La ingesta dietética de calcio e hipertensión arterial:

Revisión sistemática y meta-análisis de dosis-respuesta, de estudios de cohorte prospectivos

Dietary calcium intake and hypertension risk: a dose–response meta-analysis of prospective cohort studies

Ahmad Jayedi & Mahdieh Sadat Zargar
European Journal of Clinical Nutritionvolume 73, pages969–978 (2019)

Abstract

The association of calcium intake with risk of developing hypertension in the general population has not been established yet. We systematically searched PubMed and Scopus databases up to February 2018 to find prospective observational studies investigating the association of calcium intake with risk of developing hypertension. The reported risk estimates were pooled using a random-effects model. Eight prospective cohort studies (248,398 participants and 30,838 cases) were included. Seven studies measured dietary calcium intake, but one study measured total calcium intake (calcium from food and supplements). A significant inverse association was found for the highest versus lowest category of calcium intake (relative risk: 0.89, 95%CI: 0.86, 0.93; I2 = 0%, n = 8), and for each 500 mg/d increment (relative risk: 0.93, 95%CI: 0.90, 0.97; I2 = 64%, n = 7). Summary results were the same with the main analyses when the analyses were restricted only to dietary calcium intake. A nonlinear dose–response meta-analysis exhibited a linear inverse association, with a somewhat steeper trend within the low and moderate intakes. In conclusion, higher dietary calcium intake, independent of adiposity and intake of other blood pressure-related minerals, is slightly associated with a lower risk of developing hypertension.

Introduction

The global prevalence of hypertension has increased during the last two decades [1]. It has been estimated that the number of people with hypertension will increase up to 1.56 billion by the year 2025 [2]. The unique features of hypertension include the fact that it is not only a disease per se [3], but also is associated with higher risk of cardiovascular morbidity and mortality [4]. Despite all the improvements that have been made to control of hypertension, about 50% of hypertensives in the US [5], and 60–75% in Europe could not achieve to the optimal control of their blood pressure (<140/90 mmHg) [6]. Thus, promoting lifestyle-related changes in order to bring about primary prevention of hypertension can be considered as one of the most important public health priorities.

It has been suggested a link between dietary habits with risk of developing hypertension [7]. Several observational studies have suggested an inverse association between intake of dairy products and blood pressure levels, as well as with risk of developing hypertension [8,9,10,11,12,13]. Dairy products are dietary sources of potassium, calcium, vitamins, high biological value proteins, and some peptides; all of which have been shown to have hypotensive properties [14]. Indeed, of the above-mentioned potential, hypotensive, dietary components of dairy products, calcium has attracted a lot of attention in the past. Two previous meta-analyses of observational studies exhibited a significant negative correlation between dietary calcium intake and blood pressure levels [15, 16]. However, the longitudinal association of dietary calcium intake with risk of developing hypertension has not been established yet. Thus, this systematic review was carried out to quantify the longitudinal association of calcium intake with risk of developing hypertension in the general population, with the use of prospective cohort studies.

Materials and methods

This meta-analysis has been reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [17].

Search strategy

We systematically searched PubMed and Scopus databases, from their inception up to February 28, 2018. The terms used for the systematic search were: [“calcium” OR “dairy” OR “milk” OR “yogurt” OR “cheese”] AND [“hypertension” OR “HTN” OR “blood pressure”] AND [“prospective” OR “prospectively” OR “Cohort” OR “Cohorts” OR “Longitudinal” OR “observational” OR “Observation” OR “Follow-up” OR “Nested” OR “relative risk” OR “odds ratio” OR “hazard ratio” OR “risk”]. Also, we manually searched reference lists of related articles and reviews. The search was restricted to articles published in English.

Eligibility and study selection

Studies were considered eligible for inclusion in the current meta-analysis if they (1) had prospective observational design; (2) were conducted among the general population; (3) reported calcium intake (from either food or supplements) as exposure and across three or more categories; (4) reported the outcome of interest as hypertension incidence (either measured or self-diagnosed or physician-diagnosed); (5) provided estimates of relative risk (RR), hazard ratio, or odds ratio with corresponding 95% CIs of hypertension incidence across categories of calcium intake; and (6) reported number of cases and participants/personyears or non-cases across categories of calcium intake. Studies that reported the association as continuous (for specific amount of increase in dietary calcium intake) were also included. If more than one publication form the same study was identified, the publication with higher number of participants was included.

