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Open AccessArticle

Safety Evaluation of α-Lipoic Acid Supplementation: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Clinical Studies

1
Hypertension and Cardiovascular Risk Factors Research Group, Medical and Surgical Sciences Department, Sant’Orsola-Malpighi University Hospital, 40138 Bologna, Italy
2
Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialities (PROMISE), School of Medicine, University of Palermo, 90127 Palermo, Italy
3
Department of Endocrinology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark
4
Department of Pharmacology and Therapeutics, Trinity College Dublin and St James Hospital, Dublin 8, Ireland
5
Department of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium
6
Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, 10 000 Zagreb, Croatia
7
Faculty of Medicine, School of Health Sciences, University of Ioannina, 451 10 Ioannina, Greece
8
Diagnosis and Therapeutic Center, Hôtel-Dieu Hospital, Paris-Descartes University, 75004 Paris, France
9
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28007 Madrid, Spain
10
Lipids and Atherosclerosis Unit, Department of Internal Medicine, Reina Sofia University Hospital, 14004 Cordoba, Spain
11
Maimonides Biomedical Research Institute of Cordoba (IMIBIC), 14004 Cordoba, Spain
12
Department of Medicine (Medicine, Dermatology and Otorhinolaryngology), University of Cordoba, 14004 Cordoba, Spain
13
Amsterdam UMC—University of Amsterdam, 1100 DD Amsterdam, The Netherlands
14
Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania
15
Vilnius University Hospital Santariškių Klinikos, LT-08661 Vilnius, Lithuania
16
Third Department of Internal Medicine, First Medical Faculty, Charles University, 128 08 Prague 2, Czech Republic
*
Author to whom correspondence should be addressed.
Antioxidants 2020, 9(10), 1011; https://doi.org/10.3390/antiox9101011
Received: 19 September 2020 / Revised: 10 October 2020 / Accepted: 15 October 2020 / Published: 19 October 2020
(This article belongs to the Special Issue Role of Natural Antioxidants on Neuroprotection and Neuroinflammation)

Abstract

Alpha-lipoic acid (ALA) is a natural short-chain fatty acid that has attracted great attention in recent years as an antioxidant molecule. However, some concerns have been recently raised regarding its safety profile. To address the issue, we aimed to assess ALA safety profile through a systematic review of the literature and a meta-analysis of the available randomized placebo-controlled clinical studies. The literature search included EMBASE, PubMed Medline, SCOPUS, Google Scholar, and ISI Web of Science by Clarivate databases up to 15th August 2020. Data were pooled from 71 clinical studies, comprising 155 treatment arms, which included 4749 subjects with 2558 subjects treated with ALA and 2294 assigned to placebo. A meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of any treatment-emergent adverse event (all p > 0.05). ALA supplementation was safe, even in subsets of studies categorized according to smoking habit, cardiovascular disease, presence of diabetes, pregnancy status, neurological disorders, rheumatic affections, severe renal impairment, and status of children/adolescents at baseline.
Keywords: α-lipoic acid; thioctic acid; dietary supplement; safety; meta-analysis α-lipoic acid; thioctic acid; dietary supplement; safety; meta-analysis

1. Introduction

Alpha-lipoic acid (1, 2-dithiolane-3-pentanoic acid; ALA) or thioctic acid is a natural short-chain fatty acid that has attracted great attention in recent years as an antioxidant molecule, being largely used worldwide as a dietary supplement [1].
Previous investigations revealed that ALA can affect central and peripheral modulation of 5′-adenosine-monophosphate-activated protein kinase. Furthermore, it activates peroxisome proliferator-activated receptor (PPAR) alpha and gamma (PPAR-γ), modulates PPAR-regulated genes and upregulates the expression of PPAR-γ messenger ribonucleic acid (mRNA) and other proteins in the cardiac tissue and aorta smooth muscle [2,3]. Hence, ALA antioxidant activity is potentially able to promote weight loss and blood pressure control and ameliorate atherogenic dyslipidemia and insulin resistance [3]. For example, in obese patients with non-alcoholic fatty liver disease (NAFLD), ALA supplementation was shown to reduce adipokine concentrations and improve liver steatosis grade [4,5]. However, some concerns have been recently raised regarding ALA safety profile, after some reports suggesting a direct causal link between its use and insulin autoimmune syndrome (IAS, also known as Hirata’s disease) due to its sulfhydryl group [6]. Indeed, in about 50% of cases, IAS development is associated with drugs or dietary supplement containing a sulphur or sulfhydryl group. These cases are closely related to certain specific antigens of the major histocompatibility complex (MHC), which are more common in populations where IAS incidence is higher [7]. It is hypothesised that ALA might cause the development of antibodies to insulin and lead to a hypoglycaemic syndrome in predisposed subjects, even though evidence are inconclusive [8].
In a recent study that performed a preliminary analysis of spontaneous reports of suspected adverse reactions (ARs), ALA-containing natural products have also been associated with skin and gastrointestinal disorders, such as urticaria and abdominal pain [9].
To address safety issues related to ALA supplementation, we aimed to perform a systematic review of the literature and a meta-analysis of the available randomized placebo-controlled clinical trials.

2. Materials and Methods

The study was designed according to guidelines of the 2009 preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement [10], and was registered in the PROSPERO database (Registration number CRD42020159028).
Due to the study design, neither Institutional Review Board (IRB) approval, nor patient informed consent were required. PRISMA Checklist was reported in supplementary file A.

2.1. Search Strategy

EMBASE, PubMed Medline, SCOPUS, Google Scholar and ISI Web of Science by Clarivate databases were searched, with no language restriction, using the following search terms: (“Alpha-lipoic acid” OR “Alpha lipoic acid” OR “α-lipoic acid” OR “α lipoic acid” OR “ALA” OR “A-LA” OR “Lipoic acid” OR “Thioctic acid” OR “Tioctic acid” OR “Thioctacid”) AND (“Clinical trial” OR “Clinical study”). The wild-card term “*” was used to increase the sensitivity of the search strategy, which was limited to studies in humans. The reference list of identified papers was manually checked for additional relevant articles. Additional searches included references of review articles on that issue, and abstracts from selected congresses on the subject of the meta-analysis. Literature was searched from inception to 15th August 2020.
All paper abstracts were firstly screened by two independent reviewers (F.F. and M.R.) to remove ineligible articles. The remaining articles were obtained in full-text and assessed again by the same two researchers who evaluated each article independently and carried out data extraction and quality assessment. Disagreements were resolved by discussion with a third party (A.F.G.C.).

2.2. Study Selection Criteria

Original studies were included if they met the following criteria: (i) being a clinical trial with either parallel or cross-over design, (ii) having an appropriate controlled design for ALA supplementation, (iii) blinding participants to intervention, (iv) testing the safety of ALA, (v) reporting treatment-emergent adverse events.
Exclusion criteria were: (i) lack of randomisation for treatment allocation, (ii) lack of a control group receiving placebo (iii) lack of sufficient information about the prevalence and nature of the adverse events. Studies were also excluded if they contained overlapping subjects with other studies.

2.3. Data Extraction

Data abstracted from eligible studies were: (i) first author’s name; (ii) year of publication; (iii) study location; (iv) study design; (v) follow-up; (vi) main inclusion criteria and underlying disease; (vii) study groups; (viii) number of participants in the active and control group; (ix) age and sex of study participants; (x) treatment-emergent adverse events occurred during the trials. Missing or unpublished data were sought by trying to contact authors via e-mail and repeated messages were sent in case of no response. Extracted data were reviewed by the principal investigator before the final analysis, and doubts were resolved by mutual agreement among the authors.

2.4. Quality Assessment

A systematic assessment of risk of bias in the included studies was performed using the Cochrane criteria [11]. The following items were used: adequacy of sequence generation, allocation concealment, blinding addressing of dropouts (incomplete outcome data), selective outcome reporting, and other probable sources of bias [12]. Overall evidence was qualified using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system [13]. Risk-of-bias assessment was performed independently by two reviewers; disagreements were resolved by a consensus-based discussion.

