Alpha-Lipoic Acid
Alpha-Lipoic Acid (ALA) as a supplementation for weight loss:
Results from a Meta-Analysis of Randomized Controlled Trials
Suat Kucukgoncu,
Yale University School of Medicine, Department of Psychiatry
Elton Zhou,
Yale University School of Medicine, Department of Psychiatry
Katherine B Lucas, and
Yale University School of Medicine, Department of Psychiatry
Cenk Tek
Yale University School of Medicine, Department of Psychiatry
Abstract
Objectives—Obesity is associated with significant morbidity and mortality rates. Even modest
weight loss may be associated with health benefits. Alpha-lipoic acid (ALA) is a naturally
occurring antioxidant. Studies have suggested anti-obesity properties of ALA; however, results are
inconsistent. The purpose of this study is to conduct a meta-analysis of the effect of ALA on
weight and body mass index (BMI).
Methods—A comprehensive, systematic literature search identified 10 articles on randomized,
double-blind, placebo-controlled studies involving ALA. We conducted a meta-analysis of mean
weight and BMI change differences between ALA and placebo treatment groups.
Results—ALA treatment coincided with a statistically significant 1.27 kg (CI=0.25 to 2.29)
greater mean weight loss compared to the placebo group. A significant overall mean BMI
difference of -0.43 kg/m2
(CI=-0.82 to -0.03) was found between the ALA and placebo groups.
Meta-regression analysis showed no significance in ALA dose on BMI and weight changes. Study
duration significantly affected BMI change, but not weight change.
Conclusions—ALA treatment showed small, yet significant short-term weight loss compared to
placebo. Further research is needed to examine the effect of different doses and the long-term
benefits of ALA on weight management.
Keywords
thioctic acid; weight; body mass; diabetes; alpha lipoic acid
Corresponding author: Suat Kucukgoncu, MD, Yale University Department of Psychiatry, Connecticut Mental Health Center, Rm 10,
34 Park Street, New Haven, CT 06519, Phone: 203-974-7810, Suat.kucukgoncu@yale.edu, Suatkucukgoncu@yahoo.com.
Potential conflicts of interest: Authors report no competing interests
HHS Public Access
Author manuscript
Obes Rev. Author manuscript; available in PMC 2018 May 01.
Published in final edited form as:
Obes Rev. 2017 May ; 18(5): 594–601. doi:10.1111/obr.12528.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Introduction
Obesity is a growing worldwide epidemic with an estimated 1.9 billion overweight and 600
million obese adults (1). Obesity is associated with significant morbidity and mortality
through its close association with ailments such as cardiovascular disease and diabetes (2).
Even modest weight loss may be associated with prevention of diabetes, reduction in blood
pressure, lower cholesterol and triglyceride levels, and other health benefits (3-5).
Alpha lipoic acid (ALA), also known as thioctic acid, is a naturally occurring short chain
fatty acid which contains a thiol bond (6). It is an essential cofactor for energy production in
the mitochondria (7). ALA is also a powerful antioxidant and a free radical scavenger (6, 8,
9). ALA is marketed in the US as an over-the-counter nutritional antioxidant supplement,
alone or in combination with other antioxidants. In medicine, ALA has been shown to
reduce symptoms of diabetic polyneuropathy, and several clinical trials established some
efficacy and an excellent safety profile in this patient population (10-15).
Previous studies have suggested anti-obesity properties of ALA (16-18). In animal studies, it
has showed that ALA supplementation promotes the reduction of body weight and fat mass
by decreasing food intake and enhancing energy expenditure, possibly by suppressing
hypothalamic AMP-activated protein kinase (AMPK) activity (19-22). However, studies in
humans with ALA supplementation are limited, and the results have been inconsistent. Some
clinical trials have shown that ALA supplementation may help overweight or obese
individuals lose weight (17, 18), while other studies have observed no effects of ALA on
weight (23, 24). Nevertheless, ALA appears to have a wide range of beneficial effects on
obesity related conditions such as insulin resistance, metabolic syndrome, and type II
diabetes, including their complications such as vascular damage (7, 13).
