The effects of alpha-lipoic acid supplementation on inflammatory markers among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials

The effects of alpha-lipoic acid supplementation on inflammatory markers among patients with... Objective: This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effect of alpha-lipoic acid (ALA) supplementation on the inflammatory markers among patients with metabolic syndrome (MetS) and related disorders. Methods: We searched the following databases until November 2017: PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. Three reviewers independently assessed study eligibility, extracted data, and evaluated risk of bias of included primary studies. Statistical heterogeneity was assessed using Cochran’sQ test and I-square (I ) statistic. Data were pooled by using the random-effect model and standardized mean difference (SMD) was considered as the summary effect size. Results: Eighteen trials out of 912 potential citations were found to be eligible for our meta-analysis. The findings indicated that ALA supplementation significantly decreased C-reactive protein (CRP) (SMD = − 1.52; 95% CI, − 2.25, − 0. 80; P <0.001), interlokin-6 (IL-6) (SMD = − 1.96; 95% CI, − 2.60, − 1.32; P < 0.001), and tumor necrosis factor alpha levels (TNF-α)(SMD = − 2.62; 95% CI, − 3.70, − 1.55; P < 0.001) in patients diagnosed with metabolic diseases. Conclusion: In summary, the current meta-analysis demonstrated the promising impact of ALA administration on decreasing inflammatory markers such as CRP, IL-6 and TNF-α among patients with MetS and related disorders. Keywords: Alpha-lipoic acid, Inflammatory markers, Meta-analysis Introduction Increased chronic inflammation is associated with Increased pro-inflammatory markers and oxidative stress increased risk of metabolic disorders, including type 2 occurs in adipose tissues are the two factors that may diabetes mellitus (T2DM) [2] and arteriosclerosis, play a key role in the incidence of metabolic-related co- endothelial dysfunction, vascular calcification, increased morbidities among patients with metabolic disorders [1]. activity of metalloproteinases, oxidative damage, and degradation of collagen [3–5]. It was reported that meta- bolic syndrome (MetS) is associated with a 2-fold in- * Correspondence: Maryam.chamani.k@gmail.com; asemi_r@yahoo.com creased risk of cardiovascular disease (CVD) over the Department of Gynecology and Obstetrics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran next 5 to 10 years [6]. Inflammatory cytokines including Research Center for Biochemistry and Nutrition in Metabolic Diseases, interleukin-6 (IL-6) and tumor necrosis factor-alpha Kashan University of Medical Sciences, Kashan, I.R, Iran (TNF-α) are usually produced by different cells including Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 2 of 10 endothelial, immune and arterial smooth muscle cells in- MetS” OR “diabetes” OR “T1DM” OR “T2DM” OR ducing the migration of additional immune cells into the “overweight” OR “obese” OR “chronic kidney disease atherosclerotic lesion and the activation of the acute (CKD)” OR “hypertension” OR “high blood pressure” phase C-reactive protein (CRP) in the liver [7, 8]. OR “dyslipidemia” OR “CVD”], intervention (“alpha-li- Increased levels of CRP are associated with increased poic acid” OR “ALA” OR “α-lipoic acid” AND “supple- risk of CVD and diabetes [9, 10]. In addition to CRP, mentation” OR “intake”), and outcomes [“CRP” OR other inflammatory biomarkers such as IL-6 and TNF-α “IL-6” OR “TNF-α”]. Eligible studies were restricted to may be correlated with the development of CVD in dia- those RCTs published in English language. betic patients [11]. Complementary therapies such as antioxidants supple- Inclusion and exclusion criteria mentation are recommended in patients with metabolic RCTs were selected using the following inclusion criteria: abnormalities to improve their nutritional status and being a placebo-controlled randomized trial (either parallel boost their immune system [12]. Existing evidence has or cross-over designs), human studies conducted in adults, proved the beneficial effects of several antioxidants sup- the target population was patients diagnosed with meta- plements including pentoxifylline [13] and lycopene [14] bolic diseases, and studies reported mean changes between on reducing inflammation. Available data regarding the pre- and post-intervention CRP and/or IL-6 and/or TNF-α effects of alpha-lipoic acid (ALA) supplementation on following ALA supplementation for the intervention and inflammatory markers are controversial. In a study by placebos groups. Other types of human studies (cross-sec- Carbonelli et al. [15], obese Caucasian people showed tional, cohort studies), animal, in vitro studies, and review significant reduction in CRP and TNF-α concentrations papers were excluded. Case reports or cases series, and the following ALA supplementation (800 mg/day) for studies did not achieve the minimum quality assessment 4 months. ALA supplementation (600–1000 mg/day) score, those receiving any non-steroidal anti-inflammatory during a period ranging from 2 wk. to 1 year in patients drug or ALA supplements within the last month were also with impaired glucose tolerance showed contradictory excluded from the study. results. Zhang et al. [16] demonstrated that ALA supple- mentation decreased TNF-α and IL-6 while increased Data extraction and quality assessment adiponectin levels, however others did not observe any Three authors (VO, MM, and MA) reviewed each trial beneficial effects of ALA on inflammatory markers [17, 18]. and extracted all related data, independently. The dis- Discrepancies in these findings may be due to differences in agreement among them was resolved by discussion with a study design, characteristics of study populations, dosage of fourth author (ZA). The quality of the included RCTs was ALA used and duration of the intervention. assessed using the Cochrane Collaboration risk of bias We are aware of no systematic review or meta-ana- tool based on the following information: randomization lyses of randomized controlled trials (RCTs) evaluating generation, allocation concealment, blinding of partici- the effect of ALA supplementation on inflammatory pants and outcome assessment, incomplete outcome data, markers among patients with MetS and related disor- and selective outcome reporting, as well as