The scientific literature

Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study

Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG. Exp Clin Endocrinol Diabetes. 2008;116(10):600-5

A double blind, placebo-controlled, phase-III study of 165 patients with symmetrical, distal diabetic polyneuropathy. After 6 weeks, the NSS (Neuropathy Symptom Score) differed significantly between benfotiamine (600mg/day or 300mg/day) and placebo groups (p=0.033 in PP population). Treatment was well tolerated; improvement most pronounced at higher doses.

Benfotiamine in the treatment of diabetic polyneuropathy: a three-week randomized, controlled pilot study (BEDIP Study)

Haupt E, Ledermann H, Köpcke W. Int J Clin Pharmacol Ther. 2005;43(2):71-7

40 inpatients with diabetes and polyneuropathy received either 400mg benfotiamine daily or placebo for 3 weeks. Statistically significant improvement (p=0.0287) in neuropathy score in active group. Most pronounced effect on pain (p=0.0414).

Benfotiamine in the treatment of alcoholic polyneuropathy: an 8-week randomized controlled study (BAP study)

Woelk H, Lehrl S, Bitsch R, Köpcke W. Alcohol Alcohol. 1998;33(6):631-8

Three-armed RCT in 84 outpatients with severe alcoholic polyneuropathy. Benfotiamine produced significant improvement in vibration perception, motor function, and overall score. No therapy-specific adverse effects.

Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy

Winkler G, Pál B, Nagybéganyi E, Ory I, Porochnavec M, Kempler P. Arzneimittelforschung. 1999;49(3):220-4

36 patients in three groups; greatest improvement seen in high-dose group (320mg/day benfotiamine).

A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy

Stracke H, Lindemann A, Federlin K. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6

12-week double-blind RCT in 24 diabetic patients. Significant improvement (p=0.006) of nerve conduction velocity in peroneal nerve.

Pharmacokinetics of thiamine derivatives, especially benfotiamine

Loew D. Int J Clin Pharmacol Ther. 1996;34(2):47-50

Pharmacokinetic comparison showing benfotiamine reaches plasma and tissue thiamine concentrations several-fold higher than equivalent oral thiamine doses, owing to passive diffusion across the gut wall.

The pathobiology of diabetic complications: a unifying mechanism

Brownlee M. Diabetes. 2005;54(6):1615-25

The multifaceted therapeutic potential of benfotiamine

Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A. Pharmacol Res. 2010;61(6):482-8

Comprehensive review of benfotiamine's anti-AGE properties and research into diabetic neuropathy, nephropathy, and retinopathy.

Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy

Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Nat Med. 2003;9(3):294-9

Mechanistic study showing benfotiamine activates transketolase, redirecting metabolites away from the polyol, hexosamine, and AGE pathways that drive hyperglycemic tissue damage.

The potential role of thiamine (vitamin B1) in diabetic complications

Thornalley PJ. Curr Diabetes Rev. 2005;1(3):287-98

Argues for thiamine therapy in preventing diabetic complications via the reductive pentose phosphate pathway.

High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease

Thornalley PJ, Babaei-Jadidi R, Al Ali H. Diabetologia. 2007;50(10):2164-70

Plasma thiamine concentration was decreased 76% in type 1 and 75% in type 2 diabetic patients. Renal clearance of thiamine increased 24-fold (type 1) and 16-fold (type 2).

Thiamine deficiency in diabetes mellitus and the impact of thiamine replacement on glucose metabolism and vascular disease

Page GL, Laight D, Cummings MH. Int J Clin Pract. 2011;65(6):684-90

Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial

de Jager J. BMJ. 2010;340:c2181

Metformin treatment associated with -19% decrease in vitamin B-12 concentration; long-term metformin use increases risk of B-12 deficiency.

Metformin is a substrate and inhibitor of the human thiamine transporter, THTR-2 (SLC19A3)

Liang X. Mol Pharm. 2015;12(12):4301-10

Demonstrates metformin transports via and inhibits thiamine transporter THTR-2 in the small intestine. Implications for thiamine deficiency in metformin-treated diabetics.

Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice

Pan X, Gong N, Zhao J, Yu Z, Gu F, Chen J, Sun X, Zhao L, Yu M, Xu Z, Dong W, Qin Y, Fei G, Zhong C, Xu TL. Brain. 2010;133(Pt 5):1342-51

Mouse Alzheimer's model: benfotiamine dose-dependently enhanced spatial memory and reduced amyloid plaque and phospho-tau. Foundational preclinical evidence for benfotiamine's CNS effects.

Abnormal thiamine-dependent processes in Alzheimer’s Disease. Lessons from diabetes

Gibson GE, Hirsch JA, Cirio RT, Jordan BD, Fonzetti P, Elder J. Mol Cell Neurosci. 2013;55:17-25

Alterations of thiamine phosphorylation and of thiamine-dependent enzymes in Alzheimer’s disease

Heroux M. Metab Brain Dis. 1996;11(1)

Significantly reduced activities of thiamine phosphate dephosphorylating enzymes and thiamine-dependent enzymes in AD brain tissue.

Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers

Rieck J, Halkin H, Almog S. J Lab Clin Med. 1999;134(3):238-43

Mechanisms of thiamin deficiency in chronic alcoholism

Hoyumpa AM Jr. Am J Clin Nutr. 1980;33(12):2750-61

Reviews ethanol inhibition of intestinal thiamine transport via reduced Na-K ATPase activity.

Axonal degeneration in beriberi neuropathy

Takahashi K, Nakamura H. Arch Neurol. 1976;33(12):836-41

Mitochondrial dynamics and peripheral neuropathy

Baloh RH. Neuroscientist. 2008;14(1):12-8

Mechanism of mitochondrial dysfunction in diabetic sensory neuropathy

Fernyhough P, Huang TJ, Verkhratsky A. J Peripher Nerv Syst. 2003;8(4):227-35

Insulin and NT-3 modulate mitochondrial membrane potential in adult sensory neurons via PI 3 kinase pathway.

Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction

Flatters SJ, Bennett GJ. Pain. 2006;122(3):245-57

Paclitaxel produces atypical (swollen and vacuolated) mitochondria in both C-fibres and myelinated axons in painful peripheral neuropathy.

Mitotoxicity in distal symmetrical sensory peripheral neuropathies

Bennett GJ, Doyle T, Salvemini D. Nat Rev Neurol. 2014;10:326-336

Reviews how mitochondrial injury from chemotherapy, HIV proteins, and hyperglycemia leads to chronic neuronal energy deficit and distal axonal degeneration.

Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy

Lehmann HC, Chen W, Borzan J, Mankowski JL, Höke A. Ann Neurol. 2011;69(1):100-10

Peripheral neuropathy associated with mitochondrial disease in children

Menezes MP, Ouvrier RA. Dev Med Child Neurol. 2012;54(5):407-14

The prevalence, predictors, and consequences of peripheral sensory neuropathy in older patients

Mold JW, Vesely SK, Keyl BA, Schenk JB, Roberts M. J Am Board Fam Pract. 2004;17(5):309-18

Prevalence of bilateral sensory deficits rose from 26% (65-74 yrs) to 54% (85+). Only 40% of cases had a known cause.

Long-term, supplemental, one-carbon metabolism-related vitamin B use in relation to lung cancer risk in the Vitamins and Lifestyle (VITAL) cohort

Brasky TM, White E, Chen CL. J Clin Oncol. 2017;35(30):3440-3448

High-dose B6 and B12 supplementation linked to almost 2-fold increase in lung cancer risk in men, especially smokers.

Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment

Solomon LR. Blood Rev. 2007;21(3):113-30

An update on cobalamin deficiency in adults

Dali-Youcef N, Andrès E. QJM. 2009;102(1):17-28

Peripheral neuropathy and nerve dysfunction in individuals at high risk for type 2 diabetes: the PROMISE cohort

Lee CC, Perkins BA. Diabetes Care. 2015;38:793-800

Prevalence of peripheral neuropathy: 29% in normal glycemia, 49% in prediabetes, 50% in new-onset diabetes (p<0.001 for trend). Prediabetes was associated with similar risks of peripheral neuropathy and severity of nerve dysfunction as new-onset diabetes.