CLINICAL RESEARCH STUDY
Effects of Alpha-Lipoic Acid on Body Weight in Obese
Subjects
Eun Hee Koh, MD,a* Woo Je Lee, MD,a* Sang Ah Lee, MD,a Eun Hee Kim, MD,a Eun Hee Cho, MD,a
Eunheui Jeong, MD,a Dong Woo Kim, MD,a Min-Seon Kim, MD,a Joong-Yeol Park, MD,a Keun-Gyu Park, MD,b
Hyo-Jung Lee, PhD,c In-Kyu Lee, MD,c Soo Lim, MD,d Hak Chul Jang, MD,d Ki Hoon Lee, PhD,e Ki-Up Lee, MDa
a
Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea; bDepartment of Internal
Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea; cDepartment of Internal Medicine, and Biochemistry
and Cell Biology, Kyungpook National University School of Medicine, Daegu, Republic of Korea; dDepartment of Internal Medicine,
Seoul National University College of Medicine, and Seoul National University Bundang Hospital, Seongnam, Republic of Korea;
e
School of Business, Jeonju University, Jeonju, Republic of Korea.
ABSTRACT
PURPOSE: Alpha-lipoic acid is an essential cofactor for mitochondrial respiratory enzymes that improves
mitochondrial function. We previously reported that alpha-lipoic acid markedly reduced body weight gain
in rodents. The purpose of this study was to determine whether alpha-lipoic acid reduces body weight in
obese human subjects.
METHODS: In this randomized, double-blind, placebo-controlled, 20-week trial, 360 obese individuals
(body mass index [BMI] ⱖ30 kg/m2 or BMI 27-30 kg/m2 plus hypertension, diabetes mellitus, or
hypercholesterolemia) were randomized to alpha-lipoic acid 1200 or 1800 mg/d or placebo. The primary
end point was body weight change from baseline to end point.
RESULTS: The 1800 mg alpha-lipoic acid group lost significantly more weight than the placebo group
(2.1%; 95% confidence interval, 1.4-2.8; P ⬍ .05). Urticaria and itching sensation were the most common
adverse events in the alpha-lipoic acid groups, but these were generally mild and transient.
CONCLUSION: Alpha-lipoic acid 1800 mg/d led to a modest weight loss in obese subjects. Alpha-lipoic acid
may be considered as adjunctive therapy for obesity.
© 2011 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2011) 124, 85.e1-85.e8
KEYWORDS: Alpha-lipoic acid; Anti-obesity agent; Side effect
The prevalence of obesity is rapidly increasing around the
world.1,2 Obesity reduces life expectancy and increases the
risks of health problems, such as heart disease, type 2
diabetes, sleep apnea, certain types of cancer, and osteoarthritis.2,3 Although lifestyle modification is considered the
Funding: This work was supported by the Korea Health Industry
Development Institute (0412-DB00-0101-0006). This study was funded in
part by Dalim BioTech Co, Ltd, Seoul, Republic of Korea.
Conflict of Interest: None of the authors have any conflicts of interest
associated with the work presented in this manuscript.
Authorship: All authors had access to the data and played a role in
writing this manuscript.
*Both authors contributed equally to this work.
Requests for reprints should be addressed to Ki-Up Lee, MD, Department of Internal Medicine, University of Ulsan College of Medicine,
Pungnap-dong, Songpa-ku, Seoul 138-736, Korea.
E-mail address: [email protected]
0002-9343/$ -see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2010.08.005
first-line therapy for obesity, many common methods for
lifestyle modification have proven disappointing.
