1. Introduction
Despite the advancements in preventive and therapeutic medicine, cardiovascular diseases (CVDs) continue to be the number one cause of morbidity and mortality [
1]. Vitamin and mineral supplements are widely used for the prevention of CVDs [
2], and vitamin D, in particular, has garnered substantial attention in recent years [
3]. Vitamin D can be obtained exogenously from the diet or supplements, such as vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol), and synthesized endogenously as D3 in the skin [
4]. Adequate vitamin D supplementation and moderate sun exposure are necessary to prevent vitamin D deficiency.
Numerous observational studies have consistently shown a significantly inverse association between circulating vitamin D levels, reflected by the levels of serum 25-hydroxyvitamin D (25[OH]D), and increased risk of CVDs, as well as subclinical inflammation, endothelial dysfunction, hypertension, diabetes, and dyslipidemia [
5], [
6], [
7], [
8]. Mechanistic studies have identified nuclear vitamin D receptors in endothelial cells and cardiomyocytes, suggesting a potential link between vitamin D levels and CVD risk [
9], [
10].
However, large randomized controlled trials (RCTs) on the clinical effectiveness of vitamin D supplementation in preventing CVDs have yielded conflicting results [
3], [
4], [
11]. It has been speculated that the relationship between plasma 25[OH]D levels and CVD risk may be mediated by additional stress- and health-related variables [
12]. For example, obese individuals have much lower 25[OH]D levels than non-obese individuals, presumably owing to the sparse distribution of vitamin D in body fat. Moreover, obese individuals demonstrated a diminished response to vitamin D supplements, with smaller increases in circulating levels when administered equivalent doses to non-obese controls, suggesting the potential requirement for a higher dosage than the recommended dose [
13]. Further, age plays a role in determining the effectiveness of vitamin D supplementation. Older individuals are more vulnerable to the effects of low vitamin D levels due to their low serum 25[OH]D levels.
Recently, an RCT of 1256 Japanese men and women showed a favorable association between vitamin D levels and the incidence of type 2 diabetes (T2D) over 3.3 years (hazard ratio (HR): 0.69 (95% CI, 0.51-0.95)) [
11]. In contrast, another study conducted in the United States involving 33 951 postmenopausal women from the Women’s Health Initiative indicated that vitamin D had no effect on the incidence of T2D during a seven-year follow-up period (HR: 1.01 (95% CI, 0.94-1.10)) [
12]. More recently, a meta-analysis of 4190 participants from three RCTs was performed in Japan (HR: 0.69 (95% CI, 0.50-0.95)), the United States (HR: 0.88 (95%CI, 0.75-1.04)), and Norway (HR: 0.90 (95% CI, 0.69-1.18)), which suggested that of vitamin D supplementation has a favorable effect on diabetes risk reduction among pre-diabetic individuals [
14]. However, the summary statistics reported in this meta-analysis may not reflect the potential influence of the ethnocultural background, which could be an important modifier of the effect estimates.
To further clarify the specific sources of heterogeneity among the existing RCTs on vitamin D supplementation, we conducted this meta-analysis and evaluated whether vitamin D supplementation improved cardiometabolic risk factors. Specifically, we aimed to identify the factors that modified the effect of vitamin D on cardiometabolic risk factors in populations without obvious CVDs.
2. Material and methods
In accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines [
15], this study protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022315165), as previously reported [
16]. The RCTs included in this meta-analysis had received ethical approval from the relevant Institutional Review Boards.
2.1. Search strategy
RCTs published until March 26, 2024, were retrieved from the PubMed, Web of Science, and Embase databases, following the protocol a priori. To conduct a systematic search, the following terms were used, (“vitamin D” OR “ergocalciferols” OR “cholecalciferol” OR “calcitriol” OR “calcifediol” OR “25-hydroxyvitamin D 2”) AND (“blood pressure” OR “blood lipid” OR “cholesterol” OR “triglyceride” OR “blood glucose”). Articles assessing the effects of vitamin D on blood pressure (systolic blood pressure (SBP) and diastolic blood pressure (DBP)), blood lipids (total cholesterol (TC); high-density lipoprotein cholesterol (HDL-C); low-density lipoprotein cholesterol (LDL-C); and triglyceride (TG)), and glycemic parameters (fasting blood glucose (FBG); hemoglobin A1C (A1C); and fasting blood insulin (FBI)) were retrieved for further review.
