Exploration of Neuroprotective Therapy

Table 3. GRADE evidence profile: ALA compared to placebo/control.

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	ALA	Control	Relative (95% CI)	Absolute	Quality	Importance
HbA1C (follow-up 3 weeks to 48 months; better indicated by lower values)
4	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	No serious imprecision	Strong association²	377	364	-	SMD 0.66 lower (0.81 to 0.51 lower)	High	Critical
Neuropathy impairment score (NIS) (follow-up 5 weeks to 48 months; better indicated by lower values)
2	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	No serious imprecision	Strong association³	276	267	-	MD 1.19 lower (2.28 to 0.1 lower)	High	Important
Neuropathy impairment score-lower limbs (NIS-LL) (follow-up 5 weeks to 48 months; better indicated by lower values)
2	Randomised trials	Serious⁴	No serious inconsistency	No serious indirectness	No serious imprecision	None	275	267	-	MD 0.58 lower (1.35 lower to 0.19 higher)	Moderate	Important
Motor nerve conduction velocity (MNCV) (follow-up 4 weeks to 48 months; better indicated by lower values)
4	Randomised trials	Serious⁵	No serious inconsistency	No serious indirectness	No serious imprecision	None	318	303	-	MD 0.26 higher (0.44 lower to 0.96 higher)	Moderate	Important
Neuropathy symptoms and change (NSC) number (follow-up 4 weeks to 48 months; better indicated by lower values)
2	Randomised trials	Serious	No serious inconsistency	No serious indirectness	No serious imprecision	None	276	267	-	SMD 0.18 lower (0.35 to 0.01 lower)	Moderate	Critical
Neuropathy symptoms and change (NSC) severity (follow-up 4 weeks to 48 months; better indicated by lower values)
2	Randomised trials	Serious⁴	No serious inconsistency	No serious indirectness	No serious imprecision	None	276	267	-	SMD 0.65 lower (0.83 to 0.48 lower)	Moderate	Critical
Total severity score (TSS) (follow-up 3 weeks to 48 months; better indicated by lower values)
4	Randomised trials	Serious¹	No serious inconsistency	No serious indirectness	No serious imprecision	Very strong association²	343	334	-	SMD 0.43 lower (0.59 to 0.27 lower)	High	Critical
Neurological disability score (NDS) (follow-up 3 weeks to 6 months; better indicated by lower values)
2	Randomised trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	112	112	-	MD 0.72 lower (1.03 to 0.4 lower)	High	Critical
Visual perception threshold (VPT) (follow-up 6 months to 48 months; better indicated by lower values)
2	Randomised trials	Serious⁴	No serious inconsistency	No serious indirectness	No serious imprecision	Strong association²	324	330	-	SMD 0.35 lower (0.5 to 0.19 lower)	High	Critical
Global satisfaction (follow-up mean 5 weeks)
2	Randomised trials	Serious⁴	No serious inconsistency	No serious indirectness	No serious imprecision	None	57/102 (55.9%)	24/86 (27.9%)	OR 3.51 (1.06 to 11.61)	297 more per 1,000 (from 12 more to 539 more)	Moderate	Critical

Return to article view

GRADE Working Group grades of evidence: high quality: further research is very unlikely to change our confidence in the estimate of effect; moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. 1: Two of the included studies have a high risk of bias; 2: the outcomes are highly significant and large; 3: the outcomes are significant and large; 4: one of the included studies has a high risk of bias; 5: three included studies have a high risk of bias. ALA: alpha lipoic acid; CI: confidence interval; HbA1C: glycated hemoglobin; OR: odds ratio; MD: mean difference; SMD: standardized MD.

Declarations

Author contributions

SD: Investigation, Data curation, Formal analysis, Writing—original draft. GLV: Conceptualization, Methodology, Formal analysis, Writing—review & editing. KN: Supervision; Writing—review & editing. AK: Supervision, Writing—review & editing. SH: Investigation, Formal analysis, Writing—original draft. All authors have read and approved the submitted version.

Conflicts of interest

Authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Bansal V, Kalita J, Misra UK. Diabetic neuropathy. Postgrad Med J. 2006;82:95–100. [DOI]

Kamalarathnam SR, Varadarajan S. Diabetic peripheral neuropathy in diabetic patients attending an urban health and training centre. J Fam Med Prim Care. 2022;11:113–7. [DOI]

Jasmine A, Akila GV, Durai V, Anitha Rani M, Shriraam V, Samya V, et al. Correction to: Prevalence of peripheral neuropathy among type 2 diabetes mellitus patients in a rural health centre in South India. Int J Diabetes Dev Ctries. 2021;41:301. [DOI]

Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2163–96. [DOI]

Vinik AI, Nevoret M, Casellini C, Parson H. Diabetic Neuropathy. Endocrinol Metab Clin N Am. 2013;42:747–87. [DOI]

Yang K, Wang Y, Li Y, Chen Y, Xing N, Lin H, et al. Progress in the treatment of diabetic peripheral neuropathy. Biomed Pharmacother. 2022;148:112717. [DOI]

Khdour MR. Treatment of diabetic peripheral neuropathy: a review. J Pharm Pharmacol. 2020;72:863–72. [DOI]

Zakin E, Abrams R, Simpson DM. Diabetic Neuropathy. Semin Neurol. 2019;39:560–9.

