Abstract: 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.

Plain-language summary: The authors reviewed the results of all randomized trials that compared an aldose reductase inhibitor with a control and lasted at least six months. Many of the 32 randomized controlled trials identified had significant methodological flaws. The trials used a variety of measures to look for a benefit of treatment with aldose reductase inhibitors. The authors elected to focus primarily on changes in muscle strength and sensation. These were chosen because they are thought be the best indicator of the severity of polyneuropathy, and they have been used in a previous landmark study of the effects of intensive blood sugar control on diabetic neuropathy, as well as in studies of treatments in other types of polyneuropathy. Muscle strength or sensation were assessed in 29 trials, but sufficient data for analysis was only available in 13 studies, involving 879 treated participants and 906 controls. There was no overall significant difference between the treated and control groups. For one drug, tolrestat, there was possibly some benefit, but concerns about liver toxicity have lead to withdrawal of tolrestat from use in humans. A few trials did report that symptoms of neuropathy improved for the treated group, but this was contradicted by most other trials. No benefit was detected on electromyography (EMG) parameters (27 studies) or foot ulceration (one study). Quality of life was not assessed in any of the studies. Adverse effects were infrequent and were mostly minor, except for severe allergic reactions with sorbinil, impaired kidney function with zenarestat, and alteration of liver function with tolrestat. The authors concluded that there was no significant benefit of treatment with aldose reductase inhibitors for diabetic polyneuropathy.