the other ders. Thus, the current meta-analysis was performed to sources of bias. The extracted data included: first author, summarize the available evidence regarding the effect of publication year, demographical variables, study design, ALA supplementation on inflammatory markers among sample size, dose of intervention, duration of study, type patients with MetS and related disorders. of intervention, type of disease, the mean and standard de- viation (SD) for CRP, IL-6, and TNF-α. Materials and methods Search strategy and selection studies Data synthesis and statistical analysis We searched the following databases until November We preformed a comprehensive electronic and manual 2017: PubMed, MEDLINE, EMBASE, Web of Science, search to avoid publication bias. Additionally, Egger’s re- and Cochrane Central Register of Controlled Trials. gression test was used to assess publication bias statisti- Additionally, a manual search was conducted among the cally [19]. Statistical heterogeneity was assessed using 2 2 references lists of all eligible articles and review studies Cochran’s Q and I-square (I ) tests [20]. I greater than to identify potential articles that were not captured by 50% or P < 0.05 was considered as significant heterogen- the electronic searches. Three authors (VO, MM and eity. We estimated the difference between intervention MA) independently performed the literature search to (ALA supplementation) and placebo group by calculat- retrieve RCTs that have examined the association be- ing the standardized mean difference (SMD) with 95% tween ALA supplementation and the inflammatory confidence interval (CI) using STATA software version markers by using the following MeSH and text 12.0 (Stata Corp., College Station, TX) and RevMan keywords: patients [“Mets” OR “disorders related to V.5.3 software (Cochrane Collaboration, Oxford, UK). Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 3 of 10 Table 1 Characteristics of included studies Authors (Ref) Publication year Sample size (control/ Country/population Intervention Duration Presented data Age (y) (control, Results intervention) (name and daily dose) intervention) Hong et al. [22] 2017 32/30 China/patients with 450 mg ALA (IV) + 20 2 weeks CRP, IL-6, TNF-α 65.82 ± 11.63, Decreased CRP, IL-6 diabetic nephropathy μg alprostadil 67.24 ± 10.81 and TNF-α Sardu et al. [25] 2017 40/33 Italy/overweight patients 600 mg ALA 12 months CRP, IL-6, TNF-α 61.5 ± 8.1, Decreased CRP, IL-6 with atrial fibrilation 58.8 ± 6.7 and TNF-α Huerta et al. [30] 2016 21/19 Spain/overweight and 300 mg ALA 10 weeks CRP, IL-6 range: 20–50 Decreased CRP and obese women IL-6 Huerta et al. [30] 2016 21/17 Spain/overweight and 300 mg ALA + 1.3 g EPA 10 weeks CRP, IL-6 range: 20–50 Decreased CRP obese women Marfella et al. [28] 2015 21/22 Italy/overweight patients 600 mg ALA 12 months CRP, TNF-α 63.9 ± 5.2, Decreased CRP and with cardiomyopathy 63.7 ± 6.5 TNF-α Safa et al. [37] 2014 31/30 Iran/patients with ESRD 600 mg ALA 8 weeks TNF-α 55.20 ± 13.43, No effect on hemodialysis 59.3 ± 10.47 Ahmadi et al. [23] 2013 24/20 Iran/hemodialysis patients 600 mg ALA 2 months CRP, IL-6 48.9 ± 12.5, Decreased CRP and 48.8 ± 11.2 IL-6 Ahmadi et al. [23] 2013 24/24 Iran/hemodialysis patients 600 mg ALA + 400 IU 2 months CRP, IL-6 48.9 ± 12.5, Decreased CRP and vitamin E 53.2 ± 9.8 IL-6 El-Nakib et al. [35] 2013 22/22 Egypt/patients with CRF 600 mg ALA 3 months IL-6 46.2 ± 14.4, No effect on hemodialysis 49.1 ± 16.2 Hegazy et al. [36] 2013 15/15 Egypt/patients with T1DM 600 mg ALA + insulin 4 months TNF-α 11.1 ± 2.3, Decreased TNF-α 11.9 ± 1.4 Cinteza al. [32] 2013 14/14 Romania/post acute stroke 600 mg ALA + other 2 weeks IL-6, TNF-α 67.1 ± 10.85, Decreased IL-6 and patients nutrients 64 ± 10.85 TNF-α Nasole et al. [33] 2013 6/10 Italy/patients with chronic 600 mg ALA 2 weeks IL-6, TNF-α 72,59 Decreased IL-6 and leg wound and metabolic TNF-α disease Nasole et al. [33] 2013 6/10 Italy/patients with chronic 600 mg R-(+)-lipoic 2 weeks IL-6, TNF-α 72,72 Decreased IL-6 and leg wound and metabolic acid (RLA) TNF-α disease Khabbazi et al. [27] 2012 28/24 Iran/patients with ESRD 600 mg ALA 8 weeks CRP 54.04 ± 13.96, Decreased CRP on hemodialysis 53.83 ± 13.29 Manning et al. [24] 2012 39/34 New Zealand/patients 600 mg ALA 12 months CRP, IL-6, TNF-α 57 ± 9, 55 ± 10 No effect with MetS Zhang et al. [16] 2011 9/13 China/obese patients with 600 mg ALA (IV) 2 weeks IL-6, TNF-α 52.6 ± 6.2, Decreased IL-6 and impaired glucose tolerance 52.5 ± 8.2 TNF-α Xiang et al. [21] 2011 30/30 China/patients with 600 mg ALA (IV) 3 weeks CRP 58 ± 9, 58 ± 10 Decreased CRP impaired fasting glucose Gianturco et al. [29] 2009 7/7 Italy/patients with NIDDM 400 mg ALA 4 weeks CRP 58 ± 16, 61 ± 7 No effect Chang et al. [26] 2007 25/25 Korea/diabetic ESRD 600 mg ALA 12 weeks CRP 66 ± 7, 63 ± 6 No effect patients on hemodialysis Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 4 of 10 Table 1 Characteristics of included studies (Continued) Authors (Ref) Publication year Sample size (control/ Country/population Intervention Duration Presented data Age (y) (control, Results intervention) (name and daily dose) intervention) Sola et al. [34] 2005 14/15 USA/patients with MetS 300 mg ALA 4 weeks IL-6 44 ± 13, 46 ± 15 Decreased IL-6 Sola et al. [34] 2005 14/15 USA/patients with MetS 300 mg ALA + 150 mg 4 weeks IL-6 44 ± 13, 48 ± 12 Decreased IL-6 irbesartan Romos et al. [31] 2012 28/30 USA/patients with CKD 600 mg ALA + 666 IU 8 weeks CRP, IL-6 64.5 ± 8.8, Decreased IL-6 tocopherols 58.6 ± 12.0 ALA alpha-lipoic acid, CRF chronic renal failure, CKD chronic kidney disease, ESRD end-stage renal disease, IV intravascular, IL-6 interlokin-6, CRP C-reactive protein, MetS metabolic syndrome, NIDDM non-insulin-dependent diabetes mellitus, TNF-α tumor necrosis factor alpha, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 5 of 10 Since the indications could effect on pooled SMD were We also performed subgroup analyses according to different between included studies, we used random-ef- geographic area (Asia, European, USA, Oceania, and Af- fects models to perform meta-analyses. Subgroup and rica), dosage of ALA supplements (> 600 vs. ≤600 mg/ sensitivity analyses were conducted to assess the source day), co-administration with other nutrients (ALA vs. of heterogeneity and to explore the contribution of each ALA plus other nutrients), duration of the intervention