2.5. Data Synthesis

Meta-analysis was conducted using Comprehensive Meta-Analysis (CMA) V3 software (Biostat, NJ) [14].
Outcomes were treatment-emergent adverse events (AEs) occurring during the trials. In particular, data extracted from the studies included hypoglycaemic episodes, gastrointestinal AEs (e.g., heartburn, gastric complaints, nausea, gastrointestinal complications, duodenitis, and abdominal bloating), neurological AEs (e.g., headache, foggy thinking, drowsiness, leg weakness, legs periodic numbness and tingling, tingling in toe and fingers and intermittent bilateral toe numbness), psychiatric disorders (e.g., bipolar disorders, irritability, poor sleeping), musculoskeletal AEs (e.g., neck pain, lower back pain, and spasms), skin AEs (e.g., skin rash, disseminated maculopapular rash, itching sensation and urticaria), infections (e.g., laryngitis, pneumonia and yeast infections), cardiovascular (CV) system AEs (e.g., increase in arterial blood pressure, palpitations, myocardial infarction, heart rate and rhythm disorders, and heart valve disorders), hospitalisation and death.
The analysis was performed by excluding studies with zero events in both arms. If one or more outcomes could not be extracted from a study, the study was removed only from the analysis involving those outcomes. To avoid a double-counting problem, in trials comparing multiple treatment arms versus a single control group, the number of subjects in the control group was divided by the required comparisons [15].
To reduce the risk of bias due to effect dilution, the meta-analysis was performed considering per-protocol (PP) population.
Studies’ findings were combined using a fixed-effect model since the low level of inter-study heterogeneity, which was quantitatively assessed using the Higgins index (I2) [16]. Effect sizes were expressed as odds ratio (OR) and 95% confidence interval (95% CI) [17]. Finally, sensitivity analysis was conducted to account for the risk of bias. A leave-one-out method was used (i.e., one study was removed at a time and the analysis was repeated) [18].
Two-sided p-values < 0.05 were considered as statistically significant for all tests.

2.6. Additional Analysis

Subgroup analyses were carried out by presence of smoking habit, pregnancy, CV disease, diabetes, rheumatic disorders, neurological disorders, severe renal impairment, and status of children/adolescent at baseline.

2.7. Publication Biases

Potential publication biases were explored using visual inspection of Begg’s funnel plot asymmetry, Begg’s rank correlation test, and Egger’s weighted regression test [19]. Two-sided p-values < 0.05 were considered statistically significant for the tests.

3. Results

3.1. Flow and Characteristics of the Included Studies

After database searches performed strictly according to inclusion and exclusion criteria, 962 published articles were identified, and their abstracts reviewed. Of these, 359 did not report original data. Furthermore, 393 articles were excluded because they did not meet the inclusion criteria. Thus, 210 articles were carefully assessed and reviewed. Additional 139 papers were excluded due to being pre-print papers (n = 2), study protocols (n = 6), reporting data from studies lacking of an appropriate placebo-controlled design for the supplementation (n = 64), lacking of randomisation (n = 5), testing the acute effect of ALA supplementation (n = 7), testing ALA supplementation combined in nutraceutical compounds (n = 27), testing intravenous treatment with ALA (n = 11), testing topical treatment with ALA (n = 4), lacking sufficient information about the nature of the adverse events (n = 9), or reporting data overlapped with other publications (n = 4) (Supplementary file B). Finally, 71 studies were eligible and included in the systematic review [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90]. The study selection process is shown in Figure 1.
Data were pooled from 71 randomized placebo-controlled clinical studies, comprising 155 treatment arms (82 active arms and 73 control arms). The studies included 4749 subjects, with 2558 receiving treatment with ALA and 2294 subjects assigned to placebo. For reasons independent of the tested supplementation (i.e., withdrawal of informed consent and personal problems), 510 subjects prematurely terminated the trials in which they were enrolled. Then, the meta-analysis was performed considering the other subjects (i.e., PP population).
Eligible studies were published between 1982 and 2020 and were conducted in different locations across all continents. Follow-up periods ranged between 8 days and 4 years and several ALA regimens were tested. Selected clinical trials were designed with cross-over or parallel-group and enrolled pregnant women with gestational diabetes, children and/or adolescent, overall healthy subjects or subjects with minor or major underlying diseases (e.g., diabetes, CVD, rheumatic affections, neurological disorders, severe renal impairment).
Included clinical studies were fully or partially carried out independently and funded by the National Institutes of Health (n = 7), Health Ministries (n = 2), University Institutes (n = 42), Research Hospitals (n = 2), Private Research Institutes (n = 2), Scientific Societies (n = 3), Private Foundations (n = 8), or were financially supported by industries (n = 7).
The main characteristics of the evaluated studies are summarized in Table 1.

3.2. Risk of Bias Assessment

Almost all of the included studies were characterized by sufficient information regarding sequence generation, allocation concealment, personal and outcome assessments, incomplete outcome data, and selective outcome reporting. Details of the quality of bias assessment are reported in Table 2.
The quality of evidence for each outcome across all the studies was considered high in accordance with the GRADE approach.

3.3. Primary Outcomes

3.3.1. Hypoglycaemic Episodes

Symptoms defined as ‘similar to hypoglycaemic episodes’ were reported only by Jacob et al. and were exclusively experienced by subjects randomized to placebo. Authors did not report if an attempt for treatment rechallenging was made during the trial [44].

3.3.2. Gastrointestinal AEs

Meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of gastrointestinal AEs (OR = 1.32, 95% CI 0.97 to 1.78; p = 0.073; I2 = 0%) (Figure 2). The finding was robust in the leave-one-out sensitivity analysis (Figure S1).
Visually, the funnel plot of standard error by log OR was slightly asymmetric (Figure S2). This asymmetry was imputed to eight potentially missing studies on the left-side of the plot, which reduced the estimated effect size to 1.12 (95% CI 0.84 to 1.49). Egger’s linear regression and Begg’s rank correlation confirmed the presence of publication bias for the analysis (p < 0.05).

3.3.3. Neurological AEs

Meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of neurological AEs (OR = 1.53, 95% CI 0.88 to 2.63; p = 0.129; I2 = 0%) (Figure 3). The finding was robust in the leave-one-out sensitivity analysis (Figure S3).
Visually, the funnel plot of standard error by log OR was slightly asymmetric (Figure S4). This asymmetry was imputed to 4 potentially missing studies on the left-side of the plot, which reduced the estimated effect size to 1.26 (95% CI 0.76 to 2.10). However, neither Egger’s linear regression nor Begg’s rank correlation confirmed the presence of publication bias for the analysis (p > 0.05 for both tests).

3.3.4. Psychiatric Disorders

Meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of psychiatric disorders (OR = 1.13, 95% CI 0.64 to 1.99; p = 0.668; I2 = 0%) (Figure 4). The finding was robust in the leave-one-out sensitivity analysis (Figure S5).
Visually, the funnel plot of standard error by log OR was slightly asymmetric (Figure S6). This asymmetry was imputed to two potentially missing studies on the left-side of the plot, which reduced the estimated effect size to 1.01 (95% CI 0.59 to 1.75). Egger’s linear regression confirmed the presence of publication bias for the analysis (p < 0.01), though Begg’s rank correlation did not.

3.3.5. Musculoskeletal AEs

Meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of musculoskeletal AEs (OR = 0.76, 95% CI 0.22 to 2.64; p = 0.666; I2 = 0%) (Figure 5). The finding was robust in the leave-one-out sensitivity analysis (Figure S7).
Visually, the funnel plot of standard error by log OR was slightly asymmetric (Figure S8). This asymmetry was imputed to 2 potentially missing studies on the left-side of the plot, which reduced the estimated effect size to 0.50 (95% CI 0.17 to 1.51). However, neither Egger’s linear regression nor Begg’s rank correlation confirmed the presence of publication bias for the analysis (p > 0.05 for both tests).

