Aldose reductase inhibitors
Act by reducing the flux of glucose through the polyol pathway (a metabolic pathway that becomes overactive in hyperglycaemic states). Earlier studies with aldose reductase inhibitors showed inconsistent effects and an unacceptable rate of adverse events.[196]Pfeifer MA, Schumer MP, Gelber DA. Aldose reductase inhibitors: the end of an era or the need for different trial designs? Diabetes. 1997 Sep;46 Suppl 2:S82-9.
http://www.ncbi.nlm.nih.gov/pubmed/9285505?tool=bestpractice.com
Later studies with the investigational potent aldose reductase inhibitors fidarestat, ranirestat, and epalrestat have shown benefit in diabetic patients with peripheral neuropathy.[197]Hotta N, Toyota T, Matsuoka K, et al; SNK-860 Diabetic Neuropathy Study Group. 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 Oct;24(10):1776-82.
http://www.ncbi.nlm.nih.gov/pubmed/11574441?tool=bestpractice.com
[198]Asano T, Saito Y, Kawakami M, et al; Fidarestat Clinical Pharmacology Study Group. Fidarestat (SNK-860), a potent aldose reductase inhibitor, normalizes the elevated sorbitol accumulation in erythrocytes of diabetic patients. J Diabetes Complications. 2002 Mar-Apr;16(2):133-8.
http://www.ncbi.nlm.nih.gov/pubmed/12039395?tool=bestpractice.com
[199]Bril V, Buchanan RA. Long-term effects of ranirestat (AS-3201) on peripheral nerve function in patients with diabetic sensorimotor polyneuropathy. Diabetes Care. 2006 Jan;29(1):68-72.
https://diabetesjournals.org/care/article/29/1/68/24415/Long-Term-Effects-of-Ranirestat-AS-3201-on
http://www.ncbi.nlm.nih.gov/pubmed/16373898?tool=bestpractice.com
[200]Bril V, Hirose T, Tomioka S, et al. Ranirestat Study Group. Ranirestat for the management of diabetic sensorimotor polyneuropathy. Diabetes Care. 2009 Jul;32(7):1256-60.
https://diabetesjournals.org/care/article/32/7/1256/27025/Ranirestat-for-the-Management-of-Diabetic
http://www.ncbi.nlm.nih.gov/pubmed/19366965?tool=bestpractice.com
[201]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 Jul;25(7):818-25.
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1464-5491.2008.02490.x
http://www.ncbi.nlm.nih.gov/pubmed/18644069?tool=bestpractice.com
However, one Cochrane review found no difference between aldose reductase inhibitors and placebo when treating diabetic polyneuropathy.[202]Chalk C, Benstead TJ, Moore F. Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD004572.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004572.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/17943821?tool=bestpractice.com
Therefore, further studies regarding the use of aldose reductase inhibitors for treating DN are required.
Baicalein
The flavonoid baicalein (5,6,7-trihydroxyflavone) has been reported to counteract sorbitol accumulation, activation of 12/15-lipoxygenase, oxidative-nitrosative stress, inflammation, and impaired signalling in models of chronic disease. Animal studies suggest baicalein targets several mechanisms implicated in diabetic peripheral neuropathy (DPN).[203]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 Jul;230(1):106-13.
http://www.ncbi.nlm.nih.gov/pubmed/21515260?tool=bestpractice.com
Alpha-lipoic acid
A natural cofactor in the pyruvate dehydrogenase complex, where it binds acyl groups and transfers them from one part of the complex to another. It plays a role in the antioxidant network as a thiol-replenishing and redox-modulating agent. Trials in Europe and North America have demonstrated limited effects on neuropathic symptoms after short-term intravenous use and no benefit on electrophysiological testing.[204]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 Aug;22(8):1296-301.
http://www.ncbi.nlm.nih.gov/pubmed/10480774?tool=bestpractice.com
[205]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;107(7):421-30.
