A novel approach to alpha-lipoic acid therapy in the treatment of diabetic peripheral neuropathy

Alicja Sementina; Mateusz Cierzniakowski; Julia Rogalska; Izabela Piechowiak; Marek Spichalski; Aleksandra Araszkiewicz

doi:10.20883/medical.e714

Authors

Alicja Sementina Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0002-9303-8141
Mateusz Cierzniakowski Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0003-2939-2928
Julia Rogalska Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0002-3455-4568
Izabela Piechowiak Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0002-9506-7632
Marek Spichalski Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0001-8804-6836
Aleksandra Araszkiewicz Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences, Poland https://orcid.org/0000-0002-4955-6099

DOI:

https://doi.org/10.20883/medical.e714

Keywords:

diabetes mellitus, alpha-lipoic acid, neuropathy, insulin sensitivity, antioxidants

Abstract

Diabetic peripheral neuropathy (DPN) is a heterogenic disorder prevalent amongst patients suffering from diabetes mellitus (DM), with symptoms comprising neuropathic pain, paresthesia, and numbness in distal lower limbs. Alpha-lipoic acid (ALA) is proposed as a pathogenesis-oriented treatment option, targeting underlying causes of neural lesions such as hyperglycemia, metabolic and microvascular dysfunctions, and cellular oxidative stress. We performed a comprehensive review of controlled clinical trials demonstrating the clinical usefulness of ALA in the treatment of DPN, published in the last 5 years to determine the benefits of ALA monotherapy and combined treatments with other known antioxidants. We also investigated the differential efficacy of oral versus intravenous ALA administration. Clinical trials show the efficacy of ALA treatment, attributed to its anti-inflammatory, anti-hyperglycemic, and antioxidant properties, as well as its function in the endothelial activation and lipid metabolism parameters. ALA supplementation is associated with amelioration in nerve conduction velocity scores, clinically significant reduction of reported neuropathic pain, burning and paresthesia, as well as a decrease in serum triglycerides, improved insulin sensitivity, and quality of life.

Downloads

Download data is not yet available.

References

Vinik AI. Diabetic neuropathy: pathogenesis and therapy. Am J Med. 1999;107(2B):17S-26S. DOI: https://doi.org/10.1016/S0002-9343(99)00009-1

Fulop N, Marchase RB, Chatham JC. Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system. Cardiovasc Res. 2007;73(2):288-97. DOI: https://doi.org/10.1016/j.cardiores.2006.07.018

Cameron NE, Eaton SE, Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia. 2001;44(11):1973-88. DOI: https://doi.org/10.1007/s001250100001

Zochodne DW. Diabetic polyneuropathy: an update. Curr Opin Neurol. 2008;21(5):527-33. DOI: https://doi.org/10.1097/WCO.0b013e32830b84cb

Calcutt NA. Diabetic neuropathy and neuropathic pain: a (con)fusion of pathogenic mechanisms? Pain. 2020;161(Suppl 1):S65-S86. DOI: https://doi.org/10.1097/j.pain.0000000000001922

Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-65. DOI: https://doi.org/10.1212/WNL.0b013e3182166ebe

Diabetes Control and Complications Trial (DCCT): results of feasibility study. The DCCT Research Group. Diabetes Care. 1987;10(1):1-19. DOI: https://doi.org/10.2337/diacare.10.1.1

Arora K, Tomar PC, Mohan V. Diabetic neuropathy: an insight on the transition from synthetic drugs to herbal therapies. J Diabetes Metab Disord. 2021;20(2):1773-84. DOI: https://doi.org/10.1007/s40200-021-00830-2

Lopez Zubizarreta M, Hernandez Mezquita MA, Miralles Garcia JM, Barrueco Ferrero M. Tobacco and diabetes: clinical relevance and approach to smoking cessation in diabetic smokers. Endocrinol Diabetes Nutr. 2017;64(4):221-31. DOI: https://doi.org/10.1016/j.endien.2017.05.003

Ghavami H, Radfar M, Soheily S, Shamsi SA, Khalkhali HR. Effect of lifestyle interventions on diabetic peripheral neuropathy in patients with type 2 diabetes, result of a randomized clinical trial. Agri. 2018;30(4):165-70. DOI: https://doi.org/10.5505/agri.2018.45477

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-91s. DOI: https://doi.org/10.18433/jpps30100

Zaheer A, Zaheer F, Saeed H, Tahir Z, Tahir MW. A Review of Alternative Treatment Options in Diabetic Polyneuropathy. Cureus. 2021;13(4):e14600. DOI: https://doi.org/10.7759/cureus.14600

Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-54. DOI: https://doi.org/10.2337/dc16-2042

Araszkiewicz A, Bandurska-Stankiewicz E, Borys S, Budzyński A, Cyganek K, Cypryk K et al. 2022 Guidelines on the management of patients with diabetes. A position of Diabetes Poland. Current Topics in Diabetes. 2022;2(1).

