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J Nutr. 2020 Sep; 150(9): 2336–2345.
Published online 2020 Jul 21. doi:10.1093/jn/nxaa203
PMCID: PMC7540064
PMID: 32692358
Gerd Bobe, Alexander J Michels, Wei-Jian Zhang, Jonathan Q Purnell, Clive Woffendin, Cliff Pereira, Joseph A Vita, JAV is deceased. Nicholas O Thomas, Maret G Traber, Balz Frei, and Tory M Hagen
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ABSTRACT
Background
α-Lipoic acid (LA) is a dietary supplement for maintaining energy balance, but well-controlled clinical trials in otherwise healthy, overweight adults using LA supplementation are lacking.
Objectives
The primary objective was to evaluate whether LA supplementation decreases elevated plasma triglycerides in overweight or obese adults. Secondary aims examined if LA promotes weight loss and improves oxidative stress and inflammation.
Methods
Overweight adults [n=81; 57% women; 21–60 y old; BMI (in kg/m2)≥25] with elevated plasma triglycerides ≥100mg/dL were enrolled in a 24-wk, randomized, double-blind, controlled trial, assigned to either (R)-α-lipoic acid (R-LA; 600mg/d) or matching placebo, and advised not to change their diet or physical activity. Linear models were used to evaluate treatment effects from baseline for primary and secondary endpoints.
Results
R-LA did not decrease triglyceride concentrations, but individuals on R-LA had a greater reduction in BMI at 24 wk than the placebo group (−0.8; P=0.04). The effect of R-LA on BMI was correlated to changes in plasma triglycerides (r = +0.50, P=0.004). Improvement in body weight was greater at 24 wk in R-LA subgroups than in placebo subgroups. Women and obese participants (BMI≥35) showed greater weight loss (−5.0% and −4.8%, respectively; both P<0.001) and loss of body fat (−9.4% and −8.6%, respectively; both P<0.005). Antioxidant gene expression in mononuclear cells at 24 wk was greater in the R-LA group (Heme oxygenase 1 [HMOX1]: +22%; P=0.02) than in placebo. Less urinary F2-isoprostanes (−25%; P=0.005), blood leukocytes (−10.1%; P=0.01), blood thrombocytes (−5.1%; P=0.03), and ICAM-1 (−7.4%; P=0.04) at 24 wk were also observed in the R-LA group than in placebo.
Conclusions
Long-term LA supplementation results in BMI loss, greater antioxidant enzyme synthesis, and less potential for inflammation in overweight adults. Improved cellular bioenergetics is also evident in some individuals given R-LA.
This trial was registered at clinicaltrials.gov as NCT00765310.
Keywords: weight loss, BMI, lipoic acid, triglycerides, dietary supplements
Introduction
α-Lipoic acid (LA) is a vicinal dithiol synthesized from octanoic acid in mitochondria. This naturally occurring R-enantiomer of LA acts as a cofactor for mitochondrial α-ketoacid dehydrogenases involved in energy transduction (1).
Although de novo LA synthesis is the sole source for supplying LA as an enzyme cofactor, it is also readily available from dietary sources via uptake from the Na+-dependent multivitamin transporter (SLC5A6) (2). Consequently, LA is also available as a dietary supplement. LA supplementation changes cellular bioenergetics in rodent models, inhibiting fatty acid and triglyceride synthesis that in turn promotes lipid oxidation, hepatic triglyceride clearance, and visceral fat loss. These metabolic steps are regulated by activating AMP-dependent protein kinase (AMPK) (3–5). However, LA may also promote weight loss by suppressing excess food intake and promote physical activity via inhibition of AMPK in the hypothalamus. This effect is demonstrable, at least in the short term, in animal models (6).
Recent meta-analyses that included 13 randomized, placebo-controlled clinical trials from Asia, Europe, and New Zealand supported the use of oral LA supplements to promote modest weight loss in adults (7, 8); however, it is unclear as to the biological mechanisms involved. In part, this lack of clarity stems from trials where LA was given along with other weight-loss strategies, such as caloric restriction, or in the context of obesity-related comorbidities. Thus, there is a paucity of information that defines the extent of weight loss or its effects on the underlying metabolic sequelae associated with obesity that LA solely provides as a supplement.
Therefore, the primary objective of this study was to evaluate whether R-LA supplements at readily available over-the-counter dosages lower triglyceride concentrations as a marker of a change in energy balance in healthy, nonelderly adults with a high BMI. This randomized, double-blind, placebo-controlled trial incorporated a longer study length (24 wk) than most other clinical trials with LA, used the naturally occurring R-enantiomer at the commonly recommended dosage of 600mg/d, and focused on the effects of LA in the absence of caloric restriction in obese adults without comorbidities. Supplements with the R-form of LA demonstrate greater bioavailability and may distribute in the body differently than the S-enantiomer of LA, which is a by-product of the industrial synthetic process (9–11). Many studies do not specify the enantiomer of LA employed, which may be relevant to its biological effects.
Because we hypothesize that LA initiates fatty acid oxidation, it should promote fat loss in adults who are obese but otherwise healthy. Thus, our secondary aims included changes in body weight and body fat mass with LA supplementation. Because LA is sold as an over-the-counter antioxidant supplement with anti-inflammatory properties, we also evaluated as secondary outcomes the effect of LA supplementation on the cellular and plasma antioxidant pool. This analysis included antioxidant capacity, gene expression of antioxidant enzymes, lipid peroxidation, cellular and plasma markers of inflammation, and blood markers of immune surveillance. We chose these secondary measurements because of previous work in our laboratories showing that LA attenuates activation of inflammatory pathways and stimulates antioxidant defenses (5, 12–14).
