New pharmacological agents and emerging therapeutic targets for painful diabetic neuropathy

Painful diabetic peripheral neuropathy (PDPN) remains a serious complication of diabetes mellitus (DM). Recent clinical trials have demonstrated promising outcomes for pilavapadin (LX9211), an orally administered selective, potent inhibitor of adapter protein-2-associated kinase 1 (AAK1) and vixotrigine, a broad spectrum voltage-gated sodium channels (Navs) inhibitor. Their beneficial role was reflected in improved average daily pain (ADP) score and Patient Global Impression of Change (PGIC). Gamma-aminobutyric acid (GABA) receptor agonism has yielded favourable outcomes in preliminary studies. Experimental studies have further expanded the spectrum of potential agents, therapeutic targets and mechanisms in PDPN. Some of potential therapeutic approaches include chemokine suppression (CCR2/CCR5 or CXCR1/2 inhibition) and transient receptor potential vanilloid 1 (TRPV1) pathway suppression. Impaired mitochondrial function in PDPN is now being discussed and the inhibition of poly (adenosine diphosphate [ADP]-ribose) polymerase 1(PARP1), a mitochondrial enzyme responsible for deoxyribonucleic acid (DNA) repair is emerging. Local treatments have also been examined in animal models, such as resiniferatoxin. Limited evidence exists regarding the therapeutic potential of antidiabetic agents, glucagon-like peptide-1 receptor agonists (GLP-1RAs), being most widely studied in experimental settings. Future large clinical trials are now required to confirm the efficacy of novel promising agents and to delineate further potential favourable effects of antidiabetic agents in clinical settings.