2.2. Eligibility criteria
The inclusion criteria were as follows: the article was written in English; the study was conducted in humans; the study was an RCT with a comparable placebo or control group; and vitamin D was specified or enhanced in the trials using food or beverages as the intervention substance.
The exclusion criteria were as follows: no randomization; no relevant outcomes of blood pressure, lipid profile, and glycemic parameters; the average change or standard deviation (SD) of outcome measures was either not reported or could not be calculated; studies that used foods, beverages, or extracts without specifying or enhancing vitamin D; the intervention duration was less than one week; and for trials studying the effects of vitamin D on CVD risk factors, participants were patients with severe CVDs, mental disorders, or other severe diseases.
2.3. Study selection
Two reviewers independently conducted the literature search and identified the relevant published articles. All selected articles were reexamined by a third reviewer, and disagreements were resolved through group discussions.
2.4. Data extraction
Information extracted from eligible studies included the surname of the first author, year of publication, location of the study population, study design, number of participants in the intervention and control groups, health status of the participants, and covariates, including age, intervention diet, comparison diet, intervention dose, and intervention duration. In studies that did not report the SD of the mean difference between the baseline and endpoint cardiometabolic risk factors, the SD of the mean difference was estimated using the following formula: SD change = square root [(SD
baseline2 + SD
endpoint2)/2] [
17]. If the outcome data were presented in graphical form, WebPlotDigitizer
† was used to estimate the values.
2.5. Quality assessment of the evidence
The risk of bias was evaluated using the
Cochrane Collaboration Handbook recommendation [
18] and RevMan software (version 5.4). Six categories were used to assess the risk of bias: selection, performance, detection, attrition, reporting, and other biases.
The grading of the quality as high, moderate, low, or very low for each cardiometabolic risk factor was performed based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) [
19]. The initial GRADE quality score defaults to high, and is sorted according to pre-specified fields, including the risk of bias (over 20%), inconsistency (
I2 > 50% and
P heterogeneity < 0.1;
I2 describes the percentage of total variation that is attributable to inter-study heterogeneity, and
P heterogeneity indicates the statistical significance of
I2), indirectness (existence of limitations to the universalization of results), imprecision (95% confidence intervals (CI) overlapped the minimally important difference to be considered as benefit or harm, such as, 2 mmHg (1 mmHg = 0.133 kPa) for blood pressure [
20], 0.1 mmol·L
−1 for blood lipids [
21], 0.5% for A1C [
22], 0.56 mmol·L
−1 or 10 mg·dL
−1 for FBG [
23], and 5 pmol·L
−1 for FBI [
24]), and publication bias (significant evidence on small study effects).
2.6. Statistical analysis
The effect size was evaluated according to the Cochrane guidelines [
17]. A random-effects model was used to generate effect sizes for cardiometabolic risk factors, expressed as the weighted mean difference and 95% CI. Heterogeneity among the included studies was detected using
I2 statistics.
P < 0.1 was used to define significant heterogeneity, with
I2 > 50% regarded as evidence of considerable heterogeneity [
25], [
26]. Subsequently, subgroup analyses were performed based on the ethnocultural background (Western or non-Westerner), baseline 25[OH]D levels (< 15.0 or ≥ 15.0 ng·mL
−1), body mass index (BMI; < 30 or ≥ 30 kg·m
−2), vitamin D dosage (< 3320 or ≥ 3320 IU), age group (< 50 or ≥ 50 years), and intervention duration (< 3 or ≥ 3 months). Ethnocultural background was defined as Westerner or non-Westerner based on the geographical location of the participants’ country. Specifically, countries in Europe, North America, and South America were categorized as Western countries, while countries in the remaining regions, including Asia, Oceania, and Africa were considered non-Western countries. The median value was used to convert other subgroup analysis factors into binary variables. Heterogeneity between subgroups was tested by using meta-regression analysis. Visual inspection of the Funnel plot and Egger’s linear regression test (
P < 0.05, implied publication bias) were used to estimate possible publication bias [
27]. Sensitivity analysis was performed to assess the contribution of individual studies to the aggregate effect size by omitting one study at a time [
28]. RevMan (version 5.4) and Stata/SE (version 17.0) software were used for all statistical analyses.
