Re: 마그네슘 보충제 복용 --＞CRP 감소, 산화질소 증가 2022 RCT 논문.

[문형철]

Nutrients

. 2022 Feb 5;14(3):679. doi: 10.3390/nu14030679

Effect of Magnesium Supplementation on Inflammatory Parameters: A Meta-Analysis of Randomized Controlled Trials

Nicola Veronese 1, Damiano Pizzol 2, Lee Smith 3, Ligia J Dominguez 1,4,*, Mario Barbagallo 1

Editor: Roberto Iacone

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PMCID: PMC8838086  PMID: 35277037

Abstract

Magnesium (Mg) may have several beneficial effects on human health outcomes. One hypothesized mechanism eliciting such effects is the action of Mg on serum inflammatory parameters. However, studies on this topic to date have several important limitations. Therefore, the present systematic review and meta-analysis aimed to summarize the current state of the art of all randomized control trials (RCTs) investigating the effects of Mg supplementation versus placebo on serum parameters of inflammation. We searched several databases until 23 November 2021 for RCTs. Eligible studies were RCTs investigating the effect of oral Mg supplementation vs. placebo and having serum inflammatory markers as an outcome. Among 2484 papers initially screened, 17 randomized controlled trials (889 participants; mean age: 46 years; females: 62.5%) were included. Generally, a low risk of bias was present. In meta-analysis, Mg supplementation significantly decreased serum C reactive protein (CRP) and increased nitric oxide (NO) levels. In descriptive findings, Mg supplementation significantly reduced plasma fibrinogen, tartrate-resistant acid phosphatase type 5, tumor necrosis factor-ligand superfamily member 13B, ST2 protein, and IL-1. In conclusion, Mg supplementation may significantly reduce different human inflammatory markers, in particular serum CRP and NO levels.

마그네슘(Mg)은 

인체 건강에 여러 가지 유익한 영향을 미칠 수 있습니다. 

이러한 효과를 유발하는 것으로 추정되는 메커니즘 중 하나는 

혈청 염증 매개변수에 대한 마그네슘의 작용입니다. 

그러나 지금까지 이 주제에 대한 연구는 몇 가지 중요한 한계가 있습니다. 따라서, 본 체계적 고찰 및 메타분석은 마그네슘 보충제가 위약에 비해 염증의 혈청 매개변수에 미치는 영향을 조사하는 모든 무작위 대조 시험(RCT)의 최신 기술을 요약하는 것을 목표로 합니다. 2021년 11월 23일까지 여러 데이터베이스를 검색하여 RCT를 찾았습니다. 

적격 연구들은 경구용 마그네슘 보충제의 효과를 위약과 비교하고 혈청 염증 마커를 결과로 하는 RCT였습니다. 처음 선별된 2,484건의 논문 중 17건의 무작위 대조 시험(참가자 889명, 평균 연령: 46세, 여성: 62.5%)이 포함되었습니다. 일반적으로 비뚤림 위험이 낮았습니다. 

메타 분석에서, 

마그네슘 보충은 

혈청 C 반응성 단백질(CRP)을 현저하게 감소시키고 

산화질소(NO) 수준을 증가시켰습니다. 

설명적 결과에서, 

마그네슘 보충은 혈장 피브리노겐, 타르타르산염 저항성 산성 인산분해효소 5형, 

종양 괴사 인자-리간드 슈퍼패밀리 구성원 13B, ST2 단백질, 

그리고 IL-1을 현저하게 감소시켰습니다. 

결론적으로, 

마그네슘 보충은 다양한 인간 염증 표지자, 

특히 혈청 CRP와 NO 수준을 현저하게 감소시킬 수 있습니다.

Keywords: magnesium, inflammation, C reactive protein, tumor necrosis factor, randomized controlled trial, meta-analysis

1. Introduction

The literature regarding the health benefits of magnesium (Mg) is exponentially increasing [1]. In an umbrella review with 16 meta-analyses and 50 independent outcomes findings suggested that Mg is associated with several positive health outcomes [1]. It is widely known that Mg is involved in more than 600 enzymatic reactions [2], consequently having a wide spectrum of actions in pregnancy [3,4,5], as well as in cardiovascular [6,7], gastrointestinal [8], infectious [9], and metabolic diseases [10], such as diabetes [11,12].

