Aldose reductase inhibitors for the treatment of diabetic polyneuropathy
- 17 October 2007
- journal article
- research article
- Published by Wiley in Cochrane Database of Systematic Reviews
- Vol. 2010 (1), CD004572
- https://doi.org/10.1002/14651858.cd004572.pub2
Abstract
Polyneuropathy, a common complication of diabetes mellitus, causes pain and sensory and motor deficits in the limbs, and is also an important independent predictor of foot ulceration. Inhibiting the metabolism of glucose by the polyol pathway using aldose reductase inhibitors is a potential mechanism to slow or reverse the neuropathy's progression. To assess the effects of aldose reductase inhibitors on the progression of symptoms, signs or functional disability in diabetic polyneuropathy. We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to May 2007), EMBASE (from January 1980 to May 2007) and LILACS (from 1982 to May 2007). We reviewed bibliographies of randomized trials identified, and contacted authors and experts in the field. We included randomized controlled trials comparing an aldose reductase inhibitor with control, and lasting at least six months. The primary outcome measure was change in neurological function, measured in various ways, including strength testing, sensory examination, and composite scores of neurological examination. Secondary outcome measures were nerve conduction studies, neuropathic symptoms, quality of life, occurrence of foot ulcers and adverse effects. Trials included in the review were selected and assessed independently by at least two of us. Methodological criteria and study results were recorded on data extraction forms. Thirty-two randomized controlled trials meeting the inclusion criteria were identified. Many had significant methodological flaws. Change in neurological function, our primary outcome measure, was assessed in 29 trials, but sufficient data for meta-analysis were only available in 13 studies, involving 879 treated participants and 909 controls. There was no overall significant difference between the treated and control groups (SMD -0.25, 95% CI -0.56 to 0.05), although one subgroup analysis (four trials using tolrestat) favored treatment. A benefit for neuropathic symptoms was suggested by a group of trials using a dichotomized endpoint (improvement or not), but this was contradicted by another group of trials which measured symptoms on a continuous scale. There was no overall benefit on nerve conduction parameters (27 studies) or foot ulceration (one study). Quality of life was not assessed in any of the studies. While most adverse events were infrequent and minor, three compounds had dose limiting adverse events that lead to their withdrawal from human use: severe hypersensitivity reactions with sorbinil, elevation of creatinine with zenarestat, and alteration of liver function with tolrestat. We found no statistically significant difference between aldose reductase inhibitors and placebo in the treatment of diabetic polyneuropathy. Any future clinical trials of aldose reductase inhibitors should be restricted to compounds proven to have substantial biological or preclinical advantages over previously tested agents.This publication has 45 references indexed in Scilit:
- Three‐year inhibition of aldose reductase on development of symptomatic neuropathy in diabetic patientsJournal of the Peripheral Nervous System, 2006
- Natural Progression of Diabetic Peripheral Neuropathy in the Zenarestat Study PopulationDiabetes Care, 2004
- Clinical Efficacy of Fidarestat, a Novel Aldose Reductase Inhibitor, for Diabetic Peripheral NeuropathyDiabetes Care, 2001
- Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathyNeurology, 1999
- Tolrestat in the Primary Prevention of Diabetic NeuropathyDiabetes Care, 1995
- Treatment of diabetic autonomic neuropathy with an aldose reductase inhibitorZeitschrift für Neurologie, 1993
- Clinical and Neurophysiological Studies of Aldose Reductase Inhibitor Ponalrestat in Chronic Symptomatic Diabetic Peripheral NeuropathyDiabetes, 1991
- A multicentre trial of the aldose-reductase inhibitor, tolrestat, in patients with symptomatic diabetic neuropathyDiabetologia, 1990
- Diabetic neuropathy in the upper limb and the effect of twelve months sorbinil treatmentDiabetologia, 1988
- Limited benefit of treatment of diabetic polyneuropathy with an aldose reductase inhibitor: a 24-week controlled trialDiabetologia, 1985