An integrated approach to pathogenetic-oriented pharmacotherapy of patients with diabetes mellitus and diabetic distal polyneuropathy

Diabetes mellitus remains a global medical and social problem due to its prevalence, presence of severe complications, and high disability and mortality rates among the population. One of the most common chronic complications of diabetes mellitus is the diabetic distal neuropathy, the main risk factors for the development of which are chronic hyperglycemia, arterial hypertension, obesity, smoking, age, and genetic predisposition of the patient. Diabetic distal neuropathy stems from a complex interaction of metabolic processes, immune system, and genetic predisposition, which result in morphological changes in the form of demyelination and thickening of axons, a decrease in the number of Schwann cells, as well as disruption of the structure of the Ranvier nodes. Sensory and motor disorders are manifested by a decrease in all types of sensitivity, weakening of reflexes. Asymptomatic course is observed in 50% of patients with diabetic distal neuropathy. Ideal methods for early diagnosis and therapy of patients with diabetic distal neuropathy do not exist. Controversial issues of diabetic distal neuropathy treatment mainly concern the use of В vitamins and alpha-lipoic acid preparations. Some studies of the alpha-lipoic acid have determined its anti-inflammatory, antioxidant properties, as well as its possible effect on carbohydrate metabolism in patients with diabetic distal neuropathy. B vitamins have long been used as an additional therapy for patients with diabetic distal neuropathy. Clinical experience in treating patients with diabetic distal neuropathy shows that the best result is achieved by using a combination of alpha-lipoic acid and B1, B6, B12 vitamins which is due to their synergistic effect. This review examines the issues of complex pathogenetic therapy of diabetic distal neuropathy in patients with diabetes mellitus.

1. Khramilin V, Demidova I, Ignatova O, Zenovko M. Prevalence of diabetic polyneuropathy in new-onset type 2 diabetes mellitus. Vrach. 2009;(5):40–43. (In Russ.) Available at: https://elibrary.ru/klsaaz.

2. Trukhan DI, Druk IV. Effectiveness of use of group B vitamins in patients with diabetic polyneuropathy: A review. Consilium Medicum. 2024;26(4):269–275. (In Russ.) https://doi.org/10.26442/20751753.2024.4.202756.

3. Strokov IA, Melnichenko GA, Albekova ZhS, Zilov AV, Akhmedzhanova LT. The prevalence and risk factors of diabetic polyneuropathy in inpatients with type 1 diabetes. Nervno-Myshechnye Bolezni. 2012;(1):25–32. (In Russ.) Available at: https://nmb.abvpress.ru/jour/article/view/71.

4. Ziegler D, Papanas N, Schnell O, Nguyen BDT, Nguyen KT, Kulkantrakorn K, Deerochanawong C. Current concepts in the management of diabetic polyneuropathy. J Diabetes Investig, 2022;12(4):464–475. https://doi.org/10.1111/jdi.13401.

5. Sementina A, Cierzniakowski M, Rogalska J, Piechowiak I, SpichalskiM, Araszkiewicz A. A novel approach to alpha-lipoic acid therapy in the treatment of diabetic peripheral neuropathy. J Med Sci. 2022;91(3):e714. https://doi.org/10.20883/medical.e714.

6. Fleming T, Nawroth PP. Reactive metabolites as a cause of late diabetic complications. Biochem Soc Trans. 2014;42(2):439–442. https://doi.org/10.1042/BST20130265.

7. Kim KM, Kim YS, Jung DH, Lee J, Kim JS. Increased glyoxalase I levels inhibit accumulation of oxidative stress and an advanced glycation end product in mouse mesangial cells cultured in high glucose. Exp Cell Res. 2012;318(2):152–159. https://doi.org/10.1016/j.yexcr.2011.10.013.

8. Bönhof GJ, Herder C, Strom A, Papanas N, Roden M, Ziegler D. Emerging biomarkers, tools, and treatments for diabetic polyneuropathy. Endocr Rev. 2019;40(1):153–192. https://doi.org/10.1210/er.2018-00107.

9. Pop-Busui R, Ang L, Holmes C, Gallagher K, Feldman EL. Inflammation as a Therapeutic Target for Diabetic Neuropathies. Curr Diab Rep. 2016;16(3):29. https://doi.org/10.1007/s11892-016-0727-5.

10. Zhao Y, Zhu R, Wang D, Liu X. Genetics of diabetic neuropathy: Systematic review, meta‐analysis and trial sequential analysis. Ann Clin Transl Neurol. 2019;6(10):1996–2013. https://doi.org/10.1002/acn3.50892.

11. Capece U, Moffa S, Improta I, Di Giuseppe G, Nista EC, Cefalo CMA et al. Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features. Nutrients. 2021;15(1):18. https://doi.org/10.3390/nu15010018.

12. Mousavi SM, Shab-Bidar S, Kord-Varkaneh H, Khorshidi M, Djafarian K. Effect of alpha-lipoic acid supplementation on lipid profile: A systematic review and meta-analysis of controlled clinical trials. Nutrition. 2019;59:121–130. https://doi.org/10.1016/j.nut.2018.08.004.