Methods
Study design, funding, and ethical approval
This double-blind, randomized, placebo-controlled, parallel study (NCT00765310) was conducted between 2009 and 2013 at the Oregon Clinical and Translational Research Institute's Clinical and Translational Research Center at Oregon Health & Science University (OHSU) in Portland, Oregon. The study protocol complied with the Declaration of Helsinki and was approved by the Institutional Review Boards of both Oregon State University and OHSU.
Participants and recruiting
Participants were recruited from the greater Portland metropolitan area via websites, flyers, ads, and physician referrals to OHSU starting in October 2008. Recruiting terminated in February 2013 when funding was no longer available to recruit more participants. After an initial phone screen by a nurse, eligible participants were assessed for eligibility during a screening visit (Figure 1). Initial inclusion criteria were as follows: 18–50 y of age; weight-stable BMI ≥ 27(in kg/m2) (weight stable within ±1.0kg for the last 3 mo and at maximum lifetime body weight); fasting plasma triglycerides ≥ 150mg/dL; exercise limited to 30 min for ≤3 times/wk; and adherence to a prudent diet—as assessed using the Dietary Habit Survey (15)—at study start. Owing to low enrollment numbers, inclusion criteria were modified in January 2012 to increase the maximum age of enrollment (60 y), decrease the lower BMI limit (>25), and lower the threshold for triglycerides (>100mg/dL).
FIGURE 1
CONSORT diagram showing the progression of study participants—overweight or obese adults with elevated plasma triglycerides—through the 24-wk study period. LA, α-lipoic acid.
Exclusion criteria were formulated to exclude subjects with risk factors that could confound an analysis of R-LA's effect on otherwise relatively healthy obese individuals: C-reactive protein (CRP) concentration at baseline >10mg/L; smoking within the last 3 mo; consuming >2 alcoholic drinks per day; currently taking lipid-lowering drugs, antihypertensive drugs, insulin or oral hypoglycemic agents, anti-inflammatory drugs, weight loss medications, or hormone replacement therapy; diagnosed as having hyperglycemia (fasting glucose≥125mg/dL at baseline), cardiovascular disease, congestive heart failure, angina, thyroid disorders, cancer, inflammatory disorders, or renal, hepatic, or hematological abnormalities; having had acute medical conditions, such as hospitalizations or surgeries, ≥3 mo before entry into the study; and being pregnant, breastfeeding, or planning to become pregnant before the end of the study. Furthermore, volunteers were excluded if they were taking vitamin or antioxidant supplements, including R-LA, except standard multivitamin/mineral supplements containing not more than the Daily Value of each vitamin and mineral.
In a parallel-group design, participants were assigned to consume either a daily supplement containing 600mg (R)-α-lipoic acid (R-LA group) as a sodium salt or a matching inert tablet (Placebo group) for 24 wk (see details below). Participants were assigned to treatment groups by a covariate adaptive randomization method. The covariate blocks were set based on sex, baseline BMI (25.0–29.9; 30.0–34.9; 35.0–39.9; ≥40.0), and baseline plasma triglyceride concentrations (100–149, 150–199, 200–249, ≥250mg/dL) to ensure random allocation. CP at Oregon State University performed the block assignments and treatment allocations. Treatment group was communicated to the study site pharmacist to ensure proper blinding. All other investigators, staff, and participants remained blinded to the study supplement assignments until study completion.Table 1 shows the baseline demographic characteristics.
TABLE 1
Baseline characteristics in overweight or obese otherwise healthy adults with elevated plasma triglycerides assigned to Placebo or R-LA1
Characteristic | Placebo (n=33) | R-LA (n=31) |
---|---|---|
Age, y | 40±8 | 38±10 |
Sex, male | 16 (48) | 12 (39) |
Race, white | 31 (94) | 29 (94) |
Ethnicity, Hispanic | 2 (6) | 4 (13) |
Body weight, kg | 104.0±22.0 | 101.8±20.7 |
BMI, kg/m2 | 34.4±6.5 | 34.8±5.7 |
Body fat mass, kg | 39.9±14.2 | 39.4±11.5 |
Body fat, % | 37.7±7.3 | 38.6±7.4 |
Hip circumference, cm | 120±14 | 118±12 |
Waist circumference, cm | 112±14 | 112±13 |
Systolic BP, mm Hg | 125±10 | 127±12 |
Diastolic BP, mm Hg | 74±8 | 75±8 |
Heart rate, bpm | 71±9 | 72±8 |
Plasma metabolic biomarkers | ||
Triglycerides, mg/dL | 176±65 | 180±54 |
Total cholesterol, mg/dL | 199±32 | 207±49 |
HDL cholesterol, mg/dL | 44±12 | 44±9 |
LDL cholesterol, mg/dL | 120±25 | 127±43 |
Glucose, mg/dL | 96±9 | 96±9 |
Physical activity | ||
Energy expenditure, kcal/d | 767±274 | 767±294 |
Light activity, min/d | 194±61 | 198±60 |
Moderate activity, min/d | 126±56 | 130±46 |
Dietary intake | ||
Energy, kcal/d | 1857±576 | 1978±924 |
Total fat, % kcal | 31.1±6.7 | 31.7±5.5 |
Saturated fat, % kcal | 10.5±3.2 | 11.2±3.0 |
Total protein, % kcal | 16.3±3.1 | 16.8±4.7 |
Total carbohydrates, % kcal | 51.3±9.3 | 49.8±6.9 |
Fiber, g/Mcal | 10.9±3.6 | 9.5±3.2 |
Added sugars, g/Mcal | 30.8±19.6 | 31.9±15.2 |
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1Values are means±SEMs or n (%). BP, blood pressure; Placebo, control supplements; R-LA, 600mg (R)-α-lipoic acid/d.
Supplementation, adverse effect reporting, and compliance
Participants were advised to take either 2 capsules containing 300mg LA each or matched inert tablets, both provided by GeroNova Research, on an empty stomach 30min before breakfast with plenty of fluids. The 600-mg dose of LA was chosen for this study in order to reduce minimal adverse events (gastrointestinal upset) compared with higher dosages, and is similar to that approved in Europe for treatment of diabetes-induced polyneuropathies (16–18). This dosage is also consistent with current doses in over-the-counter supplements in the United States.