study to the reliability of the pooled mean difference, (≥8 vs. < 8 weeks), and type of diseases (diabetic, ESRD respectively. P-values < 0.05 were considered as statis- vs. other diseases). We found that heterogeneity may de- tically significant. crease by duration of the intervention (< 8 weeks = I : 2 2 89.9 and ≥ 8 weeks = I :85.1 vs. overall I :90.6%) and type 2 2 Results of diseases (diabetic = I : 75.1 and other = I :89.5 vs. The process of the step by step study selection has shown overall I :90.6%) for IL-6 and type of diseases (diabetic = 2 2 2 in Additional file 1. Overall, 18 trials out of 912 potential I : 92.8 and other = I :94.0 vs. overall I :94.3%) for 2 2 citations were found to be eligible for this meta-analysis. TNF-α levels (< 8 weeks = I : 88.2 and ≥ 8 weeks = I :92.1 Seven studies were RCTs design, and eleven were ran- vs. overall I :94.5%). The detailed of subgroup analysis domized, double-blind, placebo-controlled trials. Eleven are presented in Table 3. trials have assessed the effects of ALA supplementation In sensitivity analysis, we found no significant differ- on CRP [21–31], eleven on IL-6 [16, 22–25, 30–35], and ence between the pre- and post-sensitivity analysis for nine on TNF-α levels [16, 22, 24, 25, 28, 32, 33, 36, 37]. all inflammatory markers. The smallest and greatest Intervention duration among included studies varied from pooled SMDs in the sensitivity analyses for the level of 2 weeks to 12 months. The dosage of ALA supplements inflammatory markers are shown in Additional file 3. ranged from 300 to 600 (mg/day). Location of studies in- Egger’s regression tests showed no significant publica- cluded; four studies in Italy [25, 28, 29, 33], three in Iran tion bias for the effects of ALA on CRP (B = − 11.35, [23, 27, 37], three in China [16, 21, 22], two in Egypt P = 0.01). We found publication bias for IL-6 (B = − [35, 36], one in Spain [30], one in Romania [32], two 6.88, P = 0.00) and TNF-α (B = − 7.28, P = 0.01), so we in United States [31, 34], one in Korea [26], and one non parametric method was applied (Duval and in New Zealand [24]. Details of the included studies Tweedie) to estimate the findings of censored studies. are summarized in Table 1. The quality of included Findings showed that the summary of effect size for trials is presented in Additional file 2. IL-6 and TNF-α did not significantly changed be- tween before and after inclusion of censored studies Main outcomes for CRP (SMD = − 1.69; 95% CI, − 2.48, − 0.90), IL-6 The results of current meta-analysis showed that ALA (SMD = − 1.96; 95% CI, − 2.60, − 1.32), and TNF-α supplementation significantly decreased CRP (SMD = − (SMD = − 2.62; 95% CI, − 3.70, − 1.55). 1.52; 95% CI, − 2.25, − 0.80; P < 0.001; I : 93.7), IL-6 (SMD = − 1.96; 95% CI, − 2.60, − 1.32; P < 0.001; I : 90.6), Discussion and TNF-α levels (SMD = − 2.62; 95% CI, − 3.70, − 1.55; This systematic review and meta-analysis assessed the ef- P < 0.001; I : 94.3) in patients with MetS and related fect of ALA supplementation on inflammatory markers in disorders (Table 2 and Fig. 1). patients with MetS and related disorders. Our findings Table 2 Estimation of the standardized difference means of related indictors with CI 95% between the intervention and placebo groups Variables Number Standardized mean CI 95% Heterogeneity of study difference 2 I (%) Q P-value CRP Intervention group (after vs. before) 11 −0.88 −1.55, − 0.21 92.4 130.85 < 0.001 Placebo group (after vs. before) 11 −0.29 − 0.67, 0.09 80.3 50.87 < 0.001 Change intervention group vs. placebo group 13 −1.52 −2.25, −0.80 93.7 191.17 < 0.001 IL-6 Intervention group (after vs. before) 13 −0.99 −1.48, − 0.51 85.0 79.92 < 0.001 Placebo group (after vs. before) 13 0.03 −0.16, 0.22 17.8 14.59 0.264 Change intervention group vs. placebo group 15 −1.96 −2.60, − 1.32 90.6 149.58 < 0.001 TNF-α Intervention group (after vs. before) 10 −1.41 −2.03, −0.79 87.0 69.13 < 0.001 Placebo group (after vs. before) 10 −0.33 − 0.72, 0.05 71.4 31.50 < 0.001 Change intervention group vs. placebo group 10 −2.62 −3.70, −1.55 94.3 157.51 < 0.001 IL-6 interlokin-6, CRP C-reactive protein, TNF-α tumor necrosis factor alpha Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 6 of 10 Fig. 1 a-c Meta-analysis glycemic control standardized mean differences estimates for (a) high-sensitivity C-reactive protein, (b) for interlokin-6, and (c) for tumor necrosis factor alpha in alpha-lipoic acid supplements and placebo groups (CI = 95%) Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 7 of 10 Table 3 The assess of association between alpha-lipoic acid supplementation on inflammatory markers based on subgroup analysis 2 2 Variables Number of SMD Subgroups Pooled OR 95% CI I (%) overall I (%) included (random effect) CRP Geographic area 6 Asia −1.20 −2.02, − 0.38 90.8 93.7 5 European −2.52 −4.26, −0.78 94.8 1 USA −0.46 − 0.98, 0.07 – 1 Oceania 0.05 −0.41, 0.51 – Dosage of ALA (mg/day) 4 < 600 −1.29 −2.16, −0.42 81.4 9 ≥600 −1.64 −2.61, −0.66 95.4 Type of intervention 9 ALA −1.63 −2.67, −0.58 95.3 4 ALA plus other nutrients −1.30 −2.10, −0.50 85.0 Duration of study (week) 10 ≥8 −1.50 −2.35, −0.65 94.4 3<8 −1.63 −2.93, −0.32 88.6 Type of diseases 3 Diabetic −1.63 −2.93, −0.32 88.6 10 Other −1.50 −2.35, −0.65 94.4 IL-6 Geographic area 4 Asia −2.18 −3.34, −1.02 88.7 90.6 6 European −1.75 −2.71, −0.78 87.4 3 USA −4.10 −7.68, −0.52 96.3 1 Oceania −0.26 −0.72, 0.20 – 1 Africa −0.57 −1.17, 0.03 – Dosage of ALA (mg/day) 5 < 600 −3.59 −5.50, −1.68 94.8 10 ≥600 −1.22 − 1.70, −0.74 78.4 Type of intervention 8 ALA −2.00 −2.88, −1.11 90.9 7 ALA plus other nutrients −1.98 −3.01, −0.95 91.7 Duration of study (week) 8 ≥8 −1.07 − 1.62, −0.52 85.1 7<8 −3.30 −4.61, −1.99 89.9 Type of diseases 2 Diabetic −3.40 −5.13, −1.66 75.1 13 Other −1.72 −2.35, − 1.09 89.5 TNF-α Geographic area 3 Asia −2.44 −4.67, −0.21 95.9 94.3 5 European −2.63 −3.87, −1.39 87.2 1 Oceania −0.34 − 0.80, 0.12 – 1 Africa −6.35 −8.16, −4.54 – Dosage of ALA (mg/day) 1 < 600 −2.14 −2.77, −1.51 – 9 ≥600 −2.71 −3.94, − 1.48 94.7 Type of intervention 6 ALA −2.56 −4.08, −1.03 95.8 4 ALA plus other nutrients −2.73 −4.26, −1.20 89.3 Duration of study (week) 5 ≥8 −2.78 −4.57, −0.99 96.8 5<8 −2.40 −3.46, −1.33 80.2 Type of diseases 3 Diabetic −4.68 −7.82, −1.55 92.8 7 Other −1.89 −3.04, −0.73 94.0 ESRD end-stage renal disease, IL-6 interlokin-6, CRP C-reactive protein, TNF-α tumor necrosis factor alpha