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γ-Linolenic Acid versus α-Lipoic Acid for Treating Painful Diabetic Neuropathy in Adults: A 12-Week, Double-Placebo, Randomized, Noninferiority Trial.
Won, JC, Kwon, HS, Moon, SS, Chun, SW, Kim, CH, Park, IB, Kim, IJ, Lee, J, Cha, BY, Park, TS
Diabetes & metabolism journal. 2020;(4):542-554
Abstract
BACKGROUND This study was a multicenter, parallel-group, double-blind, double-dummy, randomized, noninferiority trial to evaluate the efficacy and safety of γ-linolenic acid (GLA) relative to α-lipoic acid (ALA) over a 12-week treatment period in type 2 diabetes mellitus (T2DM) patients with painful diabetic peripheral neuropathy (DPN). METHODS This study included 100 T2DM patients between 20 and 75 years of age who had painful DPN and received either GLA (320 mg/day) and placebo or ALA (600 mg/day) and placebo for 12 weeks. The primary outcome measures were mean changes in pain intensities as measured by the visual analogue scale (VAS) and the total symptom scores (TSS). RESULTS Of the 100 subjects who initially participated in the study, 73 completed the 12-week treatment period. Per-protocol analyses revealed significant decreases in the mean VAS and TSS scores compared to baseline in both groups, but there were no significant differences between the groups. The treatment difference for the VAS (95% confidence interval [CI]) between the two groups was -0.65 (-1.526 to 0.213) and the upper bound of the 95% CI did not exceed the predefined noninferiority margin (δ₁=0.51). For the TSS, the treatment difference was -0.05 (-1.211 to 1.101) but the upper bound of the 95% CI crossed the noninferiority margin (δ₂=0.054). There were no serious adverse events associated with the treatments. CONCLUSION GLA treatment in patients with painful DPN was noninferior to ALA in terms of reducing pain intensity measured by the VAS over 12 weeks.
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Predictors of improvement and progression of diabetic polyneuropathy following treatment with α-lipoic acid for 4 years in the NATHAN 1 trial.
Ziegler, D, Low, PA, Freeman, R, Tritschler, H, Vinik, AI
Journal of diabetes and its complications. 2016;(2):350-6
Abstract
AIMS: We aimed to analyze the impact of baseline factors on the efficacy of α-lipoic acid (ALA) over 4 years in the NATHAN 1 trial. METHODS This was a post-hoc analysis of the NATHAN 1 trial, a 4-year randomized study including 460 diabetic patients with mild-to-moderate polyneuropathy using ALA 600 mg qd or placebo. Amongst others, efficacy measures were the Neuropathy Impairment Score of the lower limbs (NIS-LL) and heart rate during deep breathing (HRDB). RESULTS Improvement and prevention of progression of NIS-LL (ΔNIS-LL≥2 points) with ALA vs. placebo after 4 years was predicted by higher age, lower BMI, male sex, normal blood pressure, history of cardiovascular disease (CVD), insulin treatment, longer duration of diabetes and neuropathy, and higher neuropathy stage. Participants treated with ALA who received ACE inhibitors showed a better outcome in HRDB after 4 years. CONCLUSIONS Better outcome in neuropathic impairments following 4-year treatment with α-lipoic acid was predicted by normal BMI and blood pressure and higher burden due to CVD, diabetes, and neuropathy, while improvement in cardiac autonomic function was predicted by ACE inhibitor treatment. Thus, optimal control of CVD risk factors could contribute to improved efficacy of α-lipoic acid in patients with higher disease burden.
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Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: a randomized, double-blind, placebo-controlled trial.
Guo, Y, Jones, D, Palmer, JL, Forman, A, Dakhil, SR, Velasco, MR, Weiss, M, Gilman, P, Mills, GM, Noga, SJ, et al
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2014;(5):1223-31
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Abstract
OBJECTIVES Chemotherapy-induced peripheral neuropathy is frequently a dose-limiting factor in cancer treatment and may cause pain and irreversible function loss in cancer survivors. We tested whether alpha-lipoic acid (ALA) could decrease the severity of peripheral neuropathy symptoms in patients undergoing platinum-based chemotherapy. METHODS Cancer patients 18 years or older were randomly selected to receive either 600 mg ALA or a placebo three times a day orally for 24 weeks while receiving chemotherapy regimens including cisplatin or oxaliplatin. Neuropathy was measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) scale and the NCI Common Toxicity Criteria for Adverse Events neurotoxicity grades. Results from timed functional tests and the Brief Pain Inventory (BPI) were secondary endpoints. RESULTS Seventy of 243 (29 %) patients completed the study (24 weeks). Both the ALA and the placebo arms had a comparable drop-out rate. No statistically significant differences were found between the ALA and the placebo groups for FACT/GOG-Ntx scores, BPI scores, and patients' functional outcomes. CONCLUSION This strategy of oral ALA administration was ineffective at preventing neurotoxicity caused by oxaliplatin or cisplatin. High attrition rates due to poor patient compliance and manner of dosage administration in this trial demonstrated a lack of feasibility for this intervention. Future studies to explore ALA as a neuroprotective agent should take heed of the barriers confronted in this study.