Two anti-obesity medications are currently approved by
the US Food and Drug Administration for long-term use:
orlistat and sibutramine. Orlistat reduces intestinal fat absorption by inhibiting pancreatic lipase, whereas sibutramine decreases appetite by inhibiting deactivation of the
brain neurotransmitters norepinephrine, serotonin, and dopamine.4-6 Both of these drugs, however, have shown limitations in terms of efficacy and side effects.4-6
Alpha-lipoic acid, a natural short-chain fatty acid containing sulfhydryl groups, is a potent antioxidant.7,8 Alpha-lipoic acid is an essential cofactor for mitochondrial
respiratory enzymes and improves mitochondrial function.9,10 Alpha-lipoic acid was shown to be effective in
reducing symptoms of diabetic polyneuropathy without
serious adverse effects11,12 and is used in clinical practice
85.e2
The American Journal of Medicine, Vol 124, No 1, January 2011
eligible subjects (n ⫽ 539) underwent the 4-week run-in
in countries such as Germany and Korea,13 with multiphase, during which they received placebo (3 tablets 30
center trials currently ongoing in Europe and North
minutes before each meal). The purpose of this phase, as
America.14
explained to all potential participants, was to identify willWe previously showed that alpha-lipoic acid markedly reing and eligible individuals who demonstrated good comduces body weight gain in rodents.15 However, it is not known
pliance, defined as taking ⬎80%
whether this drug is effective in
of study tablets during that interobese humans. We therefore evaluval. Only subjects who successated the efficacy and safety of alCLINICAL SIGNIFICANCE
fully completed the run-in phase
pha-lipoic acid in a randomized,
were randomized.
double-blind, placebo-controlled trial
● Alpha-lipoic acid at a dosage of 1800
During the run-in phase of the
in obese human subjects.
mg/d led to a modest weight loss in
trial,
all potential participants reobese subjects.
ceived dietary instructions from
PATIENTS AND METHODS
● Differences in side effects compared
registered dietitians, with the goal
with
currently
used
anti-obesity
drugs
of reducing total daily caloric inParticipant Recruitment
take by 600 kcal/d. Additional disuggest
that
alpha-lipoic
acid
may
be
This study was conducted in acetary instructions were provided at
an adjunctive treatment for obesity.
cordance with the principles depredetermined intervals during the
scribed in the Declaration of Helstudy. The diet was composed of
sinki. The study protocol was
55% to 60% carbohydrates, 20%
approved by the institutional reto 25% fat, and 15% to 20% protein, with a minimum total
view board at each center, and all subjects provided written
calorie intake of 1200 kcal/d. After the run-in phase, the 360
informed consent.
selected participants were randomized into 3 groups. To
A variety of recruitment strategies were used to attract
reduce the unpredictability of randomization, block ranpotential participants. The sponsor company developed sevdomization, with a block size of 9 or 12, was used to ensure
eral materials, including brochures, posters, and newspaper
that at no time during the study would there be a large
advertisements. All advertisements were approved by the
imbalance among the groups. A stratified block randomizainstitutional review board at each center.
tion list based on 1 stratification factor, BMI 27 to 30 kg/m2
Obese subjects aged 18 to 65 years with a body mass
2
or ⱖ30 kg/m2, was used to assign all eligible subjects to
index (BMI) ⱖ30 kg/m were recruited, as were subjects
treatment with 1200 or 1800 mg/d oral alpha-lipoic acid or
with a BMI of 27 to 30 kg/m2 if they had hypertension,
placebo. The placebo tablets were composed primarily of
diabetes mellitus, or hypercholesterolemia. Hypertension
lactose and cellulose and were indistinguishable from the
was defined as a blood pressure of ⬎140/90 mm Hg on 2
alpha-lipoic acid tablets. Each center was expected to reseparate occasions or the use of antihypertensive agents.
ceive the same number of blocks.
Diabetes mellitus was defined as a fasting plasma glucose
All subjects were instructed to take 9 tablets per day (3
concentration ⱖ126 mg/dL on 2 separate occasions or the
tablets 30 minutes before each meal), with subjects in the
use of oral hypoglycemic agents. Hypercholesterolemia was
placebo group taking 3 placebo tablets, subjects in the 1200
defined as plasma total cholesterol concentration ⬎240
mg/d group taking two 200 mg alpha-lipoic acid tablets and 1
mg/dL or use of lipid-lowering medications.
placebo tablet, and subjects in the 1800 mg/d group taking
Exclusion criteria included pregnancy; a history of allergy
three 200 mg alpha-lipoic acid tablets before each meal. Alto alpha-lipoic acid; recent changes in weight, diet, exercise
pha-lipoic acid and placebo tablets were packaged indistinactivity, or smoking habit; and a history of bariatric surgery.