3.3.6. Skin AEs

Meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of skin AEs (OR = 1.13, 95% CI 0.82 to 1.56; p = 0.469; I2 = 33.6%) (Figure 6). The finding was robust in the leave-one-out sensitivity analysis (Figure S9).
Visually, the funnel plot of standard error by log OR was slightly asymmetric (Figure S10). This asymmetry was imputed to four potentially missing studies on the left-side of the plot, which reduced the estimated effect size to 0.92 (95% CI 0.68 to 1.24). However, neither Egger’s linear regression nor Begg’s rank correlation confirmed the presence of publication bias for the analysis (p > 0.05 for both tests).

3.3.7. Infections

Meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of infections (OR = 0.93, 95% CI 0.18 to 4.65; p = 0.925; I2 = 0%) (Figure 7). The finding was robust in the leave-one-out sensitivity analysis (Figure S11).
Visually, the funnel plot of standard error by log OR was slightly asymmetric (Figure S12). This asymmetry was imputed to two potentially missing studies on the left-side of the plot, which reduced the estimated effect size to 0.31 (95% CI 0.08 to 1.13). However, neither Egger’s linear regression nor Begg’s rank correlation confirmed the presence of publication bias for the analysis (p > 0.05 for both tests).

3.3.8. CV System AEs

Meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of CV system AEs (OR = 1.25, 95% CI 0.84 to 1.85; p = 0.276; I2 = 15.8%) (Figure 8). The finding was robust in the leave-one-out sensitivity analysis (Figure S13).
Visually, the funnel plot of standard error by log OR was slightly asymmetric (Figure S14). This asymmetry was imputed to three potentially missing studies on the right-side of the plot, which increased the estimated effect size to 1.40 (95% CI 0.95 to 2.05). Egger’s linear regression confirmed the presence of publication bias for the analysis (p < 0.01), though Begg’s rank correlation did not.

3.3.9. Hospitalisation

Meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of hospitalisation (OR = 5.66, 95% CI 0.64 to 49.85; p = 0.119; I2 = 0%) (Figure 9). The finding was robust in the leave-one-out sensitivity analysis (Figure S15).

3.3.10. Death

Meta-analysis of extracted data suggested that supplementation with ALA was not associated with an increased risk of death (OR = 0.56, 95% CI 0.21 to 1.48; p = 0.242; I2 = 0%) (Figure 10). The finding was robust in the leave-one-out sensitivity analysis (Figure S16).
Visually, the funnel plot of standard error by log OR was slightly asymmetric (Figure S17). This asymmetry was imputed to three potentially missing studies on the right-side of the plot, which increased the estimated effect size to 0.71 (95% CI 0.31 to 1.64). Egger’s linear regression correlation confirmed the presence of publication bias for the analysis (p = 0.03), though Begg’s rank correlation did not.

3.4. Additional Analyses

Supplementation with ALA was not associated with a significant increased risk of any AE in subsets of studies classified by smoking habit, CV disease, diabetes, pregnancy, neurological disorders, rheumatic affections, and severe renal impairment at baseline (Table 3). Furthermore, ALA supplementation was safe in children (Table 3). The findings were robust in the leave-one-out sensitivity analysis.

4. Discussion

In the last years, the number of individuals assuming dietary supplements has been steadily increased worldwide [90,91]. Reasons for dietary supplements’ use widely varies across the countries: in Europe, it is just limited to general health and well-being, while other countries permit use for medicinal purposes [92].
Considering that dietary supplement production and marketing are usually not strictly subjected to rigid rules as drugs are, there is a need for more data in order to confirm their safe use in the general population and frail subjects.
Pooling data from 71 randomized placebo-controlled clinical studies, this meta-analysis suggests that antioxidant supplementation with ALA was not associated with an increased risk of any treatment-emergent AE. Of note, statistical significance was not even achieved in subsets of studies categorized according to smoking habit, CV disease, presence of diabetes, pregnancy status, neurological disorders, rheumatic affections, renal impairment, and status of children/adolescent.
From a certain point of view, the current analysis strengthens findings from a large observational study considering outcomes data of 610 expectant mothers and their newborns that concluded ALA supplementation is safe in pregnancy even when administered at high doses [93].
These findings are particularly important because they encourage ALA use in a number of conditions in which ALA is actually proven to be effective. As a matter of fact, even though ALA supplementation has already been demonstrated to influence a broad spectrum of metabolic pathways including inflammation and glucose homeostasis [94,95,96], to the best of our knowledge this is the first time that ALA safety profile has been comprehensively evaluated through a pooled analysis of randomized placebo-controlled clinical studies.
Once ALA safety has been established, clinical factors for predicting treatment response should be an objective for future investigations, in order to identify the patient group that might benefit from ALA supplementation the most.
In the past, several meta-analyses showed that ALA supplementation significantly improves both positive neuropathic symptoms and neuropathic deficits to a clinically meaningful degree in diabetic patients with symptomatic polyneuropathy [97,98,99]. Furthermore, ALA was shown to promote weight loss in adults and obese children and adolescents [100,101].
Despite its strengths, this systematic review and meta-analysis has some limitations that mostly inherits from the included clinical studies. First, the effect size on the risk of hypoglycaemic episodes may be affected by variations in the underlying hypoglycaemic therapy in clinical trials enrolling diabetic patients. In fact, the well-recognized euglycaemic effect of ALA may require the adjustment of antidiabetic agents and insulin doses in patients taking antidiabetic drugs [101]. Second, gastrointestinal and CV system AEs included several nosological entities, justifying the probable presence of publication biases for the analysis. However, this limitation is strongly conditioned by the way the AEs were reported in the individual clinical trials. Indeed, most of the studies included in the meta-analysis report the cumulative incidence of gastrointestinal and CV system AEs, without regard to specific type of AEs. Third, AEs were difficult to identify when they were represented by exacerbations of the underlying disease for which ALA was tested (e.g., leg cramps in patients with peripheral polyneuropathy). Moreover, clinical trials testing different ALA regimens often reported the cumulative number of AEs for the supplementation versus placebo. As a result, a sub-analysis by ALA daily dose was not provided. Furthermore, different ALA formulations were tested across the included clinical studies. Despite this, heterogeneity was low for all assessed outcomes, proving that the results were reliable for the whole population and the considered sub-groups [102]. Finally, as per other dietary supplements, a relatively large number of studies have been carried out with open design and/or without a control group, so that they could not be included in a well-carried out meta-analysis.
Future research is needed to understand if sporadic adverse events associated with ALA use are related to the production quality of the used supplements, to other components of mixed supplements and/or to concomitant treatments or diseases, while long-term safety has been already assessed in the NATHAN (Neurological Assessment of Thioctic Acid in Diabetic Neuropathy) 1 trial [84].

5. Conclusions

Pooling data from the available randomized placebo-controlled clinical studies, the current meta-analysis provides data in support of the safety of the use of ALA to improve health outcomes in overall healthy individuals and in patients affected by other diseases.

Supplementary Materials

The following are available online at https://www.mdpi.com/2076-3921/9/10/1011/s1, Figure S1: Plots showing leave-one-out sensitivity analysis for the risk of gastrointestinal AEs following ALA supplementation versus placebo, Figure S2: Funnel plot detailing publication bias for the risk of gastrointestinal AEs following ALA supplementation versus placebo, Figure S3: Plot showing leave-one-out sensitivity analysis for the risk of neurological AEs following ALA supplementation versus placebo, Figure S4: Funnel plot detailing publication bias for the risk of neurological AEs following ALA supplementation versus placebo, Figure S5: Plot showing leave-one-out sensitivity analysis for the risk of psychiatric disorders following ALA supplementation versus placebo, Figure S6: Plot showing leave-one-out sensitivity analysis for the risk of musculoskeletal AEs following ALA supplementation versus placebo, Figure S7: Funnel plot detailing publication bias for the risk of musculoskeletal AEs following ALA supplementation versus placebo, Figure S8: Plot showing leave-one-out sensitivity analysis for the risk of skin AEs following ALA supplementation versus placebo, Figure S9: Funnel plot detailing publication bias for the risk of skin AEs following ALA supplementation versus placebo, Figure S10: Plot showing leave-one-out sensitivity analysis for the risk of infections following ALA supplementation versus placebo, Figure S11: Funnel plot detailing publication bias for the risk of infections following ALA supplementation versus placebo, Figure S12: Plot showing leave-one-out sensitivity analysis for the risk of CV system AEs following ALA supplementation versus placebo, Figure S13: Funnel plot detailing publication bias for the risk of CV system AEs following ALA supplementation versus placebo, Figure S14: Plot showing leave-one-out sensitivity analysis for the risk of hospitalisation following ALA supplementation versus placebo, Figure S15: Plot showing leave-one-out sensitivity analysis for the risk of death following ALA supplementation versus placebo, Figure S16: Funnel plot detailing publication bias for the risk of death following ALA supplementation versus placebo, File A: PRISMA Checklist, File B: Studies excluded from the systematic review after assessment.

Author Contributions

Conceptualization, F.F. and A.F.G.C.; methodology, F.F. and A.F.G.C.; software, F.F.; validation, F.F., M.R. and A.F.G.C.; formal analysis, F.F.; investigation, F.F., M.R., C.K. (Christoffer Krogager), C.K. (Cormac Kennedy), C.M.G.G., T.K., E.L., A.V., P.P.-M., E.F.E.W., A.Š., M.V. and A.F.G.C.; resources, F.F. and A.F.G.C.; data curation, F.F. and A.F.G.C.; writing—original draft preparation, F.F., M.R. and A.F.G.C.; writing—review and editing, C.K. (Christoffer Krogager), C.K. (Cormac Kennedy), C.M.G.G., T.K., E.L., A.V., P.P.-M., E.F.E.W., A.Š. and M.V.; visualization, F.F. and A.F.G.C.; supervision, A.F.G.C.; project administration, F.F. and A.F.G.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

MR is currently Chief Medical and Scientific Advisor, Novo Nordisk South East Europe, Middle East and Africa (SEEMEA). The other authors declare no conflict of interest.

