醛糖还原酶抑制剂 (ARIs)
通过减少多元醇通路的葡萄糖流出发挥作用。早期研究显示醛糖还原酶抑制剂的作用不一致，且不良事件发生率过高。[226]Pfeifer MA, Schumer MP, Gelber DA. Aldose reductase inhibitors: the end of an era or the need for different trial designs? Diabetes. 1997;46:S82-89.http://www.ncbi.nlm.nih.gov/pubmed/9285505?tool=bestpractice.com后期研究证明强效醛糖还原酶抑制剂非达司他、雷尼司他和依帕司他对糖尿病周围神经病变患者有效。[227]Hotta N, Toyota T, Matsuoka K, et al. Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study. Diabetes Care. 2001;24:1776-1782.http://www.ncbi.nlm.nih.gov/pubmed/11574441?tool=bestpractice.com[228]Asano T, Saito Y, Kawakami M, et al. Fidarestat (SNK-860), a potent aldose reductase inhibitor, normalizes the elevated sorbitol accumulation in erythrocytes of diabetic patients. J Diabetes Complications. 2002;16:133-138.http://www.ncbi.nlm.nih.gov/pubmed/12039395?tool=bestpractice.com[229]Bril V, Buchanan RA. Long-term effects of ranirestat (AS-3201) on peripheral nerve function in patients with diabetic sensorimotor polyneuropathy. Diabetes Care. 2006;29:68-72.http://care.diabetesjournals.org/cgi/content/full/29/1/68http://www.ncbi.nlm.nih.gov/pubmed/16373898?tool=bestpractice.com[230]Bril V, Hirose T, Tomioka S, et al. Ranirestat Study Group. Ranirestat
for the management of diabetic sensorimotor polyneuropathy. Diabetes Care. 2009;32:1256-1260.http://care.diabetesjournals.org/content/32/7/1256.longhttp://www.ncbi.nlm.nih.gov/pubmed/19366965?tool=bestpractice.com[231]Hotta N, Kawamori R, Atsumi Y, et al. ADCT Study Group. Stratified analyses for
selecting appropriate target patients with diabetic peripheral neuropathy for
long-term treatment with an aldose reductase inhibitor, epalrestat. Diabet Med.
2008;25:818-825.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613255/http://www.ncbi.nlm.nih.gov/pubmed/18644069?tool=bestpractice.com然而，系统综述发现醛糖还原酶抑制剂和安慰剂对于糖尿病多发性神经病的治疗效果没有差异。因此，醛糖还原酶抑制剂治疗糖尿病神经病变仍需更多研究。[232]Chalk C, Benstead TJ, Moore F. Aldose reductase inhibitors for the treatment
of diabetic polyneuropathy. Cochrane Database Syst Rev. 2007;(4):CD004572.http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004572.pub2/fullhttp://www.ncbi.nlm.nih.gov/pubmed/17943821?tool=bestpractice.com
黄芩素
报告显示，类黄酮黄芩素（5,6,7-三羟基黄酮）在慢性疾病模型中可以改善山梨醇堆积、12/15-脂肪氧化酶活化、氧化-氮化应激、炎症和受损的信号通路。动物研究表明黄芩素通过数种机制作用于糖尿病周围神经病变 (DPN)。[233]Stavniichuk R, Drel VR, Shevalye H, et al. Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative-nitrosative stress and p38 MAPK activation. Exp Neurol. 2011;230:106-113.http://www.ncbi.nlm.nih.gov/pubmed/21515260?tool=bestpractice.com
α- 硫辛酸
丙酮酸脱氢酶复合体的天然辅助因子，在复合体中它结合酰基，把它们从复合物的一个部分传送到另一部分。它在抗氧化过程中提供硫醇，调节氧化还原。欧洲和北美的试验已证明，短期静脉用药后，对改善神经性症状的作用有限，对电生理检查结果无益处。[234]Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999;2:1296-1301.http://www.ncbi.nlm.nih.gov/pubmed/10480774?tool=bestpractice.com[235]Ziegler D, Reljanovic M, Mehnert H, et al. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes. 1999;07:421-430.http://www.ncbi.nlm.nih.gov/pubmed/10595592?tool=bestpractice.com[236]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;26:770-776.http://care.diabetesjournals.org/cgi/content/full/26/3/770http://www.ncbi.nlm.nih.gov/pubmed/12610036?tool=bestpractice.com[237]Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34:2054-2060.http://www.ncbi.nlm.nih.gov/pubmed/21775755?tool=bestpractice.com[238]Mijnhout GS, Kollen BJ, Alkhalaf A, et al. Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2012:456279.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272801/http://www.ncbi.nlm.nih.gov/pubmed/22331979?tool=bestpractice.com
重组神经生长因子 (rNGF)
两项随机、双盲、安慰剂对照的 2 期临床研究证明，重组神经生长因子可改善糖尿病神经病变患者的神经学检查感觉分量、定量感觉测定和症状评分。[239]Apfel SC, Kessler JA, Adornato BT, et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology. 1998;51:695-702.http://www.ncbi.nlm.nih.gov/pubmed/9748012?tool=bestpractice.com但是，一项持续 48 周的大型、随机、安慰剂对照的 3 期临床试验并未证实重组神经生长因子的疗效。[240]Apfel SC. Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold? Int Rev Neurobiol. 2002;50:393-413.http://www.ncbi.nlm.nih.gov/pubmed/12198818?tool=bestpractice.com
乙酰左旋肉碱 (ALC)
临床前研究显示，乙酰左旋肉碱能纠正神经钠/钾 ATP 酶、肌醇、一氧化氮、前列腺素和脂质过氧化的异常。临床研究显示，乙酰左旋肉碱对痛性糖尿病神经病变有一定缓解。[241]Quatraro A, Roca P, Donzella C, et al. Acetyl-L-carnitine for symptomatic diabetic neuropathy. Diabetologia. 1995;38:123.http://www.ncbi.nlm.nih.gov/pubmed/7744218?tool=bestpractice.com[242]Onofrj M, Fulgente T, Melchionda D, et al. L-acetylcarnitine as a new therapeutic approach for peripheral neuropathies with pain. Int J Clin Pharmacol Res. 1995:15:9-15.http://www.ncbi.nlm.nih.gov/pubmed/7490173?tool=bestpractice.com[243]Scarpini E, Sacilotto G, Baron P, et al. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients. J Peripher Nerv Syst. 1997;2:250-252.http://www.ncbi.nlm.nih.gov/pubmed/10975731?tool=bestpractice.com[244]Evans JD, Jacobs TF, Evans EW. Role of acetyl-L-carnitine in the treatment of
diabetic peripheral neuropathy. Ann Pharmacother. 2008;42:1686-1691.http://www.ncbi.nlm.nih.gov/pubmed/18940920?tool=bestpractice.com一项在轻度糖尿病神经病变患者中应用 ALC 的大型多中心、安慰剂对照 3 期试验中，腓肠神经活检未见有髓纤维密度无改善。[245]Sima AA, Calvani M, Mehra M, et al. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials.Diabetes Care. 2005;28:89-94.http://care.diabetesjournals.org/cgi/content/full/28/1/89http://www.ncbi.nlm.nih.gov/pubmed/15616239?tool=bestpractice.com
聚腺苷二磷酸-核糖聚合酶 (PARP) 抑制剂
PARP 激活与糖尿病肾病和周围神经病变的发病机制有关。动物研究证实 PARP 激活对于与 1 型糖尿病相关的糖尿病周围神经病变和肾脏肥大有重要作用。这些研究提供了开发和进一步研究 PARP 抑制剂用于预防、治疗这些并发症的理论依据。[246]Drel VR, Pacher P, Stavniichuk R, et al. Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice. Int J Mol Med. 2011;28:629-635.http://www.spandidos-publications.com/ijmm/28/4/629http://www.ncbi.nlm.nih.gov/pubmed/21617845?tool=bestpractice.com
C 肽
具有胰岛素样信号功能，有助于改善神经 Na+/ K+-ATP 酶和一氧化氮早期代谢异常，从而对早期神经功能障碍具有良好的预防效果。这一信号级联反应可进一步改善早期基因反应的调控，改善神经营养因子及其受体以及胰岛素受体本身的基因调控。这将预防及改善神经纤维退化、丢失，并促进躯体感觉纤维和小伤害感受性神经纤维的再生。几项小规模临床试验证实了该药对自主神经和躯体神经功能及对多种组织血流的有益作用。因此，1 型糖尿病患者应用 C 肽治疗可延缓和预防慢性并发症的证据是真实、令人鼓舞的。[247]Sima AA, Kamiya H. Is C-peptide replacement the missing link for successful
treatment of neurological complications in type 1 diabetes? Curr Drug Targets.