Jingxuan L, Litian M, Jianfang F. Different Drugs for the Treatment of Painful Diabetic Peripheral Neuropathy: A Meta-Analysis. Front Neurol. 2021;12:682244. DOI: https://doi.org/10.3389/fneur.2021.682244

Ziegler D, Tesfaye S, Spallone V, Gurieva I, Al Kaabi J, Mankovsky B, et al. Screening, diagnosis and management of diabetic sensorimotor polyneuropathy in clinical practice: International expert consensus recommendations. Diabetes Res Clin Pract. 2022;186:109063. DOI: https://doi.org/10.1016/j.diabres.2021.109063

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

Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, et al. 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):1425-33. DOI: https://doi.org/10.1007/BF00400603

Ziegler D, Papanas N, Schnell O, Nguyen BDT, Nguyen KT, Kulkantrakorn K, et al. Current concepts in the management of diabetic polyneuropathy. J Diabetes Investig. 2021;12(4):464-75. DOI: https://doi.org/10.1111/jdi.13401

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):1296-301. DOI: https://doi.org/10.2337/diacare.22.8.1296

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 Mar;26(3):770-6. doi: 10.2337/diacare.26.3.770. DOI: https://doi.org/10.2337/diacare.26.3.770

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 Nov;29(11):2365-70. DOI: https://doi.org/10.2337/dc06-1216

Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with a-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care 2011; 34: 2054–2060. DOI: https://doi.org/10.2337/dc11-0503

Agathos E, Tentolouris A, Eleftheriadou I, Katsaouni P, Nemtzas I, Petrou A, et al. Effect of alpha-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. J Int Med Res. 2018;46(5):1779-90. DOI: https://doi.org/10.1177/0300060518756540

Garcia-Alcala H, Santos Vichido CI, Islas Macedo S, Genestier-Tamborero CN, Minutti-Palacios M, Hirales Tamez O, et al. Treatment with alpha-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;2015:189857. DOI: https://doi.org/10.1155/2015/189857

Mrakic-Sposta S, Vezzoli A, Maderna L, Gregorini F, Montorsi M, Moretti S, et al. R(+)-Thioctic Acid Effects on Oxidative Stress and Peripheral Neuropathy in Type II Diabetic Patients: Preliminary Results by Electron Paramagnetic Resonance and Electroneurography. Oxid Med Cell Longev. 2018;2018:1767265. DOI: https://doi.org/10.1155/2018/1767265

Tan GCJ, Tan SMQ, Phang SCW, Ng YT, Ng EY, Ahmad B, et al. Tocotrienol-rich vitamin E improves diabetic nephropathy and persists 6-9 months after washout: a phase IIa randomized controlled trial. Ther Adv Endocrinol Metab. 2019;10:2042018819895462. DOI: https://doi.org/10.1177/2042018819895462

Karonova T, Stepanova A, Bystrova A, Jude EB. High-Dose Vitamin D Supplementation Improves Microcirculation and Reduces Inflammation in Diabetic Neuropathy Patients. Nutrients. 2020;12(9). DOI: https://doi.org/10.3390/nu12092518

Mottaghi T, Khorvash F, Maracy M, Bellissimo N, Askari G. Effect of folic acid supplementation on nerve conduction velocity in diabetic polyneuropathy patients. Neurol Res. 2019;41(4):364-8. DOI: https://doi.org/10.1080/01616412.2019.1565180

Didangelos T, Karlafti E, Kotzakioulafi E, Margariti E, Giannoulaki P, Batanis G, et al. Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2021;13(2). DOI: https://doi.org/10.3390/nu13020395

Han Y, Wang M, Shen J, Zhang Z, Zhao M, Huang J, et al. Differential efficacy of methylcobalamin and alpha-lipoic acid treatment on symptoms of diabetic peripheral neuropathy. Minerva Endocrinol. 2018;43(1):11-8. DOI: https://doi.org/10.23736/S0391-1977.16.02505-0

Zhang T, He Q, Liu Y, Chen Z, Hu H. Efficacy and Safety of Curcumin Supplement on Improvement of Insulin Resistance in People with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Evid Based Complement Alternat Med. 2021;2021:4471944. DOI: https://doi.org/10.1155/2021/4471944

