{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:30:22Z","timestamp":1788449422975,"version":"build-2803163510"},"reference-count":47,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T00:00:00Z","timestamp":1707177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"Haisco Pharmaceutical Group Co., Ltd."}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,5,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Diabetic peripheral neuropathy (DPN) is a highly prevalent chronic complication in type 2 diabetes (T2D) for which no effective treatment is available. In this multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial in China, patients with T2D with DPN received acetyllevocarnitine hydrochloride (ALC; 1,500 mg\/day; n = 231) or placebo (n = 227) for 24 weeks, during which antidiabetic therapy was maintained. A significantly greater reduction in modified Toronto clinical neuropathy score (mTCNS) as the primary end point occurred in the ALC group (\u22126.9 \u00b1 5.3 points) compared with the placebo group (\u22124.7 \u00b1 5.2 points; P &amp;lt; 0.001). Effect sizes (ALC 1.31 and placebo 0.85) represented a 0.65-fold improvement in ALC treatment efficacy. The mTCNS values for pain did not differ significantly between the two groups (P = 0.066), whereas the remaining 10 components of mTCNS showed significant improvement in the ALC group compared with the placebo group (P &amp;lt; 0.05 for all). Overall results of electrophysiological measurements were inconclusive, with significant improvement in individual measurements limited primarily to the ulnar and median nerves. Incidence of treatment-emergent adverse events was 51.2% in the ALC group, among which urinary tract infection (5.9%) and hyperlipidemia (7.9%) were most frequent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                  <\/jats:sec>","DOI":"10.2337\/db23-0377","type":"journal-article","created":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T16:35:09Z","timestamp":1707237309000},"page":"797-805","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":15,"title":["Acetyllevocarnitine Hydrochloride for the Treatment of Diabetic Peripheral Neuropathy: A Phase 3 Randomized Clinical Trial in China"],"prefix":"10.2337","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5947-8293","authenticated-orcid":false,"given":"Lixin","family":"Guo","sequence":"first","affiliation":[{"name":"1Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Pan","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifeng","family":"Cheng","sequence":"additional","affiliation":[{"name":"2Department of Endocrinology, Fourth Hospital of Harbin Medical University, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Li","sequence":"additional","affiliation":[{"name":"3Department of Endocrinology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Jiang","sequence":"additional","affiliation":[{"name":"4Department of Endocrinology, First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"5Department of Endocrinology, Kaifeng Hospital of Traditional Chinese Medicine, Kaifeng, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Li","sequence":"additional","affiliation":[{"name":"6Department of Endocrinology, Beijing Pinggu Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Qiu","sequence":"additional","affiliation":[{"name":"7Department of Endocrinology, Xinxiang First People\u2019s Hospital, Affiliated People\u2019s Hospital of Xinxiang Medical University, Xinxiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Lu","sequence":"additional","affiliation":[{"name":"8Department of Endocrinology, Chongqing General Hospital, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhang","family":"Tian","sequence":"additional","affiliation":[{"name":"9Department of Endocrinology, Luoyang Third People\u2019s Hospital, Luoyang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqin","family":"Fu","sequence":"additional","affiliation":[{"name":"10Department of Endocrinology, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangqiong","family":"Li","sequence":"additional","affiliation":[{"name":"11Haisco Pharmaceutical Group Co., Ltd., Chengdu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danqing","family":"Li","sequence":"additional","affiliation":[{"name":"11Haisco Pharmaceutical Group Co., Ltd., Chengdu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2024,2,6]]},"reference":[{"key":"2024041918505824600_B1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.2337\/diaclin.23.1.9","article-title":"Management of diabetic peripheral neuropathy","volume":"23","author":"Boulton","year":"2005","journal-title":"Clin Diabetes"},{"key":"2024041918505824600_B2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00125-018-4711-2","article-title":"Global