{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:28:01Z","timestamp":1786429681610,"version":"build-2736575974"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Alpha-lipoic acid (ALA) is widely utilized for diabetic peripheral neuropathy (DPN); however, optimal administration routes (oral, intravenous [IV], or sequential) remain debated. This study evaluates and ranks their efficacy and safety through a Bayesian network meta-analysis (NMA) equipped with rigorous bias-exclusion frameworks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The PubMed, Embase, Web of Science, Cochrane Library, and Scopus databases were systematically searched (up to 2025) to identify randomized controlled trials (RCTs) comparing oral, intravenous, and sequential ALA therapies, as well as placebo, encompassing varying dosages (600\u20131,800\u202fmg\/d) and treatment durations (3 to 208\u202fweeks), for DPN. Core outcome measures included the Total Symptom Score (TSS), Neuropathy Impairment Score (NIS), Neuropathy Impairment Score in the Lower Limbs (NIS-LL), and Global Satisfaction (GS). The NMA was conducted using a Bayesian framework in R software. Interventions were ranked by calculating the surface under the cumulative ranking curve (SUCRA), and a dual-outcome plot was constructed to evaluate the benefit\u2013risk ratio. Evidence certainty was evaluated via CINeMA, and sensitivity analyses were executed by excluding high-bias studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nine high-quality RCTs were included. Initially, sequential ALA therapy demonstrated overwhelming superiority in improving TSS and NIS. However, CINeMA evaluations revealed severe within-study bias, and sensitivity analyses exposed this initial superiority as an artifact. In the unbiased network, IV ALA emerged as the absolute optimal intervention for rapidly alleviating subjective symptoms (TSS) and overall objective signs (NIS), achieving a \u201cdual-optimal\u201d efficacy-safety profile that completely bypasses gastrointestinal risks. Confronting the most refractory distal impairment (NIS-LL), oral ALA stood alone as the sole surviving intervention supported by robust, completely homogeneous evidence (I\n                      <jats:sup>2<\/jats:sup>\n                      \u202f=\u202f0%, SUCRA: 97.4%) for structural repair. Both standalone IV and oral routes significantly enhanced global patient satisfaction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The optimal ALA administration is stage-dependent. IV ALA delivers unmatched acute neurovascular rescue, while oral ALA serves as the indispensable cornerstone for long-term distal structural repair. Importantly, rather than negating sequential therapy, these distinct phase-specific benefits fundamentally validate its core \u201cinduction-maintenance\u201d clinical rationale. While unbiased evidence for the integrated sequential regimen remains sparse\u2014necessitating future large-scale, double-blinded RCTs\u2014the sequential framework itself is robustly justified by the verified strengths of its constituent phases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>CRD420261411001.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1904967","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T05:37:11Z","timestamp":1786426631000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Oral, intravenous, or sequential alpha-lipoic acid for diabetic peripheral neuropathy? A Bayesian network meta-analysis of randomized controlled trials"],"prefix":"10.3389","volume":"17","author":[{"given":"Jinshui","family":"Shen","sequence":"first","affiliation":[{"name":"The First School of Clinical Medicine, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YuJing","family":"Zheng","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MiaoMiao","family":"Yu","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Wang","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/s41392-025-02175-1","article-title":"Diabetic neuropathy: cutting-edge research and future directions","volume":"10","author":"Yang","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41582-024-01041-y","article-title":"The global and regional burden of diabetic peripheral neuropathy","volume":"21","author":"Savelieff","year":"2025","journal-title":"Nat Rev Neurol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e002040","DOI":"10.1136\/bmjdrc-2020-002040","article-title":"Prevalence of peripheral neuropathy in pre-diabetes: a systematic review","volume":"9","author":"Kirthi","year":"2021","journal-title":"BMJ Open Diabetes Res Care"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1265372","DOI":"10.3389\/fendo.2023.1265372","article-title":"Diabetic peripheral neuropathy: Pathogenetic mechanisms and treatment","volume":"14","author":"Zhu","year":"2024","journal-title":"Front Endocrinol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"589","DOI":"10.3390\/biomedicines13030589","article-title":"Cytokine signaling in diabetic neuropathy: a key player in peripheral nerve damage","volume":"13","author":"Nashtahosseini","year":"2025","journal-title":"Biomedicine"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/S1474-4422(12)70065-0","article-title":"Diabetic neuropathy: clinical manifestations and current treatments","volume":"11","author":"Callaghan","year":"2012","journal-title":"Lancet Neurol"},{"key":"ref7","first-page":"392","article-title":"The effect of \u03b1-Lipoic acid treatment on plasma asymmetric Dimethylarginine, a biomarker of endothelial dysfunction in diabetic neuropathy","volume":"21","author":"Sztanek","year":"2025","journal-title":"Arch Med Sci"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1111\/j.1464-5491.2004.01109.x","article-title":"Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-Lipoic acid: a Meta-analysis","volume":"21","author":"Ziegler","year":"2004","journal-title":"Diabet Med J Br Diabet Assoc"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1530\/EJE-12-0555","article-title":"A systematic review and Meta-analysis of \u03b1-Lipoic acid in the treatment of diabetic peripheral neuropathy","volume":"167","author":"Han","year":"2012","journal-title":"Eur J Endocrinol"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.25750","article-title":"Effect of alpha-lipoic acid in the treatment of diabetic neuropathy: a systematic review","volume":"14","author":"Abubaker","year":"2022","journal-title":"Cureus"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"356","DOI":"10.3390\/biom9080356","article-title":"Insights on the use of \u03b1-Lipoic acid for therapeutic purposes","volume":"9","author":"Salehi","year":"2019","journal-title":"Biomolecules"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/189857","article-title":"Treatment with \u03b1-lipoic acid over 16 weeks in type 2 diabetic patients with symptomatic polyneuropathy who responded to initial 4-week high-dose loading","volume":"2015","author":"Garcia-Alcala","year":"2015","journal-title":"J Diabetes Res"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.2337\/diacare.22.8.1296","article-title":"Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-Lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III study). 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Endocrinol"},{"key":"ref33","doi-asserted-by":"publisher","DOI":"10.3390\/nu15163634","article-title":"Effects of Oral alpha-Lipoic acid treatment on diabetic polyneuropathy: a Meta-analysis and systematic review","volume":"15","author":"Hsieh","year":"2023","journal-title":"Nutrients"},{"key":"ref34","doi-asserted-by":"publisher","DOI":"10.1051\/e3sconf\/202022206032","article-title":"Comparative characteristics of dosage forms of \u03b1-Lipoic acid","volume":"222","author":"Shkolnikova","year":"2020","journal-title":"E3S Web Conf"}],"container-title":["Frontiers in 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