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Effect of alpha-lipoic acid and vitamin E supplementation on oxidative stress, inflammation, and malnutrition in hemodialysis patients.
Ahmadi, A, Mazooji, N, Roozbeh, J, Mazloom, Z, Hasanzade, J
Iranian journal of kidney diseases. 2013;(6):461-7
Abstract
INTRODUCTION Increased oxidative stress, inflammation, and malnutrition are present in hemodialysis patients and these factors exacerbate cardiovascular comorbidities. Vitamin E and alpha-lipoic acid (ALA) may have a protective role against cardiovascular disease risk factors via anti-oxidative and anti-inflammatory properties. The aim of this study was to evaluate the effect of ALA and vitamin E administration (alone or combined) on hemodialysis-induced stress oxidation, inflammation, and malnutrition. MATERIALS AND METHODS In a randomized placebo-controlled trial, we examined the effects of 2-month supplementation by vitamin E and ALA (alone or combined) on biomarkers of lipid peroxidation (malondialdehyde), inflammation (high-sensitivity C-Reactive protein and interleukin-6), and malnutrition (Subjective Global Assessment and body mass index) in 85 hemodialysis patients receiving ALA (600 mg), vitamin E (400 IU), ALA and vitamin E, and placebo. RESULTS After supplementation, no significant changes were observed in malondialdehyde level; however, there was a decrease in the ALA and vitamin E group during the period of the study. Also, a nonsignificant decrease was seen in the high-sensitivity C-Reactive protein concentration of the interventional groups. Supplementation of vitamin E with and without ALA significantly reduced interleukin-6 concentration. A significant improvement was observed in malnutrition status of all groups. CONCLUSIONS Vitamin E and ALA supplementation, especially their combination, might improve inflammation and malnutrition status, which suggest it as a potential preventive strategy against CVD among end-stage renal disease patients.
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Alpha-lipoic acid for the prevention of diabetic macular edema.
Haritoglou, C, Gerss, J, Hammes, HP, Kampik, A, Ulbig, MW, ,
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2011;(3):127-37
Abstract
INTRODUCTION To evaluate the effect of α-lipoic acid (ALA) on the occurrence of diabetic macular edema. METHODS Randomized, double-blind, placebo-controlled, multicenter, multinational study. Patients were randomized to the treatment group with 600 mg ALA per day or the placebo group. Every 6 months stereo fundus photographs, HbA1c levels, and an ophthalmological examination were documented. The primary endpoint was the occurrence of clinically significant macular edema (CSME) within a follow-up period of 2 years. RESULTS We randomized 235 patients with type II diabetes mellitus into the treatment group (mean age 58.0 years) and 232 into the placebo group (mean age 57.9 years). Mean HbA1c level was 8.1, with no significant differences between the treatment (mean 8.2, SD ± 1.35) and placebo groups (mean 8.1, SD ± 1.29). HbA1c values remained constant over time. In the treatment and placebo groups, 84 and 86 patients (35.7 and 37.1%) had insulin-dependent diabetes mellitus (IDDM) with a median duration of diabetes of 9.3 versus 9.0 years in the placebo group. Visual acuity remained unchanged during the entire trial. Concerning the primary endpoint, the study provided a negative result, i.e. 26/235 patients in the treatment group and 30/232 patients in the placebo group developed CSME. Confirmatory intention-to-treat analysis of the primary endpoint revealed no statistically significant difference between groups (log-rank test, p = 0.7108, HR = 0.9057 with CI = 0.5355-1.5317). Median follow-up was identical (2.00 years). CONCLUSIONS A daily dosage of 600 mg ALA does not prevent the occurrence of CSME in IDDM patients.
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Restoration of blood total glutathione status and lymphocyte function following alpha-lipoic acid supplementation in patients with HIV infection.