Hsieh R, Huang I, Chen C, Sung J. Effects of Oral Alpha-Lipoic Acid Treatment on Diabetic Polyneuropathy: A Meta-Analysis and Systematic Review. Nutrients. 2023;15:3634. [DOI]

10.

Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003;26:770–6. [DOI]

11.

Garcia-Alcala H, Santos Vichido CI, Islas Macedo S, Genestier-Tamborero CN, Minutti-Palacios M, Hirales Tamez O, et al. Treatment with α-Lipoic Acid over 16 Weeks in Type 2 Diabetic Patients with Symptomatic Polyneuropathy Who Responded to Initial 4-Week High-Dose Loading. J Diabetes Res. 2015;2015:1–8. [DOI]

12.

Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Möller W, et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (α-lipoic acid): A two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Free Radic Res. 1999;31:171–9. [DOI]

13.

Baicus C, Purcarea A, Von Elm E, Delcea C, Furtunescu FL. Alpha-lipoic acid for diabetic peripheral neuropathy. Cochrane Database Syst Rev. 2024. [DOI]

14.

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al.; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–6. [DOI] [PubMed] [PMC]

15.

Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64:401–6. [DOI]

16.

Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach [Internet]. [cited 2025 Jan 10]. Available from: https://gdt.gradepro.org/app/handbook/handbook.html

17.

Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schütte 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;22:1296–301. [DOI]

18.

Vijayakumar APR, Kalshetti SM, Bhatt JK. Supplementation of A-Lipoic acid in diabetic peripheral neuropathy: A prospective open label randomized controlled trial. Int J Pharm Pharm Sci. 2014;6:90–93.

19.

Hemoglobin A1C [Internet]. StatPearls; [cited 2025 Jan 10]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549816/

20.

Yarlas A, Lovley A, Brown D, Vera-Llonch M, Khella S, Karam C. The impact of inotersen on Neuropathy Impairment Score in patients with hereditary transthyretin amyloidosis with polyneuropathy. BMC Neurol. 2023;23:108. [DOI] [PubMed] [PMC]

21.

Nerve conduction velocity: Side effects and normal values [Internet]. London: Healthline Media; c2025 [cited 2025 Jan 10]. Available from: https://www.medicalnewstoday.com/articles/321721

22.

Dyck PJB, Coelho T, Waddington Cruz M, Brannagan III TH, Khella S, Karam C, et al. Neuropathy symptom and change: Inotersen treatment of hereditary transthyretin amyloidosis. Muscle Nerve. 2020;62:509–15. [DOI]

23.

Bastyr EJ, Price KL, Bril V. Development and validity testing of the neuropathy total symptom score-6: Questionnaire for the study of sensory symptoms of diabetic peripheral neuropathy. Clin Ther. 2005;27:1278–94. [DOI]

24.

Abdelalim A, Afifi L, Ashour A, Al-Athwari A. Correlation between clinical neuropathy scores and nerve conduction studies in patients with diabetic peripheral neuropathy. Egypt J Neurol Psychiatry Neurosurg. 2016;53:248. [DOI]

25.

Jung J, Kim MG, Kang YJ, Min K, Han KA, Choi H. Vibration Perception Threshold and Related Factors for Balance Assessment in Patients with Type 2 Diabetes Mellitus. Int J Environ Res Public Health. 2021;18:6046. [DOI]

26.

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;29:2365–70. [DOI]

27.

Tang J, Wingerchuk DM, Crum BA, Rubin DI, Demaerschalk BM. Alpha-lipoic acid may improve symptomatic diabetic polyneuropathy. Neurologist. 2007;13:164–7. [DOI] [PubMed]

28.

Siddique N, Awais F, Shakil M, Sarwar S, Kakar NH, Ullah MI. Effect of anti-oxidant (α-lipoic acid) treatment on the improvement of diabetic neuropathic pain. RMJ. 2021;46:33–6.

29.

Ziegler D, Low PA, Litchy WJ, Boulton AJ, Vinik AI, Freeman 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;34:2054–60. [DOI] [PubMed] [PMC]

30.

El-Nahas MR, Elkannishy G, Abdelhafez H, Elkhamisy ET, El-Sehrawy AA. Oral Alpha Lipoic Acid Treatment for Symptomatic Diabetic Peripheral Neuropathy: A Randomized Double-Blinded Placebo-Controlled Study. EMIDDT. 2020;20:1531–4. [DOI]

31.