Subjects with hypothyroidism, Cushing syndrome, malignant
guishably and labeled with a subject number. Only 1 clinical
disease, hepatic disease (serum aspartate transaminase, alanine
pharmacist who was independent of this study was aware of
aminotransferase, or alkaline phosphatase ⱖ2.5⫻ upper limit
the medication assignment code, which was kept in a sealed
of normal), congestive heart failure, renal dysfunction (creatienvelope for emergency access. None of the research personnine ⬎2.0 mg/dL), malabsorption syndrome, pancreatic disnel who enrolled, treated, or assessed the subjects were aware
ease, psychiatric illness, or known or suspected drug abuse
of subject assignments until the study was completed. All
were also excluded. During the trial, subjects were not allowed
study drugs and study-supplied concomitant medications were
to use glucocorticoids or any other medications that could
kept in a secure, safe area under recommended storage condiaffect body weight.
tions. Efforts were made by the study coordinators to maintain
adherence to study visits and study medication administration.
Study Design
Subjects received telephone calls every week. Subjects were
instructed to bring all remaining drugs at each visit and were
This randomized, double-blind, placebo-controlled 20-week
withdrawn from the study when drug consumption was ⬍80%
trial was conducted at 3 university hospitals in the Republic
of prescribed dose. Subjects were also withdrawn if they did
of Korea. The study consisted of a 4-week run-in phase
not complete the scheduled routine visit within 3 days.
followed by a 20-week treatment phase. All potentially
Koh et al
Anti-Obesity Effects of Alpha-Lipoic Acid
At each visit, subjects were asked whether they had
experienced an adverse event. The study investigators evaluated the severity and potential relationship between the
adverse event and alpha-lipoic acid use. Adverse events and
serious adverse events, defined according to the Food and
Drug Administration Code of Federal Regulations part 312,
included death, a life-threatening adverse drug experience,
inpatient hospitalization, prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a
congenital abnormality/birth defect.
The authors designed the study, gathered and analyzed the
data, and vouch for the completeness and accuracy of the data
and the analysis. The sponsor had no role in the design of the
study; the collection, management, analysis, or interpretation
of the data; or the preparation of the manuscript.
Assessments
Before enrollment, all subjects underwent a comprehensive
medical evaluation, which included medical history, a physical
examination, an electrocardiogram assessment, laboratory
tests, and a urinary pregnancy test for women of childbearing
potential. The primary outcome was change in body weight
(end point minus baseline). Secondary outcomes were mean
Table 1
85.e3
changes in waist circumference, body fat (measured by impedance meter, TANITA TBF 521, Tokyo, Japan), blood pressure,
and fasting plasma glucose, total cholesterol, triglyceride, lowdensity lipoprotein cholesterol, and high-density lipoprotein
cholesterol levels. Safety assessments included the incidence
and severity of treatment-related adverse events during the
20-week treatment period.
Statistical Analysis
All data were analyzed using the Statistical Package for the
Social Sciences (version 17.0; SPSS Inc, Chicago, IL). Data
were compared using analysis of variance and post hoc
analysis (Duncan). A P value ⬍ .05 was defined as statistically significant. Intent-to-treat analysis included all randomized subjects who received at least 1 dose of study
medication. Missing data for subjects in the intent-to-treat
population were imputed using the last observation carried
forward method. The populations of per-protocol completers, defined as subjects who completely finished the 20week double-blind treatment without major protocol deviations, were included for analyses of primary and secondary
outcomes. Laboratory parameters and vital signs were analyzed among the per-protocol completers. Changes in body
Clinical Characteristics at Randomization
Placebo
(n ⫽ 120)
Age (y)
Gender, No. (%)
Female
Male
Anthropometric measurements
Weight (kg)
BMI (kg/m2)
Waist circumference (cm)
Fat mass (kg)
Vital signs
SBP (mm Hg)
DBP (mm Hg)
Heart rate (beats/min)
Laboratory data*
Cholesterol (mg/dL)
Triglyceride (mg/dL)
HDL cholesterol (mg/dL)
Triglyceride/HDL cholesterol ratio
LDL cholesterol (mg/dL)
Fasting glucose (mg/dL)
HbA1c (%)
Comorbidities, No.