3. Results
3.1. Study selection and characteristics of eligible trials
The combined search yielded 1585 articles (
Fig. 1). Of the selected 842 articles, 577 were identified as unrelated after reviewing the titles and abstracts, and the remaining 265 articles were evaluated for suitability according to our
a priori inclusion and exclusion criteria. Studies lacking randomization (
n = 54) or relevant outcomes (
n = 49), consisting of patients with severe metabolic disorders when investigating cardiometabolic risk factors (blood pressure, blood lipids, and glycemic parameters;
n = 29), or lower than one week in duration (
n = 43) were excluded, leaving 90 articles (99 studies) for data extraction and analysis. The characteristics of the included studies are outlined in Table S1 in Appendix A.
The final analysis included 99 studies with a total of 17 656 participants aged 6-75 years (median age: 50.35 years), comprising participants from both Western (n = 48) and non-Western (n = 51) countries. The baseline range of 25[OH]D in the included participants was 5.59 to 35.01 ng·mL−1 (median values: 15.00 ng·mL−1); 45 studies reported baseline values < 15.0 ng·mL−1 and 44 studies ≥ 15.0 ng·mL−1. The BMI of the participants varied from 2.72 to 37.9 kg·m−2 (median value: 30.0 kg·m−2), with 51 studies reporting median BMI < 30.0 kg·m−2 and 32 studies ≥ 30.0 kg·m−2. Vitamin D dose ranged from 40 to 120 000 IU·day−1 (median dose: 3200 IU·day−1), with 47 studies using < 3320 IU·day−1 and 48 studies ≥ 3320 IU·day−1. The intervention lasted from six weeks to seven years.
3.2. Effect of vitamin D supplementation on blood pressure and potential effect modification
Fifty-two eligible RCTs involving 11 317 participants were evaluated to determine the effect of vitamin D supplementation on blood pressure (
Fig. 2). Vitamin D supplementation (median dose: 3320 IU·day
−1) significantly reduced both SBP and DBP in the total study population.
Subgroup analyses revealed significant reductions in SBP and DBP among individuals from both Western and non-Western countries, encompassing diverse age groups (< 50 and ≥ 50 years), as well as across studies with varying intervention durations (< 3 and ≥ 3 months). Notably, significant effects of vitamin D in reducing SBP and DBP were observed specifically in participants with baseline 25[OH]D < 15.0 ng·mL−1, BMI < 30 kg·m−2, and vitamin D supplementation dose ≥ 3320 IU·day−1, but not in participants from the corresponding subgroups. Besides, the effect of vitamin D in decreasing DBP was significant in participants receiving both higher or lower doses of vitamin D.
3.3. Effect of vitamin D supplementation on blood lipids and potential effect modification
Fifty-eight eligible RCTs involving 8401 participants were analyzed to evaluate the effect of vitamin D supplementation on blood lipid levels (
Fig. 3). Vitamin D supplementation significantly decreased TC levels, whereas LDL-C, HDL-C, and TG levels were not significantly affected in the entire study population.
Subgroup analyses revealed that LDL-C levels significantly decreased in participants with high baseline circulating 25[OH]D levels (≥ 15.0 ng·mL−1), high vitamin D dosage (≥ 3320 IU), long intervention duration (≥ 3 months), and all ages groups. TC levels improved in non-Westerners but not in Westerners, as well as in individuals with lower baseline circulating 25[OH]D levels (< 15.0 ng·mL−1), longer intervention duration (≥ 3 months), and older age groups (≥ 50 years). Furthermore, the beneficial effect of vitamin D was observed on TG in older participants (≥ 50 years), and in both longer and shorter vitamin D intervention duration groups.
Meta-regression analysis indicated a significant difference in the supplemental effect of vitamin D on TC levels between subgroups stratified by baseline 25[OH]D levels (Pmeta-regression = 0.039).
3.4. Effect of vitamin D supplementation on glycemic status and potential effect modification
Forty-six eligible RCTs involving 6343 participants were assessed to identify the impact of vitamin D on the glycemic status (
Fig. 4). Vitamin D supplementation resulted in a significant reduction in all glycemic parameters across the entire study population.