http://www.ncbi.nlm.nih.gov/pubmed/10595592?tool=bestpractice.com
[206]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 Mar;26(3):770-6.
https://diabetesjournals.org/care/article/26/3/770/29155/The-Sensory-Symptoms-of-Diabetic-Polyneuropathy
http://www.ncbi.nlm.nih.gov/pubmed/12610036?tool=bestpractice.com
[207]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 Sep;34(9):2054-60.
http://www.ncbi.nlm.nih.gov/pubmed/21775755?tool=bestpractice.com
[208]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;2012:456279.
https://www.hindawi.com/journals/ije/2012/456279
http://www.ncbi.nlm.nih.gov/pubmed/22331979?tool=bestpractice.com
Recombinant nerve growth factor (rNGF)
Two randomised, double-blind, placebo-controlled phase 2 studies of rNGF in the treatment of DN reported improvement in the sensory component of the neurological examination, in both quantitative sensory testing and a symptom score.[209]Apfel SC, Kessler JA, Adornato BT, et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology. 1998 Sep;51(3):695-702.
http://www.ncbi.nlm.nih.gov/pubmed/9748012?tool=bestpractice.com
However, a large-scale 48-week, phase 3 clinical trial of patients randomised to receive either rNGF or placebo failed to confirm its efficacy.[210]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
Acetyl-L-carnitine (ALC)
In preclinical studies, ALC treatment corrected perturbations of neural sodium/potassium-adenosine triphosphatase (ATPase), myoinositol, nitric oxide, prostaglandins, and lipid peroxidation. Clinical studies have shown modest effects of ALC on painful DN.[211]Quatraro A, Roca P, Donzella C, et al. Acetyl-L-carnitine for symptomatic diabetic neuropathy. Diabetologia. 1995 Jan;38(1):123.
http://www.ncbi.nlm.nih.gov/pubmed/7744218?tool=bestpractice.com
[212]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(1):9-15.
http://www.ncbi.nlm.nih.gov/pubmed/7490173?tool=bestpractice.com
[213]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(3):250-2.
http://www.ncbi.nlm.nih.gov/pubmed/10975731?tool=bestpractice.com
[214]Evans JD, Jacobs TF, Evans EW. Role of acetyl-L-carnitine in the treatment of
diabetic peripheral neuropathy. Ann Pharmacother. 2008 Nov;42(11):1686-91.
http://www.ncbi.nlm.nih.gov/pubmed/18940920?tool=bestpractice.com
A large multicentre placebo-controlled phase 3 trial of ALC in patients with mild DN found no improvement in myelinated fibre density in sural nerve biopsies.[215]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 Jan;28(1):89-94.
https://diabetesjournals.org/care/article/28/1/89/25830/Acetyl-l-Carnitine-Improves-Pain-Nerve
http://www.ncbi.nlm.nih.gov/pubmed/15616239?tool=bestpractice.com
Poly (ADP-ribose) polymerase (PARP) inhibitors
PARP activation has been implicated in the pathogenesis of diabetic complications, including nephropathy and peripheral neuropathy. Animal studies support an important role for PARP activation in DPN and kidney hypertrophy associated with type 1 diabetes. These studies provide a rationale for further studies of PARP inhibitors for the prevention and treatment of these complications.[216]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 Oct;28(4):629-35.