Asadi S, Gholami MS, Siassi F, Qorbani M, Khamoshian K, Sotoudeh G. Nano curcumin supplementation reduced the severity of diabetic sensorimotor polyneuropathy in patients with type 2 diabetes mellitus: A randomized double-blind placebo- controlled clinical trial. Complement Ther Med. 2019;43:253-60. DOI: https://doi.org/10.1016/j.ctim.2019.02.014

Chuar PF, Ng YT, Phang SCW, Koay YY, Ho JI, Ho LS, et al. Tocotrienol-Rich Vitamin E (Tocovid) Improved Nerve Conduction Velocity in Type 2 Diabetes Mellitus Patients in a Phase II Double-Blind, Randomized Controlled Clinical Trial. Nutrients. 2021;13(11). DOI: https://doi.org/10.3390/nu13113770

Ng YT, Phang SCW, Tan GCJ, Ng EY, Botross Henien NP, UD MP, et al. The Effects of Tocotrienol-Rich Vitamin E (Tocovid) on Diabetic Neuropathy: A Phase II Randomized Controlled Trial. Nutrients. 2020;12(5). DOI: https://doi.org/10.3390/nu12051522

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(11). DOI: https://doi.org/10.3390/nu12113254

Won JC, Kwon HS, Moon SS, Chun SW, Kim CH, Park IB, et al. gamma-Linolenic Acid versus alpha-Lipoic Acid for Treating Painful Diabetic Neuropathy in Adults: A 12-Week, Double-Placebo, Randomized, Noninferiority Trial. Diabetes Metab J. 2020;44(4):542-54. DOI: https://doi.org/10.4093/dmj.2019.0099

Memeo A, Loiero M. Thioctic acid and acetyl-L-carnitine in the treatment of sciatic pain caused by a herniated disc: a randomized, double-blind, comparative study. Clin Drug Investig. 2008;28(8):495-500. DOI: https://doi.org/10.2165/00044011-200828080-00004

Huerta AE, Prieto-Hontoria PL, Fernandez-Galilea M, Escote X, Martinez JA, Moreno-Aliaga MJ. Effects of dietary supplementation with EPA and/or alpha-lipoic acid on adipose tissue transcriptomic profile of healthy overweight/obese women following a hypocaloric diet. Biofactors. 2017;43(1):117-31. DOI: https://doi.org/10.1002/biof.1317

Guan H, Ye M, Fang C, Zhang L, Han P, Qiu S, et al. The clinical effectiveness and safety of alprostadil combined with alpha lipoic acid in the treatment of diabetic peripheral neuropathy: A protocol for systematic review and meta-analysis. Medicine (Baltimore). 2020;99(50):e23507. DOI: https://doi.org/10.1097/MD.0000000000023507

Jiang DQ, Xu LC, Jiang LL, Li MX, Wang Y. Fasudil combined with methylcobalamin or lipoic acid can improve the nerve conduction velocity in patients with diabetic peripheral neuropathy: A meta-analysis. Medicine (Baltimore). 2018;97(27):e11390. DOI: https://doi.org/10.1097/MD.0000000000011390

Zhao M, Chen JY, Chu YD, Zhu YB, Luo L, Bu SZ. Efficacy of epalrestat plus alpha-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(6):1087-95. DOI: https://doi.org/10.4103/1673-5374.233453

Wang XT, Lin HX, Xu SA, Lu YK. Lipoic Acid Combined with Epalrestat versus Lipoic Acid in Treating Diabetic Peripheral Neuropathy:A Meta-analysis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2017;39(5):656-64.

Yorek MS, Obrosov A, Shevalye H, Coppey LJ, Kardon RH, Yorek MA. Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, alpha-lipoic acid, menhaden oil or their combination: Effect on diabetic neuropathy related endpoints. Neuropharmacology. 2017;116:122-31. DOI: https://doi.org/10.1016/j.neuropharm.2016.12.022

Pieralice S, Vari R, Minutolo A, Maurizi AR, Fioriti E, Napoli N, et al. Biomarkers of response to alpha-lipoic acid +/- palmitoiletanolamide treatment in patients with diabetes and symptoms of peripheral neuropathy. Endocrine. 2019;66(2):178-84. DOI: https://doi.org/10.1007/s12020-019-01917-w

Ruhnau KJ, Meissner HP, Finn JR, Reljanovic M, Lobisch M, Schütte K, Nehrdich D, Tritschler HJ, Mehnert H and Ziegler D: Effects of 3 week oral treatment with the antioxidant thioctic acid (alpha lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med. 1999; 16: 1040 1043. DOI: https://doi.org/10.1046/j.1464-5491.1999.00190.x

Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N and Bilo HJ: Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: A meta analysis of randomized controlled trials. Int J Endocrinol 2012: 456279, 2012. DOI: https://doi.org/10.1155/2012/456279

