- Email: [email protected]
obese adults: A double-blinded, randomized, controlled, cross-over intervention trial
602
Letters to the Editor
References [1] Fournier PE, Thuny F, Richet H, et al. Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases. Clin Infect Dis 2010;51:131–40.
[2] Fournier PE, Thuny F, Grisoli D, et al. A deadly aversion to pork. Lancet 2011;377:1542. [3] Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633–8.
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.09.233
Effect of oral ALA supplementation on oxidative stress and insulin sensitivity among overweight/obese adults: A double-blinded, randomized, controlled, cross-over intervention trial Weili Yan a,b,⁎, Nong Li c,1, Xiaojuan Hu c,1, Yongdi Huang b, Weiguo Zhang b, Qian Wang b, Fugang Wang c, Chenchen Wang b, Xiaohu Zhai b, Ruiwei Xu b, Kai Yan b, Xiuhua Ding d, Xiaoling Wang d a
Department of Clinical Epidemiology, Children's Hospital of Fudan University, Shanghai 201102, China Department of Epidemiology And Biostatistics, Urumqi 830011, China People's Hospital of Kelamayi City, Kelamayi City 834000, China d Georgia Prevention Institute, Georgia Health Sciences University, GA 30912, USA b c
a r t i c l e
i n f o
Article history: Received 17 September 2012 Accepted 30 September 2012 Available online 25 October 2012 Keywords: Antioxidants Insulin sensitivity Intervention Clinical trial Cardiovascular risk
Recent studies show that oxidative stress may be the unifying mechanism in the development of major obesity-related comorbidities [1,2]. We designed the current double-blind, randomized controlled intervention trial to assess whether oral ALA supplementation will lower the risk of CVD by decreasing the level of oxidative stress (indexed by OxLDL and 8-iso-PGF2a) or improving insulin sensitivity (indexed by HOMA) in overweight/obese subjects. We screened 347 overweight Han Chinese and identified 166 subjects meeting our inclusion criteria from a physical examination setting. The inclusion criteria were: 1) body mass index (BMI)≥ 25 kg/m2; 2) 18–60 years; 3) not on any antioxidant vitamin supplement, and 4) having at least one of borderline hypertension (130 mm Hg≤SBPb 140 mm Hg or 85 mm Hg ≤DBPb 90 mm Hg), dyslipidemia (fasting total cholesterol ≥240 mg/dl or HDL-Cb 40 mg/dl), or impaired fasting glucose (fasting glucose levels between 6.1 and 7.0 mmol/l). Those with history of hypertension, diabetes, coronary heart disease, cancer or chronic liver disease, or psychiatric problems were excluded. One hundred and three subjects signed inform consent forms. Age and sex of participants did not significantly differ from the people who declined. Each subjects had 4 visits during the trial. Anthropometrics, blood pressure were examined by standard protocols and fasting blood samples were obtained for examination of fasting plasma glucose and insulin on the same day of blood drawing, as well as 8-iso-PGF2a and
OxLDL, was measured after the final test to minimize the batch effect by Human OxLDL Elisa kit and Human F2-isoprostanes Elisa kit (GBD, USA) by ElX-800 (BioRad, USA). Homeostasis model assessment (HOMA-IR) was calculated using the formula: fasting glucose (mmol/l)× fasting insulin (ìU/ml)/22.5. After baseline testing, 103 participants were randomly assigned to Group 1 or Group 2 balanced for gender. Group 1 (n= 51) received 8-week placebo followed by oral ALA intervention (1200 mg/day) for 8-week, while Group 2 (n= 52) received 8-week ALA followed by placebo for 8-week, with a wash-out of 4 weeks (Fig.1). Alpha-lipoic acid (CRLA, Glucotize) and placebo were produced by Medical Research Institute, San Francisco, CA. A pill count was conducted by the end of week 8 and week 20 to assess compliance.