It should be acknowledged that several papers have reported that Mg has positive effects on medical events likely owing to improving inflammatory parameters [13,14,15]. For example, one observational study reported an inverse relationship between dietary magnesium intake and inflammatory parameter levels (in particular C-reactive protein, CRP) in people affected by obesity [13]. However, observational studies on this topic to date have been limited by research design or heterogeneity of the participants included (e.g., gender, ethnicity, age, etc.) and likely underpowered to achieve comprehensive and reliable conclusions [14,15]. Two meta-analyses have also shown that Mg supplementation can have differing effects on some indices of inflammatory and anti-inflammatory indexes, such as CRP [14,15]. Despite the importance of these two meta-analyses [14,15], many other studies are now available although the evidence is limited to CRP as an outcome.

Although the pathophysiological mechanisms through which Mg may improve inflammatory status is not clear yet, it has been demonstrated in, animal models and human studies that Mg deficiency acts as a trigger for the inflammatory process [15]. A possible explanation is that the reduction of Mg levels stimulates macrophages and influx of calcium ions into cells [16]. The increased cell calcium levels increase the Mg necessary to block the influx of calcium ions with an increased stimulation of N-methyl-D-aspartate receptors that present high permeability to calcium [16]. Thus, the stimulation of these receptors lead to the opening of non-selective channels to cations with a consequent rise of calcium ions in neuronal cells [16]. The result is the releasing of neurotransmitters and cytokines as IL-6 that, in turn, enhance CRP release starting the inflammatory response [17].

Given this background, the present systematic review and meta-analysis aimed to summarize the current state of the art of all randomized control trials (RCTs) investigating the effects of Mg supplementation versus placebo on serum parameters of chronic inflammation.

1. 서론

마그네슘(Mg)의 건강상 이점에 관한 문헌이 기하급수적으로 증가하고 있습니다 [1]. 16개의 메타 분석과 50개의 독립적인 결과 발견을 포함한 종합 검토에서 마그네슘이 여러 가지 긍정적인 건강 결과와 관련이 있다는 사실이 밝혀졌습니다 [1].

마그네슘은

600개가 넘는 효소 반응에 관여하는 것으로 널리 알려져 있으며[2],

따라서 임신[3,4,5]뿐만 아니라 심혈관[6,7], 위장[8], 감염[9], 당뇨병[11,12]과 같은

대사성 질환[10]에도 광범위한 작용을 하는 것으로 알려져 있습니다.

여러 논문에서 마그네슘이 염증 매개 변수를 개선하여 의료 사건에 긍정적인 영향을 미칠 수 있다고 보고한 바 있습니다 [13,14,15]. 예를 들어, 한 관찰 연구에서는 비만 환자의 식이 마그네슘 섭취량과 염증 매개 변수 수준(특히 C-반응성 단백질, CRP) 사이에 역관계가 있다고 보고했습니다 [13]. 그러나 지금까지 이 주제에 대한 관찰 연구는 연구 설계 또는 포함된 참가자의 이질성(예: 성별, 민족, 연령 등)으로 인해 제한되어 왔으며, 포괄적이고 신뢰할 수 있는 결론을 얻기에는 역부족인 것으로 보입니다 [14,15]. 두 가지 메타 분석에서도 Mg 보충제가 CRP와 같은 염증 및 항염증 지표의 일부 지표에 다른 영향을 미칠 수 있음을 보여주었습니다 [14,15]. 이 두 가지 메타 분석의 중요성에도 불구하고 [14,15], CRP를 결과로 한 제한적인 증거에도 불구하고, 현재 많은 다른 연구들이 이용 가능합니다.

마그네슘이 염증 상태를 개선할 수 있는 병태생리학적 메커니즘은 아직 명확하지 않지만, 마그네슘 결핍이 염증 과정의 유발 요인 역할을 한다는 사실이 동물 모델과 인간 연구에서 입증되었습니다 [15].

그 이유 중 하나는

마그네슘 수치가 감소하면

대식세포가 자극을 받아

세포 내로 칼슘 이온이 유입되기 때문일 수 있습니다[16].