We performed a systematic review and comprehensive meta-analysis to assess the effects of
ALA as a weight-loss supplement. On the basis of the results from single studies, we
hypothesized that ALA is more effective than placebo for reducing body weight.
Methods
Studies were identified using Pubmed, PsychINFO, and Web of Science. Additionally, a
manual search was used among references cited in retrieved articles, related review articles,
and meta-analyses. Two reviewers (EZ and KL) independently conducted the literature
search using the following terms: (α-Lipoic OR alpha-lipoic OR “lipoic acid” OR thioctic
OR “α-LA”) AND (weight OR obesity OR overweight OR BMI OR “body mass” OR
diabete* OR diabeti* OR diabeto* OR “diabetes mellitus” OR “body fat” OR “fat mass”)
AND ((clinical [Title/Abstract] AND trial [Title/Abstract]).
Selection Criteria
The following inclusion criteria were used: (i) studies were randomized and placebo-
controlled, (ii) subjects were human with a mean age of ≥18 years old (iii) studies were ≥3
weeks in length, and (iv) studies reported weight and/or BMI before and after intervention
regardless if the stated aim was weight reduction or else. The present meta-analysis was
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conducted and reported according to the PRISMA (Preferred Reporting Items of Systematic
Reviews and Meta-Analysis) guidelines (25).
Data Extraction
Two reviewers (EZ and KL) independently reviewed each article and extracted all data.
After study selection and data extraction, a third reviewer (SK) checked all extracted data to
clarify any missing data. To obtain missing information, we contacted the authors to request
relevant data. Correlation coefficients were used to calculate and impute the missing
standard deviation of change from baseline applying the methods described in Cochrane
Handbook for Systematic Reviews of Interventions Version 5.1.0. (26, 27). The following
data were extracted: study design, sample size, medication dose, duration of follow-up,
demographical variables (age, gender), body weight, and body mass index (BMI). Outcomes
of overlapping samples from the same investigators were extracted from the more detailed
report.
Statistical Analyses
To avoid publication bias, we conducted a comprehensive search among published studies.
Publication bias was also assessed visually with funnel plots and statistically with Egger’s
regression test (28). Statistical heterogeneity was assessed using Q and I2
test (in which I2
≥
50% was considered to indicate heterogeneity). We examined the difference between ALA
treatment and placebo by calculating the mean difference using the software Comprehensive
Meta-Analysis Version 2 (Biostat, Englewood, NJ, USA). To combine studies, the random-
effects model was used with the results for a fixed-effects model presented on figures.
Results
Our study selection process is presented in Figure 1. A total of 728 articles excluding
duplicates were identified. After screening the title and abstract, 112 articles were selected
for further evaluation. After full-text review, 101 articles not fulfilling the selection criteria
were excluded. Of the excluded articles, 33 were not placebo controlled, 59 provided no
weight data, 4 were not randomized, and 4 included patients under 18 years of age.
Overall, we identified 11 eligible studies with 12 appropriate treatment arms for inclusion in
this review. Of these studies, eight of them reported weight outcomes and seven of them
reported BMI outcomes. Studies in this meta-analysis were carried out in various
populations, including patients with diabetes mellitus (11, 23, 29), metabolic syndrome (30),
rheumatoid arthritis (31), and non-alcoholic fatty liver disease (32). Three studies were
designed as weight loss interventions, and conducted with overweight and obese individuals
(18, 33, 34). Three studies employed dietary interventions with ALA or placebo (16, 18, 32).
Details of the studies are summarized in Table 1.
The total number of participants in these studies was 534 for the ALA group and 413 for the
placebo group. The study durations were between 8 weeks to 52 weeks. ALA doses were
between 300 mg/day to 1800 mg/day.
