The potential role of benfotiamine in the treatment of diabetic cardiac autonomic neuropathy

V.A. Serhiyenko, V.B. Segin, L.M. Serhiyenko, A.A. Serhiyenko


Background. Cardiac autonomic neuropathy is a serious complication of diabetes mellitus that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. Cardiac autonomic neuropathy manifests itself in a spectrum of things, ranging from resting tachycardia and fixed heart rate to the development of silent myocardial infarction. The significance of diabetic cardiac autonomic neuropathy has not been fully appreciated and there is no unified treatment algorithm. The purpose was to investigate the effects of benfotiamine on the heart rate variability, the corrected QT interval, QT dispersion and spatial QRS-T angle in patients with type 2 diabetes mellitus and cardiac autonomic neuropathy. Materials and methods. Thirty-two patients with type 2 diabetes mellitus and definite stage of cardiac autonomic neuropathy were allocated into two treatment groups: control (n = 15) received traditional antihyperglycaemic therapy; group 2 (n = 17) — benfotiamine 300 mg/day for three months in addition to standard treatment. Results. It was found that benfotiamine contributed to an increase in the sum of the squares of differences between adjacent normal-to-normal intervals, pNN50 (Δ% = +45.90 ± 7.91 %, p < 0.05), high-frequency component of heart rate variability during the active (Δ% = +25.80 ± 5.58 %, p < 0.05) and passive periods of the day (Δ% = +21.10 ± 4.17 %, p < 0.05), led to a decrease in the corrected QT interval (Δ% = –7.30 ± 1.36 %, p < 0.01), QT dispersion (Δ% = –27.7 ± 9.0 %, p < 0.01) and spatial QRS-T angle (Δ% = –24.4 ± 10.2 %, p < 0.01). Conclusions. The positive influence of benfotiamine suggests the feasibility of its administration to patients with type 2 diabetes mellitus and definite stage of cardiac autonomic neuropathy.


type 2 diabetes mellitus; cardiac autonomic neuropathy; benfotiamine; heart rate variability; corrected QT interval; spatial QRS-T angle

Full Text:



Spallone V, Ziegler D, Freeman R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;27(7):639‐653. doi:10.1002/dmrr.1239.

Serhiyenko VA, Serhiyenko AA. Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment. World J Diabetes. 2018;9(1):1‐24. doi:10.4239/wjd.v9.i1.1.

Spallone V. Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet. Diabetes Metab J. 2019;43(1):3‐30. doi:10.4093/dmj.2018.0259.

Serhiyenko VA, Serhiyenko AA. Diabetic cardiac autonomic neuropathy. In: Saldaña JR, ed. Diabetes Textbook: Clinical Principles, Patient Management and Public Health Issues. Basel: Springer, Cham; 2019. 825-850pp. doi: 10.1007/978-3-030-11815-0.

Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig. 2013;4(1):4‐18. doi:10.1111/jdi.12042.

Vinik AI, Nevoret ML, Casellini C, Parson H. Diabetic neuropathy. Endocrinol Metab Clin North Am. 2013;42(4):747‐787. doi:10.1016/j.ecl.2013.06.001.

Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes. 2014;5(1):17‐39. doi:10.4239/wjd.v5.i1.17.

Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136‐154. doi:10.2337/dc16-2042.

Serhiyenko V, Serhiyenko A. Diabetic cardiovascular neuropathy. Stavropol: Logos Publishers; 2018. 111 p. doi: 10.18411/dia012018.49.

Bernardi L, Spallone V, Stevens M, et al. Methods of investigation for cardiac autonomic dysfunction in human research studies. Diabetes Metab Res Rev. 2011;27(7):654‐664. doi:10.1002/dmrr.1224.

Prince CT, Secrest AM, Mackey RH, Arena VC, Kingsley LA, Orchard TJ. Cardiovascular autonomic neuropathy, HDL cholesterol, and smoking correlate with arterial stiffness markers determined 18 years later in type 1 diabetes. Diabetes Care. 2010;33(3):652‐657. doi:10.2337/dc09-1936.

Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care. 2010;33(6):1389‐1394. doi:10.2337/dc09-2082.