13. Haghighatdoost F, Hariri M. The effect of alpha-lipoic acid on inflammatory mediators: a systematic review and meta-analysis on randomized clinical trials. Eur J Pharmacol. 2019;849:115–123. https://doi.org/10.1016/j.ejphar.2019.01.065.

14. Akbari M, Ostadmohammadi V, Tabrizi R, Mobini M, Lankarani KB, Moosazadeh M et al. The effects of alpha-lipoic acid supplementation on inflammatory markers among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of rand-omized controlled trials. Nutr Metab. 2018;15:39. https://doi.org/10.1186/s12986-018-0274-y.

15. Okanović A, Prnjavorac B, Jusufović E, Sejdinović R. Alpha-lipoic acid reduces body weight and regulates triglycerides in obese patients with diabetes mellitus. Med Glas. 2015;12(2):122–127. https://doi.org/10.17392/798-15.

16. Ebada MA, Fayed N, Fayed L, Alkanj S, Abdelkarim A, Farwati H et al. Efficacy of Alpha-lipoic Acid in The Management of Diabetes Mellitus: A Systematic Review and Meta-analysis. Iran J Pharm Res. 2019;18(4):2144–2156. https://doi.org/10.22037/ijpr.2019.1100842.

17. Ziegler D, Gries FA. α-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes. 1997:46(Suppl. 2):S62–S66. https://doi.org/10.2337/diab.46.2.s62.

18. Superti F, Russo R. Alpha-Lipoic Acid: Biological Mechanisms and Health Benefits. Antioxidants. 2024;13(10):1228. https://doi.org/10.3390/antiox13101228.

19. Strokov IA, Fokina AS, Golovacheva VA. Alpha-lipoic acid in the treatment of diabetic polyneuropathy. Effective Pharmacotherapy. Endocrinology. 2013;(1 Suppl.):50–54. (In Russ.) Available at: https://umedp.ru/articles/alfalipoevaya_kislota_v_lechenii_diabeticheskoy_polineyropatii.html.

20. Nguyen N, Takemoto JK. A Case for Alpha-Lipoic Acid as an Alternative Treatment for Diabetic Polyneuropathy. J Pharm Pharm Sci. 2018;21(1s):177s–191s. https://doi.org/10.18433/jpps30100.

21. Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schütte K, Gries FA. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995;38(12):1425–1433. https://doi.org/10.1007/BF00400603.

22. Ametov A, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ et al. SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003;26(3):770–776. https://doi.org/10.2337/diacare.26.3.770.

23. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365–2370. https://doi.org/10.2337/dc06-1216.

24. Ruhnau KJ, Meissner HP, Finn JR, Reljanovic M, Lobisch M, Schütte K et al. Effects of 3-week oral treatment with the antioxidant thioctic acid (alphalipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med. 1999;16(12):1040–1043. https://doi.org/10.1046/j.14645491.1999.00190.x.

25. Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schutte K 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;22(8):1296–1301. https://doi.org/10.2337/diacare.22.8.1296.

26. Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant α-lipoic acid: a metaanalysis. Diabet Med. 2004;21(2):114–121. https://doi.org/10.1111/j.1464-5491.2004.01109.x.

27. Ziegler D, Low PA, Litchy WJ, Boulton AJ, Vinik AI, Freeman R, Samigullin R et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34(9):2054–2060. https://doi.org/10.2337/dc11-0503.

28. Abubaker SA, Alonazy AM, Abdulrahman A. Effect of Alpha-Lipoic Acid in the Treatment of Diabetic Neuropathy: A Systematic Review. Cureus. 2022;14(6):e25750. https://doi.org/10.7759/cureus.25750.

29. Hsieh RY, Huang IC, Chen C, Sung JY. Effects of Oral Alpha-Lipoic Acid Treatment on Diabetic Polyneuropathy: A Meta-Analysis and Systematic Review. Nutrients. 2023;15(16):3634. https://doi.org/10.3390/nu15163634.

30. Tavares Bello TC, Capitão RM, Sequeira Duarte J, Azinheira J, Vasconcelos C. Vitamin B12 Deficiency in Type 2 Diabetes Mellitus. Acta Med Port. 2017;30(10):719–726. https://doi.org/10.20344/amp.8860.

31. Pflipsen MC, Oh RC, Saguil A, Seehusen DA, Seaquist D, Topolski R. The prevalence of vitamin B(12) deficiency in patients with type 2 diabetes: a cross-sectional study. J Am Board Fam Med. 2009;22(5):528–534. https://doi.org/10.3122/jabfm.2009.05.090044.

32. Kril JJ. Neuropathology of thiamine deficiency disorders. Metab Brain Dis. 1996;11(1):9–17. https://doi.org/10.1007/BF02080928.

33. Scalabrino G. The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: lessons learned from its deficiency. Prog Neurobiol. 2009;88(3):203–220. https://doi.org/10.1016/j.pneurobio.2009.04.004.

34. Cvijanović M, Simić S, Kopitović A, Raičević R. Neurophysiological evaluation of short-term outcome of pharmacological treatment of diabetic neuropathy. Vojnosanit Pregl. 2017;74(8):723–727. https://doi.org/10.2298/VSP151209261C.

