The time to develop treatments for diabetic neuropathy

ABSTRACT

Background

Diabetic neuropathy is a multifaceted condition affecting up to 50% of individuals with long standing diabetes. The most common presentation is peripheral diabetic sensory neuropathy (DPN).

Methods

We carried out a systematic review of papers dealing with diabetic neuropathy on Pubmed in addition to a targeted Google search.Search terms included small fiber neuropathy,diffuse peripheral neuropathy, quantitative sensory testing, nerve conduction testing, intra-epidermal nerve fiber density, corneal confocal reflectance microscopy, aldose reductase inhbitors, nerve growth factor, alpha-lipoic acid, ruboxistaurin, nerve growth factor antibody, and cibinetide.

Results

Over the past half century, there have been a number of agents undergoing unsuccessful trials for treatment of DPN.There are several approved agents for relief of pain caused by diabetic neuropathy, but these do not affect the pathologic process.

Expert opinion

The failure to find treatments for diabetic neuropathy can be ascribed to (1) the complexity of design of studies and (2) the slow progression of the condition, necessitating long duration trials to prove efficacy.We propose a modification of the regulatory process to permit early introduction of agents with demonstrated safety and suggestion of benefit as well as prolongation of marketing exclusivity while long term trials are in progress to prove efficacy.

Keywords:

• Diabetic neuropathy
• aldose reductase inhibitors
• nerve growth factor
• nerve conduction testing
• quantitative sensory testing
• intraepidermal nerve fibers

Article highlights

• The most common form of neuropathy is diffuse peripheral neuropathy, typically sensory, with an incidence approaching 50% in longstanding diabetes. Diabetic peripheral neuropathy is a disease of the distal axon, particularly affecting small fibers. The fundamental etiology of diabetic neuropathy is hyperglycemia.

• Clinical research to develop agents to treat diabetic neuropathy has been burdened by the complexity of measures to evaluate the condition. Nerve conduction testing is considered the ‘gold standard’ surrogate measurement, but is not the best measure of changes in small fibers. Furthermore, nerve conduction parameters change very slowly over the course of years. There is significant variability in clinical measurements and quantitative sensory testing.

• There have been many agents studied to modify the course of diabetic neuropathy. These include aldose reductase inhibitors, nerve growth factor, alpha lipoic acid, and ruboxistaurin.

None have demonstrated efficacy in treatment of diabetic neuropathy over the course of studies; the longest lasted 4 years.

• Studies of pain relief are far simpler to perform and of very short duration.

• Many agents are used to relieve pain in diabetic neuropathy but do not alter the course of the disease.

• The slow course of changes in diabetic neuropathy makes it difficult to perform studies to demonstrate improvement in the time course of patent lifetimes and marketing exclusivity.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

Funding provided by the Association of Diabetes Investigators and by the Rose Salter Medical Research Foundation.