supported the beneficial impact of ALA administration on supplementation significantly decreased serum CRP levels lowering inflammatory markers in patients suffering from in patients with coronary heart disease, suggesting its po- metabolic syndrome and related disorders. tential impact on reducing inflammation in chronic condi- Few studies have reported the beneficial effects of anti- tions. In addition, supplementation with vitamin E in the oxidant supplementation on inflammatory cytokines. In form of either α-tocopherol or γ-tocopherol resulted in a a meta-analysis conducted by Ju et al. [38], selenium significant reduction in CRP concentrations [39]. Available Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 8 of 10 information regarding the effects of ALA supplementation The current meta-analysis had a few limitations. There on inflammatory cytokines is inconclusive. ALA supple- were few eligible RCTs, and most of them had a modest mentation for 12 months significantly decreased serum number of participants. Various doses of ALA were ad- levels of common markers of inflammation in ablated pa- ministered for intervention in the included studies. We tients [25]. Furthermore, dietary supplementation with were unable to evaluate the dose response association ALA for 10 weeks significantly improved systemic inflam- between supplementation dose and inflammatory mation and cardiovascular disease-related risk factors in markers due to the low number of studies included. In healthy overweight women [30]. However, no benefits of addition, we did not evaluate the residual confounding resveratrol supplementation were reported on cardiovascu- and bias of each study that could not be addressed lar risk factors in the meta-analysis conducted by Sahebkar through pooling. Considerable heterogeneity across et al. [40]. In another study, taking ALA supplements for studies made our findings complicated to interpret the 8 weeks did not affect IL-8 and TNF-α levels in main outcomes. Thus, evaluation of heterogeneity is a hemodialysis patients [37]. Increased inflammatory markers, crucial part of any meta-analysis. especially TNF-α, might promote insulin resistance, and alter expression of cytokines in adipose tissues which is con- Conclusions sidered an important link between MetS and insulin resist- Overall, the current meta-analysis supported the benefi- ance [41]. In addition, high levels of inflammatory markers cial impacts of ALA administration on decreasing in- in diabetic patients and those suffering from diabetic ne- flammatory markers such as CRP, IL-6 and TNF-α phropathy are positively correlated with the severity of albu- among patients with MetS and related disorders. minuria [42]. Local inflammation plays also an important role in the development of diabetic retinopathy [43]. Additional files ALA intake may reduce inflammatory markers through scavenging free radicals, down-regulating Additional file 1: Literature search and review flowchart for selection of pro-inflammatory redox-sensitive signal transduction studies. (DOC 44 kb) processes including nuclear factor kappa B translocation, Additional file 2: The methodological quality of included studies (risk of bias). (DOC 44 kb) leading to lower release of other free radicals and cyto- Additional file 3: The effects of alpha-lipoic acid supplementation on toxic cytokines [44, 45]. Moreover, ALA administration inflammatory markers based on sensitivity analysis. (DOC 33 kb) improves cellular antioxidant capacity and phases 2 en- zymes such as catalase, reduced glutathione, glutathione Abbreviations reductase, and glutathione-S-transferase [46]. ALA can ALA: Alpha-lipoic acid; CRF: Chronic renal failure; CRP: C-reactive protein; also inhibit the activation of serine kinases including ESRD: End-stage renal disease; IL-6: Interlokin-6; IV: Intravascular; MetS: Metabolic syndrome; NIDDM: Non-insulin-dependent diabetes mellitus; T1DM: Type 1 IKKβ to suppress inflammatory cytokines [47]. Zhang et diabetes mellitus; T2DM: Type 2 diabetes mellitus; TNF-α: Tumor necrosis al. [48] mentioned to ALA potential to inhibit factor alpha TNF-α-induced I kappa B kinase activation. It is specu- lated that the ALA treatment effects might be influenced Acknowledgements The present study was supported by a grant from the Vice-chancellor for by its baseline values and improved blood levels over time. Research, SUMS, Shiraz, and Iran. In the current meta-analysis it was not possible to con- sider the effect of baseline ALA values in determining the Funding impact of it on inflammatory markers. Furthermore, dif- The research grant provided by Research Deputy of Shiraz University of Medical Sciences (SUMS). ferent geographical latitudes where study conducted might further complicate the effect of baseline ALA values. Availability of data and materials Overall, on top of those explained above, different study The primary data for this study is available from the authors on direct request. designs, sample size, different dosages of ALA used along Authors’ contributions with characteristics of study participants might explain ZA, MA and RT contributed in conception, design, statistical analysis and the discrepancies among different studies. drafting of the manuscript. VO, KB-L, RT, MM, S-TH and FK. contributed There are several strengths for this study. Higher in conception, data collection and manuscript drafting. MM and MC contributed in revised version. The final version was confirmed by all authors for submission. numbers of studies included in this analysis and longer period of supplementation in included trials have added Ethics approval and consent to participate to the value of this meta-analysis. All included studies All procedures performed in studies involving human participants were in were placebo-controlled randomized trials with accept- accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later able methodological quality and the least probable amendments. chance of bias. Further, we relied on independent judg- ment in which different reviewers independently per- Competing interests formed the systematic review process. The authors declare that they have no competing interests. Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 9 of 10 Publisher’sNote 16. Zhang Y, Han P, Wu N, He B, Lu Y, Li S, et al. 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The effects of alpha-lipoic acid supplementation on inflammatory markers among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials

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Abstract

Objective: This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effect of alpha-lipoic acid (ALA) supplementation on the inflammatory markers among patients with metabolic syndrome (MetS) and related disorders. Methods: We searched the following databases until November 2017: PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. Three reviewers independently assessed study eligibility, extracted data, and evaluated risk of bias of included primary studies. Statistical heterogeneity was assessed using Cochran’sQ test and I-square (I ) statistic. Data were pooled by using the random-effect model and standardized mean difference (SMD) was considered as the summary effect size. Results: Eighteen trials out of 912 potential citations were found to be eligible for our meta-analysis. The findings indicated that ALA supplementation significantly decreased C-reactive protein (CRP) (SMD = − 1.52; 95% CI, − 2.25, − 0. 80; P <0.001), interlokin-6 (IL-6) (SMD = − 1.96; 95% CI, − 2.60, − 1.32; P < 0.001), and tumor necrosis factor alpha levels (TNF-α)(SMD = − 2.62; 95% CI, − 3.70, − 1.55; P < 0.001) in patients diagnosed with metabolic diseases. Conclusion: In summary, the current meta-analysis demonstrated the promising impact of ALA administration on decreasing inflammatory markers such as CRP, IL-6 and TNF-α among patients with MetS and related disorders. Keywords: Alpha-lipoic acid, Inflammatory markers, Meta-analysis Introduction Increased chronic inflammation is associated with Increased pro-inflammatory markers and oxidative stress increased risk of metabolic disorders, including type 2 occurs in adipose tissues are the two factors that may diabetes mellitus (T2DM) [2] and arteriosclerosis, play a key role in the incidence of metabolic-related co- endothelial dysfunction, vascular calcification, increased morbidities among patients with metabolic disorders [1]. activity of metalloproteinases, oxidative damage, and degradation of collagen [3–5]. It was reported that meta- bolic syndrome (MetS) is associated with a 2-fold in- * Correspondence: Maryam.chamani.k@gmail.com; asemi_r@yahoo.com creased risk of cardiovascular disease (CVD) over the Department of Gynecology and Obstetrics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran next 5 to 10 years [6]. Inflammatory cytokines including Research Center for Biochemistry and Nutrition in Metabolic Diseases, interleukin-6 (IL-6) and tumor necrosis factor-alpha Kashan University of Medical Sciences, Kashan, I.R, Iran (TNF-α) are usually produced by different cells including Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 2 of 10 endothelial, immune and arterial smooth muscle cells in- MetS” OR “diabetes” OR “T1DM” OR “T2DM” OR ducing the migration of additional immune cells into the “overweight” OR “obese” OR “chronic kidney disease atherosclerotic lesion and the activation of the acute (CKD)” OR “hypertension” OR “high blood pressure” phase C-reactive protein (CRP) in the liver [7, 8]. OR “dyslipidemia” OR “CVD”], intervention (“alpha-li- Increased levels of CRP are associated with increased poic acid” OR “ALA” OR “α-lipoic acid” AND “supple- risk of CVD and diabetes [9, 10]. In addition to CRP, mentation” OR “intake”), and outcomes [“CRP” OR other inflammatory biomarkers such as IL-6 and TNF-α “IL-6” OR “TNF-α”]. Eligible studies were restricted to may be correlated with the development of CVD in dia- those RCTs published in English language. betic patients [11]. Complementary therapies such as antioxidants supple- Inclusion and exclusion criteria mentation are recommended in patients with metabolic RCTs were selected using the following inclusion criteria: abnormalities to improve their nutritional status and being a placebo-controlled randomized trial (either parallel boost their immune system [12]. Existing evidence has or cross-over designs), human studies conducted in adults, proved the beneficial effects of several antioxidants sup- the target population was patients diagnosed with meta- plements including pentoxifylline [13] and lycopene [14] bolic diseases, and studies reported mean changes between on reducing inflammation. Available data regarding the pre- and post-intervention CRP and/or IL-6 and/or TNF-α effects of alpha-lipoic acid (ALA) supplementation on following ALA supplementation for the intervention and inflammatory markers are controversial. In a study by placebos groups. Other types of human studies (cross-sec- Carbonelli et al. [15], obese Caucasian people showed tional, cohort studies), animal, in vitro studies, and review significant reduction in CRP and TNF-α concentrations papers were excluded. Case reports or cases series, and the following ALA supplementation (800 mg/day) for studies did not achieve the minimum quality assessment 4 months. ALA supplementation (600–1000 mg/day) score, those receiving any non-steroidal anti-inflammatory during a period ranging from 2 wk. to 1 year in patients drug or ALA supplements within the last month were also with impaired glucose tolerance showed contradictory excluded from the study. results. Zhang et al. [16] demonstrated that ALA supple- mentation decreased TNF-α and IL-6 while increased Data extraction and quality assessment adiponectin levels, however others did not observe any Three authors (VO, MM, and MA) reviewed each trial beneficial effects of ALA on inflammatory markers [17, 18]. and extracted all related data, independently. The dis- Discrepancies in these findings may be due to differences in agreement among them was resolved by discussion with a study design, characteristics of study populations, dosage of fourth author (ZA). The quality of the included RCTs was ALA used and duration of the intervention. assessed using the Cochrane Collaboration risk of bias We are aware of no systematic review or meta-ana- tool based on the following information: randomization lyses of randomized controlled trials (RCTs) evaluating generation, allocation concealment, blinding of partici- the effect of ALA supplementation on inflammatory pants and outcome assessment, incomplete outcome data, markers among patients with MetS and related disor- and selective outcome reporting, as well as the other ders. Thus, the current meta-analysis was performed to sources of