https://www.spandidos-publications.com/ijmm/28/4/629
http://www.ncbi.nlm.nih.gov/pubmed/21617845?tool=bestpractice.com
C-peptide
Exerts insulin-like signalling activity, producing beneficial outcomes during the early stages of metabolic dysfunction by stabilising neural Na+/K+-ATPase activity and enhancing nitric oxide signalling. These actions may help prevent early nerve dysfunction. Downstream effects of this signalling cascade positively influence the expression of early response genes, neurotrophic factors, their receptors, and the insulin receptor itself. These mechanisms may lead to both preventive and restorative effects, including reduced nerve fibre degeneration, preservation of nerve fibres, and promotion of regeneration, particularly in sensory somatic fibres and small nociceptive nerve fibres. Several small-scale clinical trials have reported improvement in autonomic and somatic nerve function, as well as enhanced tissue blood flow, following C-peptide replacement. This has provided promising evidence that C-peptide supplementation in patients with type 1 diabetes may help slow or prevent the development of chronic complications, as well as enhanced tissue blood flow, following C-peptide replacement. This has provided promising evidence that C-peptide supplementation in patients with type 1 diabetes may help slow or prevent the development of chronic complications.[217]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 Jan;9(1):37-46.
http://www.ncbi.nlm.nih.gov/pubmed/18220711?tool=bestpractice.com
[218]Ekberg K, Brismar T, Johansson BL, et al. C-peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy. Diabetes Care. 2007 Jan;30(1):71-6.
https://diabetesjournals.org/care/article/30/1/71/28225/C-Peptide-Replacement-Therapy-and-Sensory-Nerve
http://www.ncbi.nlm.nih.gov/pubmed/17192336?tool=bestpractice.com
[219]Ekberg K, Brismar T, Johansson BL, et al. Amelioration of sensory nerve dysfunction by C-peptide in patients with type 1 diabetes. Diabetes. 2003 Feb;52(2):536-41.
https://diabetesjournals.org/diabetes/article/52/2/536/26777/Amelioration-of-Sensory-Nerve-Dysfunction-by-C
http://www.ncbi.nlm.nih.gov/pubmed/12540632?tool=bestpractice.com
However, a phase 3 clinical trial evaluating the effects of pegylated C-peptide in patients with type 1 diabetes and mild to moderately severe DPN reported no benefit.[220]ClinicalTrials.gov. Safety and efficacy of CBX129801 in patients with type 1 diabetes. Jan 2015 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT01681290
L-methylfolate, methylcobalamin, and pyridoxal-5'-phosphate (LMF-MC-PLP)
Animal studies have suggested that a combination of L-methylfolate, methylcobalamin, and pyridoxal-5'-phosphate may be beneficial in DPN. A multicentre, randomised, double-blind, placebo-controlled trial involving 214 patients with type 2 diabetes and neuropathy (baseline vibration perception threshold: 25-45 volts) randomly assigned patients to treatment with either LMF-MC-PLP or placebo. There was no significant improvement in the primary outcome measure (vibration perception threshold) after 24 weeks. However, there was a significant improvement in Neuropathy Total Symptom Score-6 scores at week 16 and week 24.[221]Fonseca VA, Lavery LA, Thethi TK, et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med. 2013 Feb;126(2):141-9.
https://www.amjmed.com/article/S0002-9343(12)00586-4/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/23218892?tool=bestpractice.com
Neuronal nicotinic receptor (NNR) agonist
Preclinical and clinical studies suggest that neuronal nicotinic receptor (NNR) agonists may be a novel and effective therapy for numerous painful conditions, including DN. Analgesic efficacy and safety of the highly selective alpha-4-beta-2 NNR agonist ABT-894 was evaluated in 2 randomised, double-blind, multicentre, placebo-controlled trials in patients with painful DPN. Neither study demonstrated a significant benefit of ABT-894 over placebo at any dose.[222]Rowbotham MC, Arslanian A, Nothaft W, et al. Efficacy and safety of the alpha(4)beta(2) neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain. Pain. 2012 Apr;153(4):862-8.
http://www.ncbi.nlm.nih.gov/pubmed/22386472?tool=bestpractice.com
In contrast, one of the trials showed a statistically significant improvement in pain with duloxetine compared to placebo. These findings indicate that NNR agonists may not be a viable strategy for treating neuropathic pain.