Placebo and R-LA capsules were identical in size, appearance, and taste. Compliance was measured by counting the returned capsules at the 3-, 12-, and 24-wk study visits. Subjects were advised to continue eating a prudent diet while taking the supplements, and continue their habitual exercise regimen during the study. At the start of the study, participants were given information on signs and symptoms of adverse events associated with LA supplementation (i.e., modest indigestion) and instructions on whom to contact if they suspected they were experiencing an adverse event. Participants were asked about adverse events every 3 wk via phone call as well as at their 3-, 12-, and 24-wk visits by a physician or nurse. A generalized severity scale and a 5-point attribution scale were used for adverse events; adverse events were reviewed by the OHSU Institutional Review Board to ensure participant safety. Supplemental Table 1 shows the results for compliance and adverse events.
Activity monitoring and dietary assessment
Physical activity was monitored for 2–4 wk around baseline, 12, and 24 wk using the Actical® accelerometer (Philips Respironics). The device was worn at the hip and logged the estimated total energy expenditure (kcal/d) as well as the amount of time (min/d) spent doing no, mild, moderate, and vigorous activity. For statistical analysis, we calculated the median of 7 consecutive days (minimum: 4 d) for these measures. To avoid days when the device was not worn in most of the wakeful hours, we excluded from the calculation those days with <5% of time spent being physically active, as well as the first and the last day the device was worn.
Food intake was assessed using three 24-h food recalls around baseline as well as 24 wk. The food recalls were done via phone by the Arizona Diet, Behavior, and Quality of Life Assessment Center (University of Arizona Cancer Center, Tucson, AZ). Nutrient intakes from each 24-h recall were calculated using the Minnesota Nutrient Data System for Research (University of Minnesota Nutrition Coordinating Center). For statistical analysis, we calculated the 3-d mean for these measures.
Sample collection and anthropometric analysis
Anthropometric measures and vital signs (heart rate, blood pressure) were determined after overnight fasting at baseline, 12, and 24 wk by a trained nurse. Height, circumference of the waist (horizontal plane around the abdomen at the level of the iliac crest), and circumference of the hip (horizontal plane around the hips at the level of maximum prominence of the buttocks) were measured in centimeters. Hip and waist measures were repeated until duplicates agreed to within 0.5cm. Total body weight and body fat mass were measured in duplicate within 10g by air-displacement plethysmography using the BOD POD® 2000A from Life Measurement, Inc. Body fat percentage was calculated as body fat mass divided by body weight multiplied by 100.
Overnight fasting blood samples were collected at baseline, 12, 23 (for triglyceride measurements only), and 24 wk and stored at −80° C until analysis. Plasma concentrations of triglycerides, cholesterol (total, HDL, VLDL, and LDL), and glucose and hematological measures were analyzed using standard clinical assays in the Clinical Core Laboratory at OHSU. Morning urine samples were collected at baseline, 12, and 24 wk and stored at −80° C until analysis. Table1 shows anthropometric measures, vital signs, and metabolic profiles of the study participants at baseline.
Plasma biomarkers
Plasma concentrations of acute-phase proteins, cytokines, and soluble adhesion molecules were measured using commercially available ELISA kits (R&D Systems). The interassay and intra-assay CVs were as follows: CRP, 7.0% and 3.8%; vascular cell adhesion molecule 1 (VCAM1) , 7.7% and 3.5%; intercellular adhesion molecule 1 (ICAM1), 4.4% and 5.0%; soluble E-selectin (SELE), 8.7% and 5.7%; IL-6, 7.2% and 7.8%; TNFA, 7.2% and 4.3%; and CCL2, 5.8% and 4.7%, respectively. Plasma total antioxidant capacity was measured using the ferric ion reducing antioxidant potential (FRAP) assay. The interassay and intra-assay variations between the samples were <3.0% and <1.0%, respectively.
For plasma ascorbic acid and uric acid analyses, samples were stabilized by the addition (1:1, vol:vol) of 15% perchloric acid (EMD Millipore) containing 1mM diethylenetriaminepentaacetic acid (DTPA) (Sigma-Aldrich), a metal chelator, and analyzed using HPLC. Briefly, extracts were diluted in a sodium acetate:methanol:water mobile phase (0.3%:7.5%:92% wt:vol) containing Q12 ion-pairing reagent (Regis Technologies) and pH-adjusted with KH2PO4 (pH 9.8). Samples were separated on a Waters 2695 instrument using an LC-8 Supelco column (Sigma-Aldrich) under an applied potential of 600mV using an electrochemical detector (BAS). Samples were run in duplicate, and uric acid concentrations were used to normalize ascorbic acid values in order to minimize any variations detected. Under these conditions, the intra-assay CV was <5%, whereas the interassay CV was <15%. Supplemental Table 1 shows the baseline concentrations of plasma biomarkers.
Cellular biomarkers
Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized venous blood of the subjects. Briefly, 20mL peripheral venous heparinized blood was collected and PBMCs were isolated by gradient centrifugation at room temperature (25° C) on Lymphoprep (Sigma-Aldrich) at 1200× g for 20min and then washed and resuspended to 1×107 cells/mL in HBSS. Monocytes were identified by May-Grunwald-Giemsa staining.
For gene expression analysis, total RNA was isolated using TRIzol Reagent (Invitrogen). cDNA synthesis was performed using the high-capacity cDNA archive kit (Applied Biosystems). All primers and probes for the human genes IL1B, IL6, CCL2, TNFA, HMOX1, GCLC, NQO1, and GAPDH were purchased as Assays on Demand kits from Applied Biosystems. TaqMan qPCR was performed as described previously using TaqMan Universal PCR Master Mix (Applied Biosystems) in 96-well plates with the ABI Prism 7500 Sequence Detection System (Applied Biosystems) (19, 20). To obtain relative quantification, 2 standard curves were constructed in each plate with 1 target gene and GAPDH as an endogenous control. Standard curves were generated by plotting the threshold cycle number values against the log of the amount of input cDNA and used to quantify the expression of the various target genes and GAPDH in the same sample. After normalization to GAPDH, the results were expressed as fold of baseline within the same group.
To determine intracellular glutathione and glutathione disulfide concentrations, we adapted the method of Fariss and Reed (21). Briefly, PBMCs were isolated from freshly drawn human blood, immediately acidified with an equal volume of 15% perchloric acid (wt:vol) containing 10mM DTPA, and stored at −80° C until ready for use. After deproteinization, iodoacetic acid was added to acetylate acid–soluble thiols, and pH-adjusted PBMC samples were derivatized with 1-fluoro-2,4-dinitrobenzene (0.1%, vol:vol). Reduced and oxidized glutathione were subsequently measured by a Shimadzu HPLC (Shimadzu Scientific Instruments, Inc.) using UV detection at 365nm with a Hypersil 3-aminopropyl column (Thermo Scientific). For intracellular ascorbate and urate analysis, acid extracts were analyzed using HPLC as described already for the plasma ascorbic acid and uric acid analyses. Supplemental Table 1 shows the baseline concentrations of cellular biomarkers.
Urinary biomarkers
Urine F2-isoprostanes, including 8-iso-PGF2α and its metabolites, and PGE2 concentrations were analyzed by a solid phase extraction process coupled to LC-tandem MS, and standardized to urinary creatinine concentrations. The assay for urinary 8-iso-PGF2α has a within-day precision of ±7% and an accuracy of 100% (22, 23). PGE2 and F2-isoprostanes are expressed as ng/mg creatinine. Supplemental Table 1 shows the baseline concentrations of urinary biomarkers.
Statistical analysis
The primary objective of this clinical trial was to evaluate changes in plasma triglycerides. The study was designed to show a statistically significant (P≤0.025) 14.6% decrease in triglycerides with 80% power as the main effect. The power calculation was based on an SD of 46.6mg/dL for triglycerides and 50 subjects/treatment group. Secondary aims were to determine if R-LA affects body weight and body fat mass, the cellular and plasma antioxidant pool and capacity, gene expression of antioxidant enzymes, lipid peroxidation, cellular and plasma markers of inflammation, and blood markers of immune surveillance, which were all defined at the study design stage.
The original statistical analysis plan specified 3-visit repeated-measures-in-time analysis. During the primary study analysis, it became apparent that several Placebo participants showed pronounced changes to body weight in the first 12 wk that were not sustained and often reversed after 24 wk. By contrast, gradual changes were observed in R-LA participants. As such, we analyzed changes per time point and modified the statistical analysis plan accordingly. In addition, several participants withdrew consent from the study and were effectively lost to follow-up for any endpoints. Because no data for these participants existed, we analyzed all participants with follow-up data instead of utilizing a method to impute the missing data.
All statistical analyses were performed as intention-to-treat analysis using SAS (SAS/Stat version 9.2, SAS Institute). Fisher's exact test was used to compare the numbers of participants experiencing adverse events. We calculated absolute and percentage changes from baseline at 12 wk and at 24 wk of treatment. Generalized linear models (PROC GLM) were used to evaluate treatment effects on the percentage changes from baseline as well as for absolute changes from baseline for primary and secondary endpoints. Fixed effects in the model were supplementation (Placebo, R-LA), sex (male, female), baseline BMI (25.0–29.9; 30.0–34.9; 35.0–39.9; ≥40), age at baseline (21–30, 31–40, 41–50, 51–60 y), and plasma triglyceride concentrations at baseline (<150; 150–199; 200–249; ≥250mg/dL). Changes in circulating metabolites, vital signs, and body weight and composition have been reported as absolute change and proportional change with similar P values. We chose proportional change for the other endpoints to clarify the magnitude of the changes and make the extent of the changes more comparable.
We tested for effect modification by sex, baseline BMI, age, and plasma triglycerides. Significant interactions were observed only for sex (male compared with female) and for baseline BMI (<35.0 compared with ≥35.0). If significant interactions were observed, the data were analyzed stratified by sex or baseline BMI. A stratified analysis but no power analysis of a stratified analysis were part of the statistical plan at the study design stage.
The results are reported as least-squares means±SEMs. Reported P values refer to differences between the Placebo and R-LA groups. Statistical significance was set at P≤0.05. No adjustments for multiplicity were performed because this was not part of the statistical plan at the study design stage.
Results
Baseline characteristics, compliance, and adverse events
Demographics and initial clinical measures were all collected from study participants at baseline (Table1). Blood samples from these participants were also evaluated for biomarkers of inflammation and redox status (Supplemental Table 1). Overall, the population groups appeared evenly matched for the comparison of treatments.
During the study, the median compliance based on pill recount for the R-LA group was 97% (range: 79%–100%) and for the placebo group 94% (68%–100%). Most subjects tolerated R-LA well. The major adverse event in subjects supplemented with R-LA was heartburn, which persisted throughout the study (R-LA compared with placebo: 33%compared with 5%; P=0.003) (Supplemental Table 2). Some subjects receiving R-LA reported a strong odor of their urine (18%compared with 0%; P=0.01). A total of 13 subjects withdrew (Figure1), 6 of them (4 subjects in the R-LA group, 2 in placebo) because of adverse events (placebo: heartburn, headache; R-LA: heartburn, hospitalization, lower back pain). No deaths occurred during the study. All subjects that withdrew did so before week 12 and their samples were not analyzed. One participant was excluded from the final analysis when it was determined retrospectively that they met 1 of the exclusion criteria for the protocol.
LA supplementation did not change fasting triglyceride, glucose, or cholesterol status
The primary endpoint, changes in fasting plasma triglyceride concentrations, did not differ between the R-LA and placebo groups (Table 2). Similarly, fasting blood concentrations of glucose, total, HDL, and LDL cholesterol did not differ between the R-LA and placebo groups.
TABLE 2
Changes to plasma metabolic biomarkers in overweight or obese otherwise healthy adults with elevated plasma triglycerides from placebo or R-LA groups at 12 and 24 wk of supplementation1
Week 12 | Week 24 | |||||
---|---|---|---|---|---|---|
Placebo | R-LA | P value | Placebo | R-LA | P value | |
Triglycerides, mg/dL | −18±12 | −12±12 | 0.69 | +8±13 | −1±13 | 0.56 |
Total cholesterol, mg/dL | −1.5±4.6 | +2.3±4.5 | 0.49 | −0.4±4.2 | −1.3±4.3 | 0.86 |
HDL cholesterol, mg/dL | −1.3±1.4 | −2.4±1.3 | 0.50 | +0.7±1.4 | −2.1±1.4 | 0.08 |
LDL cholesterol, mg/dL | +1.4±4.4 | +6.6±4.3 | 0.32 | +0.3±4.0 | +1.0±4.1 | 0.89 |
Glucose, mg/dL | +1.3±2.2 | +1.8±2.2 | 0.84 | +0.5±2.0 | +0.6±1.9 | 0.96 |
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1Values are means±SEMs of absolute change from baseline, with P values indicating differences in changes between groups. Placebo, control supplements (n=33); R-LA, 600mg (R)-α-lipoic acid/d (n=31).
LA supplementation reduces BMI and body fat in women and severely obese participants
At week 24, the decrease in BMI was greater in the R-LA group than in placebo (P=0.04) (Table 3). Body-weight loss occurred in a sex-specific manner (see below). This change in body weight was not explainable by changes in energy intake (caloric intake) or physical activity (Supplemental Table 3). This suggests that any observed changes in body weight or fat mass (see below) were independent of these factors. In study participants receiving R-LA, weight loss was linearly correlated with lower plasma triglyceride concentrations (r = +0.50, P=0.004) and lower VLDL-cholesterol concentrations (r = +0.44, P=0.01; not shown). This correlation was not observed in participants receiving placebo (Figure 2).
FIGURE 2
Associations between the change in body weight and change in plasma triglycerides in the placebo (A) and R-LA groups (B) from baseline to the end of the 24-wk supplementation period in overweight or obese otherwise healthy adults with elevated plasma triglycerides. The solid line indicates a significant linear relation in the R-LA group (r = +0.50, P=0.004) that was absent from the placebo group (r = +0.24; P=0.17), using Pearson correlation coefficients. Placebo, control supplements (n=33); R-LA, 600mg (R)-α-lipoic acid/d (n=31).
TABLE 3
Changes to anthropometric measures in overweight or obese otherwise healthy adults with elevated plasma triglycerides from placebo or R-LA groups at 12 and 24 wk of supplementation1
Week 12 | Week 24 | |||||
---|---|---|---|---|---|---|
Placebo | R-LA | P value | Placebo | R-LA | P value | |
Body weight, % | −0.5±0.6 | −0.8±0.6 | 0.68 | +0.1±1.0 | −1.7±1.0 | 0.11 |
BMI, kg/m2 | −0.1±0.2 | −0.3±0.2 | 0.44 | +0.2±0.3 | −0.6±0.3 | 0.04 |
Body fat mass, kg | −0.9±0.5 | −0.4±0.5 | 0.47 | +0.3±0.8 | −0.9±0.8 | 0.18 |
Body fat mass, % | −2.8±1.6 | −0.4±1.5 | 0.18 | −0.3±2.4 | −1.8±2.4 | 0.59 |
Body fat, % | −0.9±0.4 | −0.0±0.4 | 0.06 | −0.2±0.6 | −0.3±0.5 | 0.79 |
Hip circumference, cm | −0.8±0.6 | −1.2±0.6 | 0.60 | −0.9±0.7 | −1.4±0.7 | 0.59 |
Hip circumference, % | −0.7±0.5 | +0.9±0.5 | 0.71 | −0.8±0.6 | −1.0±0.5 | 0.74 |
Waist circumference, cm | +0.1±1.3 | +0.1±1.3 | 1.00 | +0.1±1.5 | −0.8±1.5 | 0.59 |
Waist circumference, % | +0.1±1.2 | +0.2±1.2 | 0.91 | +0.1±1.4 | −0.7±1.4 | 0.62 |
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1Values are means±SEMs of absolute or proportional change from baseline, with P values indicating differences in changes between groups. Placebo, control supplements (n=33); R-LA, 600mg (R)-α-lipoic acid/d (n=31).
As an exploratory analysis of the data, we tested for effect modification of change in BMI by sex, age, baseline BMI, and baseline plasma triglycerides. Of these, only female sex (Supplemental Table 4) and baseline BMI (Supplemental Table 5) independently modified the effect of R-LA supplementation on anthropometric measures. Women, but not men, lost more body weight in the R-LA group than in placebo (Figure 3). Women supplemented with R-LA lost body weight (−1.4%±0.5% and −3.2%±0.8% at 12 and 24 wk, respectively) (Figure3A), which was primarily body fat (−2.3%±1.2% and −6.5%±1.9% at 12 and 24 wk, respectively) (Figure3C, Supplemental Table 4). By contrast, body fat or body weight did not decrease in men in the R-LA group (Figures3B, ,D);D); body weight, but not body fat, decreased in men in the placebo group by 24 wk, specifically in those with <30% body fat (n=5).
FIGURE 3
Percentage changes of body weight (A, B) and body fat mass (C, D) from baseline in overweight or obese otherwise healthy women (A, C) or men (B, D) at 12 and 24 wk of supplementation. The horizontal dotted line indicates no change from baseline measures. Symbols represent individuals, whereas solid lines are mean values with 95% CIs. For women: Placebo (n=16); R-LA (n=19); for men: Placebo (n=17); R-LA (n=12). *Different from placebo at P<0.05. Placebo, control supplements (n=33); R-LA, 600mg (R)-α-lipoic acid/d (n=31).
Clinically meaningful weight loss, defined as ≥5% decline in body mass, was achieved by 42% (8 of 19) of women after 24 wk of R-LA supplementation. This was significantly greater than for women in the placebo group (interaction P=0.004). The weight loss associated with R-LA supplementation was more pronounced after 24 than after 12 wk of the study. Women in the R-LA group decreased waist and hip circumference after 24 wk (Supplemental Table 4), but no group differences in waist-to-hip ratio were observed (results not shown).
To define the effect of initial BMI status in more detail, we separated participants into 2 groups: those with severe obesity (BMI≥35) and those with a lower BMI (BMI<35) (Figure 4). Severely obese participants lost more body weight after 24 wk of supplementation on R-LA than on placebo (−2.4%±1.0%) (Figure4B), which was primarily body fat (−4.3%±2.4%) (Figure4D, Supplemental Table 5). In these participants, 38% (5 of 13) of those taking R-LA showed clinically significant weight loss, which was greater than placebo participants who showed none of these changes over time. On the other hand, participants who were less heavy (BMI<35) in the R-LA group did not lose more body weight or fat mass than placebo-supplemented participants (Figure4A, ,C).C). Conversely, body fat mass decreased in the placebo-treated group at 12 wk (Figure4C), which may have been driven by the male participants who also decreased body weight (Figure3B) in that treatment arm.
FIGURE 4
Percentage changes of body weight (A, B) and body fat mass (C, D) from baseline in overweight or obese otherwise healthy adults with a BMI (in kg/m2) <35 (A, C) or ≥35 (B, D) at 12 and 24 wk of supplementation. The horizontal dotted line indicates no change from baseline measures. Symbols represent individuals, whereas solid lines are mean values with 95% CIs. For participants with BMI <35: Placebo (n=13); R-LA (n=13); for participants with BMI >35: Placebo (n=20); R-LA (n=18). *Different from placebo at P<0.05. Placebo, control supplements (n=33); R-LA, 600mg (R)-α-lipoic acid/d (n=31).
LA supplementation has mixed effects on vital signs and blood hematology
Whereas vital signs—blood pressure and heart rate—did not differ between treatment groups, participants on R-LA had greater leukocyte and platelet count decreases than those on placebo (Supplemental Table 6). However, leukocyte numbers remained within normal reference ranges.
LA supplementation has mixed effects on plasma, urinary, and cellular biomarkers of inflammation or redox status
The participants uniformly had low concentrations of inflammatory biomarkers, which was anticipated from the subject inclusion criteria. R-LA supplementation did not affect the concentrations of many inflammatory biomarkers (Table 4, Supplemental Table 7). However, the R-LA group had greater increases in plasma concentrations of TNFA than placebo had (P=0.003) (Table4). It is worth noting that in all participants TNFA stayed within normal reference ranges (24).
TABLE 4
Changes to biomarkers of inflammation and redox status in overweight or obese adults with elevated plasma triglycerides from placebo or R-LA groups at 12 and 24 wk of supplementation1
Week 12 | Week 24 | |||||
---|---|---|---|---|---|---|
Placebo | R-LA | P value | Placebo | R-LA | P value | |
Plasma inflammatory biomarkers | ||||||
CRP, mg/L | +6±10 | +8±10 | 0.88 | +8±11 | +5±11 | 0.78 |
TNFA, pg/mL | +2.9±6.1 | +17.7±6.1 | 0.05 | −2.4±6.8 | +22.9±6.7 | 0.003 |
IL-6, pg/mL | +2±11 | +15±11 | 0.32 | −1±10 | +17±10 | 0.13 |
CCL2, pg/mL | −0.6±5.5 | −5.7±5.5 | 0.44 | +9.5±5.7 | −1.5±5.6 | 0.11 |
VCAM1, μg/mL | +5.6±2.7 | +6.5±2.6 | 0.79 | +6.0±2.6 | +10.5±2.5 | 0.13 |
ICAM1, μg/mL | +4.4±2.6 | +1.0±2.5 | 0.27 | +1.5±2.6 | −4.8±2.5 | 0.04 |
SELE, μg/mL | −1.7±3.6 | −2.1±3.5 | 0.93 | −0.3±4.3 | −7.7±4.2 | 0.15 |
Women | +2.4±3.9 | −3.5±3.6 | 0.25 | +5.4±4.8 | −11.9±4.4 | 0.01 |
Men | −8.2±8.3 | −0.8±8.5 | 0.47 | −10.7±8.8 | −6.2±9.1 | 0.68 |
BMI<35kg/m2 | −11.4±5.0 | −0.1±4.6 | 0.05 | −6.7±6.0 | −2.3±5.4 | 0.52 |
BMI≥35kg/m2 | +2.7±3.9 | −7.1±3.9 | 0.05 | +2.3±7.3 | −14.4±7.3 | 0.07 |
Plasma antioxidants | ||||||
Ascorbate, μM | +12.9±8.6 | +2.9±8.3 | 0.32 | +5.9±9.3 | −1.1±9.1 | 0.53 |
Urate, μM | +4.2±3.5 | +2.9±3.4 | 0.77 | +1.5±3.6 | +0.1±3.5 | 0.74 |
FRAP, trolox equivalents | −2.8±2.7 | +0.8±2.6 | 0.25 | −0.1±3.1 | −2.2±2.9 | 0.54 |
Urinary isoprostanes | ||||||
Total F2-isoprostanes, ng/mg creatinine | +2±6 | +4±5 | 0.69 | +13±6 | −12±6 | 0.002 |
5 Series F2-isoprostanes, ng/mg creatinine | +7±7 | −1±7 | 0.36 | +13±9 | −10±8 | 0.03 |
15 Series F2-isoprostanes, ng/mg creatinine | +1±6 | +5±6 | 0.62 | +14±7 | −15±7 | 0.002 |
8-Iso-PGF2α, ng/mg creatinine | +2±6 | +1±6 | 0.82 | +7±8 | −11±8 | 0.07 |
15(R)-8-iso-PGF2α, ng/mg creatinine | +7±8 | −4±8 | 0.27 | +2±9 | −10±9 | 0.24 |
8-Iso-PGF2α metabolites, ng/mg creatinine | +2±6 | +5±6 | 0.61 | +14±7 | −15±7 | 0.002 |
2,3-Dinor-8-iso-PGF2α, ng/mg creatinine | +3±6 | +4±6 | 0.82 | +13±7 | −9±7 | 0.007 |
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1Values are means±SEMs of absolute change from baseline, with P values indicating differences in changes between groups. CRP, C-reactive protein; FRAP, ferric ion reducing antioxidant potential; ICAM1, intercellular adhesion molecule 1; placebo, control supplements (n=33); R-LA, 600mg (R)-α-lipoic acid/d (n=31); SELE, soluble E-selectin; VCAM1, vascular cell adhesion molecule 1.