세포 내 칼슘 수치가 증가하면

칼슘에 대한 높은 투과성을 가진 N-메틸-D-아스파르트산 수용체의 자극이 증가하여

칼슘 이온의 유입을 차단하는 데 필요한 마그네슘이 증가합니다[16].

따라서

이러한 수용체의 자극은 비선택적 채널을 통해 양이온이 유입되도록 유도하고,

그 결과 신경 세포에서 칼슘 이온이 증가하게 됩니다[16].

그 결과,

신경전달물질과 사이토카인인 IL-6가 방출되면서,

CRP 방출이 촉진되어 염증 반응이 시작됩니다 [17].

이러한 배경을 고려하여, 본 체계적 고찰 및 메타분석은 만성 염증의 혈청 매개변수에 대한 마그네슘 보충제와 위약의 효과를 조사하는 모든 무작위 대조 시험(RCT)의 최신 기술을 요약하는 것을 목표로 합니다.

2. Materials and Methods

This systematic review adhered to the PRISMA statement [18] and followed a pre-planned, but unpublished protocol enclosed in the Supplementary Material.

2.1. Data Sources and Searches

Two investigators (NV and DP) independently conducted a literature search using several databases including PubMed/Medline, EMBASE, EBSCO, Web of Science from database inception until 23 November 2021, including RCTs investigating the effect of oral Mg vs. placebo on serum inflammatory parameters (outcome).

In PubMed, the following search strategy was used: (‘magnesium’) AND (‘inflammation’ OR ‘inflammatory’ OR ‘interferons’ OR ‘interferon’ OR ‘TNF’ OR ‘tumor necrosis factor’ OR ‘IL’ OR ‘interleukin’ OR ‘TGF’ OR ‘transforming growth factor’ OR ‘CRP’ OR ‘C-reactive protein’ OR ‘cytokines’ OR ‘cytokine’) AND (‘clinical trial’ OR ‘randomized controlled trial’ OR ‘placebo’), adapting the search according to the database. Any inconsistencies were resolved by consensus with a third author (LS).

2.2. Study Selection

Inclusion criteria for this meta-analysis were: (i) RCT; (ii) double-blind design; (iii) use of oral Mg supplementation; (iv) assessment of serum inflammatory parameters at follow-up eval‎uation; (v) written in English. Studies were excluded if: (i) did not include humans; (ii) used a control group taking other substances than placebo; (iii) lack of sufficient information regarding serum inflammatory parameters.

2.3. Data Extraction

Two independent investigators (NV and DP) extracted key data from the included articles in a standardized Excel spread sheet and a third independent investigator (LS) checked the data. For each article, we extracted data on author names, year of publication, country, condition, study design (crossover or parallel), Mg daily dosage, and follow-up duration (in weeks). Moreover, we extracted data by Mg or placebo in relation to mean age, body mass index (BMI), and number of females at baseline.

2.4. Outcomes

The primary outcomes were the values of serum parameters of inflammatory markers after treatment with Mg compared to placebo.

2.5. Quality Assessment

Two authors (NV and DP) completed scoring using the risk of bias (RoB) tool suggested by the Cochrane group [19]. This tool assesses several domains of the quality of each RCT, including: adequacy of random sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete data outcome (assessment of dropouts), selective outcome reporting, and the presence of other sources of bias. The potential answers were, as the Cochrane Handbook suggests, low risk of bias, high or unclear [20].

2.6. Data Synthesis and Analysis

All analyses were performed using STATA version 14.0 (StataCorp, College Station, TX, USA). Outcomes with at least three studies were meta-analyzed, whilst outcomes with less than three studies were reported descriptively.

The primary analysis compared serum parameters of inflammatory markers between participants treated with oral Mg supplementation vs. placebo at the follow-up eval‎uation. We calculated the difference between the means of the treatment and placebo groups using follow-up data through standardized mean differences (SMD) with their 95% confidence intervals (CIs), applying a random-effect model [21]. Heterogeneity across studies was assessed by the I2 metric and χ2 statistics. Given significant heterogeneity (I2 ≥ 50%, p < 0.05) and for outcomes having at least ten studies, we conducted a series of meta-regression analyses, according to follow-up (weeks), daily Mg dose, and differences at the baseline eval‎uation between treated with Mg and placebo in mean BMI, age, CRP serum levels, and percentage of females.

