Following the identification of potent, orally active inhibitors of aldose reductase, the next challenge comes in demonstrating clinical utility in the treatment of diabetic complications. It is not feasible to conduct pivotal studies in all indications within the same trial and neuropathy evolved as the lead indication. There was little precedent for clinical trials in any diabetic complication and one of the challenges has been the derivation of standardized methodology for quantifying changes. In order to establish the value of any intervention in a chronic disease, it is necessary to demonstrate sustained benefit in long-term trials. This has been complicated by the absence of quantitative prospective data on the natural history of the disease process. In well-controlled clinical trials, patients are likely to improve their diabetic control which will have an additional effect over and above the usual placebo effect seen in any trial. In the absence of any standard therapy, the definition of clinical as opposed to statistical significance of any effect needs to be established. In the case of neuropathy this is further complicated by the heterogeneity of the disease and questions over the relevance of small changes in electrophysiology as an index of improvement in histopathology. The majority of the animal studies have concentrated on prevention of changes rather than reversal. However, in diabetics, complications develop slowly and significant tissue damage has occurred before clinical signs can be detected. To date, all clinical studies have concentrated on treatment of complications. The dose of ARI chosen for such studies has been based on the surrogate of erythrocyte aldose reductase activity confirmed by short-term studies on disease reversal. However, recent studies in both neuropathy and retinopathy have shown that the degree of aldose reductase inhibition required for long-term protection is much greater than that required for a short-term effect. The clinical studies which have been reported to date have not shown convincing proof of efficacy but, against this background, it is doubtful whether the aldose reductase hypothesis has really been tested. © 1990.