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Figure 1. Flow chart of the number of studies identified and included in the systematic review.
Figure 1. Flow chart of the number of studies identified and included in the systematic review.
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Figure 2. Forest plot for the risk of gastrointestinal adverse events (AEs) following alpha-lipoic acid (ALA) supplementation versus placebo.
Figure 2. Forest plot for the risk of gastrointestinal adverse events (AEs) following alpha-lipoic acid (ALA) supplementation versus placebo.
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Figure 3. Forest plot for the risk of neurological AEs following ALA supplementation versus placebo.
Figure 3. Forest plot for the risk of neurological AEs following ALA supplementation versus placebo.
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Figure 4. Forest plot for the risk of psychiatric AEs following ALA supplementation versus placebo.
Figure 4. Forest plot for the risk of psychiatric AEs following ALA supplementation versus placebo.
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Figure 5. Forest plot for the risk of musculoskeletal AEs following ALA supplementation versus placebo.
Figure 5. Forest plot for the risk of musculoskeletal AEs following ALA supplementation versus placebo.
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Figure 6. Forest plot for the risk of skin AEs following ALA supplementation versus placebo.
Figure 6. Forest plot for the risk of skin AEs following ALA supplementation versus placebo.
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Figure 7. Forest plot for the risk of infections following ALA supplementation versus placebo.
Figure 7. Forest plot for the risk of infections following ALA supplementation versus placebo.
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Figure 8. Forest plot for the risk of CV system AEs following ALA supplementation versus placebo.
Figure 8. Forest plot for the risk of CV system AEs following ALA supplementation versus placebo.
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Figure 9. Forest plot for the risk of hospitalisation following ALA supplementation versus placebo.
Figure 9. Forest plot for the risk of hospitalisation following ALA supplementation versus placebo.
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Figure 10. Forest plot for the risk of death following ALA supplementation versus placebo.
Figure 10. Forest plot for the risk of death following ALA supplementation versus placebo.
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Table 1. Main characteristics of the clinical trials testing safety of treatment with α-lipoic acid.
Table 1. Main characteristics of the clinical trials testing safety of treatment with α-lipoic acid.
Author, YearLocationStudy DesignTreatment DurationMain Inclusion Criteria and Underlying DiseaseStudy GroupEnrolled Subjects
(n)
Age
(years; mean ± SD)
Male
[n (%)]
Ahmadi, 2013 [20]IranRandomized, single-blind, placebo-controlled, parallel-group, clinical study2 monthsEnd-stage renal disease on haemodialysis (≥2 times/week for ≥1 year)600 mg/day α-lipoic acid2048.8 ± 11.214 (70)
Placebo2448.9 ± 12.59 (38)
Ansar, 2011 [21]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study8 weeksType 2 diabetes mellitus
FPG > 126 mg/dL
300 mg/day α-lipoic acid2949 ± 9.16 (21)
Placebo2851.8 ± 8.38 (29)
Aslfalah, 2019a [22]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study8 weeksGestational diabetes mellitus100 mg/day α-lipoic acid3030.96 ± 0.930 (0)
Placebo3031.1 ± 0.920 (0)
Aslfalah, 2019b [23]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study8 weeksGestational diabetes mellitus100 mg/day α-lipoic acid3030.96 ± 0.930 (0)
Placebo3031.1 ± 0.920 (0)
Baumgartner, 2017 [24]The NetherlandsRandomized, double-blind, placebo-controlled, crossover, clinical study4 weeksImpaired glucose tolerance or non-insulin-dependent type 2 diabetes
BMI ≥ 20 kg/m2 and ≤35 kg/m2
600 mg/day α-lipoic acid2063.1 ± 5.816 (80)
Placebo
Baziar, 2020 [25]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study8 weeksNon-insulin-dependent diabetes mellitus
HbA1c < 7%
BMI ≥ 18.5 kg/m2 and ≤29.9 kg/m2
1200 mg/day α-lipoic acid3552.66 ± 4.8115 (43)
Placebo3553.34 ± 4.4516 (46)
Bobe, 2020 [26]United States of AmericaRandomized, double-blind, placebo-controlled, parallel-group, clinical study24 weeksSedentary lifestyle
BMI ≥ 27 kg/m2
TG ≥ 150 mg/dL
FPG < 125 mg/dL
600 mg/day α-lipoic acid4038 ± 10 *12 (39) *
Placebo4140 ± 816 (48) *
Boriani, 2017 [27]ItalyRandomized, double-blind, placebo-controlled, parallel-group, clinical study40 daysPrimary tunnel carpal syndrome
at least one of the following findings: anaesthesia or paraesthesia in the median nerve territory, positive Tinel sign, Phalen or reverse Phalen manoeuvres, and positive nerve conduction studies irrespective of severity
800 mg/day α-lipoic acid3257.3 ± 1213 (41)
Placebo3258.5 ± 119 (28)
Carbone, 2009 [28]ItalyRandomized, double-blind, placebo-controlled, parallel-group, clinical study8 weeksBurning mouth syndrome800 mg/day α-lipoic acid22NANA
Placebo22NANA
Cavalcanti, 2009 [29]BrazilRandomized, double-blind, placebo-controlled, crossover, clinical study30 daysBurning mouth syndrome600 mg/day α-lipoic acid3863.1 (36–78) §4 (11)
Placebo
Durastanti, 2016 [30]ItalyRandomized, double-blind, placebo-controlled, parallel-group, pilot clinical study2 yearsRelapsing-remitting multiple sclerosis
EDSS score ≤ 3.5
800 mg/day α-lipoic acid during the first year and 400 mg/day α-lipoic acid during the second year733 (26–43) °2 (29)
Placebo628.5 (22.5–44.3) °1 (17)
El Amrousy, 2020 [31]EgyptRandomized, double-blind, placebo-controlled, parallel-group, clinical study3 monthsObese healthy children and adolescents
BMI > 95th percentile for age and sex
600 mg/day α-lipoic acid4012.3 ± 1.516 (40)
Placebo4012.4 ± 1.418 (45)
Falardeau, 2019 [32]United States of AmericaRandomized, double-blind, placebo-controlled, parallel-group, clinical study6 weeksUnilateral acute optic neuritis1200 mg/day α-lipoic acid1541.2 ± 10.517 (47)
Placebo1636.1 ± 9.844 (25)
Femiano, 2002 [33]SpainRandomized, double-blind, placebo-controlled, parallel-group, clinical study2 monthsBurning mouth syndrome600 mg/day α-lipoic acid3045 (22–68) §18 (30)
Placebo30
Georgakouli, 2018 [34]GreeceRandomized, double-blind, placebo-controlled, crossover, clinical study4 weeksHealthy status600 mg/day α-lipoic acid838.4 ± 5.68 (100)
Placebo
Gianturco, 2009 [35]ItalyRandomized, double-blind, placebo-controlled, parallel-group, clinical study4 weeksDiabetes mellitus
HbA1c < 7%
400 mg/day α-lipoic acid761 ± 74 (57)
Placebo758 ± 164 (57)
Gilron, 2020 [36]CanadaRandomized, double-blind, placebo-controlled, crossover, clinical study5 weeksFibromyalgia
daily moderate pain (≥4/10 on a NRS) for ≥3 months
600 mg/day α-lipoic acid during the first week; 1200 mg/day α-lipoic acid during the second week; 1800 mg/day α-lipoic acid during the third and the fourth weeks2757 (25–74) §5 (19)
Placebo