Publication bias was assessed by visually inspecting funnel plots and using the Begg–Mazumdar Kendall tau [22] and the Egger bias test [23].

For all analyses, a p-value less than 0.05 was considered statistically significant.

3. Results3.1. Search Results

As shown in Figure 1, among 2501 records initially screened, 31 were retrieved as full-texts: of them, 17 papers [17,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39] were included in the systematic review with 15 contributing to the meta-analysis.

Figure 1.

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PRISMA flow-chart.

3.2. Study and Patient Characteristics

Full details regarding descriptive findings are reported in Table 1.

Table 1.

Descriptive findings of the randomized controlled trials included.

MagnesiumPlaceboAuthor, YearCountryConditionInflammatory ParametersDaily MgDoses (mg)Type of MgFollow-Up (Weeks)Sample SizeAge (SD) (Years)Women (%)BMI(SD)Sample SizeAge (SD) (Years)Women (%)BMI(SD)

Alonso, 2020 [34]	USA	Cardiovascular Diseases	CRP, NO, TAC, GSH, MDA, Tartrate-resistant acid phosphatase type 5, ST2 protein, Interleukin-1 receptor type 1	400	Oxide	10	24	62 ± 5	88	28.3 ± 5.01	28	62 ± 6	61	27.8 ± 4.2
Asemi, 2015 [17]	Iran	Pregnancy	CRP, NO, TAC, MDA	250	Oxide	6	35	29.1 ± 4.6	100	29.6 ± 5.4	35	29.4 ± 3.1	100	29.1 ± 3.5
Chacko, 2010 [25]	USA	Overweight	CRP, IL-6, TNF-alfa	500	Citrate	4	13	47 ± 13.8	43	28.3 ± 1.6	13	41.9 ± 12.7	24	28.1 ± 2.2
Cosaro, 2014 [28]	Italy	Family history of metabolic syndrome	CRP	368	Pidolate	8	8				6
Hosseini, 2016 [37]	Iran	Asthma	IL-17	340	Citrate	8	50	36.38 ± 9.72	50	25.6 ± 3.8	50	34.56 ± 8.28	44	26.19 ± 3.69
Joris, 2017 [31]	The Netherlands	Overweight/ obese	CRP, IL-6, IL-8, TNF-alfa, amyloid	350	Citrate	24	26				25
Kazaks, 2010 [24]	USA	Asthma	CRP	340	Citrate	26	27	37 ± 2	50	29 ± 1	25	37 ± 2	61.1	28 ± 1
Lima de Souza E Silva, 2014 [29]	Brasil	Metabolic Syndrome	CRP	400	Chelate	12	35	44.6 ± 9.7		35.5 ± 8.2	37	46.6 ± 12.3		35.1 ± 6.3
Mortazavi, 2013 [27]	USA	Hemodialysis patients	CRP	440	Oxide	24	27	56.93 ± 12.19	48.3		25	56.36 ± 11.15	48
Moslehi, 2012 [36]	Iran	Overweight	CRP, IL-6, fibrinogen	250	Oxide	8	35		100	27.9 ± 3.2	34		100	27.9 ± 3
Mousavi, 2021 [39]	Iran	Polycystic ovary syndrome	CRP, TAC, MDA, TNF-alfa	250	Oxide	8	21	25.6 ± 4.9	100	28.0 ± 3.2	20	26.2 ± 5.7	100	26.9 ± 3.8
Razzaghi, 2018 [32]	Iran	Diabetic foot ulcer	CRP, NO, TAC, GSH, MDA, ERS	250	Oxide	12	35	60.1 ± 11.1	37.1	28.2 ± 5.2	35	59 ± 10.1	31.4	26.3 ± 4.2
Rodriguez-Hernandez, 2010 [35]	Mexico	Obese	CRP	450	Chloride	16	19	44.2 ± 10.8	63.6	30.5 ± 4.4	19	43.2 ± 7.8	63.6	35.1 ± 7.9
Simental-Mendia, 2012 [26]	Mexico	Prediabetes	CRP, IL-6, IL-10, TNF-alfa	382	Chloride	12	11	44.2 ± 10.8	63.6	30.5 ± 4.4	11	43.2 ± 7.8	63.6	35.1 ± 7.9
Simental-Mendia, 2014 [30]	Mexico	Prediabetes	CRP	382	Chloride	12	29	39.8 ± 16	55.2	30.5 ± 5.7	28	41.1 ± 13.1	60.7	30 ± 5.7
Talari, 2019 [33]	Iran	Diabetic hemodialysis	CRP, NO, TAC, GSH, MDA	250	Oxide	24	27	58.8 ± 10.1	51.9	27.2 ± 5.6	27	61.8 ± 10.2	55.6	26.2 ± 4.4
Zanforlini, 2021 [38]	Italy	Chronic obstructive pulmonary disease	CRP, TNF-alfa	300	Citrate	24	21	73 ± 8.9	24	26.9 ± 4.3	20	72.2 ± 11	20.8	26.9 ± 3.8
Total						Median = 12	447	47.1 ± 9.3	62.5	29.0 ± 4.4	442	46.8 ± 8.7	59.6	29.2 ± 4.4

