ALDOSE REDUCTASE INHIBITORS - THE END OF AN ERA OR THE NEED FOR DIFFERENT TRIAL DESIGNS

Despite numerous attempts over 16 years, the results of aldose reducta se inhibitor (ARI) trials for the treatment of diabetic neuropathy hav e not proven efficacy. this paper reviews each of the ARI trials, exam ines confounding factors, and proposes a future course. The confoundin g factors considered are pharmacokinetics (ARI penetration of human ne rve), length of trial (in terms of the natural history of diabetic neu ropathy), trial endpoints (reversibility or slowing of progression), r eproducibility of clinical measurements (in terms of power calculation s), standardization and quality control of endpoints, and clinically m eaningful differences in endpoints. We conclude that ARIs are most lik ely to have a beneficial effect in the management of diabetic distal s ymmetrical polyneuropathy and autonomic neuropathy but that the clinic al role of ARIs is to slow the progression of diabetic neuropathy rath er than to reverse it. Future trials should be designed with adequate statistical power, with consideration of the variability of the endpoi nt measurements for long enough duration, and with rigourous quality c ontrol to definitively confirm the utility of ARIs in the treatment of diabetic distal symmetrical polyneuropathy and autonomic neuropathy.