Data extraction and quality assessment

Two independent investigators (A.J., M.S.Z.) recorded the following characteristics from eligible studies: first author’s name, date of publication, study name, country, age range and/or mean age (year), sample size, number of cases, method used for dietary assessment, exposure levels, reported effect estimates and the 95%CI of hypertension across categories of calcium intake, and list of variables used for the multivariate analysis. We selected effect estimates based on models with the most comprehensive covariate adjustments from each study. Two studies did not report the range of calcium intake in each category [18, 19]. We contacted with the authors of those studies, but we did not receive any feedbacks. The quality of studies was quantified with the use of the Newcastle–Ottawa Scale, and studies with ≥7 stars were considered high quality [20]. Furthermore, we applied the new-developed NutriGrade scoring system (a maximum of 10 points) for judgment about the quality of meta-evidence [21]. Any disagreements were resolved through discussion and consensus.

Statistical analysis

The RR and 95%CI was considered as the effect size. The reported hazard ratios were considered as equal as RR. For the main analysis, the effect sizes of the highest compared with the lowest categories were combined using the DerSimonian and Laird random-effects model [22]. In one study, the effect size was reported only as continuous, and for a 1 gr/d increment in calcium intake [23], and we used the following method to translate per a 1 gr/d increment risk estimate to the high vs. low RR: first, we calculated the differences between the median points of the highest and lowest categories in other studies included in the analysis. Then, the mean difference between the medians of the highest and lowest categories was calculated. Finally, per a 1 gr/d increment risk estimate was translated to per “calculated mean difference” and was included in the analysis. Subgroup analyses were carried out according to gender, source of calcium, geographic location, method of dietary assessment, median intake, follow-up duration, number of cases, and adjustment for main confounders. Between-studies heterogeneity was explored using Cochrane’s Q test and quantified by I2statistic (P < 0.05) [24]. Publication bias was assessed by the inspection of the funnel plots asymmetry and measured by Egger’s asymmetry test [25] and Begg’s test (P < 0.10) [26].

The linear dose–response relation was measured using a generalized least-squares trend estimation, according to the methods developed by Greenland and Longnecker [27, 28]. The method needs distribution of cases and participants/personyears or non-cases and adjusted RR and its 95%CI across categories of calcium intake. A random-effects model was used to pool data from all studies. The RR and its 95%CI were calculated for a 500 mg/d increment in calcium intake. If the number of participants/cases or personyears have not been reported in the primary studies, we estimated them by dividing the total number of participants/cases or personyears by the number of categories, if the exposure was defined as quantiles [29]. In one study, the range of calcium intake in each category has been reported as a form of nutrient density (per 1000 kcal/day energy intake) [19], and thus, we estimated the range of calcium intake in each category by using the median energy intake of the whole participants. A potential non-linear association was examined by modeling dietary calcium intake levels using restricted cubic splines with three knots at fixed percentiles (10%, 50%, and 90%) of the distribution [30]. A P-value for non-linearity of the meta-analysis was calculated by testing the null hypothesis that the coefficient of the second spline was equal to zero. All analyses were conducted with Stata software, version 13 (Stata Corp., College Station, TX, USA). A P-value < 0.05 was considered statistically significant.

Results

The systematic literature search identified 7744 articles, plus two articles through hand searching. We excluded 858 duplicate articles, as well as 6830 articles after screening the title and abstract. Finally, 58 full text articles were assessed for inclusion in the present meta-analysis; on these, another 50 articles were excluded, which respective reasons for study exclusion are detailed in Fig. 1. Ultimately, eight prospective cohort studies with 248,398 participants and 30,838 incident cases of hypertension were included in the final analysis [18, 19, 23, 31,32,33,34,35]. One study measured total calcium intake (dietary calcium + supplemental calcium) [31], but other studies considered dietary calcium intake in their dietary assessments. All of the studies controlled for body mass index, most studies controlled for alcohol intake (n = 7), and some of the studies controlled for smoking (n = 4) and physical activity (n = 5). Only three studies controlled for intake of dietary sodium [18, 33, 34], and dietary potassium and magnesium [18, 33, 35]. One study did not report the range of calcium intake in each category, and thus, was not suitable for dose–response meta-analysis [18]. The general characteristics of the studies are presented in Table 1and the number of participants/cases and reported effect size in each category of calcium intake in the primary studies are provided in Supplementary Table 1.

Fig. 1
figure1

Literature search and study selection process for inclusion in meta-analysis of dietary calcium intake and risk of developing hypertension

Table 1 General characteristics of the studies included in meta-analysis of dietary calcium intake and risk of developing hypertension
High vs. low meta-analysis