Gosselin, 2019 [37]United States of AmericaRandomized, double-blind, placebo-controlled, crossover, clinical study1 monthSedentary lifestyle
FPG ≥ 100 mg/dL and ≤125 mg/dL
BMI ≥ 25 kg/m2 and ≤40 kg/m2
600 mg/day α-lipoic acid1247.1 ± 2.94 (33)
Placebo
Guo, 2014 [38]United States of AmericaRandomized, double-blind, placebo-controlled, parallel-group, clinical study24 weeksCancer patients receiving chemotherapy with cisplatin or oxaliplatin1800 mg/day α-lipoic acid12255 ± 1166 (54)
Placebo12157 ± 1263 (52)
Haghighian, 2015 [39]IranRandomized, triple-blind, placebo-controlled, parallel-group, clinical study12 weeksIdiopathic asthenozoospermia
BMI < 30 kg/m2
600 mg/day α-lipoic acid2432.98 ± 5.35 *24 (100)
Placebo2434.12 ± 4.79 *24 (100)
Hejazi, 2018 [40]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study10 daysCandidates for enteral feeding and expected to stay in the intensive care unit for ≥7 days2700 mg/day α-lipoic acid4051.2 ± 1717 (43)
Placebo4057.4 ± 1925 (63)
Huang, 2008 [41]United States of AmericaRandomized, double-blind, placebo-controlled, parallel-group, clinical study3 monthsPubertal or postpubertal adolescents with type 1 diabetes600–1200 mg/day (14–21 mg/kg/day) α-lipoic acid3014 ± 2.413 (43)
Placebo1015 ± 1.97 (70)
Huerta, 2016 [42]SpainRandomized, double-blind, placebo-controlled, parallel-group, clinical study10 weeksSedentary lifestyle
BMI ≥ 27.5 kg/m2 and ≤40 kg/m2
300 mg/day α-lipoic acid635.5 ± 8.40 (0)
Placebo641.8 ± 6.60 (0)
Huerta, 2015 [43]SpainRandomized, double-blind, placebo-controlled, parallel-group, clinical study10 weeksHealthy status
regular menstrual cycles
BMI ≥ 27.5 kg/m2 and ≤40 kg/m2
300 mg/day α-lipoic acid2639 ± 8 *0 (0)
Placebo3138 ± 7 *0 (0)
Jacob, 1999 [44]GermanyRandomized, double-blind, placebo-controlled, parallel-group, clinical study4 weeksWell-controlled type 2 diabetes mellitus1800 mg/day α-lipoic acid1862.1 ± 310 (56)
1200 mg/day α-lipoic acid1860.9 ± 2.211 (61)
600 mg/day α-lipoic acid1958.1 ± 2.810 (53)
Placebo1960.4 ± 2.412 (63)
Jamshidi, 2020 [45]IranRandomized, double-blind, placebo-controlled, crossover, clinical study8 weeksβ-thalassemia major600 mg/day α-lipoic acid2023.5 ± 5.4713 (65)
Placebo
Jariwalla, 2008 [46]United States of AmericaRandomized, double-blind, placebo-controlled, parallel-group, clinical study6 monthsHIV infection
HIV-RNA viral load > 10.000 copies/cm3 despite HAART
CD4+ cell count ≥ 50 cells/mm3
900 mg/day α-lipoic acid1847.2 ± 6.829 (88)
Placebo1543.7 ± 7.6
Khabbazi, 2012 [47]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study8 weeksPatients with end-stage renal disease on haemodialysis600 mg/day α-lipoic acid3153.83 ± 13.2916 (52)
Placebo3254.04 ± 13.9618 (56)
Khalili, 2017 [48]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 weeksRelapsing-remitting multiple sclerosis1200 mg/day α-lipoic acid1532.3 ± 6.2 *5 (42) *
Placebo1632.2 ± 10.5 *1 (8) *
Khalili, 2014 [49]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 weeksRelapsing-remitting multiple sclerosis1200 mg/day α-lipoic acid2631.4 ± 6.2 *7 (27)
Placebo3428.7 ± 9 *9 (26)
Kim, 2020 [50]South KoreaRandomized, double-blind, placebo-controlled, parallel-group, clinical study18 monthsGeographic atrophy1200 mg/day α-lipoic acid2680.6 ± 6.58 (31)
Placebo2779 ± 711 (41)
Kim, 2016 [51]South KoreaRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 weeksChronic schizophrenia in rehabilitation
significant weight gain after starting treatment with atypical antipsychotics
600–1800 mg/day α-lipoic acid1040.5 ± 6.654 (40)
Placebo1240.08 ± 9.147 (58)
Koh, 2011 [52]Republic of KoreaRandomized, double-blind, placebo-controlled, parallel-group, clinical study20 weeksBMI ≥ 30 kg/m2 or BMI ≥ 27.5 kg/m2 and ≤40 kg/m2 if hypertension, diabetes mellitus and/or hypercholesterolemia coexisted1800 mg/day α-lipoic acid12041.4 ± 182 (68)
1200 mg/day α-lipoic acid12041.6 ± 1.179 (66)
Placebo12040.7 ± 1.174 (62)
Lampitella, 2005 [53]ItalyRandomized, double-blind, placebo-controlled, parallel-group, clinical study6 monthsType 2 diabetes mellitus600 mg/day α-lipoic acid20NANA
Placebo20NANA
Lee, 2017 [54]Republic of KoreaRandomized, double-blind, placebo-controlled, parallel-group, clinical study24 weeksDiabetic cardiac autonomic neuropathy600-1200 mg/day α-lipoic acid4664.37 ± 7.827 (59)
Placebo4562.4 ± 9.120 (44)
Loy, 2018 [55]United States of AmericaRandomized, double-blind, placebo-controlled, parallel-group, pilot clinical study2 yearsMultiple sclerosis disability progression in absence of clinical relapse for 5 years
EDSS ≤ 6.0
ability to walk ≥ 25 feet without aid
1200 mg/day α-lipoic acid1155.8 ± 5.75 (45)
Placebo1055.7 ± 4.15 (50)
López-D’alessandro, 2011 [56]ArgentinaRandomized, double-blind, placebo-controlled, parallel-group, clinical study2 monthsBurning mouth syndrome600 g/day α-lipoic acid20NANA
Placebo60NANA
López-Jornet, 2009 [57]SpainRandomized, double-blind, placebo-controlled, parallel-group, clinical study8 weeksBurning mouth syndrome800 mg/day α-lipoic acid3064.37 ± 11.616 (10)
Placebo30
Magis, 2007 [58]BelgiumRandomized, double-blind, placebo-controlled, parallel-group, clinical study3 monthsMigraine with or without aura600 mg/day α-lipoic acid2637.46 ± 13.434 (15)
Placebo1838.94 ± 8.052 (11)
Manning, 2013 [59]New ZelandRandomized, double-blind, placebo-controlled, parallel-group, clinical study1 yearMetabolic syndrome600 mg/day α-lipoic acid3455 ± 1014 (41)
Placebo4057 ± 915 (38)
Marfella, 2016 [60]ItalyRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 monthsTakotsubo cadiomyopathy600 mg/day α-lipoic acid2463.7 ± 6.50 (0)
Placebo2463.9 ± 5.20 (0)
Marshall, 1982 [61]United KingdomRandomized, double-blind, placebo-controlled, parallel-group, clinical study24 weeksAlcohol related liver disease300 mg/day α-lipoic acid2050.7 ± 1.917 (85)
Placebo2046.4 ± 2.715 (75)
Martins, 2009 [62]BrazilRandomized, double-blind, placebo-controlled, parallel-group, clinical study3 monthsSickle cell disease200 mg/day α-lipoic acid1017.7 ± 9.66 (60)
Placebo1017 ± 115 (50)
Sickle cell trait200 mg/day α-lipoic acid1031.3 ± 15.42 (20)
Placebo1029.7 ± 10.82 (20)
Healthy status200 mg/day α-lipoic acid1023.5 ± 114 (40)
Placebo1023.3 ± 113 (30)
Mendes, 2014 [63]BrazilRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 weeksArterial hypertension600 mg/day α-lipoic acid32NANA
Placebo28NANA
Mendoza-Núñez, 2019 [64]MexicoRandomized, double-blind, placebo-controlled, parallel-group, clinical study6 monthsType 2 diabetes mellitus without complications or comorbidity, treated with two tablets of glibenclamide/metformin (5/500 mg) per day
BMI < 35 kg/m2
sedentary lifestyle
600 mg/day α-lipoic acid5063 ± 1 *NA
Placebo5064 ± 1 *NA
Mirtaheri, 2014 [65]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study8 weeksRheumatoid arthritis1200 mg/day α-lipoic acid3536.09 ± 8.77 *0 (0)
Placebo3538.28 ± 8.63 *0 (0)
Mohammadi, 2018 [66]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 weeksPrevious thrombotic or embolic stroke
BMI ≥ 18.5 kg/m2 and ≤35 kg/m2
600 mg/day α-lipoic acid4062.33 ± 6.19NA
Placebo4064.23 ± 8.01NA
Mohammadi, 2015 [67]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 weeksSpinal cord injury since ≥ 1 year