Jariwalla, RJ, Lalezari, J, Cenko, D, Mansour, SE, Kumar, A, Gangapurkar, B, Nakamura, D
Journal of alternative and complementary medicine (New York, N.Y.). 2008;(2):139-46
Abstract
OBJECTIVES To determine whether supplementation with alpha-lipoic acid (ALA), a glutathione-replenishing disulfide, modulates whole blood total glutathione (GSH + GSSG) levels and improves lymphocyte function in human immunodeficiency virus (HIV)-infected subjects with history of unresponsiveness to highly active antiretroviral treatment (HAART). DESIGN AND SETTING Randomized, double-blinded, placebo-controlled trial conducted at two study sites: an eye clinic at a county hospital in San Jose and a research clinic in San Francisco, California. SUBJECTS A total of 33 HIV-infected men and women with viral load >10,000 copies/cm(3), despite HAART, aged 44-47 years, approximately 36% nonwhite, were enrolled. INTERVENTION Patients were randomly assigned to receive either ALA (300 mg three times a day) or matching placebo for 6 months. MAIN OUTCOME MEASURES The change over 6 months in blood total glutathione status, lymphocyte proliferation response to T-cell mitogens, CD4 cell count, and viral load in patients receiving ALA compared to placebo. RESULTS The mean blood total glutathione level in ALA-supplemented subjects was significantly elevated after 6 months (1.34+/-0.79 vs. 0.81+/-0.18 mmol/L) compared to insignificant change (0.76+/-0.34 vs. 0.76+/-0.22 mmol/L) in the placebo group (ALA vs. placebo: p=0.04). The lymphocyte proliferation response was significantly enhanced or stabilized after 6 months of ALA supplementation compared to progressive decline in the placebo group (ALA vs. placebo: p<0.001 with phytohemagglutinin; p=0.02 with anti-CD3 monoclonal antibody). A positive correlation was seen between blood total glutathione level and lymphocyte response to anti-CD3 stimulation (R(2)=0.889). There was no significant change in either HIV RNA level or CD4 count over 6 months in the ALA-supplemented compared to the control group. CONCLUSION Supplementation with alpha-lipoic acid may positively impact patients with HIV and acquired immune deficiency syndrome by restoring blood total glutathione level and improving functional reactivity of lymphocytes to T-cell mitogens.
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Alpha-lipoic acid may improve symptomatic diabetic polyneuropathy.
Tang, J, Wingerchuk, DM, Crum, BA, Rubin, DI, Demaerschalk, BM
The neurologist. 2007;(3):164-7
Abstract
OBJECTIVE In patients with symptomatic diabetic polyneuropathy, is oral alpha-lipoic acid (ALA) effective in improving neuropathic symptoms compared with placebo? METHODS The question was addressed with a structured evidence-based clinical neurologic practice review via videoconferencing between 3 academic institutions. Participants included consultant and resident neurologists, clinical epidemiologists, medical librarians, and clinical content experts. A critically appraised topic format was employed, with a clinical scenario, structured question, search strategy, appraisal, results, summary of evidence, commentary, and bottom-line conclusions. RESULTS A single modestly valid randomized controlled trial demonstrated that oral ALA in doses of 600 mg, 1200 mg, and 1800 mg was effective in reducing neuropathic symptoms of diabetic distal symmetric polyneuropathy (DSP) at 5 weeks, as assessed by the Total Symptom Score (>or=50% reduction), with number needed to treat (NNT) (95% CI) of 2.7 (1.8 to 5.8), 4.1 (2.3 to 20.2), and 3.2 (2.0 to 8.6), respectively. Adverse events, including nausea, vomiting, and vertigo, were identified but occurred most frequently with ALA doses of 1200 mg and 1800 mg. Overall, treatment emergent adverse events for ALA 600 mg were not significantly different than placebo, but ALA 1200 mg and 1800 mg had number needed to harm (95% CI) of 4.5 (2.4 to 31.0) and 3.0 (1.9 to 7.1), respectively. CONCLUSION Oral ALA may improve neuropathic symptoms in diabetic DSP. A single modestly valid RCT demonstrated that 600 mg was an effective and well-tolerated dose, with NNT 2.7 to significantly reduce neuropathic pain symptoms over a 5-week period. ALA's role and place in an algorithm among other commonly prescribed oral treatments for symptomatic relief of neuropathic pain in diabetic DSP remains unclear.