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Among the 17 RCTs included, six were conducted in Asia, eight in North or South America, and three in Europe. The conditions ranged from metabolic disorders (including diabetes, pre-diabetes, overweight/obesity) present in 12 RCTs, pregnancy (n = 1), cardiovascular (n = 1), and respiratory conditions (n = 2). The median follow-up was 12 weeks, with a range between 4 and 26. The majority of the studies (n = 7) used a quantity of 250 mg/daily of Mg oxide (n = 5).

Altogether, 447 participants were randomized to Mg treatment: these participants had a mean age of 47.1 ± 9.3 years, were mainly female (=62.5%) with a mean BMI of 29.0 kg/m2. Conversely, 442 participants were randomized to the placebo group, having a similar mean age (46.8 ± 8.7 years), % of females (59.6%), and mean BMI (29.2 kg/m2) to the intervention group (Table 1).

3.3. Meta-Analysis of Mg Supplementation versus Placebo on Serum Inflammatory Parameters

Table 2 shows the effect of Mg on serum inflammatory parameters. Among 737 participants in 15 RCTs, compared to placebo, Mg supplementation significantly decreased serum CRP (SMD = −0.356; 95% CI: −0.659 to −0.054; p = 0.02) (Figure 2), although a high heterogeneity (I2 = 74.8%) was observed. Similarly, Mg supplementation increased nitric oxide levels (n = 3 studies; 194 participants; SMD = 0.321; 95% CI: 0.037 to 0.604; p = 0.026; I2 = 0%) (Figure 3). On the contrary, in the meta-analyses performed with at least three studies, Mg supplementation did not affect the serum levels of IL-6, total antioxidant capacity, glutathione (GSH), tumor necrosis factor alpha, whilst the effect on malondialdehyde (MDA) was at the limits of statistical significance (SMD = −0.604; 95% CI: −1.224 to 0.017; p = 0.057; I2 = 77.8%) (Table 2). Visual inspection of funnel plots and the Begg–Mazumdar Kendall tau and the Egger bias tests did not suggest the presence of publication bias.

Table 2.

Meta-analysis of magnesium supplementation on serum inflammatory parameters.

Inflammatory ParameterNumber of ComparisonsNumber of ParticipantsSMD95% CIp ValueI2Egger’s Test (p-Value)

CRP	15	737	−0.356	−0.659	−0.054	0.02	74.8	−0.28 (0.92)
IL-6	3	142	−0.258	−1.083	0.567	0.54	81.3	0.94 (0.38)
NO	3	194	0.321	0.037	0.604	0.03	0	0.67 (0.40)
TAC	4	235	0.189	−0.491	0.869	0.59	84.8	8.86 (0.53)
GSH	3	194	−0.181	−0.463	0.102	0.21	0	3.00 (0.61)
MDA	3	194	−0.604	−1.224	0.02	0.06	77.8	−13.9 (0.68)
TNF-a	3	112	0.168	−0.433	0.768	0.58	58.8	3.84 (0.68)

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Figure 2.