Eight prospective cohort studies reported sufficient information for high vs. low analysis [18, 19, 23, 31,32,33,34,35]. Highest compared with the lowest category of calcium intake was associated with an 11% lower risk of hypertension (relative risk: 0.89, 95%CI: 0.86, 0.93), with no indication of heterogeneity, I2 = 0%, 95%CI: 0%, 71%; Pheterogeneity = 0.53 (Fig. 2). In the sensitivity analysis, stepwise exclusion of each study at a time minimally altered the association (RR altered between 0.88 and 0.90). Of the eight studies included in this analysis, only one study measured total calcium intake (dietary calcium + supplemental calcium) [31], and the association did not change when this study was removed from the pooled analysis. In the subgroup analyses, a significant inverse association was observed only in studies conducted in the US compared with Europe, studies with longer follow-up durations (>5 years vs. <5 years), and studies with higher number of cases (>3000 vs. <3000) (Table 2). A significant inverse association appeared stronger among studies with lower median calcium intake (<700 vs. ≥700 mg/d: 0.86 vs. 0.92, respectively), and persisted even after adjustment for intake of magnesium, potassium, and sodium (Table 2). There was no evidence of publication bias based on Egger’s test (P = 0.66) and Begg’s test (P = 0.17) (Supplementary Figure 1).

Fig. 2
figure2
Meta-analysis of dietary calcium intake and risk of developing hypertension (highest vs. lowest category analysis). ES effect size
Table 2 Relative risk of incident hypertension for the highest compared with the lowest category of calcium intake
Dose–response meta-analysis

Seven prospective cohort studies were eligible for inclusion in dose–response analysis [19, 23, 31,32,33,34,35]. A 500 mg/d increment in calcium intake was associated with a 7% lower risk of developing hypertension (RR: 0.93, 95%CI: 0.90, 0.97), with high heterogeneity, I2 = 64%, 95%CI: 30%, 87%; Pheterogeneity = 0.01 (Fig. 3). The association stayed significant with the stepwise exclusion of each study in turn (RR ranged between 0.92 and 0.94). None of the excluded studies accounted for the observed heterogeneity in the data. There was a linear inverse association between calcium intake with risk of developing hypertension, with a somewhat steeper trend within the low and moderate intakes (P for nonlinearity = 0.18, Fig. 4).

Fig. 3
figure3

Relative risk of hypertension for a 500 mg/d increment in dietary calcium intake. ES effect size

Fig. 4
figure4

Dose–response associations of dietary calcium intake and risk of developing hypertension (P for nonlinearity = 0.18). Sold line and long dashed lines represent relative risk and its 95% confidence interval

Quality of meta-evidence

All studies included in this meta-analysis were at high quality (≥7 scores) based on the Newcastle–Ottawa Scale. Additionally, the NutriGrade meta-evidence rating was “moderate” in this meta-analysis (the NutriGrade score: 6); which suggests that there is a moderate confidence in effect estimate.

Discussion

The present study summarized existing evidence about the longitudinal association of dietary calcium intake with risk of developing hypertension. Our review indicates that the risk of developing hypertension decreases by 11% for the highest compared with the lowest category of dietary calcium intake, and by 7% for each 500 mg/d increment in calcium intake. All of the studies controlled for body mass index. Also, subgroup analyses showed significant inverse associations in the subgroups of studies that controlled for intake of sodium, magnesium, and potassium. Thus, we showed that higher intake of calcium, independent of adiposity and intake of other blood pressure-related minerals, is associated with a lower risk of developing hypertension.

Our results are in agreement with those of previous meta-analyses of prospective studies, which have indicated that higher intake of calcium-rich foods, such as dairy products, were associated with a significant lower risk of developing hypertension [29, 36, 37]. Dairy products are good dietary sources of potassium, essential amino acids, high biological value proteins, and some peptides; all of which have been proposed to have hypotensive properties [14]. Also, dairy products are the main dietary sources of calcium in Western diet; in a way that about 80% of daily calcium intake in the US population are from dairy products [14]. Thus, it has been proposed that some parts of hypotensive properties of dairy products can be attributable to their great content of calcium.

Several reasonable mechanisms have been proposed to explain the observed relationship. Higher intake of dietary calcium, mainly through decreasing the production of 1.25 (OH)2 vitamin D, and subsequent decreasing calcium influx in cells, especially in vascular smooth muscle cells, exerts its hypotensive properties [38]. Reducing intracellular calcium levels suppresses vascular smooth muscle cells contractions [39], increases adipocyte lipolysis [40], and decreases lipogenesis [41]; all of which are associated with lower blood pressure levels. Higher dietary calcium intake may decrease plasma renin activity [42]. Additionally, calcium plays a regulatory role in energy metabolism [43], has a contributing role in weight management [44]; and as a result, may be negatively associated with weight gain [41]. Also, higher dietary calcium intake is negatively associated with insulin resistance [45, 46], one of the most important underlying causes of hypertension [47].

Some important considerations must be acknowledged when interpreting the present results. Of the eight studies included in the present meta-analysis, seven studies were from Western countries, where the main dietary sources of calcium are dairy products [48, 49]. Dairy products are good dietary sources of potassium, the nutrient that has been shown to have an inverse relationship with blood pressure [50,51,52]. Additionally, milk proteins are rich in peptides with hypotensive properties [53]. Thus, despite the significant inverse association in the subgroup that controlled for dietary potassium, it is difficult to exclude the residual effects of these confounding variables.