Ghrelin
Ghrelin, a hormone released by the stomach and an endogenous ligand for the growth hormone secretagogue receptor, has been shown to reduce cumulative meal-related symptom scores and improve liquid gastric emptying in studies of gastroparesis.[69]Murray CD, Martin NM, Patterson M, et al. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut. 2005 Dec;54(12):1693-8.
https://gut.bmj.com/content/54/12/1693.full
http://www.ncbi.nlm.nih.gov/pubmed/16085693?tool=bestpractice.com
[223]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 Nov 1;22(9):847-53.
http://www.ncbi.nlm.nih.gov/pubmed/16225494?tool=bestpractice.com
In a double-blind 28-day study, TZP-102 (a novel, macrocyclic, selective, oral ghrelin receptor agonist) had no effect on gastric emptying, but did lead to improvements in patient-reported symptoms on the Gastroparesis Cardinal Symptom Index (GCSI), as well as in both patient and physician global treatment assessments.[224]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 Feb;25(2):e140-50.
http://www.ncbi.nlm.nih.gov/pubmed/23279217?tool=bestpractice.com
However, in a subsequent 12-week, phase 2b study of 201 patients with diabetic gastroparesis, TZP-102 did not produce significant improvements in either GCSI scores or overall treatment assessments.[225]McCallum RW, Lembo A, Esfandyari T, et al; TZP-102 Phase 2b Study Group. Phase 2b, randomized, double-blind 12-week studies of TZP-102, a ghrelin receptor agonist for diabetic gastroparesis. Neurogastroenterol Motil. 2013 Nov;25(11):e705-17.
http://www.ncbi.nlm.nih.gov/pubmed/23848826?tool=bestpractice.com
Treatment for diabetic amyotrophy
In patients with particularly severe amyotrophy, prednisolone, intravenous immunoglobulin (IVIG), and plasmapheresis have shown some promise in open-label, uncontrolled studies. These interventions were associated with a halt in disease progression and subsequent improvement in symptoms. However, since spontaneous gradual improvement also occurs in untreated patients, the true effectiveness of these therapies remains unproven.[226]Krendel DA, Costigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol. 1995 Nov;52(11):1053-61.
http://www.ncbi.nlm.nih.gov/pubmed/7487556?tool=bestpractice.com
[227]Krendel DA, Zacharias A, Younger DS. Autoimmune diabetic neuropathy. Neurol Clin. 1997 Nov;15(4):959-71.
http://www.ncbi.nlm.nih.gov/pubmed/9367975?tool=bestpractice.com
[228]Pascoe MK, Low PA, Windebank AJ, et al. Subacute diabetic proximal neuropathy. Mayo Clin Proc. 1997 Dec;72(12):1123-32.
http://www.ncbi.nlm.nih.gov/pubmed/9413291?tool=bestpractice.com
[229]Jaradeh SS, Prieto TE, Lobeck LJ. Progressive polyradiculoneuropathy in diabetes: correlation of variables and clinical outcome after immunotherapy. J Neurol Neurosurg Psychiatry. 1999 Nov;67(5):607-12.
https://pmc.ncbi.nlm.nih.gov/articles/PMC1736606
http://www.ncbi.nlm.nih.gov/pubmed/10519866?tool=bestpractice.com
Non-pharmacological interventions
One systematic review of physical therapies for managing balance dysfunction in patients with DPN provided a moderate recommendation in favour of lower extremity strengthening exercises.[230]Ites KI, Anderson EJ, Cahill ML, et al. Balance interventions for diabetic peripheral neuropathy: a systematic review. J Geriatr Phys Ther. 2011 Jul-Sep;34(3):109-16.
http://www.ncbi.nlm.nih.gov/pubmed/21937901?tool=bestpractice.com
In contrast, there was insufficient evidence to recommend other techniques, including monochromatic infrared energy therapy, vibrating insoles, and use of a walking stick.