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Meta-analyses
Weight Change—Overall weight loss was 1.27 kg (CI=-2.29 to -0.25) greater in ALA
treatment compared to that in placebo group (Figure 2). We found no evidence of
publication bias in the body weight change analysis (Egger’s test intercept = -1.659, CI =
-5.10 to 1.78). There was a significant heterogeneity across interventions (I2=68.12, d.f.=8,
p<0.001).
Meta-regression analysis showed that neither intervention duration (P.E.=-2.00, CI=-4.02 to
0.01, p = 0.051) nor ALA dose had a significant effect on weight change (P.E.=-0.956,
CI=-3.08 to 1.16, p=0.377).
BMI Change—Meta-analysis of BMI changes between ALA and placebo groups is shown
in Figure 3. A significant overall mean BMI difference was found -0.40 kg/m2
(CI=-0.76 to
-0.03) between the ALA and placebo groups. We found no evidence of publication bias in
the body weight change analysis (Egger’s test intercept = -0.04, CI = -4.87 to 4.77). There
was a significant heterogeneity across interventions (I2=73.24, d.f.=8, p<0.001).
Meta-regression analysis showed no significant effect of ALA dose (P.E.=-0.16, CI=-0.48 to
0.14, p=0.29) on BMI change. Intervention duration significantly affects BMI change
(P.E.=-0.50, CI=-0.76 to -0.25, p<0.001).
Sub-group analyses—We employed two separate sub-group analyses to test the
effectiveness of ALA in weight loss interventions (16, 18, 33) and in studies with diet
intervention (16, 18, 32). In the first analysis, we found no significant difference on
effectiveness of ALA in weight loss interventions (-1.27, CI=-2.04 to -0.53) compared to
those non-weight loss interventions (-1.14 CI=-2.99 to 0.69) (Q=0.01, d.f.=1, p=0.90).
Cumulative analysis of BMI reduction in weight loss interventions (-0.48 kg/m2
CI=-0.88 to
-0.08) was similar to those non-weight loss interventions (-0.30 kg/m2
CI=-0.80 to 0.28)
(Q=0.23, d.f.=1, p=0.63). There was no significant heterogeneity in body weight (Q=2.95,
d.f.=3, p=0.399) and BMI (Q=2.47, d.f.=2, p=0.291) analyses in weight loss interventions.
In the second sub-group analysis, we found no significant difference between body weight
changes in ALA with diet intervention studies (-1.26 kg, CI=-2.14 to -0.37) compared to
those only ALA intervention studies (-1.29kg, CI=-3.03 to 0.44)(Q=0.001, d.f.=1, p=0.97).
Cumulative analysis of BMI reduction in ALA with diet interventions (-0.50 kg/m2
CI=-0.83
to -0.17) were similar to those ALA without diet interventions (-0.26 kg/m2
CI=-0.97 to
-0.43)(Q=0.35, d.f.=1, p=0.55). There was no significant heterogeneity in body weight
(Q=2.47, d.f.=2, p=0.290) and BMI (Q=4.09, d.f.=2, p=0.129) analyses in diet interventions.
Safety—Only three studies in this meta-analysis reported intervention related side effects
and related withdrawal rates (11, 18, 33). Two of these studies specifically described the
types of side effects (18, 33). The most commonly reported side effects that were related
with ALA in these two studies were gastrointestinal symptoms, such as abdominal pain and
nausea, and dermatological symptoms, such as urticaria and itching sensation. No severe
side effects were reported in any of the studies. Cumulative analysis of the percentage of
subjects who experienced side effects (O.R.=1.25, CI=0.84 to 1.85) and withdrawal rates
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due to the side effects (O.R.= 0.43, CI=0.19 to 0.98) did not differ among the ALA and
placebo groups.
Discussion
Cumulative results in this meta-analysis showed significant reduction of body weight and
BMI with ALA treatment compared to placebo, regardless if it was used for weight loss or
other purposes. Meta-regression analyses showed that shorter duration of ALA intervention
achieved greater BMI reduction than longer interventions. Incidences of side effects and all-
cause discontinuation was similar between ALA and placebo.