2008;9:37-46. Review.http://www.ncbi.nlm.nih.gov/pubmed/18220711?tool=bestpractice.com[248]Ekberg K, Brismar T, Johansson BL, et al. C-Peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy. Diabetes Care. 2007;30:71-76.http://care.diabetesjournals.org/content/30/1/71.longhttp://www.ncbi.nlm.nih.gov/pubmed/17192336?tool=bestpractice.com[249]Ekberg K, Brismar T, Johansson BL, et al. Amelioration of sensory nerve dysfunction by C-Peptide in patients with type 1 diabetes. Diabetes. 2003;52:536-541.http://diabetes.diabetesjournals.org/content/52/2/536.longhttp://www.ncbi.nlm.nih.gov/pubmed/12540632?tool=bestpractice.com一项 3 期临床试验评估了聚乙二醇 C 肽在 1 型糖尿病和轻至中重度糖尿病周围神经病变中的作用，结果发现无益处。[250]ClinicalTrials.gov. Safety and efficacy of CBX129801 in patients with type 1 diabetes. January 2015. http://clinicaltrials.gov (last accessed 16 May 2016).http://clinicaltrials.gov/show/NCT01681290
L-甲基叶酸盐、甲钴胺和 5-磷酸吡哆醛 (LMF-MC-PLP)
动物研究已表明，L-甲基叶酸盐、甲钴胺和 5-磷酸吡哆醛联用可能对糖尿病周围神经病变有益。一项涉及 214 名 2 型糖尿病和神经病变（基线振动觉阈值：25-45 V）患者的多中心、随机、双盲、安慰剂对照试验对患者进行了随机分配，使其接受 LMF-MC-PLP 或安慰剂治疗。24 周后，主要结局指标（振动知觉阈）无显著改善。不过，第 16 周和第 24 周时，神经病变总症状评分问卷 (NTSS-6) 评分有显著改善。[251]Fonseca VA, Lavery LA, Thethi TK, et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med. 2013;126:141-149.http://www.amjmed.com/article/S0002-9343(12)00586-4/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/23218892?tool=bestpractice.com
神经元烟碱受体 (NNR) 激动剂
临床前和临床研究表明，神经元烟碱受体 (NNR) 激动剂可能是一种全新有效的治疗包括糖尿病神经病变在内的多种疼痛的疗法。高选择性 α-4-β-2 神经元烟碱受体激动剂 ABT-894 对糖尿病周围神经病变性疼痛患者的镇痛效果和安全性在 2 项独立的随机、双盲、多中心、安慰剂对照的临床试验中进行了评估。令人失望的是，在这两项试验中，没有一个 ABT-894 剂量组表现出疗效，而在其中一项研究中，度洛西汀效果优于安慰剂。这说明神经元烟碱受体激动剂可能不是治疗神经病性疼痛的可行方法。[252]Rowbotham MC, Arslanian A, Nothaft W, et al. Efficacy and safety of the α4β2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain. Pain. 2012;153:862-8.http://www.ncbi.nlm.nih.gov/pubmed/22386472?tool=bestpractice.com
胃饥饿素
胃饥饿素是生长激素促分泌素受体的一种内源性配体，从胃中分泌，在胃轻瘫研究中显示可使膳食相关的累计症状得分下降，并可改善液体排空。[62]Murray CD, Martin NM, Patterson M, et al. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut. 2005;54:1693-1698.http://gut.bmj.com/cgi/content/full/54/12/1693http://www.ncbi.nlm.nih.gov/pubmed/16085693?tool=bestpractice.com[253]Tack J, Depoortere I, Bisschops R, et al. Influence of ghrelin on gastric emptying and meal-related symptoms in idiopathic gastroparesis. Aliment Pharmacol Ther. 2005;22:847-853.http://www.ncbi.nlm.nih.gov/pubmed/16225494?tool=bestpractice.com在一项双盲、28-天的研究中，TZP-102（一种新型的大环、选择性、口服胃饥饿素受体激动剂）对胃排空没有作用，但改善了患者报告的胃轻瘫主要症状指数 (GCSI)，并且患者和医生的总体治疗评估得到改善。