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Forrest plot of the effect of magnesium versus placebo on serum C-reactive protein [17,24,25,26,27,28,29,30,31,32,33,35,36,38,39].

Figure 3.

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Forrest plot of the effect of magnesium versus placebo on serum nitric oxide [17,32,33].

Among the inflammatory parameters having less than three RCTs, Mg supplementation significantly reduced plasma fibrinogen, tartrate-resistant acid phosphatase type 5, tumor necrosis factor ligand superfamily member 13B, Tumorigenicity 2 protein, and IL(interleukin)-1, while no significant variations were observed on IL-8, IL-10, IL-17, erythrocyte sedimentation rate, and serum amyloid.

3.4. Risk of Bias

The risk of bias assessment is fully reported in Supplementary Table S1. In general, the risk of bias was generally low. Only one RCT [35] had a suspicious high risk of bias in sequence generation, allocation concealment and blinding of participants, personnel and outcome assessors. However, in the sequence generation 7/17, in the allocation concealment and in blinding of participants, personnel and outcome assessors 3 RCTs over 17 were at unclear risk of bias.

3.5. Meta-Regression Analysis

Supplementary Table S2 reports the data of the meta-regression taking the difference between treated with Mg and treated with placebo in serum CRP at the follow-up eval‎uation, as outcome. The only factor that was able to explain the heterogeneity of this outcome (I2 = 75.6%) was the difference in the percentage of women between the two groups (beta = 0.06; 95% CI: 0.004 to 0.11; p = 0.03) meaning that each increase in one percentage point in the difference of women between groups corresponded to an increase in 0.06 units of CRP (R2 = 39%).

4. Discussion

The present meta-analysis including 17 RCTs with more than 800 participants found that, when compared to placebo, Mg supplementation significantly reduced serum CRP levels, thus supporting previous literature [14,15]. In addition, we found that Mg supplementation increased NO levels.

Considering the inflammatory markers, assessed at least from three RCTs, no other significant variations were reported comparing the treated vs. placebo groups. Interestingly, although not statistically significant, three such important markers IL-6, GSH and MDA showed a reduction in treated groups compared to the baseline indicating that further studies are required to confirm‎ these findings and render possible the formulation of stronger conclusions. In particular, it is important to understand the effects of Mg intake on IL-6 levels [40], which is secreted by T cells and macrophages and acts as both a pro-inflammatory and an anti-inflammatory cytokine. Therefore, IL-6 may be both an indicator of acute inflammation, or undetected infection [40]. In addition, as this topic is attracting increasing attention, recent evidence reported that Mg supplementation significantly improved the reduction of plasma fibrinogen [36,41], tartrate-resistant acid phosphatase type 5, TNF ligand superfamily member 13B, ST2 protein, and IL-1 [34,42].

Moreover, it has been reported that Mg deficiency, in animal models, may increase the recruitment of phagocytic cells to perform their effector functions, which ultimately leads to the generation of reactive oxygen species leading to an increased production of several cytokines involved in the inflammatory cascade, such as TNF-α [43]. At the same time, the release of these cytokines is induced by an increased level of intracellular Ca2+, which is considered a signal to start the inflammatory process and this condition could occur in case of Mg deficiency [44]. Moreover, other in animal and in vitro studies have indicated that pro-inflammatory cytokine production induced in case of Mg deficiency involves the pathway of NFκβ, with a consequent higher production of TNF-α and IL-1β [45]. Therefore, it is likely that all the systems involved in Mg deficiency may affect the inflammatory response in several ways and, in particular, through a modulation of intracellular calcium that regulates several pathways involved in inflammation [42].

Furthermore, this is the first meta-analysis showing that Mg can improve NO levels. This find could be crucial not only in terms of inflammatory mechanisms, but also from a cardiovascular point of view with a potential clinical impact. Interestingly, there is evidence showing that low Mg levels are associated with increased atrial fibrillation and coronary heart disease risk, while Mg supplementation is implied in the secondary prevention of cardiac arrhythmias [46,47]. Indeed, in vitro and in vivo animal studies have discovered a number of new electrophysiological properties of NO [48].