trends in diabetes complications: a review of current evidence","volume":"62","author":"Harding","year":"2019","journal-title":"Diabetologia"},{"key":"2024041918505824600_B3","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1007\/s11892-019-1212-8","article-title":"Epidemiology of peripheral neuropathy and lower extremity disease in diabetes","volume":"19","author":"Hicks","year":"2019","journal-title":"Curr Diab Rep"},{"key":"2024041918505824600_B4","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.mcna.2013.03.008","article-title":"Epidemiology of foot ulceration and amputation: can global variation be explained?","volume":"97","author":"Margolis","year":"2013","journal-title":"Med Clin North Am"},{"key":"2024041918505824600_B5","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jdiacomp.2014.10.013","article-title":"Healthcare utilization and costs in diabetes relative to the clinical spectrum of painful diabetic peripheral neuropathy","volume":"29","author":"Sadosky","year":"2015","journal-title":"J Diabetes Complications"},{"key":"2024041918505824600_B6","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1001\/jama.2021.22208","article-title":"Prevalence and treatment of diabetes in China, 2013-2018","volume":"326","author":"Wang","year":"2021","journal-title":"JAMA"},{"key":"2024041918505824600_B7","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res Clin Pract"},{"key":"2024041918505824600_B8","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1093\/brain\/awab079","article-title":"Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management","volume":"144","author":"Jensen","year":"2021","journal-title":"Brain"},{"key":"2024041918505824600_B9","doi-asserted-by":"crossref","first-page":"748","DOI":"10.2337\/diacare.24.4.748","article-title":"Glycemic control is related to the morphological severity of diabetic sensorimotor polyneuropathy","volume":"24","author":"Perkins","year":"2001","journal-title":"Diabetes Care"},{"key":"2024041918505824600_B10","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.2337\/diacare.21.10.1749","article-title":"Glycemic control is related to the electrophysiologic severity of diabetic peripheral sensorimotor polyneuropathy","volume":"21","author":"Tkac","year":"1998","journal-title":"Diabetes Care"},{"key":"2024041918505824600_B11","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1111\/jphp.13241","article-title":"Treatment of diabetic peripheral neuropathy: a review","volume":"72","author":"Khdour","year":"2020","journal-title":"J Pharm Pharmacol"},{"key":"2024041918505824600_B12","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.clnesp.2019.03.015","article-title":"Alpha-lipoic acid (ALA) supplementation effect on glycemic and inflammatory biomarkers: a systematic review and meta- analysis","volume":"32","author":"Rahimlou","year":"2019","journal-title":"Clin Nutr ESPEN"},{"key":"2024041918505824600_B13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1080\/03007995.2018.1497958","article-title":"Non-pharmacologic treatments for symptoms of diabetic peripheral neuropathy: a systematic review","volume":"35","author":"Amato Nesbit","year":"2019","journal-title":"Curr Med Res Opin"},{"key":"2024041918505824600_B14","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/s41572-019-0092-1","article-title":"Diabetic neuropathy","volume":"5","author":"Feldman","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"2024041918505824600_B15","doi-asserted-by":"crossref","first-page":"674987","DOI":"10.1155\/2014\/674987","article-title":"Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets","volume":"2014","author":"Sandireddy","year":"2014","journal-title":"Int J Endocrinol"},{"key":"2024041918505824600_B16","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.bj.2017.06.007","article-title":"The etiology of oxidative stress in insulin resistance","volume":"40","author":"Hurrle","year":"2017","journal-title":"Biomed J"},{"key":"2024041918505824600_B17","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/9781119329725.ch24","volume-title":"Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants.","author":"Beger","year":"2018","edition":"1st ed"},{"key":"2024041918505824600_B18","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.3390\/ijms23052717","article-title":"The role of L-carnitine in mitochondria, prevention of metabolic inflexibility and disease initiation","volume":"23","author":"Virmani","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2024041918505824600_B19","doi-asserted-by":"crossref","first-page":"6358","DOI":"10.3390\/ijms21176358","article-title":"Novel insights and mechanisms of lipotoxicity-driven insulin resistance","volume":"21","author":"Lair","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2024041918505824600_B20","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.cmet.2007.10.013","article-title":"Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance","volume":"7","author":"Koves","year":"2008","journal-title":"Cell Metab"},{"key":"2024041918505824600_B21","doi-asserted-by":"crossref","first-page":"22840","DOI":"10.1074\/jbc.M109.032888","article-title":"Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control","volume":"284","author":"Noland","year":"2009","journal-title":"J Biol Chem"},{"key":"2024041918505824600_B22","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S1056-8727(99)00052-5","article-title":"Carnitine deficiency in diabetes mellitus complications","volume":"13","author":"Tamamo\u011fullari","year":"1999","journal-title":"J Diabetes Complications"},{"key":"2024041918505824600_B23","first-page":"631","article-title":"The effects of L-carnitine supplementation on glycemic control: a systematic review and meta-analysis of randomized controlled trials","volume":"18","author":"Fathizadeh","year":"2019","journal-title":"EXCLI J"},{"key":"2024041918505824600_B24","doi-asserted-by":"crossref","first-page":"333","DOI":"10.17219\/acem\/61609","article-title":"L-carnitine treatment of insulin resistance: a systematic review and meta-analysis","volume":"26","author":"Xu","year":"2017","journal-title":"Adv Clin Exp Med"},{"key":"2024041918505824600_B25","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.clnu.2019.01.020","article-title":"The effect of L-carnitine supplementation on lipid profile and glycaemic control in adults with cardiovascular risk factors: a systematic review and meta-analysis of randomized controlled clinical trials","volume":"39","author":"Asadi","year":"2020","journal-title":"Clin Nutr"},{"key":"2024041918505824600_B26","doi-asserted-by":"crossref","first-page":"692","DOI":"10.4103\/1673-5374.230297","article-title":"Treatment with acetyl-L-carnitine exerts a neuroprotective effect in the sciatic nerve following loose ligation: a functional and microanatomical study","volume":"13","author":"Tomassoni","year":"2018","journal-title":"Neural Regen Res"},{"key":"2024041918505824600_B27","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.2147\/JPR.S190231","article-title":"Acetyl-L-carnitine in painful peripheral neuropathy: a systematic review","volume":"12","author":"Di Stefano","year":"2019","journal-title":"J Pain Res"},{"key":"2024041918505824600_B28","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1016\/j.bjps.2009.05.039","article-title":"Acetyl-L-carnitine increases nerve regeneration and target organ reinnervation - a morphological study","volume":"63","author":"Wilson","year":"2010","journal-title":"J Plast Reconstr Aesthet Surg"},{"key":"2024041918505824600_B29","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1111\/jdi.12493","article-title":"Effects of acetyl-L-carnitine and methylcobalamin for diabetic peripheral neuropathy: a multicenter, randomized, double-blind, controlled trial","volume":"7","author":"Li","year":"2016","journal-title":"J Diabetes Investig"},{"key":"2024041918505824600_B30","doi-asserted-by":"crossref","first-page":"223","DOI":"10.2165\/00126839-200203040-00001","article-title":"Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study","volume":"3","author":"De Grandis","year":"2002","journal-title":"Drugs R D"},{"key":"2024041918505824600_B31","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2337\/diacare.28.1.89","article-title":"Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials","volume":"28","author":"Sima","year":"2005","journal-title":"Diabetes Care"},{"key":"2024041918505824600_B32","first-page":"CD011265","article-title":"Acetyl-L-carnitine for the treatment of diabetic peripheral neuropathy","volume":"6","author":"Rolim","year":"2019","journal-title":"Cochrane Database Syst Rev"},{"key":"2024041918505824600_B33","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/mus.21661","article-title":"Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial","volume":"42","author":"Dyck","year":"2010","journal-title":"Muscle Nerve"},{"key":"2024041918505824600_B34","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1111\/j.1464-5491.2009.02667.x","article-title":"Reliability and validity of the modified Toronto clinical neuropathy score in diabetic sensorimotor polyneuropathy","volume":"26","author":"Bril","year":"2009","journal-title":"Diabet Med"},{"key":"2024041918505824600_B35","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.2337\/diacare.25.11.2048","article-title":"Validation of the Toronto clinical scoring system for diabetic polyneuropathy","volume":"25","author":"Bril","year":"2002","journal-title":"Diabetes