Using corneal confocal microscopy to compare Mecobalamin intramuscular injections vs oral tablets in treating diabetic peripheral neuropathy: a RCT

Yuanjin Zhang, Dongsheng Fan, Yixuan Zhang, Shuo Zhang, Haikun Wang, Ziyuan Liu, Hongli Wang, Yuanjin Zhang, Dongsheng Fan, Yixuan Zhang, Shuo Zhang, Haikun Wang, Ziyuan Liu, Hongli Wang

Abstract

This randomized controlled study used corneal confocal microscopy (CCM) to compare the efficacy of Mecobalamin intramuscular injections vs oral tablets in treating mild to moderate diabetic peripheral neuropathy (DPN) by detecting early nerve fiber repair. Enrolled patients were randomized approximately 1:1 to receive Mecobalamin intramuscular injections (0.5 mg/day, 3 times/week) or Mecobalamin oral tablets (1.5 mg/day) for 8 weeks. Primary outcome was change of inferior whorl length (IWL) from baseline. Secondary outcomes included changes of corneal nerve fibre length (CNFL), corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and the Survey of Autonomic Symptoms (SAS). 15 (93.75%) patients in the injection group and 17 (89.47%) patients in the tablet group completed the study. The injection treatment significantly improved patients' IWL from baseline (21.64 ± 3.00 mm/mm2 vs 17.64 ± 4.83 mm/mm2, P < 0.01) while the tablet treatment didn't. Additionally, the injection treatment led to significantly improved CNFL, CNBD and SAS from baseline (all P < 0.05) while the tablet treatment did not. No patient experienced any adverse events. In conclusion, CCM is sensitive enough to detect the superior efficacy of 8-week Mecobalamin intramuscular injection treatment for DPN compared to the oral tablet treatment.ClinicalTrials.gov registration number: NCT04372316 (30/04/2020).

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s).

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Corneal confocal microscopic images of morphological changes of the inferior whorl (IW) nerve complex pattern and the conventional sub-basal nerve plexus pattern around the central cornea after Mecobalamin treatment. (a,b) The IW nerve complex patterns before (a) and after (b) Mecobalamin intramuscular injection treatment. (c,d) The IW nerve complex conventional sub-basal nerve plexus pattern around the central cornea patterns before (c) and after (d) oral Mecobalamin tablet treatment. (e,f) The conventional sub-basal nerve plexus pattern around the central cornea patterns before (e) and after (f) Mecobalamin intramuscular injection treatment. (g,h) The conventional sub-basal nerve plexus pattern around the central cornea patterns before (g) and after (h) oral Mecobalamin tablet treatment.