Hypertension
Diabetes mellitus
Hypercholesterolemia
40.7 ⫾ 1.1
ALA 1200 mg
(n ⫽ 120)
ALA 1800 mg
(n ⫽ 120)
41.6 ⫾ 1.1
41.4 ⫾ 1.0
46 (38%)
74 (62%)
41 (34%)
79 (66%)
38 (31%)
82 (69%)
89.6 ⫾ 15.7
33.1 ⫾ 4.0
103.5 ⫾ 10.0
41.9 ⫾ 8.4
89.2 ⫾ 14.9
33.2 ⫾ 4.2
103.8 ⫾ 9.5
42.3 ⫾ 7.7
88.8 ⫾ 15.9
33.3 ⫾ 4.0
103.9 ⫾ 10.6
43.6 ⫾ 6.8
133.0 ⫾ 13.0
82.0 ⫾ 9.0
75.0 ⫾ 11.0
133.0 ⫾ 14.0
82.0 ⫾ 10.0
75.0 ⫾ 10.0
133.0 ⫾ 13.0
81.0 ⫾ 9.0
75.0 ⫾ 10.0
182.9 ⫾ 3.2
145.8 ⫾ 7.3
48.7 ⫾ 0.9
3.2 ⫾ 0.2
108.7 ⫾ 3.1
108.9 ⫾ 2.4
6.0 ⫾ 0.1
186.0 ⫾ 3.3
150.4 ⫾ 7.6
48.6 ⫾ 0.9
3.4 ⫾ 0.2
110.9 ⫾ 3.0
112.1 ⫾ 3.4
6.1 ⫾ 0.1
188.2 ⫾ 3.2
144.6 ⫾ 6.8
48.6 ⫾ 0.9
3.3 ⫾ 0.2
114.3 ⫾ 3.1
109.2 ⫾ 2.1
6.1 ⫾ 0.1
32
31
27
44
33
26
33
34
25
ALA ⫽ alpha-lipoic acid; BMI ⫽ body mass index; SBP ⫽ systolic blood pressure; DBP ⫽ diastolic blood pressure; HDL ⫽ high-density lipoprotein;
LDL ⫽ low-density lipoprotein; HbA1c ⫽ hemoglobin A1c.
Data are given as mean ⫾ standard deviation.
*Data are given as mean ⫾ standard error of the mean.
85.e4
The American Journal of Medicine, Vol 124, No 1, January 2011
Figure 1
Disposition of subjects enrolled in the study. LA ⫽ alpha-lipoic acid.
weight from baseline to each visit were analyzed using
paired t tests. Subgroup analyses were performed on subjects
with hypertension, diabetes mellitus, or hypercholesterolemia.
Differences in the percentage of responders, defined as subjects
who achieved ⱖ5% weight loss from baseline over 20 weeks,
were analyzed using chi-square tests. All parameters are reported as mean ⫾ standard error of the mean, whereas demographic data are reported as mean ⫾ standard deviation.
1800 mg/d alpha-lipoic acid groups, average weight decreased
significantly from baseline, starting as early as 4 weeks (Figure
2). At 20 weeks, the mean body weight reduction was significantly greater in the 1800 mg/d alpha-lipoic acid group than in
the placebo group. Similarly, analyses of both the intent-totreat and per-protocol completer populations showed that
weight loss at 20 weeks was significantly greater in the 1800
RESULTS
Clinical Characteristics
Of the 539 recruited subjects, 360 were randomly assigned
to the 3 groups; there were no differences in baseline characteristics among the 3 groups (Table 1). Of the 360 randomized subjects, 228 completed the 20-week double-blind
trial (Figure 1). There were no significant differences in
baseline clinical or laboratory characteristics between subjects who completed the study and those who were withdrawn (data not shown). Overall withdrawal rates did not
differ among the 3 groups, and alpha-lipoic acid treatment
was not associated with increased withdrawal rates because
of adverse events. The primary reasons for premature withdrawal are shown in Figure 1.
Body Weight
Changes in body weight during the 20-week treatment period
are shown in Figures 2 and 3 and Table 2. In both the 1200 and
Figure 2 Mean change in body weight from baseline during
20 weeks of treatment with placebo or 1200 or 1800 mg/d
alpha-lipoic acid (intent-to-treat subjects). Data are reported as
mean ⫾ standard error of the mean. *P ⬍ .05 vs baseline for
that group; **P ⬍ .05 vs placebo. LA ⫽ alpha-lipoic acid.
Koh et al
Anti-Obesity Effects of Alpha-Lipoic Acid
85.e5
Figure 3 Mean weight loss at 20 weeks in intent-to-treat subjects (A) and per-protocol
completers (B). Data are reported as mean ⫾ standard error of the mean. *P ⬍ .05 vs
placebo. LA ⫽ alpha-lipoic acid; ITT ⫽ intent-to-treat; PPC ⫽ per-protocol completers.
mg/d alpha-lipoic acid group than in the placebo group (Table
2; Figure 3). The average weight loss in the 1200 mg/d alphalipoic acid group was between that of the placebo and the 1800
mg/d alpha-lipoic acid groups, but the mean weight loss in this
group did not differ significantly from that in the placebo group
(Table 2).
Analyses of the intent-to-treat and per-protocol completer populations showed that reduction in BMI was significantly greater in the 1800 mg/d alpha-lipoic acid group
than in the placebo group. Moreover, analysis of per-protocol completers showed that reduction in waist circumference was significantly greater in the 1800 mg/d alpha-lipoic
acid group than in the placebo group (Table 2), as was the
percentage of subjects who achieved a ⱖ5% reduction in
baseline body weight (21.6% vs 10.0%, P ⬍ .01) (Figure 4).
No significant changes were observed in triglyceride concentrations and triglyceride/high-density lipoprotein cholesterol ratios among the 3 groups (Table 2). When responders
were compared with non-responders (ie, those with ⬍5%
weight loss or positive weight change), we observed no
significant differences in initial clinical or laboratory parameters (data not shown).
Subgroup Analyses
We separately analyzed the results in subjects with BMI 27
to 30 kg/m2 plus additional risk factors, such as hypertension, diabetes, or hypercholesterolemia. Although the number of subjects in each subgroup was relatively small, the
reductions in body weight and BMI were significantly
greater in those treated with 1800 mg/d alpha-lipoic acid
than in those treated with placebo. Subjects with diabetes
randomized to 1800 mg/d alpha-lipoic acid showed a mean
0.38% reduction from baseline in hemoglobin-A1c level
(P ⬍ .05). Treatment with alpha-lipoic acid, however, was
not associated with significant reductions in blood pressure
or fasting plasma glucose and cholesterol concentrations
(Table 3).
Safety
Consistent with previous findings,16 itching sensation or
urticaria was the most common adverse event in subjects
treated with alpha-lipoic acid (Table 4). However, the degree of body weight reduction was not related to itching
sensation or urticaria, and body weight change did not differ
between patients who did and did not report skin symptoms.
One subject in the 1800 mg/d alpha-lipoic acid group and 3
subjects in the 1200 mg/d alpha-lipoic acid group withdrew
because of itching sensation.
Overall, the percentage of subjects with at least 1 adverse
event during the treatment did not differ among the 1200 and
1800 mg/d alpha-lipoic acid groups and placebo group (24%,
24%, and 20%, respectively). A total of 16 subjects withdrew
because of adverse events, 9 in the placebo group, 3 in the
1200 mg/d alpha-lipoic acid group, and 4 in the 1800 mg/d
alpha-lipoic acid group (Table 4). Two subjects in the placebo
group and 1 subject in the 1800 mg/d alpha-lipoic acid group
withdrew because of intercurrent illnesses, but these illnesses
were not considered related to study medication.
Severe unexpected adverse events were not observed, as
determined by physical examination, clinical laboratory tests,
and electrocardiograms. No deaths occurred during this study.
DISCUSSION
To our knowledge, this is the first study to show that alphalipoic acid treatment led to a significant weight reduction in
obese human subjects. Subjects who completed 20 weeks of
treatment with 1800 mg/d alpha-lipoic acid showed modest but
statistically significant reductions in body weight and BMI.
Moreover, the percentage of subjects with a ⱖ5% loss in initial
body weight was significantly higher in the 1800 mg/d alphalipoic acid group than in the placebo group.