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 (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med. 1999;16:1040–3. [DOI]

32.

Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic Acid and diabetic neuropathy. Rev Diabet Stud. 2009;6:230–6. [DOI] [PubMed] [PMC]

33.

Rani PU, Padmaja M, Sireesha K, Sravansandhya P. Alpha lipoic acid a boon for diabetic peripheral neuropathy: A systematic review and meta-analysis. Biomed Res. 2023;34:1–8.

34.

Casadei G, Filippini M, Brognara L. Glycated Hemoglobin (HbA1c) as a Biomarker for Diabetic Foot Peripheral Neuropathy. Diseases. 2021;9:16. [DOI]

35.

Nozawa K, Ikeda M, Kikuchi S. Association Between HbA1c Levels and Diabetic Peripheral Neuropathy: A Case–Control Study of Patients with Type 2 Diabetes Using Claims Data. Drugs - Real World Outcomes. 2022;9:403–14. [DOI]

36.

Elbadawy AM, Abd Elmoniem RO, Elsayed AM. Alpha lipoic acid and diabetes mellitus: potential effects on peripheral neuropathy and different metabolic parameters. Alex J Med. 2021;57:113–20. [DOI]

37.

Millan-Guerrero RO, Garcia-Ramirez AL, Trujillo-Hernandez B, Caballero-Hoyos R, Gonzalez-Perez O, Isais-Millan S, et al. Efficacy of α-lipoic acid in the treatment of diabetic polyneuropathy. A Randomized, Double–Blind Study. Glob Adv Res J Med Med Sci. 2018;7:214–20.

38.

Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N, Bilo HJG. Alpha Lipoic Acid for Symptomatic Peripheral Neuropathy in Patients with Diabetes: A Meta-Analysis of Randomized Controlled Trials. Int J Endocrinol. 2012;2012:1–8. [DOI]

39.

Lv SL, Fang C, Hu J, Huang Y, Yang B, Zou R, et al. Assessment of Peripheral Neuropathy Using Measurement of the Current Perception Threshold with the Neurometer® in patients with type 1 diabetes mellitus. Diabetes Res Clin Pract. 2015;109:130–4. [DOI] [PubMed]

40.

Medakkel AA, Sheela P. Vibration Perception Threshold Values and Clinical Symptoms of Diabetic Peripheral Neuropathy. J Clin Diagn Res. 2018;12:LC20–3. [DOI]

41.

Lekhanya PK, Mokgalaboni K. Exploring the effectiveness of vitamin B₁₂complex and alpha-lipoic acid as a treatment for diabetes mellitus/neuropathy: a protocol for systematic review and meta-analysis of randomised controlled trials. BMJ Open. 2022;12:e065630. [DOI]

42.

Naik M, Vasudevan D, Mukaddam Q. Efficacy and safety of methylcobalamin, alpha lipoic acid and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes associated impaired peripheral neuropathic condition. [MAINTAIN]: Results of a pilot study. Ann Indian Acad Neurol. 2014;17:19–24. [DOI]

43.

Didangelos T, Karlafti E, Kotzakioulafi E, Kontoninas Z, Margaritidis C, Giannoulaki P, et al. Efficacy and Safety of the Combination of Superoxide Dismutase, Alpha Lipoic Acid, Vitamin B12, and Carnitine for 12 Months in Patients with Diabetic Neuropathy. Nutrients. 2020;12:3254. [DOI]

44.

Wang X, Lin H, Xu S, Jin Y, Zhang R. Alpha lipoic acid combined with epalrestat: a therapeutic option for patients with diabetic peripheral neuropathy. DDDT. 2018;12:2827–40. [DOI]

45.

Zhao M, Chen JY, Chu YD, Zhu YB, Luo L, Bu SZ. Efficacy of epalrestat plus α-lipoic acid combination therapy versus monotherapy in patients with diabetic peripheral neuropathy: a meta-analysis of 20 randomized controlled trials. Neural Regen Res. 2018;13:1087–95. [DOI]

46.

Xu Q, Pan J, Yu J, Liu X, Liu L, Zuo X, 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]

47.

Tang C, Han R, Wu J, Fang F. Effects of baicalin capsules combined with α-lipoic acid on nerve conduction velocity, oxidative stress and inflammatory injury in patients with diabetic peripheral neuropathy. Am J Transl Res. 2021;13:2774–83. [PubMed] [PMC]

48.

Gilron I, Robb S, Tu D, Holden RR, Jackson AC, Duggan S, et al. Randomized, double-blind, controlled trial of a combination of alpha-lipoic acid and pregabalin for neuropathic pain: the PAIN-CARE trial. Pain. 2023;165:461–9. [DOI]