Voulgari C, Moyssakis I, Perrea D, Kyriaki D, Katsilambros N, Tentolouris N. The association between the spatial QRS-T angle with cardiac autonomic neuropathy in subjects with Type 2 diabetes mellitus. Diabet Med. 2010;27(12):1420‐1429. doi:10.1111/j.1464-5491.2010.03120.x.

Voulgari C, Pagoni S, Tesfaye S, Tentolouris N. The spatial QRS-T angle: implications in clinical practice. Curr Cardiol Rev. 2013;9(3):197‐210. doi:10.2174/1573403x113099990031.

Gungor M, Celik M, Yalcinkaya E, et al. The Value of Frontal Planar QRS-T Angle in Patients without Angiographically Apparent Atherosclerosis. Med Princ Pract. 2017;26(2):125‐131. doi:10.1159/000453267.

Walsh JA 3rd, Soliman EZ, Ilkhanoff L, et al. Prognostic value of frontal QRS-T angle in patients without clinical evidence of cardiovascular disease (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol. 2013;112(12):1880‐1884. doi:10.1016/j.amjcard.2013.08.017.

Raposeiras-Roubín S, Virgós-Lamela A, Bouzas-Cruz N, et al. Usefulness of the QRS-T angle to improve long-term risk stratification of patients with acute myocardial infarction and depressed left ventricular ejection fraction. Am J Cardiol. 2014;113(8):1312‐1319. doi:10.1016/j.amjcard.2014.01.406.

Deli G, Bosnyak E, Pusch G, Komoly S, Feher G. Diabetic neuropathies: diagnosis and management. Neuroendocrinology. 2013;98(4):267‐280. doi:10.1159/000358728.

Serhiyenko VA, Serhiyenko AA. Diabetic cardiac autonomic neuropathy: Do we have any treatment perspectives?. World J Diabetes. 2015;6(2):245‐258. doi:10.4239/wjd.v6.i2.245.

Serhiyenko VA, Serhiyenko AA. Omega-3 polyunsaturated fatty acids in the treatment of diabetic cardiovascular autonomic neuropathy: A review. In: Moore SJ, ed. Omega-3: Dietary sources, biochemistry and impact on human health. New York: Nova Science Publishers; 2017. pp. 79-154.

Serhiyenko V, Hotsko M, Snitynska O, Serhiyenko A. Benfotiamine and type 2 diabetes mellitus. MOJ Public Health. 2018;7(1):00200. doi: 10.15406/mojph.2018.07.00200.

Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996;93(5):1043‐1065.

Adamec J, Adamec R. ECG Holter: Guide to electrocardiographic interpretation. New York: Springer-Verlag US; 2008. doi: 10.1007/978-0-387-78187-7 1.

Bazett HC. An analysis of the time-relations of electrocardiograms. Ann Noninvasive Electrocardiol. 1997;2(2):177-194. doi: 10.1111/j.1542-474X.1997.tb00325.x.

Borleffs CJ, Scherptong RW, Man SC, et al. Predicting ventricular arrhythmias in patients with ischemic heart disease: clinical application of the ECG-derived QRS-T angle. Circ Arrhythm Electrophysiol. 2009;2(5):548‐554. doi:10.1161/CIRCEP.109.859108.

Lonsdale D. Dysautonomia, a heuristic approach to a revised model for etiology of disease. Evid Based Complement Alternat Med. 2009;6(1):3‐10. doi:10.1093/ecam/nem064.

Berrone E, Beltramo E, Solimine C, Ape AU, Porta M. Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose. J Biol Chem. 2006;281(14):9307‐9313. doi:10.1074/jbc.M600418200.

Rašić-Milutinović Z, Gluvić Z, Peruničić-Peković Z, Miličević D, Lačković M, Penčić B. Improvement of heart rate variability with benfothiamine and alpha-lipoic acid in type 2 diabetic patients – Pilot study. J Cardiol Ther. 2014;2(1):49-55. doi: 10.12970/2311-052X.2014.02.01.9.

Oh SH, Witek RP, Bae SH, et al. Detection of transketolase in bone marrow-derived insulin-producing cells: benfotiamine enhances insulin synthesis and glucose metabolism. Stem Cells Dev. 2009;18(1):37‐46. doi:10.1089/scd.2007.0255.

Stirban A, Pop A, Tschoepe D. A randomized, double-blind, 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. doi:10.1111/dme.12240.