BMI ≥ 18.5 kg/m2
600 mg/day α-lipoic acid2839 ± 6.4428 (100)
Placebo3036.8 ± 7.4830 (100)
Mollo, 2012 [68]ItalyRandomized, double-blind, placebo-controlled, parallel-group, clinical study5 weeksType 1 diabetes600 mg/day α-lipoic acid2643 ± 915 (58)
Placebo2546 ± 1112 (48)
Monroy Guízar, 2018 [69]MexicoRandomized, double-blind, placebo-controlled, parallel-group, clinical study3 monthsIdiopathic carpal tunnel syndrome600 mg/day α-lipoic acid1045.3 1 (10)
Placebo1048.4 1 (10)
Palacios-Sánchez, 2015 [70]SpainRandomized, double-blind, placebo-controlled, parallel-group, clinical study2 monthsBurning mouth syndrome600 mg/day α-lipoic acid3062.13 (36–86) §5 (8)
Placebo30
Porasuphatana, 2012 [71]ThailandRandomized, double-blind, placebo-controlled, parallel-group, clinical study6 monthsType 2 diabetes mellitus with microalbuminuria1200 mg/day α-lipoic acid747.07 ± 2.181 (14)
900 mg/day α-lipoic acid744 ± 21 (14)
600 mg/day α-lipoic acid845.7 ± 1.683 (38)
300 mg/day α-lipoic acid842.5 ± 1.124 (50)
Placebo842.9 ± 2.521 (13)
Pourghasem Gargari, 2014 [72]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study8 weeksRheumatoid arthritis
DAS28 < 5.1
BMI < 40 kg/m2
1200 mg/day α-lipoic acid3536.1 ± 8.80 (0)
Placebo3538.3 ± 8.60 (0)
Rahmanabadi, 2019 [4]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 weeksNon-alcoholic fatty liver disease
BMI ≥ 30 kg/m2 and ≤40 kg/m2
1200 mg/day α-lipoic acid2540.28 ± 5.513 (52)
Placebo2537.52 ± 9.6714 (56)
Ruhnau, 1999 [73]GermanyRandomized, double-blind, placebo-controlled, parallel-group, clinical study3 weeksType 2 diabetes mellitus with distal symmetrical polyneuropathy1800 mg/day α-lipoic acid1260.5 ± 6.96 (50)
Placebo1262.1 ± 4.56 (50)
Safa, 2014 [74]IranRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 monthsEnd-stage renal disease on haemodialysis ≥ 6 months600 mg/day α-lipoic acid3059.3 ± 10.4721 (70)
Placebo3155.2 ± 13.4321 (68)
Sammour, 2019 [75]EgyptRandomized, triple-blind, placebo-controlled, parallel-group, clinical study6 weeksPrimary caesarean section in singleton term pregnancy1200 mg/day α-lipoic acid5125.3 ± 5.10 (0)
Placebo5125.1 ± 5.40 (0)
Sardu, 2017 [76]ItalyRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 monthsParoxysmal, symptomatic atrial fibrillation ≥ 6 months refractory to ≥1 class 1–3 antiarrhythmic drugs and treated with catheter ablation600 mg/day α-lipoic acid3358.8 ± 6.715 (45)
Placebo4061.5 ± 8.123 (58)
Scaramuzza, 2015 [77]ItalyRandomized, double-blind, placebo-controlled, parallel-group, pilot clinical study6 monthsType 1 diabetes
endothelial dysfunction
800 mg/day α-lipoic acid2516.1 ± 3.115 (60)
Placebo2716 ± 3.416 (59)
Sola, 2005 [78]United Stated of AmericaRandomized, double-blind, placebo-controlled, parallel-group, clinical study4 weeksMetabolic syndrome300 mg/day α-lipoic acid1546 ± 155 (33)
Placebo1444 ± 136 (43)
Spain, 2017 [79]United Stated of AmericaRandomized, double-blind, placebo-controlled, parallel-group, clinical study2 yearsMultiple sclerosis disability progression in absence of clinical relapse for 5 years1200 mg/day α-lipoic acid2757.9 ± 6.711 (41)
Placebo2459.7 ± 69 (38)
Sun, 2012 [80]ChinaRandomized, blind, placebo-controlled, parallel-group, clinical study3 monthsDry form of age-related macular degeneration600 mg/day α-lipoic acid3265.8 ± 7.911 (35)
Placebo3064.5 ± 8.110 (33)
Tromba, 2019 [81]ItalyRandomized, double-blind, placebo-controlled, parallel-group, clinical study12 weeksBMI ≥ 85th percentile for age and sex800 mg/day α-lipoic acid3411.5 ± 1.9 *16 (50) *
Placebo3311.1 ± 2.1 *20 (63) *
Udupa, 2013 [82]IndiaRandomized, double-blind, placebo-controlled, parallel-group, clinical study90 daysType 2 diabetes mellitus
FGP ≥ 110 mg/dL and ≤250 mg/dL
300 mg/day α-lipoic acid2553.5 ± 1.412 (48)
Placebo2553.8 ± 2.115 (60)
Vincent, 2007 [83]United States of AmericaRandomized, double-blind, placebo-controlled, parallel-group, clinical study3 monthsABI ≥ 0.3 and ≤0.9
claudication pain with walking
600 mg/day α-lipoic acid1675.1 ± 8.29 (56)
Placebo1270.7 ± 18.96 (50)
Yadav, 2005 [84]United States of AmericaRandomized, double-blind, placebo-controlled, parallel-group, pilot clinical study14 daysMultiple sclerosis
EDSS score ≤ 7.5
2400 mg/day α-lipoic acid844.5 (34–56) §0 (0)
1200 mg/day α-lipoic acid16NA2 (13)
Placebo950 (36–66) §2 (22)
Yan, 2013 [85]ChinaRandomized, double-blind, placebo-controlled, crossover, clinical study8 weeksBMI ≥ 25 kg/m2
≥1 of borderline hypertension, dyslipidemia, or impaired FPG
1200 mg/day α-lipoic acid103NANA
Placebo
Zembron-Lacny, 2013 [86]PolandRandomized, double-blind, placebo-controlled, crossover, clinical study10 daysHealthy status1200 mg/day α-lipoic acid1620.7 ± 0.916 (100)
Placebo
Zembron-Lacny, 2009 [87]PolandRandomized, double-blind, placebo-controlled, crossover, clinical study8 daysPhysical education students
healthy status
forced training experience
≥3 years
1200 mg/day α-lipoic acid1325.5 ± 613 (100)
Placebo
Ziegler, 2011 [88]Canada, Croatia, Denmark, France, Italy, Spain, The Netherlands, United Kingdom, United States of AmericaRandomized, double-blind, placebo-controlled, parallel-group, clinical study4 yearsType 1 or 2 diabetes (duration ≥1 year)
stage 1 or 2a distal symmetric sensorimotor polyneuropathy due to diabetes
stable insulin regimen
NIS[LL]+7 ≥ 2
one of the following abnormalities: abnormal nerve conduction attributes in two separate nerves ≥ 99th percentile for distal latency or ≤1st percentile for nerve conduction velocity or amplitude OR HRBD ≥ 1st percentile or TSS in the feet< 5
600 mg/day α-lipoic acid23153.3 ± 8.3152 (66)
Placebo22553.9 ± 7.6154 (67)
Ziegler, 2006 [89]Israel and RussiaRandomized, double-blind, placebo-controlled, parallel-group, clinical study5 weeksType 1 or 2 diabetes
HbA1c < 10%
symptomatic distal symmetric polyneuropathy due to diabetes
TSS > 7.5
NIS[LL] ≥ 2
absent or decreased pain sensation according to pin-prick test
1800 mg/day α-lipoic acid4659 ± 919 (41)
1200 mg/day α-lipoic acid4759 ± 1219 (40)
600 mg/day α-lipoic acid4556 ± 1220 (44)
Placebo4357 ± 1115 (35)
* data refer to safety population; § data reported as median (variation range); ° data reported as median (interquartile range); data reported as mean; ABI = Ankle brachial index; BMI = Body mass index; CVD = Cardiovascular disease; DAS28 = Disease activity score in 28 joints; EDSS = Expanded disability status scale; HIV = Human immunodeficiency virus; HRBD = Heart rate during deep breathing; NA = Not available; NIS[LL] = Neuropathy impairment score — subscore for lower limbs; NIS[LL]+7 = Neuropathy impairment score—subscore for lower limbs and seven nerve conduction tests score; NRS = Numerical rating scale; FPG = Fasting plasma glucose; TSS = Total symptom score.
Table 2. Quality of bias assessment of the included studies according to Cochrane guidelines.
Table 2. Quality of bias assessment of the included studies according to Cochrane guidelines.
Author, YearSequence GenerationAllocation ConcealmentBlinding to Participants, Personnel and Outcome AssessmentIncomplete Outcome DataSelective Outcome ReportingOther Potential Threats to Validity