Finally, another interesting result of our systematic review and meta-analysis is that in meta-regression analyses the difference in percentage of females at baseline between treated and placebo groups was associated with a higher effect of Mg supplementation on serum CRP levels. Whilst it is known that males and females have significantly different levels of Mg not only in serum, but also in other biological fluids [49], the exact reason of the effect of Mg being more efficacious in females than in males in lowering serum CRP levels is not known and, therefore, future research is warranted.

The results of this meta-analysis should be considered taking in account its limitations. First, the RCTs included were small in sample size, had a limited follow-up time, and used different doses and types of Mg; therefore, the clinical applicability of our findings should be confirmed in higher quality RCTs. Second, several studies did not include the assessment of Mg introduced in the diet. However, it may be hypothesized that no significant difference in this parameter was present between treated and placebo groups due to randomization. The role of dietary Mg on the effect of Mg supplementation should be better determined. Third, for several outcomes, we were not able to run a meta-analysis since these outcomes were included in less than 3 studies. Finally, when considering the outcome with the largest number of studies, i.e., serum CRP, it was characterized by a high heterogeneity that we were able to explain only partly with the meta-regression analyses.

5. Conclusions

This systematic review and meta-analysis showed the beneficial effects of Mg supplementation in significantly reducing different inflammatory markers, in particular CRP and increasing NO levels. These data open new scenarios in clinical practice suggesting the importance of considering Mg supplementation in patient categories, with particular focus on cardiovascular diseases. Considering the presence of inconsistent but potentially useful data regarding Mg supplementation, further studies are desirable to corroborate and better clarify these findings.

4. 토론

800명 이상의 참가자를 대상으로 한

17건의 RCT를 포함한 현재의 메타 분석에 따르면, 위약과 비교했을 때,

마그네슘 보충제는 혈청 CRP 수치를 현저하게 감소시켰으며,

따라서 이전의 문헌을 뒷받침하는 것으로 나타났습니다 [14,15].

또한,

마그네슘 보충제는

NO 수치를 증가시켰습니다.

적어도 3건의 RCT에서 평가된 염증성 마커를 고려할 때, 치료군과 위약군을 비교했을 때 다른 유의미한 차이가 보고되지 않았습니다. 흥미롭게도, 통계적으로 유의미하지는 않지만, IL-6, GSH, MDA와 같은 중요한 지표 3개가 기준치에 비해 치료군에서 감소한 것으로 나타났습니다. 따라서 이러한 결과를 확인하고 더 강력한 결론을 도출하기 위해서는 추가 연구가 필요합니다. 특히, T세포와 대식세포에 의해 분비되어 전염증성 사이토카인과 항염증성 사이토카인 역할을 모두 하는 IL-6 수치에 대한 마그네슘 섭취의 영향을 이해하는 것이 중요합니다. 따라서, IL-6는 급성 염증 또는 감지되지 않은 감염의 지표가 될 수 있습니다 [40]. 또한, 이 주제에 대한 관심이 높아짐에 따라 최근의 연구 결과에 따르면, 마그네슘 보충제가 혈장 피브리노겐 [36,41], 타르트레이트 내성 산성 인산분해효소 5형, TNF 리간드 슈퍼패밀리 멤버 13B, ST2 단백질, IL-1의 감소를 크게 개선한다는 사실이 보고되었습니다 [34,42].

또한 동물 모델에서 Mg 결핍이 식세포의 모집을 증가시켜 식세포의 이펙터 기능을 수행하게 하고, 이는 궁극적으로 TNF-α와 같은 염증 캐스케이드에 관여하는 여러 사이토카인의 생산 증가로 이어지는 활성 산소 종의 생성을 유발할 수 있다는 보고가 있습니다 [43]. 동시에, 이러한 사이토카인의 방출은 염증 과정을 시작하는 신호로 간주되는 세포 내 Ca2+의 증가된 수준에 의해 유발되며, 이러한 상태는 마그네슘 결핍의 경우에 발생할 수 있습니다 [44]. 또한, 동물 및 시험관 내 연구에 따르면 마그네슘 결핍의 경우에 유도되는 전염증성 사이토카인 생산은 NFκβ의 경로를 포함하며, 그 결과 TNF-α 및 IL-1β의 생산이 증가합니다 [45]. 따라서, Mg 결핍과 관련된 모든 시스템이 여러 가지 방식으로 염증 반응에 영향을 미칠 수 있으며, 특히 염증과 관련된 여러 경로를 조절하는 세포 내 칼슘의 조절을 통해 영향을 미칠 수 있습니다 [42].