bias. The extracted data included: first author, summarize the available evidence regarding the effect of publication year, demographical variables, study design, ALA supplementation on inflammatory markers among sample size, dose of intervention, duration of study, type patients with MetS and related disorders. of intervention, type of disease, the mean and standard de- viation (SD) for CRP, IL-6, and TNF-α. Materials and methods Search strategy and selection studies Data synthesis and statistical analysis We searched the following databases until November We preformed a comprehensive electronic and manual 2017: PubMed, MEDLINE, EMBASE, Web of Science, search to avoid publication bias. Additionally, Egger’s re- and Cochrane Central Register of Controlled Trials. gression test was used to assess publication bias statisti- Additionally, a manual search was conducted among the cally [19]. Statistical heterogeneity was assessed using 2 2 references lists of all eligible articles and review studies Cochran’s Q and I-square (I ) tests [20]. I greater than to identify potential articles that were not captured by 50% or P < 0.05 was considered as significant heterogen- the electronic searches. Three authors (VO, MM and eity. We estimated the difference between intervention MA) independently performed the literature search to (ALA supplementation) and placebo group by calculat- retrieve RCTs that have examined the association be- ing the standardized mean difference (SMD) with 95% tween ALA supplementation and the inflammatory confidence interval (CI) using STATA software version markers by using the following MeSH and text 12.0 (Stata Corp., College Station, TX) and RevMan keywords: patients [“Mets” OR “disorders related to V.5.3 software (Cochrane Collaboration, Oxford, UK). Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 3 of 10 Table 1 Characteristics of included studies Authors (Ref) Publication year Sample size (control/ Country/population Intervention Duration Presented data Age (y) (control, Results intervention) (name and daily dose) intervention) Hong et al. [22] 2017 32/30 China/patients with 450 mg ALA (IV) + 20 2 weeks CRP, IL-6, TNF-α 65.82 ± 11.63, Decreased CRP, IL-6 diabetic nephropathy μg alprostadil 67.24 ± 10.81 and TNF-α Sardu et al. [25] 2017 40/33 Italy/overweight patients 600 mg ALA 12 months CRP, IL-6, TNF-α 61.5 ± 8.1, Decreased CRP, IL-6 with atrial fibrilation 58.8 ± 6.7 and TNF-α Huerta et al. [30] 2016 21/19 Spain/overweight and 300 mg ALA 10 weeks CRP, IL-6 range: 20–50 Decreased CRP and obese women IL-6 Huerta et al. [30] 2016 21/17 Spain/overweight and 300 mg ALA + 1.3 g EPA 10 weeks CRP, IL-6 range: 20–50 Decreased CRP obese women Marfella et al. [28] 2015 21/22 Italy/overweight patients 600 mg ALA 12 months CRP, TNF-α 63.9 ± 5.2, Decreased CRP and with cardiomyopathy 63.7 ± 6.5 TNF-α Safa et al. [37] 2014 31/30 Iran/patients with ESRD 600 mg ALA 8 weeks TNF-α 55.20 ± 13.43, No effect on hemodialysis 59.3 ± 10.47 Ahmadi et al. [23] 2013 24/20 Iran/hemodialysis patients 600 mg ALA 2 months CRP, IL-6 48.9 ± 12.5, Decreased CRP and 48.8 ± 11.2 IL-6 Ahmadi et al. [23] 2013 24/24 Iran/hemodialysis patients 600 mg ALA + 400 IU 2 months CRP, IL-6 48.9 ± 12.5, Decreased CRP and vitamin E 53.2 ± 9.8 IL-6 El-Nakib et al. [35] 2013 22/22 Egypt/patients with CRF 600 mg ALA 3 months IL-6 46.2 ± 14.4, No effect on hemodialysis 49.1 ± 16.2 Hegazy et al. [36] 2013 15/15 Egypt/patients with T1DM 600 mg ALA + insulin 4 months TNF-α 11.1 ± 2.3, Decreased TNF-α 11.9 ± 1.4 Cinteza al. [32] 2013 14/14 Romania/post acute stroke 600 mg ALA + other 2 weeks IL-6, TNF-α 67.1 ± 10.85, Decreased IL-6 and patients nutrients 64 ± 10.85 TNF-α Nasole et al. [33] 2013 6/10 Italy/patients with chronic 600 mg ALA 2 weeks IL-6, TNF-α 72,59 Decreased IL-6 and leg wound and metabolic TNF-α disease Nasole et al. [33] 2013 6/10 Italy/patients with chronic 600 mg R-(+)-lipoic 2 weeks IL-6, TNF-α 72,72 Decreased IL-6 and leg wound and metabolic acid (RLA) TNF-α disease Khabbazi et al. [27] 2012 28/24 Iran/patients with ESRD 600 mg ALA 8 weeks CRP 54.04 ± 13.96, Decreased CRP on hemodialysis 53.83 ± 13.29 Manning et al. [24] 2012 39/34 New Zealand/patients 600 mg ALA 12 months CRP, IL-6, TNF-α 57 ± 9, 55 ± 10 No effect with MetS Zhang et al. [16] 2011 9/13 China/obese patients with 600 mg ALA (IV) 2 weeks IL-6, TNF-α 52.6 ± 6.2, Decreased IL-6 and impaired glucose tolerance 52.5 ± 8.2 TNF-α Xiang et al. [21] 2011 30/30 China/patients with 600 mg ALA (IV) 3 weeks CRP 58 ± 9, 58 ± 10 Decreased CRP impaired fasting glucose Gianturco et al. [29] 2009 7/7 Italy/patients with NIDDM 400 mg ALA 4 weeks CRP 58 ± 16, 61 ± 7 No effect Chang et al. [26] 2007 25/25 Korea/diabetic ESRD 600 mg ALA 12 weeks CRP 66 ± 7, 63 ± 6 No effect patients on hemodialysis Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 4 of 10 Table 1 Characteristics of included studies (Continued) Authors (Ref) Publication year Sample size (control/ Country/population Intervention Duration Presented data Age (y) (control, Results intervention) (name and daily dose) intervention) Sola et al. [34] 2005 14/15 USA/patients with MetS 300 mg ALA 4 weeks IL-6 44 ± 13, 46 ± 15 Decreased IL-6 Sola et al. [34] 2005 14/15 USA/patients with MetS 300 mg ALA + 150 mg 4 weeks IL-6 44 ± 13, 48 ± 12 Decreased IL-6 irbesartan Romos et al. [31] 2012 28/30 USA/patients with CKD 600 mg ALA + 666 IU 8 weeks CRP, IL-6 64.5 ± 8.8, Decreased IL-6 tocopherols 58.6 ± 12.0 ALA alpha-lipoic acid, CRF chronic renal failure, CKD chronic kidney disease, ESRD end-stage renal disease, IV intravascular, IL-6 interlokin-6, CRP C-reactive protein, MetS metabolic syndrome, NIDDM non-insulin-dependent diabetes mellitus, TNF-α tumor necrosis factor alpha, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 5 of 10 Since the indications could effect on pooled SMD were We also performed subgroup analyses according to different between included studies, we used random-ef- geographic area (Asia, European, USA, Oceania, and Af- fects models to perform meta-analyses. Subgroup and rica), dosage of ALA supplements (> 600 vs. ≤600 mg/ sensitivity analyses were conducted to assess the source day), co-administration with other nutrients (ALA vs. of heterogeneity and to explore the contribution of each ALA plus other nutrients), duration of the intervention study to the reliability of the pooled mean difference, (≥8 vs. < 8 weeks), and