Ahmadi, 2013 [20]LLHLLU
Ansar, 2011 [21]LLLLUL
Aslfalah, 2019a [22]LLLLLL
Aslfalah, 2019b [23]LLLLLL
Baumgartner, 2017 [24]LLLLLL
Baziar, 2020 [25]LLLLLL
Bobe, 2020 [26]LLLLLL
Boriani, 2017 [27]LLLLLL
Carbone, 2009 [28]LLLLLL
Cavalcanti, 2009 [29]LLLLLL
Durastanti, 2016 [30]LLLUUU
El Amrousy, 2020 [31]LLLLLL
Falardeau, 2019 [32]LLLLLL
Femiano, 2002 [33]ULLLUU
Georgakouli, 2018 [34]LLLLLL
Gianturco, 2009 [35]LLLLUL
Gilron, 2020 [36]LLLLLL
Gosselin, 2019 [37]LLLLLL
Guo, 2014 [38]LLLLLL
Haghighian, 2015 [39]LLLLLL
Hejazi, 2018 [40]LLLLLL
Huang, 2008 [41]LLLLLL
Huerta, 2016 [42]LLLLLL
Huerta, 2015 [43]LLLLLL
Jacob, 1999 [44]LLLLUH
Jamshidi, 2020 [45]LLLLLL
Jariwalla, 2008 [46]LLLLUH
Khabbazi, 2012 [47]LLLLLL
Khalili, 2017 [48]LLLLLL
Khalili, 2014 [49]LLLLLL
Kim, 2020 [50]LLLLLL
Kim, 2016 [51]LLLLLL
Koh, 2011 [52]LLLLLL
Lampitella, 2005 [53]LUULLU
Lee, 2017 [54]LLLLLL
Loy, 2018 [55]LLLLLL
López- D’Alessandro, 2011 [56]LLLHHU
López-Jornet, 2009 [57]LLLLLL
Magis, 2007 [58]LLLLLL
Manning, 2013 [59]LLLLLL
Marfella, 2016 [60]LLULLU
Marshall, 1982 [61]LLLLLL
Martins, 2009 [62]LLULLU
Mendes, 2014 [63]LLLLHU
Mendoza-
Núñez, 2019 [64]
LLLLLL
Mirtaheri, 2014 [65]LLLLLL
Mohammadi, 2018 [66]LLLLLL
Mohammadi, 2015 [67]LLLLLL
Mollo, 2012 [68]LLLLLL
Monroy Guízar, 2018 [69]LLLLLL
Palacios-
Sánchez, 2015 [70]
LLLLLL
Porasuphatana, 2012 [71]LLLLLH
Pourghasem Gargari, 2014 [72]LLLLLL
Rahmanabadi, 2019 [4]LLLLLL
Ruhnau, 1999 [73]LLLLLL
Safa, 2014 [74]LLLLLL
Sammour, 2019 [75]LLLLLL
Sardu, 2017 [76]LLLLLL
Scaramuzza, 2015 [77]LLLLLL
Sola, 2005 [78]LLLLLL
Spain, 2017 [79]LLLLLL
Sun, 2012 [80]LUULLU
Tromba, 2019 [81]LLLLLL
Udupa, 2013 [82]LLLLLL
Vincent, 2007 [83]LLLLLL
Yadav, 2005 [84]LLLLLL
Yan, 2013 [85]LLLLLL
Zembron-
Lacny, 2013 [86]
LLLLLL
Zembron-
Lacny, 2009 [87]
LLLLLL
Ziegler, 2011 [88]LLLLLL
Ziegler, 2006 [89]LLLLLL
H = High risk of bias; L = Low risk of bias; U = Unclear risk of bias.
Table 3. Subgroup analyses for the risk of treatment-emergent AEs, stratified by smoking habit, cardiovascular disease, presence of diabetes, pregnancy, neurological disorders, rheumatic affections, age, and severe renal impairment at baseline.
Table 3. Subgroup analyses for the risk of treatment-emergent AEs, stratified by smoking habit, cardiovascular disease, presence of diabetes, pregnancy, neurological disorders, rheumatic affections, age, and severe renal impairment at baseline.
AEsSmoking HabitCardiovascular DiseaseDiabetesPregnancyNeurological DisordersRheumatic AffectionsChildren and/or AdolescentsSevere Renal Impairment
YesNoYesNoYesNoYesNoYesNoYesNoYesNoYesNo
Gastrointestinal AEsNumber of reported AEs (active arm/placebo arm)-/-4/22/097/88137/7717/143/2180/97144/76-/-5/24/33/2180/97-/-94/81
Odd ratio-1.1922.7341.1031.2671.1551.5311.3131.295-2.8411.4331.7051.309-1.158
95% CI (lower limit; upper limit)-0.265; 5.3610.273; 27.3830.781; 1.5580.879; 1.8270.540; 2.4680.245; 9.5740.966; 1.7840.897; 1.869-0.500; 16.1380.300; 6.8330.260; 11.1560.964; 1.779-0.811;
1.653
Z-value-0.2290.8560.5561.2680.3710.4561.7401.382-1.1780.4510.5561.724-0.809
I2 (%)-0005000048-0000-0
P-value-0.8190.3920.5780.2050.7110.6490.0820.167-0.2390.6520.5780.085-0.418
Neurological AEsNumber of reported AEs (active arm/placebo arm)-/-6/21/019/1810/018/14-/-50/2325/9-/-8/60/1-/-50/23-/-22/16
Odd ratio-1.0243.0781.1532.3681.268-1.5261.718-1.4740.315-1.526-3.078
95% CI (lower limit; upper limit)-0.236; 4.4420.122; 77.9050.544; 2.4420.884; 2.6340.552; 2.914-0.884; 2.6340.742; 3.977-0.432; 5.0270.012; 7.999-0.884; 2.634-0.122;
77.905
Z-value-0.0320.6820.3711.5170.560-1.5171.264-0.619−0.700-1.517-0.682
I2 (%)-00000-00-00-0-0
P-value-0.9740.4950.7110.1290.575-0.1290.206-0.5360.484-0.129-0.495
Psychiatric AEsNumber of reported AEs (active arm/placebo arm)-/-2/0-/-30/2526/254/0-/-30/2526/25-/--/-2/0-/-30/25-/-28/25
Odd ratio-5.145-1.1311.0145.071-1.1311.014--5.145-1.131-1.073
95% CI (lower limit; upper limit)-0.238; 111.087-0.644;
1.986
0.566;
1.817
0.582;
44.174
-0.644;
1.986
0.566;
1.817
--0.238; 111.087-0.644; 1.986-0.605; 1.903
Z-value-1.045-0.4290.0481.470-0.4290.048--1.045-0.429-0.242
I2 (%)-0-000-00--0-0-0
P-value-0.296-0.6680.9620.142-0.6680.962--0.296-0.668-0.809
Musculoskeletal AEsNumber of reported AEs (active arm/placebo arm)-/-1/0-/-3/5-/-3/4-/-5/54/4-/-0/11/0-/-5/5-/-3/5
Odd ratio-3.000-0.625-0.738-0.7610.683-0.3213.000-0.761-0.625
95% CI (lower limit; upper limit)-0.118;
76.161
-0.147;
2.661
-0.146;
3.723
-0.220;
2.635
0.156;
2.997
-0.013;
8.241
0.118;
76.161
-0.220;
2.635
-0.147; 2.661
Z-value-0.666-−0.636-−0.368-−0.431−0.505-−0.6860.666-−0.431-−0.636
I2 (%)-0-0-0-00-00-0-0
P-value-0.506-0.525-0.713-0.6660.614-0.4930.506-0.666-0.525
Skin AEsNumber of reported AEs (active arm/placebo arm)-/-21/4-/-92/9483/9014/6-/-139/10383/911/0-/--/--/-139/1032/0104/95
Odd ratio-2.821-0.9120.8162.258-1.1270.8193.353---1.1271.5450.932
95% CI (lower limit; upper limit)-0.899; 8.850-0.635; 1.3080.559; 1.1910.851;
5.992
-0.815; 1.5590.563; 1.1920.120; 93.835---0.815; 1.5590.067; 35.4310.653; 1.331
Z-value-1.778-−0.502−1.0521.636-0.724−1.0410.712---0.7240.272−0.387
I2 (%)-0-2900-3400---34036
P-value-0.075-0.6160.2930.102-0.4690.2980.477---0.4690.7850.699
InfectionsNumber of reported AEs (active arm/placebo arm)-/-3/0-/-1/3-/-1/3-/-5/31/3-/--/--/--/-5/3-/-4/3
Odd ratio-3.316-0.310-0.310-0.9260.310----0.926-0.780
95% CI (lower limit; upper limit)-0.167; 65.718-0.028; 3.364-0.028; 3.364-0.184; 4.6470.028; 3.364----0.184; 4.647-0.121; 5.028
Z-value-0.787-−0.963-−0.963-−0.094−0.963----−0.094-−0.262
I2 (%)-0-0-0-00----0-32
P-value-0.432-0.335-0.335-0.9250.335----0.925-0.793
CV system AEsNumber of reported AEs (active arm/placebo arm)-/-0/10/271/5371/541/3-/-73/6071/54-/--/-0/1-/-73/60-/-71/57
Odd ratio-0.1490.1911.4411.4090.450-1.2471.409--0.333-1.247-1.313
95% CI (lower limit; upper limit)-0.006; 3.7330.009; 4.2140.950; 2.1860.932; 2.1300.056; 3.608-0.838; 1.8540.932; 2.130--0.012; 9.068-0.838; 1.854-0.875; 1.972
Z-value-−1.159−1.0491.7201.625−0.752-1.0891.625--−0.652-1.089-1.314
I2 (%)-00000-160--0-16-27
P-value-0.2470.2940.0850.1040.452-0.2760.104--0.515-0.276-0.189
HospitalisationNumber of reported AEs (active arm/placebo arm)-/-4/0-/-2/0-/-2/0-/-4/0-/--/--/-2/0-/-4/02/02/0
Odd ratio-5.657-5.145-5.145-5.657---5.145-5.6576.2245.145
95% CI (lower limit; upper limit)-0.642; 49.849-0.238; 111.087-0.238; 111.087-0.642; 49.849---0.238; 111.087-0.642; 49.8490.285; 135.7840.238; 111.087
Z-value-1.561-1.045-1.045-1.561---1.045-1.5611.1631.045
I2 (%)-0-0-0-0---0-000
P-value-0.119-0.296-0.296-0.119---0.296-0.1190.2450.296
DeathNumber of reported AEs (active arm/placebo arm)-/-0/24/5-/--/-1/2-/-6/121/3-/--/--/--/-6/120/26/9
Odd ratio-0.2150.777--0.529-0.5580.468----0.5580.2150.657
95% CI (lower limit; upper limit)-0.010; 4.6900.192; 3.142--0.046; 6.109-0.210; 1.4830.066; 3.300----0.210; 1.4830.010; 4.6900.222; 1.947
Z-value-−0.977−0.354--−0.510-−1.169−0.762----−1.169−0.977−0.758
I2 (%)-00--0-00----000
P-value-0.3280.724--0.610-0.2420.446----0.2420.3280.448
AEs = Adverse events; CI = Confidence Intervals.
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