35. Stirban A, Pop A, Tschoepe D. A randomized, doubleblind, crossover, placebo-controlled trial of 6 weeks benfotiamine treatment on postprandial vascular function and variables of autonomic nerve function in Type 2 diabetes. Diabet Med. 2013;30(10):1204–1208. https://doi.org/10.1111/dme.12240.

36. Karaganis S, Song XJ. B vitamins as a treatment for diabetic pain and neuropathy. J Clin Pharm Ther. 2021;46(5):1199–1212. https://doi.org/10.1111/jcpt.13375.

37. Khattab R, Albannawi M, Alhajjmohammed D, Alkubaish Z, Althani R, Altheeb L et al. Metformin-Induced Vitamin B12 Deficiency among Type 2 Diabetes Mellitus’ Patients: A Systematic Review. Curr Diabetes Rev. 2023;19(4):e180422203716. https://doi.org/10.2174/1573399818666220418080959.

38. Hagopian W, Lee HS, Liu E, Rewers M, She JX, Ziegler AG et al. Cooccurrence of Type 1 Diabetes and Celiac Disease Autoimmunity. Pediatrics. 2017;140(5):e20171305. https://doi.org/10.1542/peds.2017-1305.

39. Mrozikiewicz-Rakowska B, Chylińska A, Sieńko D, Czupryniak L. Vitamin B12 in diabetes – a new treatment paradigm? Clin Diabetol. 2020;9(6):489–496. https://doi.org/10.5603/DK.2020.0060.

40. Buesing S, Costa M, Schilling JM, Moeller-Bertram T. Vitamin B12 as a Treatment for Pain. Pain Physician. 2019;22(1):E45–E52. https://doi.org/10.36076/ppj/2019.22.E45.

41. Li S, Chen X, Li Q, Du J, Liu Z, Peng Y et al. Effects of acetyl-L-carnitine and methylcobalamin for diabetic peripheral neuropathy: A multicenter, randomized, double-blind, controlled trial. J Diabetes Investig. 2016;7(5):777–785. https://doi.org/10.1111/jdi.12493.

42. Calderón-Ospina CA, Nava-Mesa MO. B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin. CNS Neurosci Ther. 2020;26(1):5–13. https://doi.org/10.1111/cns.13207.

43. Cuyubamba O, Braga CP, Swift D, Stickney JT, Viel C. The Combination of Neurotropic Vitamins B1, B6, and B12 Enhances Neural Cell Maturation and Connectivity Superior to Single B Vitamins. Cells. 2025;14(7):477. https://doi.org/10.3390/cells14070477

44. Simeonov S, Pavlova M, Mitkov M, Mincheva L, Troev D. Therapeutic efficacy of “Milgamma” in patients with painful diabetic neuropathy. Folia Med. 1997;39(4):5–10. Available at: https://pubmed.ncbi.nlm.nih.gov/9575643/.

45. Winkler G, Pál B, Nagybéganyi E, Ory I, Porochnavec M, Kempler P. Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Arzneimittelforschung. 1999;49(3):220–224. https://doi.org/10.1055/s-0031-1300405.

46. Abbas ZG, Swai AB. Evaluation of the efficacy of thiamine and pyridoxine in the treatment of symptomatic diabetic peripheral neuropathy. East Afr Medj. 1997;74(12):803–808. Available at: https://pubmed.ncbi.nlm.nih.gov/9557427/.

47. Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104(4):311–316. https://doi.org/10.1055/s-0029-1211460.

48. Fonseca VA, Lavery LA, Thethi TK, Daoud Y, DeSouza C, Ovalle F et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med. 2013;126(2):141–149. https://doi.org/10.1016/j.amjmed.2012.06.022.

49. Dubinina II, Berstneva SV, Baranov VV, Azimkova LV. Efficacy of combined therapy of diabetic distal neuropathy in patients with type 2 diabetes mellitus. Diabetes Mellitus. 2016;19(4):315–321. (In Russ.) https://doi.org/10.14341/DM7637.

50. Popa AR, Bungau S, Vesa CM, Bondar AC, Pantis C, Maghiar O et al. Evaluating the Efficacy of the Treatment with Benfotiamine and Alphalipoic Acid in Distal Symmetric Painful Diabetic Polyneuropathy. Rev Chim. 2019;70(9):3108–3114. https://doi.org/10.37358/RC.19.9.7498.

51. Rotaru A, Albu CV, Tudorascu DR, Catalin B, Gheonea M, Udristoiu I, Iancau M. Thioctic Acid and Vitamin B Complex Improves Clinical Sings in Diabetic Peripheral Neuropathy. Rev Chim. 2019;70(10):3614–3617. https://doi.org/10.37358/RC.19.10.7607.

52. Rotaru A, TÂrtea GC, IancĂu M. The Neuroprotective Role of Alpha Thioctic Acid and Vitamin B Complex in Diabetic Neuropathy – an Experimental Study. Curr Health Scij. 2020;46(2):150–155. https://doi.org/10.12865/CHSJ.46.02.08.