In contrast, participants taking R-LA compared with placebo controls had greater decreases in circulating concentrations of soluble ICAM1 (P=0.04), a biomarker of immune cell recruitment, endothelial cell adhesion, and tissue infiltration (Table4). Although SELE did not change at 12 or 24 wk in the R-LA group when compared with placebo (Table4), subgroup analysis revealed that women had a greater decline in SELE at 24 wk in the R-LA group than in placebo (P=0.01).
R-LA supplementation did not change low molecular weight antioxidant status (ascorbate, glutathione, urate) of either plasma or PBMCs or the antioxidant potential (FRAP) of plasma (P>0.1 for all markers) (Table4, Supplemental Table 7). Antioxidant-responsive gene expression in PBMCs, as exemplified by HMOX1, GCLC, and NQO1 mRNA at 24 wk, tended to increase more in participants on R-LA than on placebo (P<0.1 for all), but only reached significance for HMOX1 (P=0.02) (Supplemental Table 7). No group differences were observed in genes involved in inflammatory responses at 24 wk. Lastly, participants on R-LA had greater decreases in urinary concentrations of F2-isoprostanes, a well-established biomarker of lipid peroxidation (Table4).
Discussion
Obesity and its associated comorbidities are a worldwide public health issue (25). Currently, more than two-thirds of the US population have a BMI≥25 and about half of those people are considered obese (BMI≥30). Increased adiposity initiates and exacerbates chronic inflammation and oxidative tissue damage, and is thus an important underlying risk factor for cardiovascular disease and type 2 diabetes (25). Few adults with obesity are able to achieve and sustain a clinically meaningful weight loss of >5% with caloric restriction and exercise alone. Thus, many obese people look for alternatives to help them lose weight.
In this 24-wk randomized, double-blind, placebo-controlled trial in US adults who were overweight or obese, daily supplementation with 600mg of the R-enantiomer of LA promoted modest loss of body weight (−1.7±0.9kg) and decreased BMI (−0.6±0.3), especially in certain subgroups as discussed below. Although the R-LA group did not experience a significant change in triglycerides, those individuals who lost weight showed a proportional decrease in elevated plasma triglyceride concentrations. Our results are consistent with those of other placebo-controlled clinical trials from Asia, Europe, and New Zealand (7, 8). Of those 13 clinical trials, 10 reported at least weight loss or a decrease in BMI compared with the placebo group. In those trials, the average placebo-adjusted BMI change was lower than our observed effects on body mass (7, 8). We hypothesize that our results can be partly explained by the use of the R-enantiomer of LA, which may have a greater bioavailability than the S-enantiomer or the racemic mixture (9, 26).
Currently approved drugs for long-term weight loss cause 35%–73% of adults who are overweight or obese to lose a clinically meaningful (≥5%) amount of body mass (27). In our study, only 26% of participants taking R-LA lost ≥5% of their body weight. The question thus arises as to why only one-quarter of the participants benefited from R-LA supplementation. One potential reason is that participants were advised to maintain their dietary patterns and limit physical activity to avoid confounding effects of changes in energy intake or expenditure. In rodents, LA reduces caloric intake by suppressing AMPK activity in the hypothalamus (6). LA may also decrease endogenous energy stores by improving cellular energy sensing and metabolism through AMPK activation in peripheral tissues (19).
Although changes in AMPK activity may result in increased physical activity and decreased impulsive eating in adults (18), these effects were not observed in our study. Physical activity and calorie intake were unchanged, even when the analysis was limited to those participants who lost weight. Although this points to possible increases in nonexercise energy expenditure, the limitations of the study design prevented an accurate determination of energy balance in all participants. Therefore, R-LA supplementation may be more effective as a weight loss supplement if combined with intentional calorie restriction or an exercise regimen (28).
Interestingly, in our study women benefited from R-LA supplementation but men at lower BMIs did not. To our knowledge, there are no previous studies that reported sex-specific effects of LA on weight loss (17, 20). Furthermore, effects based on initial BMI were also not expected. We can only hypothesize that our results stem from differences in cellular energy metabolism, LA pharmaco*kinetics, and how these relate to the degree of adiposity in our study population.