type of diseases (diabetic, ESRD respectively. P-values < 0.05 were considered as statis- vs. other diseases). We found that heterogeneity may de- tically significant. crease by duration of the intervention (< 8 weeks = I : 2 2 89.9 and ≥ 8 weeks = I :85.1 vs. overall I :90.6%) and type 2 2 Results of diseases (diabetic = I : 75.1 and other = I :89.5 vs. The process of the step by step study selection has shown overall I :90.6%) for IL-6 and type of diseases (diabetic = 2 2 2 in Additional file 1. Overall, 18 trials out of 912 potential I : 92.8 and other = I :94.0 vs. overall I :94.3%) for 2 2 citations were found to be eligible for this meta-analysis. TNF-α levels (< 8 weeks = I : 88.2 and ≥ 8 weeks = I :92.1 Seven studies were RCTs design, and eleven were ran- vs. overall I :94.5%). The detailed of subgroup analysis domized, double-blind, placebo-controlled trials. Eleven are presented in Table 3. trials have assessed the effects of ALA supplementation In sensitivity analysis, we found no significant differ- on CRP [21–31], eleven on IL-6 [16, 22–25, 30–35], and ence between the pre- and post-sensitivity analysis for nine on TNF-α levels [16, 22, 24, 25, 28, 32, 33, 36, 37]. all inflammatory markers. The smallest and greatest Intervention duration among included studies varied from pooled SMDs in the sensitivity analyses for the level of 2 weeks to 12 months. The dosage of ALA supplements inflammatory markers are shown in Additional file 3. ranged from 300 to 600 (mg/day). Location of studies in- Egger’s regression tests showed no significant publica- cluded; four studies in Italy [25, 28, 29, 33], three in Iran tion bias for the effects of ALA on CRP (B = − 11.35, [23, 27, 37], three in China [16, 21, 22], two in Egypt P = 0.01). We found publication bias for IL-6 (B = − [35, 36], one in Spain [30], one in Romania [32], two 6.88, P = 0.00) and TNF-α (B = − 7.28, P = 0.01), so we in United States [31, 34], one in Korea [26], and one non parametric method was applied (Duval and in New Zealand [24]. Details of the included studies Tweedie) to estimate the findings of censored studies. are summarized in Table 1. The quality of included Findings showed that the summary of effect size for trials is presented in Additional file 2. IL-6 and TNF-α did not significantly changed be- tween before and after inclusion of censored studies Main outcomes for CRP (SMD = − 1.69; 95% CI, − 2.48, − 0.90), IL-6 The results of current meta-analysis showed that ALA (SMD = − 1.96; 95% CI, − 2.60, − 1.32), and TNF-α supplementation significantly decreased CRP (SMD = − (SMD = − 2.62; 95% CI, − 3.70, − 1.55). 1.52; 95% CI, − 2.25, − 0.80; P < 0.001; I : 93.7), IL-6 (SMD = − 1.96; 95% CI, − 2.60, − 1.32; P < 0.001; I : 90.6), Discussion and TNF-α levels (SMD = − 2.62; 95% CI, − 3.70, − 1.55; This systematic review and meta-analysis assessed the ef- P < 0.001; I : 94.3) in patients with MetS and related fect of ALA supplementation on inflammatory markers in disorders (Table 2 and Fig. 1). patients with MetS and related disorders. Our findings Table 2 Estimation of the standardized difference means of related indictors with CI 95% between the intervention and placebo groups Variables Number Standardized mean CI 95% Heterogeneity of study difference 2 I (%) Q P-value CRP Intervention group (after vs. before) 11 −0.88 −1.55, − 0.21 92.4 130.85 < 0.001 Placebo group (after vs. before) 11 −0.29 − 0.67, 0.09 80.3 50.87 < 0.001 Change intervention group vs. placebo group 13 −1.52 −2.25, −0.80 93.7 191.17 < 0.001 IL-6 Intervention group (after vs. before) 13 −0.99 −1.48, − 0.51 85.0 79.92 < 0.001 Placebo group (after vs. before) 13 0.03 −0.16, 0.22 17.8 14.59 0.264 Change intervention group vs. placebo group 15 −1.96 −2.60, − 1.32 90.6 149.58 < 0.001 TNF-α Intervention group (after vs. before) 10 −1.41 −2.03, −0.79 87.0 69.13 < 0.001 Placebo group (after vs. before) 10 −0.33 − 0.72, 0.05 71.4 31.50 < 0.001 Change intervention group vs. placebo group 10 −2.62 −3.70, −1.55 94.3 157.51 < 0.001 IL-6 interlokin-6, CRP C-reactive protein, TNF-α tumor necrosis factor alpha Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 6 of 10 Fig. 1 a-c Meta-analysis glycemic control standardized mean differences estimates for (a) high-sensitivity C-reactive protein, (b) for interlokin-6, and (c) for tumor necrosis factor alpha in alpha-lipoic acid supplements and placebo groups (CI = 95%) Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 7 of 10 Table 3 The assess of association between alpha-lipoic acid supplementation on inflammatory markers based on subgroup analysis 2 2 Variables Number of SMD Subgroups Pooled OR 95% CI I (%) overall I (%) included (random effect) CRP Geographic area 6 Asia −1.20 −2.02, − 0.38 90.8 93.7 5 European −2.52 −4.26, −0.78 94.8 1 USA −0.46 − 0.98, 0.07 – 1 Oceania 0.05 −0.41, 0.51 – Dosage of ALA (mg/day) 4 < 600 −1.29 −2.16, −0.42 81.4 9 ≥600 −1.64 −2.61, −0.66 95.4 Type of intervention 9 ALA −1.63 −2.67, −0.58 95.3 4 ALA plus other nutrients −1.30 −2.10, −0.50 85.0 Duration of study (week) 10 ≥8 −1.50 −2.35, −0.65 94.4 3<8 −1.63 −2.93, −0.32 88.6 Type of diseases 3 Diabetic −1.63 −2.93, −0.32 88.6 10 Other −1.50 −2.35, −0.65 94.4 IL-6 Geographic area 4 Asia −2.18 −3.34, −1.02 88.7 90.6 6 European −1.75 −2.71, −0.78 87.4 3 USA −4.10 −7.68, −0.52 96.3 1 Oceania −0.26 −0.72, 0.20 – 1 Africa −0.57 −1.17, 0.03 – Dosage of ALA (mg/day) 5 < 600 −3.59 −5.50, −1.68 94.8 10 ≥600 −1.22 − 1.70, −0.74 78.4 Type of intervention 8 ALA −2.00 −2.88, −1.11 90.9 7 ALA plus other nutrients −1.98 −3.01, −0.95 91.7 Duration of study (week) 8 ≥8 −1.07 − 1.62, −0.52 85.1 7<8 −3.30 −4.61, −1.99 89.9 Type of diseases 2 Diabetic −3.40 −5.13, −1.66 75.1 13 Other −1.72 −2.35, − 1.09 89.5 TNF-α Geographic area 3 Asia −2.44 −4.67, −0.21 95.9 94.3 5 European −2.63 −3.87, −1.39 87.2 1 Oceania −0.34 − 0.80, 0.12 – 1 Africa −6.35 −8.16, −4.54 – Dosage of ALA (mg/day) 1 < 600 −2.14 −2.77, −1.51 – 9 ≥600 −2.71 −3.94, − 1.48 94.7 Type of intervention 6 ALA −2.56 −4.08, −1.03 95.8 4 ALA plus other nutrients −2.73 −4.26, −1.20 89.3 Duration of study (week) 5 ≥8 −2.78 −4.57, −0.99 96.8 5<8 −2.40 −3.46, −1.33 80.2 Type of diseases 3 Diabetic −4.68 −7.82, −1.55 92.8 7 Other −1.89 −3.04, −0.73 94.0 ESRD end-stage renal disease, IL-6 interlokin-6, CRP C-reactive protein, TNF-α tumor necrosis factor alpha supported the beneficial impact of ALA administration on supplementation significantly