Current Evidence For Treating Diabetic Neuropathy

Abstract

At least one of three diabetic patients is affected by polyneuropathy which represents a major health problem, as it may present with partly excruciating neuropathic pain and is responsible for substantial morbidity, increased mortality, and impaired quality of life. Treatment is based on four cornerstones: 1.) causal treatment aimed at (near)‐normoglycaemia, 2.) treatment based on pathogenetic mechanisms, 3.) symptomatic treatment, and 4.) avoidance of risk factors and complications. Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. Several pathogenetic mechanisms are being discussed which, however, in contrast to previous years are no longer regarded as separate hypotheses but in the first place as a complex interplay with multiple interactions between metabolic and vascular factors. From the clinical point of view it is important to note that, based on these pathogenetic mechanisms, therapeutic approaches could be derived, some of which are currently being evaluated in clinical studies. These treatments include the inhibition of the increased flux through the polyol pathway by aldose reductase inhibitors, correction of the deficits in essential fatty acid and prostanoid metabolism by substitution of γ‐linolenic acid contained in evening primrose oil, administration of antioxidants (α‐lipoic acid) to reduce the enhanced formation of reactive oxygen species that induce increased oxidative stress, improvement in endoneurial blood flow and resulting hypoxia by vasodilating agents such as ACE inhibitors and protein kinase C (PKC) ß inhibitors, neurotrophic support by administration of NGF, inhibition of non‐enzymatic glycation and formation of AGEs, correction of C‐peptide deficiency by substitution of C‐peptide, and immunosuppressive treatment. Currently only α‐lipoic acid is available for treatment in several countries. Randomized controlled clinical trials using this agent have demonstrated that 1.) short‐term treatment for 3 weeks (600 mg/day i.v.) reduces the chief symptoms and deficits due to diabetic polyneuropathy. 2.) Oral treatment for 4‐7 months tends to ameliorate neuropathic deficits and cardiac autonomic neuropathy. 3.) Preliminary data over 2 years indicate possible long‐term improvement in motor and sensory nerve conduction in the lower limbs. Clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of the drug. Despite the recently accelerating publication rate for controlled trials demonstrating significant pain relief with several agents, the pharmacologic treatment of chronic painful diabetic neuropathy remains a challenge for the physician. A simple measure of therapeutic efficacy (number needed to treat: NNT) permits to estimate the risk‐benefit‐ratio for each agent on the basis of the available controlled trials. In recent meta‐analyses, the NNTs have been calculated for several drugs employed in the treatment of painful diabetic neuropathy which may serve the physician in deciding for the individual treatment. Epidemiological data indicate that not only increased alcohol consumption but also the traditional cardiovascular risk factors such as hypertension, smoking, and cholesterol play a role in development and progression of diabetic neuropathy and, hence, need to be prevented or treated.