Current concepts in the management of diabetic polyneuropathy

Abstract

Diabetic sensorimotor polyneuropathy (DSPN) is encountered in approximately one-third of people with diabetes. This, in turn, might markedly impoverish their quality of life, mainly owing to neuropathic pain and foot ulcerations. Painful DSPN might be as frequent as 25% in diabetes patients. Symptoms as a result of DSPN typically comprise pain, paresthesia and numbness in the distal lower limbs. Asymptomatic DSPN might reach 50% among patients with this condition. Unfortunately, DSPN is still not adequately diagnosed and treated. Its management has three priorities: (i) lifestyle improvement, near-normoglycemia and multifactorial cardiovascular risk intervention; (ii) pathogenesis-oriented pharmacotherapy; and (iii) symptomatic alleviation of pain. Intensive diabetes therapy showed evidence for favorable effects on the incidence and deterioration of DSPN in type 1 diabetes, but not type 2 diabetes. Among pathogenesis-oriented treatments, α-lipoic acid, actovegin, benfotiamine and epalrestat are currently authorized to treat DSPN in several countries. Symptomatic therapy uses analgesics, notably antidepressants, opioids and anticonvulsants, reducing pain by ≥50% in approximately 50% of individuals, but might be limited, particularly by central nervous system-related adverse events. Local treatment with the capsaicin 8% patch might offer an alternative. In addition to pain relief, therapy should improve sleep, mobility and quality of life. In conclusion, multimodal treatment of DSPN should consider the individual risk profile, pathogenetic treatment and pain management using pharmacotherapy (combinations, if required), as well as non-pharmacological options.

Keywords: Diabetic polyneuropathy; Diagnosis; Pharmacotherapy.

Figure 1

Pathways underlying diabetic neuropathy at the cellular level with corresponding pathogenesis‐derived therapies. Pathogenesis‐derived agents are linked to these pathways by the green boxes and the red lines terminating in a crossbar (indicate blocking of the corresponding pathways). Asterisks indicate randomized placebo‐controlled clinical trials of diabetic sensorimotor polyneuropathy as yet not available. AGEs, advanced glycation end‐products; AMPK, 59 adenosine monophosphate‐activated protein kinase; BiP, binding immunoglobulin protein; CHOP, CCAAT/enhancer‐binding protein homologous protein; CR, cytokine receptor; DNA, deoxyribonucleic acid; ER, endoplasmic reticulum; FFA, free fatty acid; G6P, glucose‐6‐phosphate; GLP‐1 RA, glucagon‐like peptide‐1 receptor agonist; GLUT, glucose transporter; IKK, IκB kinase; IL, interleukin; IR, insulin receptor; JNK, c‐Jun N‐terminal kinase; NAD+, oxidized nicotinamide adenine dinucleotide; RAGE, receptor of advanced glycation end‐products; ROS, reactive oxygen species; TLR, Toll‐like receptor; TNFα, tumor necrosis factor‐α; UPR, unfolded protein response. Reproduced with permission from Bönhof et al., Endocrine Reviews, 2019 ²⁶ . Copyright and all rights reserved.

Figure 2

Treatment algorithm for diabetic sensorimotor polyneuropathy (DSPN). ⁺Also improves deficits/impairment/signs; *pain interferes with quality of life. CVD, cardiovascular disease; FREMS, frequency‐modulated electromagnetic neural stimulation; TCA, tricyclic antidepressants; TENS, transcutaneous electrical nerve stimulation.