또한,

이것은 Mg가 NO 수준을 향상시킬 수 있다는 것을 보여주는

최초의 메타 분석입니다.

이 발견은 염증 메커니즘뿐만 아니라

잠재적인 임상적 영향을 가진 심혈관 측면에서도 매우 중요할 수 있습니다.

흥미롭게도,

낮은 마그네슘 수치가 심방 세동과 관상 동맥 심장 질환의 위험 증가와 관련이 있다는 증거가 있는 반면,

마그네슘 보충제는 심장 부정맥의 2차 예방에 도움이 된다는 것이 암시되고 있습니다 [46,47].

실제로, 체외 및 체내 동물 연구에서 NO의 새로운 전기 생리학적 특성이 다수 발견되었습니다 [48].

마지막으로, 체계적인 검토와 메타분석의 또 다른 흥미로운 결과는 메타 회귀 분석에서 치료군과 위약군 간의 기준선 여성 비율의 차이가 혈청 CRP 수준에 대한 Mg 보충제의 높은 효과와 관련이 있다는 것입니다. 남성과 여성의 혈청 내 Mg 수치는 물론 다른 체액 내에서도 현저한 차이가 있는 것으로 알려져 있지만[49], 혈청 CRP 수치를 낮추는 데 있어 Mg가 남성보다 여성에게 더 효과적인 이유는 정확히 밝혀지지 않았기 때문에 향후 연구가 필요합니다.

이 메타 분석의 결과는 그 한계를 고려하여 해석해야 합니다. 첫째, 포함된 RCT의 표본 크기가 작고, 추적 기간이 제한적이며, Mg의 용량과 유형이 다양했기 때문에, 우리의 연구 결과에 대한 임상적 적용 가능성은 더 높은 품질의 RCT에서 확인되어야 합니다. 둘째, 여러 연구에서 식이요법에 도입된 Mg의 평가가 포함되지 않았습니다. 그러나 무작위 배정 때문에 치료군과 위약군 사이에 이 매개변수에 유의미한 차이가 존재하지 않았을 것이라는 가설을 세울 수 있습니다. 식이성 마그네슘이 마그네슘 보충제의 효과에 미치는 역할은 더 잘 밝혀져야 합니다. 셋째, 몇몇 결과의 경우, 3개 미만의 연구에 포함되었기 때문에 메타 분석을 수행할 수 없었습니다. 마지막으로, 가장 많은 수의 연구가 포함된 결과, 즉 혈청 CRP를 고려할 때, 이 결과는 높은 이질성을 특징으로 하며, 메타 회귀 분석을 통해 부분적으로만 설명할 수 있었습니다.

5. 결론

이 체계적인 검토와 메타 분석은 마그네슘 보충제가 다양한 염증 표지자, 특히 CRP를 현저하게 감소시키고 NO 수준을 증가시키는 데 유익한 효과가 있음을 보여주었습니다. 이러한 데이터는 임상 실습에서 새로운 시나리오를 열어 주며, 특히 심혈관 질환에 초점을 맞추어 환자 범주에서 마그네슘 보충제를 고려하는 것이 중요하다는 것을 시사합니다. 마그네슘 보충제에 관한 일관성이 없지만 잠재적으로 유용한 데이터가 존재한다는 점을 고려할 때, 이러한 결과를 확증하고 더 명확하게 하기 위한 추가 연구가 바람직합니다.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu14030679/s1, supplementary Table S1: Risk of bias in the randomized controlled trials included; supplementary Table S2: Meta-regression analyses.

Click here for additional data file. (752.8KB, zip)

Author Contributions

Conceptualization: N.V. and M.B.; data curation: D.P., L.S. and N.V.; formal analysis: N.V.; methodology: N.V.; supervision: M.B.; roles/writing—original draft: L.J.D. and N.V.; writing—review & editing: L.S. and M.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Ethical review and approval were waived for this study due to the inclusion of already published works.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data and the databases are available upon reasonable request to the Corresponding Author.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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