Pácal L, Kuricová K, Kaňková K. Evidence for altered thiamine metabolism in diabetes: Is there a potential to oppose gluco- and lipotoxicity by rational supplementation?. World J Diabetes. 2014;5(3):288‐295. doi:10.4239/wjd.v5.i3.288.

González-Ortiz M, Martínez-Abundis E, Robles-Cervantes JA, Ramírez-Ramírez V, Ramos-Zavala MG. Effect of thiamine administration on metabolic profile, cytokines and inflammatory markers in drug-naïve patients with type 2 diabetes. Eur J Nutr. 2011;50(2):145‐149. doi:10.1007/s00394-010-0123-x.

Luong KV, Nguyen LT. The impact of thiamine treatment in the diabetes mellitus. J Clin Med Res. 2012;4(3):153‐160. doi:10.4021/jocmr890w.

Katare R, Caporali A, Emanueli C, Madeddu P. Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response. J Mol Cell Cardiol. 2010;49(4):625‐638. doi:10.1016/j.yjmcc.2010.05.014.

Kempler P. Review: Autonomic neuropathy: a marker of cardiovascular risk. Br J Diabetes Vasc. Dis. 2003;3(2):84-90. doi: 10.1177/14746514030030020201.

Boghdadi MA, Afify HE, Sabri N, Makbout K, Elmazar M. Comparative study of vitamin B complex combined with alpha lipoic acid versus vitamin B complex in the treatment of diabetic polyneuropathy in type 2 diabetic patients. J Clin Exp Pharmacol. 2017;7(4):241.

Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes. 2008;116(10):600‐605. doi:10.1055/s-2008-1065351.

Pácal L, Tomandl J, Svojanovsky J, et al. Role of thiamine status and genetic variability in transketolase and other pentose phosphate cycle enzymes in the progression of diabetic nephropathy. Nephrol Dial Transplant. 2011;26(4):1229‐1236. doi:10.1093/ndt/gfq550.

Moss CJ, Mathews ST. Thiamin status and supplementation in the management of diabetes mellitus and its vascular comorbidities. Vitam Min. 2013;2:111. doi:10.4172/vms.1000111.

Pillai JN, Madhavan S. Cardiac autonomic neuropathy and QTc Interval in type 2 diabetes. Heart India. 2015;3(1):8-11. doi: 10.4103/2321-449X.153279.

Veglio M, Borra M, Stevens LK, Fuller JH, Perin PC. The relation between QTc interval prolongation and diabetic complications. The EURODIAB IDDM Complication Study Group. Diabetologia. 1999;42(1):68‐75. doi:10.1007/s001250051115.

Valensi PE, Johnson NB, Maison-Blanche P, Extramania F, Motte G, Coumel P. Influence of cardiac autonomic neuropathy on heart rate dependence of ventricular repolarization in diabetic patients. Diabetes Care. 2002;25(5):918‐923. doi:10.2337/diacare.25.5.918.

Kardys I, Kors JA, van der Meer IM, Hofman A, van der Kuip DA, Witteman JC. Spatial QRS-T angle predicts cardiac death in a general population. Eur Heart J. 2003;24(14):1357‐1364. doi:10.1016/s0195-668x(03)00203-3.

Shoeb M, Ramana KV. Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages. Free Radic Biol Med. 2012;52(1):182‐190. doi:10.1016/j.freeradbiomed.2011.10.444.

Koufopoulos G, Pafili K, Papanas N. Correlation between type 2 diabetes mellitus and ankle-brachial index in a geographically specific Greek population without peripheral arterial disease. Mìžnarodnij endokrinologìčnij žurnal. 2019;15(7):517-522. doi: 10.22141/2224-0721.15.7.2019.186053.

Ziegler D, Schleicher E, Strom A, et al. Association of transketolase polymorphisms with measures of polyneuropathy in patients with recently diagnosed diabetes. Diabetes Metab Res Rev. 2017;33(4):10.1002/dmrr.2811. doi:10.1002/dmrr.2811.

Copyright (c) 2020 V.A. Serhiyenko, V.B. Segin, L.M. Serhiyenko, A.A. Serhiyenko

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.


© "Publishing House "Zaslavsky", 1997-2020


   Seo анализ сайта