explore the potential quantitative model.
This meta-analysis of RCTs included 3,810 people from the general population, which provides a substantial statistical power to detect the potential effects and thereby enhances the generalizability of our findings. However, our study also contains several potential limitations. First, because most studies did not record the changes of diet, sun exposure or latitudes, genetic factors, and educational status, we are not able to answer the questions of whether these factors would modify the effect of the intervention. Second, there are several trials that did not reach enough power (they were below 80%) to detect any weak difference between interventional and placebo groups because of the small sample size and high rate of noncompliance (13,20,53). In addition, although we stratified the duration of follow-up (the maximum is 2.0 years) and found no significant difference between subgroups, it remains unclear whether there are any long-term (>2 years) effects of vitamin D to improve blood pressure levels. However, we may conclude that vitamin D supplementation will not affect blood pressure short-term.
The results of this meta-analysis indicate that supplementation with vitamin D does not lower blood pressure in the general population. On the basis of this finding, we do not recommend using vitamin D supplementation to prevent hypertension. However, future RCTs with long-term interventions and sufficient sample sizes of people with low vitamin D levels are needed to replicate this finding.
Note: This article is based on “Effect of Vitamin D on Blood Pressure and Hypertension in the General Population: An Update Meta-Analysis of Cohort Studies and Randomized Controlled Trials” written by Dongdong Zhang, MD, 1 Cheng Cheng, MD, 2 Yan Wang, MD, 1 Hualei Sun, MD, 1 Songcheng Yu, MD, 1 Yuan Xue, MD, 1 Yiming Liu, MD, 1 Wenjie Li, MD, PhD, 1 and Xing Li, MDcorresponding author 1 , dated 2020 Jan 9 and published in PMC
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