Cell and molecular studies have shown that LA exerts strong antioxidant and anti-inflammatory effects (1, 12, 13), but few of these effects were noted in our study. Participants in the R-LA group showed lower plasma concentrations of soluble ICAM1 and, in women and subjects with a BMI≥35, SELE, indicating that LA may attenuate monocyte recruitment, vascular adhesion, and tissue infiltration (12). R-LA supplementation also reduced urinary F2-isoprostanes, a marker of lipid peroxidation, and increased the expression of HMOX1 in PBMCs. Changes in circulating TNFA are not surprising because it is an adipokine at the nexus of triglyceride production and insulin signaling (29). However, an increase of circulating TNFA is worth noting, despite remaining within normal reference ranges. Because PBMC TNFA concentrations did not change, it is possible this change in circulating TNFA is due to changes in adipose tissue during weight loss.
Although this study only marginally supports previous work that LA improves antioxidant capacity (5), these data must be couched in their proper context. This study population did not display overt inflammation or oxidative stress despite their level of obesity. Therefore, LA may be a useful adjunct in obese individuals who have yet to progress to a chronically inflamed status. LA may potentially limit inflammation-mediated sequelae associated with obesity and further progression to metabolic syndrome or other chronic disease.
Several strengths and limitations of our study have to be considered. LA can influence many cell-signaling pathways. The influence of LA in the progression of obesity-associated disorders requires specifically designed studies. The effects of R-LA on fatty acid metabolism through an evaluation of plasma triglyceride concentrations was initially chosen as a primary outcome to explore its value in reducing cardiovascular disease risk. Although our clinical trial was not intended to be mechanistic, because of the pluripotent nature of LA we decided to examine various systems (redox, immune function, bioenergetics) to explore potential pathways of efficacy and evaluate the safety of supplementation. In order to accomplish this, the study had to accommodate multiple measures during its duration. Although some false negatives at P<0.05 may be present, we focused our interpretations of the data on significant effects which were consistently observed within each system. Although the study was sufficiently powered to determine an overall effect of R-LA on the chosen endpoints, it appears that only some participants benefited from R-LA supplementation as revealed via effect modification analysis. Although we were not able to pinpoint why only some participants benefited from R-LA supplementation, our results indicate that there was a variable effect on lipid metabolism in adipose tissue, liver tissue, or both. Further studies are clearly needed to define the precise mechanisms associated with R-LA supplementation and its roles in weight loss.
The study length (24 wk) and LA dosage (600mg/d) and chemical form (R-enantiomer) appeared to be appropriate to detect significant long-term effects of LA supplementation. The LA dose used in this study can be obtained as an over-the-counter dietary supplement. Although overweight adults have an interest in LA for weight loss, many obese individuals are also taking additional medications, e.g., to normalize blood pressure levels, or glucose or cholesterol concentrations. This “medicated” population was not included because our goal was to focus on the effect of LA on the management of obesity independently of impaired glucose metabolism, hepatic lipidosis, chronic inflammation, or other comorbidities. Because our study methodology did not focus on weight loss as our primary outcome, we were not able to ascertain the reason for any of these observed effects. This will need to be a focus of future studies for this compound. The major adverse effect was heartburn, but despite this side effect, participants taking R-LA did complete the trial. In the future, LA supplements could be improved to avoid adverse digestive effects.
In summary, the premise behind the design of this clinical trial was to assess the ability of R-LA to decrease endogenous energy stores in overweight or obese adults with elevated plasma triglycerides via decreased triglyceride synthesis. Although R-LA supplementation did not decrease plasma triglyceride concentrations, long-term R-LA supplementation resulted in BMI loss, greater antioxidant enzyme synthesis, less lipid peroxidation, and less potential for inflammation. Some individuals (women>men; more obese>less obese) may also benefit from improved cellular bioenergetics, which may help with body weight and fat loss and less plasma triglycerides. The sex- and weight-specific effects and potential for LA to downregulate aspects of the innate and adaptive immune pathways and increase TNFA concentrations require further study.
Supplementary Material
nxaa203_Supplemental_File
Click here for additional data file.(38K, docx)
Acknowledgments
The authors’ responsibilities were as follows—W-JZ, JQP, CW, CP, MGT, JAV, BF, and TMH: designed the research; AJM, W-JZ, JQP, and CW: conducted the research; GB, AJM, W-JZ, CP, and TMH: analyzed the data; GB, AJM, BF, NOT, and TMH: wrote the manuscript; TMH: had primary responsibility for the final content; and all authors with the exception of JAV: read and approved the final manuscript.
Notes
Supported by National Center for Complementary and Alternative Medicine grant P01 AT002034 (to BF) and NIH National Center for Advancing Translational Sciences grant UL1TR000128 (to JQP).
Author disclosures: MGT is part of The Journal of Nutrition’s Editorial Board. All other authors report no conflicts of interest.
Supplemental Tables 1–7 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/jn/.
Abbreviations used: AMPK, AMP-dependent protein kinase; CRP, C-reactive protein; DTPA, diethylenetriaminepentaacetic acid; FRAP, ferric ion reducing antioxidant potential; ICAM1, intercellular adhesion molecule 1; LA, α-lipoic acid; OHSU, Oregon Health & Science University; PBMC, peripheral blood mononuclear cell; R-LA, (R)-α-lipoic acid; SELE, soluble E-selectin.
Contributor Information
Gerd Bobe, Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
Alexander J Michels, Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
Wei-Jian Zhang, Linus Pauling Institute, Oregon State University, Corvallis, OR, USA. Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA.
Jonathan Q Purnell, Department of Medicine, Oregon Health & Science University, Portland, OR, USA.
Clive Woffendin, Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR, USA.
Cliff Pereira, Department of Statistics, Oregon State University, Corvallis, OR, USA.
Joseph A Vita, Evans Department of Medicine and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Nicholas O Thomas, Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
Maret G Traber, Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
Balz Frei, Linus Pauling Institute, Oregon State University, Corvallis, OR, USA. Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA.
Tory M Hagen, Linus Pauling Institute, Oregon State University, Corvallis, OR, USA. Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA.
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