Alpha-lipoic acid was generally well tolerated with no
serious adverse effects. As previously reported,16 we found
that the most common adverse effects of alpha-lipoic acid
85.e6
The American Journal of Medicine, Vol 124, No 1, January 2011
Table 2 Changes in Body Weight, Waist Circumference, Fat Mass, Body Mass Index, and Triglyceride/High-Density Lipoprotein
Cholesterol Ratio
ITT
Placebo
(n ⫽ 120)
⫺0.77 ⫾ 0.34
(⫺0.86 ⫾ 0.38)
Waist circumference, cm (%) ⫺1.69 ⫾ 0.43
(⫺1.58 ⫾ 0.39)
Fat mass, kg (%)
⫺0.45 ⫾ 0.26
(⫺0.96 ⫾ 0.66)
BMI, kg/m2 (%)
⫺0.28 ⫾ 0.13
(⫺0.87 ⫾ 0.38)
Triglyceride, mg/dL
HDL cholesterol, mg/dL
Triglyceride/HDL cholesterol
ratio
Weight loss, kg (%)
PPC
LA 1200 mg
(n ⫽ 120)
LA 1800 mg
(n ⫽ 120)
Placebo
(n ⫽ 73)
LA 1200 mg
(n ⫽ 73)
LA 1800 mg
(n ⫽ 82)
⫺1.07 ⫾ 0.24
(⫺1.18 ⫾ 0.28)
⫺1.33 ⫾ 0.29
(⫺1.28 ⫾ 0.28)
⫺0.53 ⫾ 0.20
(⫺1.15 ⫾ 0.54)
⫺0.38 ⫾ 0.09
(⫺1.10 ⫾ 0.28)
⫺1.83 ⫾ 0.34*
(⫺2.08 ⫾ 0.35*)
⫺2.00 ⫾ 0.33
(⫺1.93 ⫾ 0.32)
⫺0.93 ⫾ 0.24
(⫺2.04 ⫾ 0.63)
⫺0.72 ⫾ 0.12*
(⫺2.17 ⫾ 0.35*)
⫺0.94 ⫾ 0.45
(⫺1.03 ⫾ 0.49)
⫺1.39 ⫾ 0.43
(⫺1.32 ⫾ 0.42)
⫺0.42 ⫾ 0.36
(⫺0.99 ⫾ 0.98)
⫺0.33 ⫾ 0.16
(⫺1.03 ⫾ 0.49)
2.98 ⫾ 0.18
3.23 ⫾ 0.19
0.25 ⫾ 0.18
⫺1.49 ⫾ 0.38
(⫺1.65 ⫾ 0.45)
⫺2.13 ⫾ 0.43
(⫺2.04 ⫾ 0.41)
⫺0.59 ⫾ 0.32
(⫺1.15 ⫾ 0.87)
⫺0.57 ⫾ 0.14
(⫺1.65 ⫾ 0.45)
3.39 ⫾ 0.29
3.61 ⫾ 0.32
0.23 ⫾ 0.22
⫺2.76 ⫾ 0.53*
(⫺3.04 ⫾ 0.54*)
⫺3.03 ⫾ 0.49*
(⫺2.89 ⫾ 0.47*)
⫺1.41 ⫾ 0.31
(⫺3.12 ⫾ 0.75)
⫺1.06 ⫾ 0.17†
(⫺3.14 ⫾ 0.54†)
3.08 ⫾ 0.23
3.18 ⫾ 0.23
0.10 ⫾ 0.19
ITT ⫽ intent to treat; PPC ⫽ per-protocol completer; LA ⫽ alpha-lipoic acid; BMI ⫽ body mass index; HDL ⫽ high-density lipoprotein.
Data are given as mean ⫾ standard error of the mean.
*P ⬍ .05 vs placebo.
†P ⬍ .01 vs placebo.
treatment were allergic skin reactions, including urticaria
and itching sensation, but these skin lesions were not a
major reason for withdrawal from this drug. Although gastrointestinal symptoms, including abdominal pain, nausea,
vomiting, and diarrhea, have also been reported,12 we found
no differences in the incidences of gastrointestinal symptoms among the placebo and treatment groups. The main
adverse effects of orlistat are gastrointestinal, whereas those
of sibutramine are increased blood pressure and pulse.4-6
Thus, the side effects of alpha-lipoic acid differ from those
of currently used anti-obesity drugs.