Bondar A, Popa AR, Papanas N, Popoviciu M, Vesa CM, Sabau M, et al. Diabetic neuropathy: A narrative review of risk factors, classification, screening and current pathogenic treatment options (Review). Exp Ther Med. 2021;22(1):690. DOI: https://doi.org/10.3892/etm.2021.10122

Yadav V, Marracci GH, Munar MY, Cherala G, Stuber LE, Alvarez L, et al. Pharmacokinetic study of lipoic acid in multiple sclerosis: comparing mice and human pharmacokinetic parameters. Mult Scler. 2010;16(4):387-97. DOI: https://doi.org/10.1177/1352458509359722

Zhang Y, Han P, Wu N, He B, Lu Y, Li S, et al. Amelioration of lipid abnormalities by alpha-lipoic acid through antioxidative and anti-inflammatory effects. Obesity (Silver Spring). 2011;19(8):1647-53. DOI: https://doi.org/10.1038/oby.2011.121

Tolunay O, Celik T, Komur M, Gezgin AE, Kaya MS, Celik U. A rare cause of status epilepticus; alpha lipoic acid intoxication, case report and review of the literature. Eur J Paediatr Neurol. 2015;19(6):730-2. DOI: https://doi.org/10.1016/j.ejpn.2015.07.002

Salehi B, Berkay Yilmaz Y, Antika G, Boyunegmez Tumer T, Fawzi Mahomoodally M, Lobine D, et al. Insights on the Use of alpha-Lipoic Acid for Therapeutic Purposes. Biomolecules. 2019;9(8). DOI: https://doi.org/10.3390/biom9080356

Brufani M, Figliola R. (R)-alpha-lipoic acid oral liquid formulation: pharmacokinetic parameters and therapeutic efficacy. Acta Biomed. 2014;85(2):108-15.

Tibullo D, Li Volti G, Giallongo C, Grasso S, Tomassoni D, Anfuso CD, et al. Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential. Inflamm Res. 2017;66(11):947-59. DOI: https://doi.org/10.1007/s00011-017-1079-6

Serhiyenko VA, Serhiyenko LM, Sehin VB, Serhiyenko AA. Effect of alpha-lipoic acid on arterial stiffness parameters in type 2 diabetes mellitus patients with cardiac autonomic neuropathy. Endocr Regul. 2021;55(4):224-33. DOI: https://doi.org/10.2478/enr-2021-0024

Sola S, Mir MO, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation 2005 Jan 25;111(3):343-8. DOI: https://doi.org/10.1161/01.CIR.0000153272.48711.B9

Theodosis-Nobelos P, Papagiouvannis G, Tziona P, Rekka EA. Lipoic acid. Kinetics and pluripotent biological properties and derivatives. Mol Biol Rep. 2021;48(9):6539-50. DOI: https://doi.org/10.1007/s11033-021-06643-z

Packer L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. Free Radic Biol Med. 1995;19(2):227-50. DOI: https://doi.org/10.1016/0891-5849(95)00017-R

El-Senousey HK, Chen B, Wang JY, Atta AM, Mohamed FR, Nie QH. Effects of dietary vitamin C, vitamin E, and alpha-lipoic acid supplementation on the antioxidant defense system and immune-related gene expression in broilers exposed to oxidative stress by dexamethasone. Poult Sci. 2018;97(1):30-8. DOI: https://doi.org/10.3382/ps/pex298

Liu W, Shi LJ, Li SG. The Immunomodulatory Effect of Alpha-Lipoic Acid in Autoimmune Diseases. Biomed Res Int. 2019;2019:8086257. DOI: https://doi.org/10.1155/2019/8086257

Salinthone S, Schillace RV, Marracci GH, Bourdette DN, Carr DW. Lipoic acid stimulates cAMP production via the EP2 and EP4 prostanoid receptors and inhibits IFN gamma synthesis and cellular cytotoxicity in NK cells. J Neuroimmunol. 2008;199(1-2):46-55. DOI: https://doi.org/10.1016/j.jneuroim.2008.05.003

Dydoń-Pikor, Małgorzata. Peroksydacja lipidów we krwi oraz narządach zwierząt utrzymanych na diecie wysokotłuszczowej z dodatkiem kwasu liponowego. Diss. Katedra i Zakład Biochemii, 2021.

Yang Y, Li W, Liu Y, Li Y, Gao L, Zhao JJ. Alpha-lipoic acid attenuates insulin resistance and improves glucose metabolism in high fat diet-fed mice. Acta Pharmacol Sin. 2014;35(10):1285-92. DOI: https://doi.org/10.1038/aps.2014.64