Care"},{"key":"2024041918505824600_B36","first-page":"24","article-title":"Clinical and nerve conduction study correlation in patients of diabetic neuropathy","volume":"62","author":"Kakrani","year":"2014","journal-title":"J Assoc Physicians India"},{"key":"2024041918505824600_B37","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1080\/13543784.2023.2219388","article-title":"First-in-human phase I studies of YJ001 spray applied to local skin in healthy subjects and patients with diabetic neuropathic pain","volume":"32","author":"Yang","year":"2023","journal-title":"Expert Opin Investig Drugs"},{"key":"2024041918505824600_B38","doi-asserted-by":"crossref","first-page":"68","DOI":"10.2337\/diacare.29.01.06.dc05-1447","article-title":"Long-term effects of ranirestat (AS-3201) on peripheral nerve function in patients with diabetic sensorimotor polyneuropathy","volume":"29","author":"Bril","year":"2006","journal-title":"Diabetes Care"},{"key":"2024041918505824600_B39","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.2337\/dc08-2110","article-title":"Ranirestat for the management of diabetic sensorimotor polyneuropathy","volume":"32","author":"Bril","year":"2009","journal-title":"Diabetes Care"},{"key":"2024041918505824600_B40","doi-asserted-by":"crossref","first-page":"5383797","DOI":"10.1155\/2016\/5383797","article-title":"Effect of ranirestat on sensory and motor nerve function in Japanese patients with diabetic polyneuropathy: a randomized double-blind placebo-controlled study","volume":"2016","author":"Satoh","year":"2016","journal-title":"J Diabetes Res"},{"key":"2024041918505824600_B41","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1111\/jdi.12890","article-title":"Aldose reductase inhibitor ranirestat significantly improves nerve conduction velocity in diabetic polyneuropathy: a randomized double-blind placebo-controlled study in Japan","volume":"10","author":"Sekiguchi","year":"2019","journal-title":"J Diabetes Investig"},{"key":"2024041918505824600_B42","doi-asserted-by":"crossref","first-page":"S65","DOI":"10.1097\/j.pain.0000000000001922","article-title":"Diabetic neuropathy and neuropathic pain: a (con)fusion of pathogenic mechanisms?","volume":"161","author":"Calcutt","year":"2020","journal-title":"Pain"},{"key":"2024041918505824600_B43","doi-asserted-by":"crossref","first-page":"112717","DOI":"10.1016\/j.biopha.2022.112717","article-title":"Progress in the treatment of diabetic peripheral neuropathy","volume":"148","author":"Yang","year":"2022","journal-title":"Biomed Pharmacother"},{"key":"2024041918505824600_B44","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s12272-022-01391-5","article-title":"Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: a glucose-independent effect through AMPK signaling","volume":"45","author":"Abdelkader","year":"2022","journal-title":"Arch Pharm Res"},{"key":"2024041918505824600_B45","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1111\/dme.14194","article-title":"Diabetic peripheral neuropathy in people with type 2 diabetes: too little too late","volume":"37","author":"Javed","year":"2020","journal-title":"Diabet Med"},{"key":"2024041918505824600_B46","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.3390\/nu12113254","article-title":"Efficacy and safety of the combination of superoxide dismutase, alpha lipoic acid, vitamin B12, and carnitine for 12 months in patients with diabetic neuropathy","volume":"12","author":"Didangelos","year":"2020","journal-title":"Nutrients"},{"key":"2024041918505824600_B47","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1080\/17512433.2021.1917381","article-title":"Quantitative efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients","volume":"14","author":"Wang","year":"2021","journal-title":"Expert Rev Clin Pharmacol"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/73\/5\/797\/754384\/db230377.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/73\/5\/797\/754384\/db230377.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T14:51:47Z","timestamp":1713538307000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/73\/5\/797\/154206\/Acetyllevocarnitine-Hydrochloride-for-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,6]]},"references-count":47,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,2,6]]},"published-print":{"date-parts":[[2024,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db23-0377","relation":{"has-preprint":[{"id-type":"doi","id":"10.2337\/figshare.25137440.v1","asserted-by":"object"},{"id-type":"doi","id":"10.2337\/figshare.25137440.v2","asserted-by":"object"},{"id-type":"doi","id":"10.2337\/figshare.25137440","asserted-by":"object"}]},"ISSN":["0012-1797"],"issn-type":[{"value":"0012-1797","type":"print"}],"subject":[],"published":{"date-parts":[[2024,2,6]]}}}