Clinical trials in patients with diabetic peripheral neuropathy have shown that administration of oral racemic
alpha-lipoic acid, at concentrations as high as 1800 mg/d for
6 months and as high as 1200 mg/d for 2 years, did not
result in serious adverse effects.17-19 Because the usual
dosage of alpha-lipoic acid (600 mg/d) used to treat
peripheral neuropathy does not result in weight loss, we
selected the 2 higher dosages (1200 and 1800 mg/d) for
a first test in human subjects. Although the maximum
tolerated dose of alpha-lipoic acid in human subjects has
not been well defined, a recent study has suggested that
humans can tolerate several grams per day of oral alphalipoic acid.20 Thus, the dosages used in this study were
lower than those previously found to be tolerated by
human subjects.
In this study, we used racemic alpha-lipoic acid. Only the
R-isomer of alpha-lipoic acid is synthesized naturally, whereas
conventional chemical synthesis results in a 50/50 (racemic)
mixture of the 2 optical isomers, R- and S-alpha-lipoic acid.
Pharmacokinetic studies have shown that humans absorb
approximately 30% to 40% of an oral dose of racemic
alpha-lipoic acid.10 Plasma alpha-lipoic acid concentration
generally peaks within 1 hour after administration and then
declines rapidly.21 Thus, after oral administration, the maximum plasma concentration of alpha-lipoic acid may rapidly
decrease without reaching an effective therapeutic concentration. Additional studies are needed to evaluate the
dose of alpha-lipoic acid that can lead to weight loss and
assess the long-term safety and efficacy of this dosage.
We and others have found that alpha-lipoic acid significantly improves insulin sensitivity and prevents vascular
Figure 4 Percentage of subjects in each group who lost ⱖ5%
of initial body weight (intent-to-treat subjects). *P ⬍ .01 vs placebo. LA ⫽ alpha-lipoic acid.
Koh et al
Table 3
Anti-Obesity Effects of Alpha-Lipoic Acid
85.e7
Changes in Body Weight and Parameters of Cardiovascular Risk Factors in Obese Subjects with Additional Risk Factors
Subgroup
Outcomes
Placebo
LA 1200 mg
LA 1800 mg
Hypertension
Weight loss, kg (%)
⫺0.00 ⫾ 0.34
(⫺0.10 ⫾ 0.42)
131.95 ⫾ 3.03
132.30 ⫾ 2.52
0.35 ⫾ 3.55
79.95 ⫾ 1.49
80.15 ⫾ 1.87
0.20 ⫾ 2.09
0.38 ⫾ 0.27
(0.50 ⫾ 0.32)
127.58 ⫾ 6.06
138.05 ⫾ 7.81
10.55 ⫾ 6.89
7.21 ⫾ 0.24
7.66 ⫾ 0.39
0.45 ⫾ 0.23
⫺0.63 ⫾ 0.84
(⫺0.70 ⫾ 0.96)
178.44 ⫾ 11.26
180.13 ⫾ 14.26
1.68 ⫾ 10.62
⫺0.96 ⫾ 0.39
(⫺1.10 ⫾ 0.48)
137.48 ⫾ 2.36
128.96 ⫾ 2.27
⫺8.52 ⫾ 2.84
84.67 ⫾ 1.59
79.03 ⫾ 1.58
⫺5.64 ⫾ 1.68
⫺0.96 ⫾ 0.47
(⫺1.00 ⫾ 0.54)
147.88 ⫾ 10.81
147.12 ⫾ 9.79
⫺0.76 ⫾ 8.50
7.28 ⫾ 0.30
7.16 ⫾ 0.34
⫺0.12 ⫾ 0.18
⫺0.27 ⫾ 0.33
(⫺0.40 ⫾ 0.39)
189.00 ⫾ 12.22
199.15 ⫾ 13.16
10.15 ⫾ 10.85
⫺2.73 ⫾ 0.88*
(⫺2.90 ⫾ 0.80*)
132.97 ⫾ 2.79
129.41 ⫾ 2.45
⫺3.56 ⫾ 2.28
82.40 ⫾ 1.86
79.10 ⫾ 1.83
⫺3.30 ⫾ 1.53
⫺2.20 ⫾ 0.61*
(⫺2.60 ⫾ 0.72*)
130.96 ⫾ 5.40
134.27 ⫾ 4.91
3.31 ⫾ 4.10
7.17 ⫾ 0.21
6.77 ⫾ 0.16
⫺0.40 ⫾ 0.15*
⫺3.57 ⫾ 1.09*
(⫺3.80 ⫾ 1.00*)
176.35 ⫾ 9.00
188.30 ⫾ 9.83
11.95 ⫾ 9.63
Systolic blood pressure (mm Hg)
Initial 20-wk change
Diastolic blood pressure (mm Hg)
Initial 20-wk change
Diabetes
Weight loss, kg (%)
Fasting serum glucose, mg/dL
Initial 20-wk change
HbA1c,%
Initial 20-wk change
Hypercholesterolemia
Weight loss, kg (%)
Total cholesterol (mg/dL)
Initial 20-wk change
LA ⫽ alpha-lipoic acid; HbA1c ⫽ hemoglobin A1c.
All results are reported as mean ⫾ standard error of the mean.
*P ⬍ .05 vs placebo.
dysfunction and fatty liver in obese rodents.22-26 The beneficial effects of this drug have been attributed to its activation of 5’-AMP–activated protein kinase, the metabolic
master switch that responds to changes in cellular energy. In
addition, alpha-lipoic acid is a cofactor for several important
respiratory enzymes in mitochondria9,10 and functions as an
antioxidant.27 In this regard, it is noteworthy that patients
with diabetes who received 1800 mg/d alpha-lipoic acid
showed a mean 0.38% reduction from baseline in hemoglobin-A1c level. Further studies in large numbers of patients
Table 4
with diabetes are needed to determine the effects of alphalipoic acid on hemoglobin-A1c.
LIMITATIONS
Our study has several limitations. The length of the trial
(20 weeks) was relatively short. Moreover, because all
participants were prescribed a hypocaloric diet, our findings may be applicable only in the context of energy
restriction. It should also be highlighted that our study
Overall Incidence of Treatment-Related Adverse Events in At Least 1% Of Subjects and Withdrawal Rates
Placebo (n ⫽ 120)
Headache
Fever
Dizziness
Palpitation
Epigastric soreness
Abdominal pain
Urticaria
Itching sensation*
LA 1200 mg (n ⫽ 120)
LA 1800 mg
(n ⫽ 120)
Event
Withdrawal
Event
Withdrawal
Event
Withdrawal
3
0
0
3
4
1
4
3
1
0
0
1
2
2
0
0
0
1
2
1
4
5
7
13
0
1
0
0
3
0
0
3
4
3
2
0
1
0
8
13
0
3
0
0
0
0
0
1
(2.5)
(2.5)
(3.3)
(0.8)
(3.3)
(2.5)
(0.8)
(1.7)
(0.8)
(3.3)
(4.2)
(5.8)
(10.8)*
(3.3)
(2.5)
(1.7)
(0.8)
(6.7)
(10.8)*
LA ⫽ alpha-lipoic acid.
Some patients experienced ⬎ 1 adverse event. Data are reported as number of adverse events (%)/numbers who withdrew.
*P ⬍ .05.
85.e8
was conducted in Korea. The adiposity and metabolic
characteristics of Asian individuals differ from those of
Western or other populations.28 Thus, additional studies
are required to determine whether alpha-lipoic acid is
effective in other populations. Finally, head-to-head
comparisons are needed to compare the effects of alphalipoic acid with those of other anti-obesity drugs.
CONCLUSIONS
We showed that 1800 mg/d of oral alpha-lipoic acid was
effective in achieving significant weight loss in obese subjects. Although the therapeutic potency of alpha-lipoic acid
was modest, no serious side effects were observed. Differences in side effects from currently used anti-obesity drugs
suggest that alpha-lipoic acid may be effective as an adjunctive medication for obesity. Further studies are needed
to determine the adequate dosage of alpha-lipoic acid and its
long-term safety and efficacy. Moreover, head-to-head comparisons are needed to compare the safety and efficacy of
alpha-lipoic acid with those of other anti-obesity drugs.
ACKNOWLEDGMENTS
The authors acknowledge all dietitians, clinical pharmacists,
and coordinators who helped with this study. The authors
also thank Sang-Ki Kim, Young-Taek Kim, and Chan-Hee
Kim of Dalim BioTech Co, Ltd, for support of the study.
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