When subdivided according to the ethnocultural background, vitamin D improved all glycemic parameters in non-Westerners, whereas no effect was observed in Westerners. Further subgroup analyses revealed that vitamin D supplementation significantly improved all glycemic parameters in participants with lower baseline circulating 25[OH]D levels, lower BMI, higher vitamin D dosage, older age, and longer intervention duration. A lower dose of vitamin D supplementation also improved the FBG and FBI levels. Additionally, short-term vitamin D interventions were found to reduce the A1C and FBI levels.
Meta-regression analysis indicated a significant difference in the supplemental effect of vitamin D on the FBI between subgroups stratified by baseline 25[OH]D levels (Pmeta-regression = 0.005) and BMI (Pmeta-regression = 0.045).
4. Discussion
This study evaluated the effectiveness of vitamin D supplementation in improving cardiometabolic risk factors and explored the potential effect modification by ethnocultural background (Western and non-Western), baseline 25[OH]D levels, BMI, vitamin D dosage, age, and intervention duration on the primary prevention of CVDs. Overall, our results suggest that vitamin D supplementation significantly improved SBP, DBP, all glycemic parameters, and TC levels in the entire study population. The efficacy of vitamin D appears to be more pronounced in non-Westerners, individuals with lower baseline circulating 25[OH]D levels, lower BMIs, higher or equal to 50 years old, and those with a longer intervention duration, particularly regarding glycemic-related outcomes.
The effect modification by ethnocultural background observed with vitamin D supplementation may have several causes and important clinical implications. First, vitamin D receptor gene polymorphisms may differ among ethnic groups, potentially influencing an individual’s response to vitamin D interventions, as demonstrated in previous studies [
29]. Second, according to the serum vitamin D levels in the present study (i.e., Westerners: (14.79 ± 4.32) ng·mL
−1; non-Westerners: (12.27 ± 7.19) ng·mL
−1) and previous studies [
14], [
30] (e.g., Japan: (20.9 ± 6.1) ng·mL
−1, Norway: (24.0 ± 8.8) ng·mL
−1, and USA: (28.0 ± 10.2) ng·mL
−1), non-Western populations have lower serum vitamin D levels and thus have a higher likelihood of benefiting from vitamin D supplementation. This hypothesis is supported by our analysis of the incremental effect of vitamin D among participants with different baseline serum 25[OH]D levels. A similar modifying effect was observed in participants receiving calcium supplementation, where the protective effects of calcium on cardiovascular health were observed only in low-to-moderate-calcium-intake Asian populations and not in higher-calcium-intake American or European populations [
31]. These findings collectively support the theory that ethnocultural background may be an important modifier of vitamin D levels, indicating that high levels of vitamin D are required in non-Western populations to maintain cardiometabolic health.
Anthropometric differences, specifically in the BMI, were identified as additional factors that modified the effect of vitamin D supplementation on cardiometabolic risk factors. Notably, individuals with a lower BMI exhibited a more pronounced benefit from vitamin D supplementation in this study. Obesity inhibits the bioactivation of vitamin D by CYP2R1, resulting in 25[OH]D depletion, whereas weight loss enhances CYP2R1 expression [
32]. In overweight or obese individuals, vitamin D may exhibit diminished efficacy because of the impaired ability to completely convert vitamin D to 25[OH]D, thus diminishing the beneficial effect of completely activated vitamin D on pancreatic beta cells [
33]. In a previous study, vitamin D supplementation resulted in a 26% reduction in the incidence of T2D in participants with a lower baseline BMI, whereas no discernible effect was observed among those with a BMI above or approximately 30 kg·m
−2 [
14]. These findings are consistent with our results that SBP and glycemic parameters were significantly improved in participants with a lower BMI (< 30.0 kg·m
−2) but not in those with a higher BMI (≥ 30.0 kg·m
−2).
Serum 25[OH]D levels tend to decrease with age [
34], which may explain the more significant CVDs prevention benefit observed with vitamin D supplementation in the older population in this study. This hypothesis is supported by additional evidence. A positive correlation between vitamin D deficiency and hypertriglyceridemia was demonstrated in individuals aged 50-65 years [
35]. In addition to CVDs risk, older adults with low vitamin D levels experience exacerbation of bone health issues [
36]. Given the uncertainty regarding the complications, diet, sun exposure, and other factors in the older population, the Institute of Medicine has increased the recommended daily intake of vitamin D for older individuals to 800 IU·day
−1 [
37].
