Table 2—

Treatment of diabetic neuropathy based on the putative pathogenetic mechanisms

AbnormalityCompoundAim of treatmentStatus of RCTs
Polyol pathway↑Aldose reductase inhibitorsNerve sorbitol↓
SorbinilWithdrawn (AE)
TolrestatWithdrawn (AE)
PonalrestatIneffective
ZopolrestatWithdrawn (marginal effects)
ZenarestatWithdrawn (AE)
LidorestatWithdrawn (AE)
FidarestatEffective in RCTs, trials ongoing
AS-3201Effective in RCTs, trials ongoing
EpalrestatMarketed in Japan
Myo-inositol↓Myo-inositolNerve myo-inositol↑Equivocal
Oxidative stress↑α-Lipoic acidOxygen free radicals↓Effective in RCTs, trials ongoing
Nerve hypoxia↑VasodilatorsNBF↑
ACE inhibitorsEffective in one RCT
Prostaglandin analogsEffective in one RCT
phVEGF165 gene transferAngiogenesis↑RCTs ongoing
Protein kinase C↑Protein kinase C-β inhibitor (ruboxistaurin)NBF↑RCTs ongoing
C-peptide↓C-peptideNBF↑Studies ongoing
Neurotrophism↓Nerve growth factor (NGF)Nerve regeneration, growth↑Ineffective
BDNFNerve regeneration, growth↑Ineffective
LCFA metabolism↓Acetyl-l-carnitineLCFA accumulation↓Ineffective
GLA synthesis↓γ-Linolenic acid (GLA)EFA metabolism↑Withdrawn
NEG↑AminoguanidineAGE accumulation↓Withdrawn
  • AE, adverse event; AGE: advanced glycation end product; BDNF, brain-derived neurotrophic factor; EFA: essential fatty acid; LCFA, long-chain fatty acid; NBF, nerve blood flow; NEG, nonenzymatic glycation; RCT, randomized clinical trial.