Screened (n=347)
Randomized (n=103)
Placebo (n=51)
ALA (n=52)
Baseline testing
Baseline testing 8 week intervention
Placebo (n=44)
ALA (n=46)
2nd testing
2nd testing 4 week wash out
ALA (n=42)
Placebo (n=41)
3rd testing
3rd testing 8 week intervention
⁎ Corresponding author at: Department of Clinical Epidemiology, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai 201102, China. Tel./ fax: +86 21 64931215. E-mail address: [email protected] (W. Yan). 1 The authors contribute equally to this work.
ALA (n=41)
Placebo (n=39)
4th testing
4th testing Fig. 1. Participants' flow chart.
Letters to the Editor
603
Table 1 Estimates of mixed-effect linear model for the primary end points at week 8. Measurements OxLDL 8-Iso-PGF2a (pg/ml) HOMA-IR BMI, mg/m2 Weight, kg Waist, cm
Treatment
Baseline values
Sex
Beta
P
Beta
Period P
Beta
P
Beta
P
Baseline BMI Beta
P
0.257 2.804 0.464 − 0.337 − 1.06 − 1.03
0.272 0.627 0.173 0.004 0.001 0.028
0.503 28.4 − 0.337 −0.180 −0.41 0.000
0.027 b0.001 0.003 0.118 0.189 1.000
0.332 0.943 0.149 0.990 0.993 0.927
b 0.001 b 0.001 0.001 b 0.001 b 0.001 b 0.001
0.250 − 9.73 0.134 − 0.103 − 0.24 − 0.37
0.021 0.816 0.724 0.151 0.548 0.532
− 0.003 − 0.657 0.237 – – –
0.876 0.946 b0.001 – – –
Age was included in the model too, but it was not significant for any tested variables.
Block randomization (block size= 2) and allocation were generated by excel based on the inclusion sequence number by gender. An envelope enclosing the true treatment was concealed for each study participant, which would not be opened unless emergency situation occurs. The drug distributor and investigators involving in data collection were blinded to the group information. Written informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by Ethical Committee of Xinjiang Medical University and Medical College of Georgia (now Georgia Health Science University). The authors of this manuscript have certified that they comply with the principles of ethnical publishing in the International Journal of Cardiology. A mixed-effect linear model was performed to analyze the primary outcome variables including HOMA, OxLDL and 8-iso-PGF2a and secondary outcomes after intervention according to intent-to-treat by using STATA11.0. The protocol of this trial was registered at Clinicaltrials.org (NCT00994513). Ninety-two subjects and 94 subjects completed the placebo arm and ALA arm respectively (Fig. 1). It showed no significant between-group differences in baseline age, sex, BMI, blood pressure, fasting glucose or insulin, HOMA-IR, OxLDL or 8-iso-PGF2a levels after randomization. Sixty out of the 94 (63.8%) in ALA arm and 60 of control arm (65.2%) had a compliance rate over 90%. There was no significant difference in HOMA, OxLDL or 8-iso-PGF2a between two groups after 8 weeks' intervention (Table 1 ). Greater baseline HOMA and BMI were associated with greater HOMA at week 8 (P = 0.001 and P b 0.001, respectively). There was an overall decrease in HOMA at the end of the study (phase 2 versus phase 1, beta = −0.337, P = 0.003). Females had a higher OxLDL levels at week 8 than males. A period effect was also observed for both OxLDL and 8-iso-PGF2a with the levels of period 2 higher than period 1. We observed that treatment of ALA was associated with significant lower BMI, weight and waist circumference after 8 weeks. The rates of treatment-emergent adverse events were 14% (13) in the placebo arm and 20% (19) in the ALA arm (P = 0.33 vs. placebo), with similar manifestations. Recent large scale clinical trials demonstrated significant effects of ALA on improving neuropathic symptoms and deficits in diabetic patients [4–6], it is a reasonable hypothesis that anti-oxidant supplementation may have some effect in reducing the biomarkers of oxidative stress or insulin sensitivity among overweight/obese adults. The hypothesis was not supported by previous large scale clinical trials in which antioxidants vitamin supplementation (vitamin E or C) were used as anti-oxidants and CVD morbidity or mortality [7,8] were used for primary outcomes. The