Mirogabalin
Mirogabalin is a gabapentinoid approved for the treatment of peripheral neuropathic pain in Japan. In a phase 3 randomised controlled trial of Asian patients with type 1 or 2 diabetes and painful DPN, mirogabalin provided modest reductions in pain compared to placebo.[231]Baba M, Matsui N, Kuroha M, et al. Mirogabalin for the treatment of diabetic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase III study in Asian patients. J Diabetes Investig. 2019 Sep;10(5):1299-306.
https://onlinelibrary.wiley.com/doi/10.1111/jdi.13013
http://www.ncbi.nlm.nih.gov/pubmed/30672128?tool=bestpractice.com
The most common adverse events were nasopharyngitis, somnolence, and dizziness.[231]Baba M, Matsui N, Kuroha M, et al. Mirogabalin for the treatment of diabetic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase III study in Asian patients. J Diabetes Investig. 2019 Sep;10(5):1299-306.
https://onlinelibrary.wiley.com/doi/10.1111/jdi.13013
http://www.ncbi.nlm.nih.gov/pubmed/30672128?tool=bestpractice.com
Further studies are warranted in patients of non-Asian ethnicity.
Transdermal glyceryl trinitrate patch
While glyceryl trinitrate spray is included as an option in the American Academy of Neurology painful diabetic polyneuropathy guidelines, transdermal glyceryl trinitrate patches remain under clinical investigation for this indication.[63]Price R, Smith D, Franklin G, et al. Oral and topical treatment of painful diabetic polyneuropathy: practice guideline update summary. Report of the AAN Guideline Subcommittee. Neurology. 2022 Jan 4;98(1):31-43.
https://n.neurology.org/content/98/1/31
http://www.ncbi.nlm.nih.gov/pubmed/34965987?tool=bestpractice.com
In a small trial of 20 patients, those who applied a transdermal glyceryl trinitrate patch (worn for 12 to 14 hours) experienced greater reductions in pain than those randomised to a placebo patch.[232]Taheri A, Farbood A, Heshmat R, et al. The effect of transdermal nitroglycerin on pain control in diabetic patients with peripheral neuropathy. J Diabetes Metab Disord. 2015 Dec 1;14:86.
https://link.springer.com/article/10.1186/s40200-015-0217-3
http://www.ncbi.nlm.nih.gov/pubmed/26629480?tool=bestpractice.com
Another small study of 18 patients found that 44% experienced a reduction in pain following 24-hour wear of a transdermal glyceryl trinitrate patch.[233]Rayman G, Baker NR, Krishnan ST. Glyceryl trinitrate patches as an alternative to isosorbide dinitrate spray in the treatment of chronic painful diabetic neuropathy. Diabetes Care. 2003 Sep;26(9):2697-8.
https://diabetesjournals.org/care/article/26/9/2697/22574/Glyceryl-Trinitrate-Patches-as-an-Alternative-to
http://www.ncbi.nlm.nih.gov/pubmed/12941745?tool=bestpractice.com
Adverse events in both studies included headache and adhesion-site reactions.[232]Taheri A, Farbood A, Heshmat R, et al. The effect of transdermal nitroglycerin on pain control in diabetic patients with peripheral neuropathy. J Diabetes Metab Disord. 2015 Dec 1;14:86.
https://link.springer.com/article/10.1186/s40200-015-0217-3
http://www.ncbi.nlm.nih.gov/pubmed/26629480?tool=bestpractice.com
[233]Rayman G, Baker NR, Krishnan ST. Glyceryl trinitrate patches as an alternative to isosorbide dinitrate spray in the treatment of chronic painful diabetic neuropathy. Diabetes Care. 2003 Sep;26(9):2697-8.
https://diabetesjournals.org/care/article/26/9/2697/22574/Glyceryl-Trinitrate-Patches-as-an-Alternative-to
http://www.ncbi.nlm.nih.gov/pubmed/12941745?tool=bestpractice.com
Larger-scale trials are needed to confirm the efficacy and safety of transdermal glyceryl trinitrate patches in painful DN.