decreased serum CRP levels lowering inflammatory markers in patients suffering from in patients with coronary heart disease, suggesting its po- metabolic syndrome and related disorders. tential impact on reducing inflammation in chronic condi- Few studies have reported the beneficial effects of anti- tions. In addition, supplementation with vitamin E in the oxidant supplementation on inflammatory cytokines. In form of either α-tocopherol or γ-tocopherol resulted in a a meta-analysis conducted by Ju et al. [38], selenium significant reduction in CRP concentrations [39]. Available Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 8 of 10 information regarding the effects of ALA supplementation The current meta-analysis had a few limitations. There on inflammatory cytokines is inconclusive. ALA supple- were few eligible RCTs, and most of them had a modest mentation for 12 months significantly decreased serum number of participants. Various doses of ALA were ad- levels of common markers of inflammation in ablated pa- ministered for intervention in the included studies. We tients [25]. Furthermore, dietary supplementation with were unable to evaluate the dose response association ALA for 10 weeks significantly improved systemic inflam- between supplementation dose and inflammatory mation and cardiovascular disease-related risk factors in markers due to the low number of studies included. In healthy overweight women [30]. However, no benefits of addition, we did not evaluate the residual confounding resveratrol supplementation were reported on cardiovascu- and bias of each study that could not be addressed lar risk factors in the meta-analysis conducted by Sahebkar through pooling. Considerable heterogeneity across et al. [40]. In another study, taking ALA supplements for studies made our findings complicated to interpret the 8 weeks did not affect IL-8 and TNF-α levels in main outcomes. Thus, evaluation of heterogeneity is a hemodialysis patients [37]. Increased inflammatory markers, crucial part of any meta-analysis. especially TNF-α, might promote insulin resistance, and alter expression of cytokines in adipose tissues which is con- Conclusions sidered an important link between MetS and insulin resist- Overall, the current meta-analysis supported the benefi- ance [41]. In addition, high levels of inflammatory markers cial impacts of ALA administration on decreasing in- in diabetic patients and those suffering from diabetic ne- flammatory markers such as CRP, IL-6 and TNF-α phropathy are positively correlated with the severity of albu- among patients with MetS and related disorders. minuria [42]. Local inflammation plays also an important role in the development of diabetic retinopathy [43]. Additional files ALA intake may reduce inflammatory markers through scavenging free radicals, down-regulating Additional file 1: Literature search and review flowchart for selection of pro-inflammatory redox-sensitive signal transduction studies. (DOC 44 kb) processes including nuclear factor kappa B translocation, Additional file 2: The methodological quality of included studies (risk of bias). (DOC 44 kb) leading to lower release of other free radicals and cyto- Additional file 3: The effects of alpha-lipoic acid supplementation on toxic cytokines [44, 45]. Moreover, ALA administration inflammatory markers based on sensitivity analysis. (DOC 33 kb) improves cellular antioxidant capacity and phases 2 en- zymes such as catalase, reduced glutathione, glutathione Abbreviations reductase, and glutathione-S-transferase [46]. ALA can ALA: Alpha-lipoic acid; CRF: Chronic renal failure; CRP: C-reactive protein; also inhibit the activation of serine kinases including ESRD: End-stage renal disease; IL-6: Interlokin-6; IV: Intravascular; MetS: Metabolic syndrome; NIDDM: Non-insulin-dependent diabetes mellitus; T1DM: Type 1 IKKβ to suppress inflammatory cytokines [47]. Zhang et diabetes mellitus; T2DM: Type 2 diabetes mellitus; TNF-α: Tumor necrosis al. [48] mentioned to ALA potential to inhibit factor alpha TNF-α-induced I kappa B kinase activation. It is specu- lated that the ALA treatment effects might be influenced Acknowledgements The present study was supported by a grant from the Vice-chancellor for by its baseline values and improved blood levels over time. Research, SUMS, Shiraz, and Iran. In the current meta-analysis it was not possible to con- sider the effect of baseline ALA values in determining the Funding impact of it on inflammatory markers. Furthermore, dif- The research grant provided by Research Deputy of Shiraz University of Medical Sciences (SUMS). ferent geographical latitudes where study conducted might further complicate the effect of baseline ALA values. Availability of data and materials Overall, on top of those explained above, different study The primary data for this study is available from the authors on direct request. designs, sample size, different dosages of ALA used along Authors’ contributions with characteristics of study participants might explain ZA, MA and RT contributed in conception, design, statistical analysis and the discrepancies among different studies. drafting of the manuscript. VO, KB-L, RT, MM, S-TH and FK. contributed There are several strengths for this study. Higher in conception, data collection and manuscript drafting. MM and MC contributed in revised version. The final version was confirmed by all authors for submission. numbers of studies included in this analysis and longer period of supplementation in included trials have added Ethics approval and consent to participate to the value of this meta-analysis. All included studies All procedures performed in studies involving human participants were in were placebo-controlled randomized trials with accept- accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later able methodological quality and the least probable amendments. chance of bias. Further, we relied on independent judg- ment in which different reviewers independently per- Competing interests formed the systematic review process. The authors declare that they have no competing interests. Akbari et al. Nutrition & Metabolism (2018) 15:39 Page 9 of 10 Publisher’sNote 16. Zhang Y, Han P, Wu N, He B, Lu Y, Li S, et al. 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Nutrition & MetabolismSpringer Journals

Published: Jun 5, 2018

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