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.09.232
current trial instead, uses the ALA with stronger anti-oxidative effect, and uses subclinical biomarkers as primary outcomes, however, fails to provide evidence that an 8-week oral ALA supplementation significantly reduce the levels of oxidative stress or insulin sensitivity biomarkers among overweight/obese subjects. To the negative findings that are contradictory to the hypothesis, there are several possible explanations. First, oral intake of ALA may not be able to directly activate antioxidant role in human body, instead, it is more likely to indirectly induce or maintain endogenous antioxidant levels, as reviewed by Shay et al. [9]. There is no evidence up to date that oral intake of ALA has any effect on regulating the endogenous production of 8-iso-PGF2a in human body. Second, oral supplementation of ALA may not be as effective as intravenous intake to human subjects. The present trial documents the oral ALA for 8 weeks cannot improve insulin sensitivity among non-diabetic overweight adults. The observed mild but significant reduction of body weight, BMI, and waist circumference in ALA group compared with control group, which is similar to reports from previous studies [6,10], still remains unclear on its mechanism. We thank all participants, doctors and nurses who contributed to this work but not in author list. We also thank MRI for their free ALA and placebo pills.
References [1] Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol 2004;24:816–23. [2] Vincent HK, Taylor AG. Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Int J Obes (Lond) 2006;30:400–18. [3] Foster TS. Efficacy and safety of alpha-lipoic acid supplementation in the treatment of symptomatic diabetic neuropathy. Diabetes Educ 2007;33:111–7. [4] Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 2003;26:770–6. [5] Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 2006;29:2365–70. [6] Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297:842–57. [7] Riccioni G, Bucciarelli T, Mancini B, Di Ilio C, Capra V, D'Orazio N. The role of the antioxidant vitamin supplementation in the prevention of cardiovascular diseases. Expert Opin Investig Drugs 2007;16:25–32. [8] Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta 2009;1790:1149–60. [9] Ziegler D, Reljanovic M, Mehnert H, Gries FA. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes 1999;107:421–30.
Letters to the Editor
References [1] Fournier PE, Thuny F, Richet H, et al. Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases. Clin Infect Dis 2010;51:131–40.
[2] Fournier PE, Thuny F, Grisoli D, et al. A deadly aversion to pork. Lancet 2011;377:1542. [3] Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633–8.
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.09.233
Effect of oral ALA supplementation on oxidative stress and insulin sensitivity among overweight/obese adults: A double-blinded, randomized, controlled, cross-over intervention trial Weili Yan a,b,⁎, Nong Li c,1, Xiaojuan Hu c,1, Yongdi Huang b, Weiguo Zhang b, Qian Wang b, Fugang Wang c, Chenchen Wang b, Xiaohu Zhai b, Ruiwei Xu b, Kai Yan b, Xiuhua Ding d, Xiaoling Wang d a
Department of Clinical Epidemiology, Children's Hospital of Fudan University, Shanghai 201102, China Department of Epidemiology And Biostatistics, Urumqi 830011, China People's Hospital of Kelamayi City, Kelamayi City 834000, China d Georgia Prevention Institute, Georgia Health Sciences University, GA 30912, USA b c
a r t i c l e
i n f o