Small but significant reduction of body weight with ALA intervention is in line with
previous open label (17, 35) and randomized studies (16, 18, 33, 36). Although there was no
indication of publication bias for all outcome measures in our analysis, significant
heterogeneity across studies was detected. Possible explanations of this heterogeneity can be
the diversity of study samples, as well as study aims. Of these 10 studies, only three were
designed as a weight management intervention, which specifically recruited overweight and
obese individuals (16, 18, 33). Furthermore, most of the studies included in our analysis
were conducted in various samples, including patients with diabetes mellitus, metabolic
syndrome, and Takotsubo syndrome (11, 23, 29, 37). These studies focused on various
effects of ALA intervention, such as anti-inflammatory or anti-diabetic effects (11, 23, 29,
37). On the other hand, previous open label studies have well documented the effectiveness
of ALA on weight loss in overweight and obese individuals (17, 35). Although, our sub-
group analyses revealed no significant differences on body weight and BMI changes with
ALA treatment in weight loss and non-weight loss interventions, as well as in diet and non-
diet interventions, ALA yielded more robust effects when it is used in weight loss
interventions or when it is used in addition to a diet intervention. These results conclude that
ALA supplementation with diet intervention may provide more beneficial effects on body
weight management in overweight and obese individuals.
Previous studies have suggested that weight reduction from ALA can be time and dose
dependent (18, 33). In our analyses, we found that intervention duration, but not ALA dose,
significantly related with the reduction of BMI. Studies in our meta-analysis explored
various doses of ALA intervention (300 mg/day to 1800 mg/day) on different intervention
durations (8 weeks to 52 weeks). Only one placebo controlled study compared the
effectiveness of different doses of ALA on body weight (18). Koh et al. (18) explored the
effects of 1200 mg/day and 1800 mg/day ALA intervention on body weight loss. They found
that the higher dose of ALA resulted in significant weight loss and BMI reduction
throughout the study compared to placebo. The lower dose of ALA led to significant weight
loss in the first weeks of this study, however this effect was not sustainable through the
entire duration of the study. From these findings, we can argue that the effect of ALA on
body weight is limited to the short term, especially when it is used at lower doses with an
adaptation mechanism taking over later. This may have implications for future study
designs, for example phasic use of the medication may be tried.
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In our meta-analysis, the incidences of side effects were similar between the ALA and
placebo treatment arms. Withdrawal rates due to side effects were lower in ALA treated
patients than those in the placebo group. ALA has been reported as a well-tolerated
supplementation with no serious side effects (14, 18, 33). Although the maximum dose of
ALA has not been defined, previous studies have shown that ALA can be used safely up to
as high as 1800 mg/day (18). Only a small number of studies in our meta-analysis reported
the side effect details. Therefore, we were not able to compare the incidences of specific side
effects between the ALA and placebo groups.
Given our findings, it is important to note some limitations of this meta-analysis. The
number of studies and included patients were small. Furthermore, studies, study populations,
and main results in cumulative analyses were heterogeneous. Due to the relatively small
number of studies, our meta-regression analyses had limited power. Although there was no
evidence of publication bias for all outcome measures on funnel plots and Egger’s Tests, the
relatively small number of studies also limits the assessment of publication bias.
Finally, in our meta-analysis we were not able to evaluate the effects of ALA on specific
compositions of body weight, such as lean mass, fat mass or body water composition. The
reason of this limitation is that only one study (18) in our meta-analysis reported body fat
mass changes measured by impedance meter. In this study treatment with 1800 mg/day ALA
resulted more body fat loss compared to the other arms, however this difference was not
significant. On the other hand, previous ALA studies in animals demonstrated significant
reductions in body fat mass measured by weighing removed fat mass (38, 39). Measurement
methods of body compositions may explain this discrepancy between human and animal
studies. Future studies are needed to evaluate the effects of ALA on specific body weight
compositions.