[254]Ejskjaer N, Wo JM, Esfandyari T, et al. A phase 2a, randomized, double-blind 28-day study of TZP-102 a ghrelin receptor agonist for diabetic gastroparesis. Neurogastroenterol Motil. 2013;25:e140-e150.http://onlinelibrary.wiley.com/doi/10.1111/nmo.12064/fullhttp://www.ncbi.nlm.nih.gov/pubmed/23279217?tool=bestpractice.com不过，在后续有 201 名糖尿病胃轻瘫患者参加的一项 12 周 2b 期研究中，GCSI 或总体治疗评估无显著改善。[255]McCallum RW, Lembo A, Esfandyari T, et al. Phase 2b, randomized, double-blind 12-week studies of TZP-102, a ghrelin receptor agonist for diabetic gastroparesis. Neurogastroenterol Motil. 2013;25:e705-e717.http://onlinelibrary.wiley.com/doi/10.1111/nmo.12184/fullhttp://www.ncbi.nlm.nih.gov/pubmed/23848826?tool=bestpractice.com
阿伐那非
该磷酸二酯酶-5 抑制剂在 2013 年 4 月在欧洲获得治疗成年男性勃起功能障碍的上市许可，但尚未在美国获得批准。
局部用前列地尔
一种局部用前列地尔乳膏制剂，已在 10 个欧洲国家和加拿大被批准用于治疗勃起功能障碍，但尚未在美国得到批准。
糖尿病性肌萎缩治疗
对于特别严重的肌萎缩患者，开放性、无对照研究显示泼尼松龙、静脉内免疫球蛋白 (IVIG) 和血浆置换有一定疗效。进行这些治疗后，病情停止恶化，开始改善。但是，由于未接受治疗的患者也逐渐恢复，因此无法证明这些治疗的有效性。[256]Krendel DA, Costigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol. 1995;52:1053-1061.http://www.ncbi.nlm.nih.gov/pubmed/7487556?tool=bestpractice.com[257]Krendel DA, Zacharias A, Younger DS: Autoimmune diabetic neuropathy. Neurol Clin. 1997;15:959-971.http://www.ncbi.nlm.nih.gov/pubmed/9367975?tool=bestpractice.com[258]Pascoe MK, Low PA, Windebank AJ, et al. Subacute diabetic proximal neuropathy. Mayo Clin Proc. 1997;72:1123-1132.http://www.ncbi.nlm.nih.gov/pubmed/9413291?tool=bestpractice.com[259]Jaradeh SS, Prieto TE, Lobeck LJ. Progressive polyradiculoneuropathy in diabetes: correlation of variables and clinical outcome after immunotherapy. J Neurol Neurosurg Psychiatry. 1999;67:607-612.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1736606/pdf/v067p00607.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/10519866?tool=bestpractice.com
非药物干预
对治疗 DPN 患者平衡功能障碍的物理疗法的一项系统评价给出了下肢强化锻炼的合理建议。[260]Ites KI, Anderson EJ, Cahill ML, et al. Balance interventions for diabetic peripheral neuropathy: a systematic review. J Geriatr Phys Ther. 2011;34:109-116.http://www.ncbi.nlm.nih.gov/pubmed/21937901?tool=bestpractice.com对于包括单红外能量疗法、振动鞋垫、使用拐杖在内的其他方法，尚无充足的证据支持使用。