Article history: Received 17 September 2012 Accepted 30 September 2012 Available online 25 October 2012 Keywords: Antioxidants Insulin sensitivity Intervention Clinical trial Cardiovascular risk
Recent studies show that oxidative stress may be the unifying mechanism in the development of major obesity-related comorbidities [1,2]. We designed the current double-blind, randomized controlled intervention trial to assess whether oral ALA supplementation will lower the risk of CVD by decreasing the level of oxidative stress (indexed by OxLDL and 8-iso-PGF2a) or improving insulin sensitivity (indexed by HOMA) in overweight/obese subjects. We screened 347 overweight Han Chinese and identified 166 subjects meeting our inclusion criteria from a physical examination setting. The inclusion criteria were: 1) body mass index (BMI)≥ 25 kg/m2; 2) 18–60 years; 3) not on any antioxidant vitamin supplement, and 4) having at least one of borderline hypertension (130 mm Hg≤SBPb 140 mm Hg or 85 mm Hg ≤DBPb 90 mm Hg), dyslipidemia (fasting total cholesterol ≥240 mg/dl or HDL-Cb 40 mg/dl), or impaired fasting glucose (fasting glucose levels between 6.1 and 7.0 mmol/l). Those with history of hypertension, diabetes, coronary heart disease, cancer or chronic liver disease, or psychiatric problems were excluded. One hundred and three subjects signed inform consent forms. Age and sex of participants did not significantly differ from the people who declined. Each subjects had 4 visits during the trial. Anthropometrics, blood pressure were examined by standard protocols and fasting blood samples were obtained for examination of fasting plasma glucose and insulin on the same day of blood drawing, as well as 8-iso-PGF2a and
OxLDL, was measured after the final test to minimize the batch effect by Human OxLDL Elisa kit and Human F2-isoprostanes Elisa kit (GBD, USA) by ElX-800 (BioRad, USA). Homeostasis model assessment (HOMA-IR) was calculated using the formula: fasting glucose (mmol/l)× fasting insulin (ìU/ml)/22.5. After baseline testing, 103 participants were randomly assigned to Group 1 or Group 2 balanced for gender. Group 1 (n= 51) received 8-week placebo followed by oral ALA intervention (1200 mg/day) for 8-week, while Group 2 (n= 52) received 8-week ALA followed by placebo for 8-week, with a wash-out of 4 weeks (Fig.1). Alpha-lipoic acid (CRLA, Glucotize) and placebo were produced by Medical Research Institute, San Francisco, CA. A pill count was conducted by the end of week 8 and week 20 to assess compliance.
Screened (n=347)
Randomized (n=103)
Placebo (n=51)
ALA (n=52)
Baseline testing
Baseline testing 8 week intervention
Placebo (n=44)
ALA (n=46)
2nd testing
2nd testing 4 week wash out
ALA (n=42)
Placebo (n=41)
3rd testing
3rd testing 8 week intervention
⁎ Corresponding author at: Department of Clinical Epidemiology, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai 201102, China. Tel./ fax: +86 21 64931215. E-mail address: [email protected] (W. Yan). 1 The authors contribute equally to this work.
ALA (n=41)
Placebo (n=39)
4th testing
4th testing Fig. 1. Participants' flow chart.
Letters to the Editor
603
Table 1 Estimates of mixed-effect linear model for the primary end points at week 8. Measurements OxLDL 8-Iso-PGF2a (pg/ml) HOMA-IR BMI, mg/m2 Weight, kg Waist, cm
Treatment
Baseline values
Sex
Beta
P
Beta
Period P
Beta
P
Beta
P
Baseline BMI Beta
P
0.257 2.804 0.464 − 0.337 − 1.06 − 1.03
0.272 0.627 0.173 0.004 0.001 0.028
0.503 28.4 − 0.337 −0.180 −0.41 0.000
0.027 b0.001 0.003 0.118 0.189 1.000
0.332 0.943 0.149 0.990 0.993 0.927
b 0.001 b 0.001 0.001 b 0.001 b 0.001 b 0.001
0.250 − 9.73 0.134 − 0.103 − 0.24 − 0.37
0.021 0.816 0.724 0.151 0.548 0.532
− 0.003 − 0.657 0.237 – – –
0.876 0.946 b0.001 – – –
Age was included in the model too, but it was not significant for any tested variables.