In accordance with this hypothesis, our subgroup analysis showed a significant inverse association only with dairy calcium intake, but not with nondairy calcium. A recent meta-analysis of 11 prospective observational studies showed similar results, in which higher intake of diary calcium, but not nondairy calcium, was associated with a lower risk of stroke [54]. This difference may be, in part, explained by different nutritional content of dietary sources of calcium; as well as by different bioavailability of calcium in different foods [55]. However, only two studies assessed the distinct association of dairy and nondairy calcium with risk of hypertension [33, 35]. Additionally, the Singapore Chinese Health Study in Singapore [33]; where dairy products accounted for only about 20% of dietary calcium intake, showed a significant inverse association between dietary calcium intake and hypertension risk. Also, an evaluation within the Nurses’ Health Study exhibited that higher intakes of both dairy and nondairy calcium were associated with a lower risk of developing hypertension; with a somewhat stronger inverse association with nondairy calcium [35]. Thus, increasing the consumption of dietary calcium, both from dairy and nondairy foods, may be a good dietary advice for primary prevention of hypertension. Further prospective observational studies are needed to evaluate the distinct association of diary and nondairy calcium, or calcium from low-fat and high-fat dairy products, with risk of developing hypertension.

Evidence from interventional studies suggests that calcium supplementation can decrease blood pressure levels, in both hypertensive and normotensive populations [56, 57]. However, their results indicated that supplementation with calcium can slightly reduce blood pressure levels; and as a result, there is no convincing evidence that promotes calcium supplementation for treating or preventing hypertension.

A nonlinear dose–response meta-analysis showed an inverse linear association between calcium intake with risk of developing hypertension. Two previous meta-analyses of prospective observational studies have suggested a possible U-shaped or reverse J-shaped association between calcium intake with risk of cardiovascular morbidity and mortality [54, 58]. The highest median intake among the upper categories of dietary calcium intake in our primary studies (1400 mg/d) was much lower than the corresponding intakes in those two previous meta-analyses (1800–2000 mg/d). In addition, only in one study in the present meta-analysis, the median intake in the highest category was >1100 mg/d. Thus, we have no conclusive evidence regarding calcium intake of ≥1100 mg/d.

The present meta-analysis has several strengths. For the first time, we showed the longitudinal association of dietary calcium intake with risk of developing hypertension, with the use of large-scale, high-quality, prospective cohort studies. Additionally, we showed a significant inverse association in the subgroup of studies than controlled for intake of sodium, potassium, and magnesium; which has suggested a possible independent association between dietary calcium and hypertension risk.

We also were faced with some limitations. First, participants in the upper categories of dairy products intake, especially low-fat dairy products, generally have healthier lifestyle-related behaviors [18, 33, 34]; which in turn are associated with a lower risk. Second, only one study was from Asia, where the main dietary sources of calcium are completely different from Western countries. As above mentioned, about four-fifths of dietary calcium intake in the US population come from dairy products [14]. Whereas, in the Singapore Chinese Health Study in Singapore, about 60% of dietary calcium intake were form vegetables, whole grains, soy products, fruits, and seafoods [59]. Therefore, further studies are needed to evaluate the association of dietary calcium intake with risk of hypertension in Asian population. Finally, although publication bias tests did not show any evidence of publication bias; however, due to the low number of studies (n < 10), their results may be due to the chance. Thus, we may have reached an over-estimated conclusion.

Conclusion

The present meta-analysis of prospective observational studies indicates that higher dietary calcium intake, independent of adiposity and intake of other blood pressure-related minerals including sodium, potassium, and magnesium; is associated with a lower risk of developing hypertension. Considering the distinct association of dietary sources of calcium with risk of the diseases, further observational studies are needed to evaluate the possible distinct association of dairy and nondairy calcium, or calcium from low-fat and high-fat dairy products, with risk of developing hypertension.

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Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author contributions
Research idea and study design: A.J., M.S.Z.; data acquisition: A.J., M.S.Z.; data analysis/interpretation: A.J., M.S.Z.; statistical analysis: A.J., supervision: A.J., A.J. is the guarantor. All authors have read and approved the final manuscript. All authors had full access to all the data and take responsibility for the integrity of the data and the accuracy of the data analysis.
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Affiliations
Food (Salt) Safety Research Center, Semnan University of Medical Sciences, Semnan, Iran
Ahmad Jayedi
Nursing Care Research Center, Semnan University of Medical Sciences, Semnan, Iran
Mahdieh Sadat Zargar
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The authors declare that they have no conflict of interest.
Fuente: nature.com. 10-08-2018