In summary, findings from this meta-analysis suggest that ALA may be a useful
supplementation for weight loss in overweight and obese individuals. The benefits of ALA
compared to placebo appear smaller than that of available prescription weight loss
medications (40-42). However, ALA can be considered in clinical practice due to its benign
side-effect profile, other beneficial effects such as in diabetic neuropathy, and low cost
comparing to the available weight loss medications. Further research is needed to examine
the effect of different doses and the long-term benefits of ALA on weight management.
Acknowledgments
The study was funded by a grant to me from the U.S. National Institutes of Health (DK093924)
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Figure 1. Flow Chart Depicting Selection of Studies
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Figure 2. Mean body weight differences between ALA treatment and placebo
Heterogeneity: Tau
2=1.45; I
2=68.12%; Q=25.98, d.f=8, p<0.001
Overall effect: Z=-2.442, p=0.015
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Figure 3. Mean BMI differences between ALA treatment and placebo
Heterogeneity: Tau
2=0.18; I
2=73.24%; Q=29.90, d.f=8, p<0.001
Overall effect: Z=-2.139, p=0.033
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Kucukgoncu et al. Page 13
Table 1
Included ALA Studies
Study Sample Diet Study Duration Study Size (ALA/Control) Dose (mg PO QD) ALA Weight Change (mean ± SD) Control Weight Change (mean ± SD) ALA BMI Change (mean ± SD) Control BMI Change (mean ± SD)
Ansar et al., 2011
(23)
Patients with
Diabetes Mellitus 8 weeks 29/28 300 -2.08 ± 5.15 -1.12 ± 5.87
Gargari et al.,
2015 (31)
Women with
Rheumatoid
Arthritis
8 weeks 33/32 1200 -0.06 ± 6.85 0.32 ± 5.59 -0.01 ± 2.89 0.14 ± 2.08
Gianturco et al.,
2013 (32)
Patients with
nonalcoholic fatty
liver disease
Energy restricted diet 52 weeks 52/46 400 -0.3 ± 1.69 0.3 ± 0.92
Huerta et al.,
2015 (16)
BMI 27.5 to 40
women individuals Energy restricted diet 10 weeks 20/22 300 -7 ± 3.1 -5.2 ± 2.5
Kim et al., 2016
(33)
Patients with
schizophrenia who
gained ≥ 10% body
weight with
antipsychotic
treatment
12 weeks 10/12
600-1800
as
tolerated;
mean
1620.0
-1.34 ± 6.48 1.74 ± 5.93 -0.52 ± 1.99 0.14 ± 1.99
Koh et al., 2011
(18) BMI ≥ 27 Calorie-restricted diet 20 weeks 120/120 1200 -1.49 ± 3.24 -0.94 ± 3.84 -0.57 ± 1.19 -0.33 ± 1.36
Koh et al., 2011
(18) BMI ≥ 27 Calorie-restricted diet 20 weeks 120/120 1800 -2.76 ± 4.79 -0.94 ± 3.84 -1.06 ± 1.53 -0.33 ± 1.36
Manning et al.,
2013 (30)
Patients with
metabolic
syndrome
12 months 34/40 600 0.33 ± 3.76 -0.05 ± 3.53 0.15 ± 1.27 -0.01 ± 1.29
Marfella et al.,
2016 (37)
Patients with
Takotsubo
syndrome
12 months 24/24 600 -0.13 ± 0.89 -0.33 ± 0.91
Mohammadi et
al., 2015 (36)
Male patients with
chronic spinal cord
injury
12 weeks 28/30 600 -3.7 ± 4.4 0.38 ± 1.4 -1 ± 0.6 0.09 ± 0.6
Udupa et al.,
2012 (29)
Patients with
Diabetes Mellitus 90 days 25/25 300 -0.8 ± 7.02 -1.16 ± 1.12
Ziegler et al.,
1997 (11)
Patients with
Diabetes Mellitus 4 months 39/34 800 -1.2 ± 5.28 0.7 ± 7.11
Obes Rev. Author manuscript; available in PMC 2018 May 01.