Block randomization (block size= 2) and allocation were generated by excel based on the inclusion sequence number by gender. An envelope enclosing the true treatment was concealed for each study participant, which would not be opened unless emergency situation occurs. The drug distributor and investigators involving in data collection were blinded to the group information. Written informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by Ethical Committee of Xinjiang Medical University and Medical College of Georgia (now Georgia Health Science University). The authors of this manuscript have certified that they comply with the principles of ethnical publishing in the International Journal of Cardiology. A mixed-effect linear model was performed to analyze the primary outcome variables including HOMA, OxLDL and 8-iso-PGF2a and secondary outcomes after intervention according to intent-to-treat by using STATA11.0. The protocol of this trial was registered at Clinicaltrials.org (NCT00994513). Ninety-two subjects and 94 subjects completed the placebo arm and ALA arm respectively (Fig. 1). It showed no significant between-group differences in baseline age, sex, BMI, blood pressure, fasting glucose or insulin, HOMA-IR, OxLDL or 8-iso-PGF2a levels after randomization. Sixty out of the 94 (63.8%) in ALA arm and 60 of control arm (65.2%) had a compliance rate over 90%. There was no significant difference in HOMA, OxLDL or 8-iso-PGF2a between two groups after 8 weeks' intervention (Table 1 ). Greater baseline HOMA and BMI were associated with greater HOMA at week 8 (P = 0.001 and P b 0.001, respectively). There was an overall decrease in HOMA at the end of the study (phase 2 versus phase 1, beta = −0.337, P = 0.003). Females had a higher OxLDL levels at week 8 than males. A period effect was also observed for both OxLDL and 8-iso-PGF2a with the levels of period 2 higher than period 1. We observed that treatment of ALA was associated with significant lower BMI, weight and waist circumference after 8 weeks. The rates of treatment-emergent adverse events were 14% (13) in the placebo arm and 20% (19) in the ALA arm (P = 0.33 vs. placebo), with similar manifestations. Recent large scale clinical trials demonstrated significant effects of ALA on improving neuropathic symptoms and deficits in diabetic patients [4–6], it is a reasonable hypothesis that anti-oxidant supplementation may have some effect in reducing the biomarkers of oxidative stress or insulin sensitivity among overweight/obese adults. The hypothesis was not supported by previous large scale clinical trials in which antioxidants vitamin supplementation (vitamin E or C) were used as anti-oxidants and CVD morbidity or mortality [7,8] were used for primary outcomes. The
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.09.232
current trial instead, uses the ALA with stronger anti-oxidative effect, and uses subclinical biomarkers as primary outcomes, however, fails to provide evidence that an 8-week oral ALA supplementation significantly reduce the levels of oxidative stress or insulin sensitivity biomarkers among overweight/obese subjects. To the negative findings that are contradictory to the hypothesis, there are several possible explanations. First, oral intake of ALA may not be able to directly activate antioxidant role in human body, instead, it is more likely to indirectly induce or maintain endogenous antioxidant levels, as reviewed by Shay et al. [9]. There is no evidence up to date that oral intake of ALA has any effect on regulating the endogenous production of 8-iso-PGF2a in human body. Second, oral supplementation of ALA may not be as effective as intravenous intake to human subjects. The present trial documents the oral ALA for 8 weeks cannot improve insulin sensitivity among non-diabetic overweight adults. The observed mild but significant reduction of body weight, BMI, and waist circumference in ALA group compared with control group, which is similar to reports from previous studies [6,10], still remains unclear on its mechanism. We thank all participants, doctors and nurses who contributed to this work but not in author list. We also thank MRI for their free ALA and placebo pills.
References [1] Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol 2004;24:816–23. [2] Vincent HK, Taylor AG. Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Int J Obes (Lond) 2006;30:400–18. [3] Foster TS. Efficacy and safety of alpha-lipoic acid supplementation in the treatment of symptomatic diabetic neuropathy. Diabetes Educ 2007;33:111–7. [4] Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 2003;26:770–6. [5] Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 2006;29:2365–70. [6] Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297:842–57. [7] Riccioni G, Bucciarelli T, Mancini B, Di Ilio C, Capra V, D'Orazio N. The role of the antioxidant vitamin supplementation in the prevention of cardiovascular diseases. Expert Opin Investig Drugs 2007;16:25–32. [8] Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta 2009;1790:1149–60. [9] Ziegler D, Reljanovic M, Mehnert H, Gries FA. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes 1999;107:421–30.