Some interventional studies have demonstrated that higher vitamin D doses might be more efficacious in reducing T2D incidence than lower doses [
14], [
30], which aligns with our results. We found that a higher vitamin D supplementation dose (≥ 3320 IU·day
−1) yields more pronounced benefits for SBP, LDL-C, and A1C, than lower doses. In addition, a longer intervention duration improved LDL-C, TC, and FBG levels compared with shorter durations. The Institute of Medicine Committee to
Review Dietary Reference Intakes for Calcium and Vitamin D 2011 established an upper vitamin D intake limit of 4000 IU·day
−1 for adults [
38], which may be a conservative estimate because of insufficient safety data. Well-designed, high-quality studies are warranted to validate our hypothesis that higher vitamin D supplementation could reduce cardiometabolic risk.
Other factors, such as magnesium status, which has been shown to affect the synthesis and metabolism of vitamin D, may be additional regulatory factors. The activity of enzymes involved in converting vitamin D into activated 1,25(OH)
2D, such as 1α-hydroxylase, is magnesium dependent [
39], [
40]. The interaction between vitamin D and magnesium has been supported by evidence from both observation studies [
41], [
42] and interventional studies [
43]. In addition, adequate magnesium ameliorates vitamin D deficiency and its associated adverse effects [
44]. Survey data have revealed that racial or ethnic differences existed in the magnesium intake, and Westerners (median: 358.6 mg) consumed more magnesium daily than non-Westerners (median: 246 mg) [
45], [
46], [
47], suggesting that Westerners may be less vitamin D deficient and experience fewer complications caused by vitamin D deficiency. However, magnesium intake and baseline magnesium levels were largely unexplored in the trials included in this meta-analysis.
Several limitations must be considered when interpreting the results of the current analysis. First, there was a lack of evidence regarding the improvement in cardiovascular outcome events and incidence of T2D, making it difficult to interpret whether the modifying factors obtained in this study also ameliorated the occurrence of CVD events. Second, the intervention periods in some RCTs were not sufficiently long. Third, the evidence indicated high heterogeneity and serious inconsistencies in most results, which may be due to the wide time range, variations in the length of the intervention, and broad range of vitamin D doses used in the included RCTs. The primary objective of this study was to investigate the impact of vitamin D supplementation on improving CVDs risk factors in relatively healthy individuals and preventing the onset of CVDs. Due to the slow process of CVDs development and challenges associated with analyzing RCTs for CVDs outcomes, there is currently insufficient evidence to statistically analyze the effect of vitamin D on CVDs event outcomes. Given the inconsistent and insufficient clinical results, uncertainty and controversies persist regarding the potential benefits of vitamin D supplementation in patients with CVDs. To bolster the existing evidence on the effectiveness of vitamin D supplementation in modifying cardiometabolic risk factors, high-quality, longitudinal, well-designed studies are urgently needed.
5. Conclusions
The results of this study showed that vitamin D exerted overall beneficial effects on blood pressure, blood lipid levels, and glycemic parameters among RCT participants. However, the benefits of vitamin D were more pronounced in non-Westerners, individuals with lower baseline circulating 25[OH]D (< 15.0 ng·mL−1), lower BMI (< 30 kg·m−2), older age (≥ 50 years), or longer intervention cycles (≥ 3 months). Our findings suggest that higher vitamin D levels are required to maintain cardiovascular health in non-Westerners, obese, and older populations. Consequently, consideration should be given to administering higher doses for longer durations when designing personalized intervention strategies aimed at enhancing cardiometabolic health in these populations.
Acknowledgments
This work was supported by the National Key Research and Development Program of China (2023YFF1105201), the China Dairy Industry Association Dairy Science and Technology Innovation Fund (CDIAKCJJ-MN-2023-001), the National High Level Hospital Clinical Research Funding (bj-2023-72), and the 111 project from the Education Ministry of China (B18053).
Compliance with ethics guidelines
Peng An, Sitong Wan, Langrun Wang, Tiancheng Xu, Teng Xu, Yonghui Wang, Jin Liu, Keji Li, Xifan Wang, Jingjing He, and Simin Liu declare that they have no conflict of interest or financial conflicts to disclose.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.eng.2024.07.010.
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