Federica Fogacci, Manfredi Rizzo, Christoffer Krogager, Cormac Kennedy, Coralie M.G. Georges, Tamara Knežević, Evangelos Liberopoulos, Alexandre Vallée, Pablo Pérez-Martínez, Eliane F.E. Wenstedt, Agnė Šatrauskienė, Michal Vrablík, and Arrigo F.G. Cicero
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
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