References

    1. Selvarajah D, et al. Diabetic peripheral neuropathy: Advances in diagnosis and strategies for screening and early intervention. Lancet Diab. Endocrinol. 2019;7:938–948. doi: 10.1016/S2213-8587(19)30081-6.
    1. Malik RA. Pathology of human diabetic neuropathy. Handb. Clin. Neurol. 2014;126:249–259. doi: 10.1016/B978-0-444-53480-4.00016-3.
    1. Singh R, Kishore L, Kaur N. Diabetic peripheral neuropathy: current perspective and future directions. Pharmacol. Res. 2014;80:21–35. doi: 10.1016/j.phrs.2013.12.005.
    1. Yao H, et al. Comparison of the effects of prophylactic and therapeutic administrations on peripheral neuropathy in streptozotocin-diabetic rats with gliclazide or methylcobalamin. Exp. Clin. Endocrinol. Diabetes. 2020;128:635–643. doi: 10.1055/a-0635-0672.
    1. Malik RA. Diabetic neuropathy: A focus on small fibres. Diabetes Metab. Res. Rev. 2020;36:3255. doi: 10.1002/dmrr.3255.
    1. Jacobs AM, Cheng D. Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate. Rev. Neurol. Dis. 2011;8:39–47.
    1. Tavakoli M, et al. Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation. Diabetes. 2013;62:254–260. doi: 10.2337/db12-0574.
    1. Wang, M. et al. Diagnostic utility of corneal confocal microscopy in type 2 diabetic peripheral neuropathy [published online ahead of print, 2020 Aug 3]. J. Diabetes Investig. 2020;10.1111/jdi.13381. doi:10.1111/jdi.13381.
    1. Hossain P, Sachdev A, Malik RA. Early detection of diabetic peripheral neuropathy with corneal confocal microscopy. Lancet. 2005;366:1340–1343. doi: 10.1016/S0140-6736(05)67546-0.
    1. Yan A, et al. Relationship between corneal confocal microscopy and markers of peripheral nerve structure and function in Type 2 diabetes. Diabet. Med. 2020;37:326–334. doi: 10.1111/dme.13952.
    1. Tavakoli M, et al. Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet. Med. 2011;28:1261–1267. doi: 10.1111/j.1464-5491.2011.03372.x.
    1. Mehra S, et al. Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care. 2007;30:2608–2612. doi: 10.2337/dc07-0870.
    1. Brines M, et al. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol. Med. 2015;20:658–666. doi: 10.2119/molmed.2014.00215.
    1. Azmi S, et al. Corneal confocal microscopy shows an improvement in small-fiber neuropathy in subjects with type 1 diabetes on continuous subcutaneous insulin infusion compared with multiple daily injection. Diab. Care. 2015;38:e3–e4. doi: 10.2337/dc14-1698.
    1. Lewis EJH, et al. Effect of omega-3 supplementation on neuropathy in type 1 diabetes: A 12-month pilot trial. Neurology. 2017;88:2294–2301. doi: 10.1212/WNL.0000000000004033.
    1. Azmi S, et al. Early nerve fibre regeneration in individuals with type 1 diabetes after simultaneous pancreas and kidney transplantation. Diabetologia. 2019;62:1478–1487. doi: 10.1007/s00125-019-4897-y.
    1. Culver DA, et al. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest. Ophthalmol. Vis. Sci. 2017;58:52–60. doi: 10.1167/iovs.16-21291.
    1. Azmi S, et al. Bariatric surgery leads to an improvement in small nerve fibre damage in subjects with obesity. Int. J. Obes. (Lond). 2021;45:631–638. doi: 10.1038/s41366-020-00727-9.
    1. Adam S, et al. Improvements in Diabetic Neuropathy and Nephropathy After Bariatric Surgery: a Prospective Cohort Study. Obes. Surg. 2021;31:554–563. doi: 10.1007/s11695-020-05052-8.
    1. Ponirakis, G. et al. Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar Study. BMJ Open Diab. Res. Care8, e001420 (2020).
    1. Ishibashi F, Taniguchi M, Kosaka A, Uetake H, Tavakoli M. Improvement in neuropathy outcomes with normalizing HbA1c in patients with type 2 diabetes. Diab. Care. 2019;42:110–118. doi: 10.2337/dc18-1560.
    1. Jia X, et al. In vivo corneal confocal microscopy detects improvement of corneal nerve parameters following glycemic control in patients with type 2 diabetes. J. Diab. Res. 2018;2018:8516276.
    1. Petropoulos, IN. et al. Corneal confocal microscopy: A biomarker for diabetic peripheral neuropathy. Clin Ther.S0149–2918(21), 00197–1 (2021).
    1. Sawangjit R, Thongphui S, Chaichompu W, Phumart P. Efficacy and safety of mecobalamin on peripheral neuropathy: A systematic review and meta-analysis of randomized controlled trials. J. Altern. Complement. Med. 2020;26:1117–1129. doi: 10.1089/acm.2020.0068.
    1. Xu Q, et al. Meta-analysis of methylcobalamin alone and in combination with lipoic acid in patients with diabetic peripheral neuropathy. Diabetes Res. Clin. Pract. 2013;101:99–105. doi: 10.1016/j.diabres.2013.03.033.
    1. Jiang, D. Q. et al. Prostaglandin E1 plus methylcobalamin combination therapy versus prostaglandin E1 monotherapy for patients with diabetic peripheral neuropathy: A meta-analysis of randomized controlled trials. Medicine (Baltimore)97, e13020 (2018).
    1. Deng H, et al. Meta-analysis of methylcobalamin alone and in combination with prostaglandin E1 in the treatment of diabetic peripheral neuropathy. Endocrine. 2014;46:445–454. doi: 10.1007/s12020-014-0181-6.
    1. Consensus on diagnosis and treatment of diabetic peripheral neuropathy. Chin. J. Neurol. 46,787–789 (2013).
    1. Tesfaye, S. et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments [published correction appears in Diabetes Care. 2010 Dec;33(12):2725]. Diabetes Care33, 2285–2293 (2010).
    1. Petropoulos IN, et al. The Inferior Whorl For Detecting Diabetic Peripheral Neuropathy Using Corneal Confocal Microscopy. Invest. Ophthalmol. Vis. Sci. 2015;56:2498–2504. doi: 10.1167/iovs.14-15919.
    1. Kalteniece A, et al. Greater corneal nerve loss at the inferior whorl is related to the presence of diabetic neuropathy and painful diabetic neuropathy. Sci. Rep. 2018;8:3283. doi: 10.1038/s41598-018-21643-z.
    1. Tavakoli M, Malik RA. Corneal confocal microscopy: a novel non-invasive technique to quantify small fibre pathology in peripheral neuropathies. J. Vis. Exp. 2011;47:2194.
    1. Abraham A, et al. Toronto Clinical Neuropathy Score is valid for a wide spectrum of polyneuropathies. Eur. J. Neurol. 2018;25:484–490. doi: 10.1111/ene.13533.
    1. Bril V, Perkins BA. Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy. Diabetes Care. 2002;25:2048–2052. doi: 10.2337/diacare.25.11.2048.
    1. Peng, H. Y & Gong, Y. Y. Analysis of the effect of probucol-mecobalamin tablets combination on oxidative stress in patients with diabetic peripheral neuropathy. Neurosci. Lett.741, 135484 (2021).
    1. Zilliox L, et al. Assessing autonomic dysfunction in early diabetic neuropathy: The Survey of Autonomic Symptoms. Neurology. 2011;76:1099–1105. doi: 10.1212/WNL.0b013e3182120147.
    1. Smith AG, et al. Lifestyle intervention for prediabetic neuropathy. Diab. Care. 2006;29:1294–1299. doi: 10.2337/dc06-0224.
    1. Asghar O, et al. Corneal confocal microscopy detects neuropathy in subjects with impaired glucose tolerance. Diabetes Care. 2014;37:2643–2646. doi: 10.2337/dc14-0279.
    1. Wang, Y. J., Feng, S. M, Xin, R. D & Shi, Y. P. Methycobalamine: pharmacology and clinical applications. Shandong J Pharmaceuticals22, 21–24 (2002) (Article in Chinese).
    1. Jiang YQ, Liu GL, Wang QY, Wang YZ. The efficacy of mecobalamin in the treatment of diabetic peripheral neuropathy. Med. J. Liaoning. 1998;12:100–101.
    1. Han Y, et al. Differential efficacy of methylcobalamin and alpha-lipoic acid treatment on symptoms of diabetic peripheral neuropathy. Minerva Endocrinol. 2018;43:11–18. doi: 10.23736/S0391-1977.16.02505-0.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel