The Efficacy of Aldose Reductase Inhibitors in the Management of Diabetic Complications

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Abstract
Recently, aldose reductase inhibitors (ARIs) have been registered in several countries for the improvement of glycaemic control. However, their efficacy is still controversial. ARIs inhibit the enhanced flux of glucose through the polyol pathway. As such, they can never be more effective than normoglycaemia, and so their potential benefits and limitations should be considered relative to the effects of prolonged euglycaemia. The clinical effects of ARIs can be put into perspective by assessing the effects of improved glycaemic control attained in randomised trials of intensive insulin treatment [such as the Diabetes Control and Complications Trial (DCCT)] and after pancreatic transplantation. Although direct comparison of these 3 interventions is hampered by differences in patient populations, duration and methods of follow-up and in the potency of ARIs, the effects of these 3 metabolic interventions and their course in time appear remarkably similar. For neuropathy, all 3 interventions induce an increase in average motor nerveconduction velocity of approximately 1 m/sec during the first months of treatment. At the same time, improvement of painful symptoms may occur. These changes probably largely represent a metabolic amelioration of the condition of the nerves. Around the second year of treatment with all 3 forms of metabolic improvement, an acceleration of nerve conduction of a similar magnitude occurs, with signs of structural nerve regeneration and some sensory recuperation. Experience with ARIs in nephropathy is still limited, but similar improvements in glomerular filtration rate and, less consistently, in urinary albumin excretion were found during short term normoglycaemia produced by all 3 forms of treatment. Comparison of a small number of studies, however, shows differences between intensive insulin regimens, pancreatic transplantation and ARIs in effects on retinopathy. Retinopathy often temporarily deteriorates in the early phases of improved glycaemic control, but this is not noted with ARIs. New microaneurysm formation was slightly reduced in a single long term study with the ARI sorbinil, but the preventive effects on the overall levels of retinopathy seemed less strong than in normoglycaemia trials of similar duration. However, the pharmacodynamic effects on inhibiting the polyol pathway differ among ARIs, and the half-life of the inhibiting effect of sorbinil may have been too short for a complete reduction of polyol pathway activity. The trials of prolonged intensive insulin therapy and pancreatic transplantation have demonstrated that very strict metabolic control must be maintained continuously for many years before a significant reduction of complications can be demonstrated. In practice, this will often be impossible, especially in type 2 diabetic patients who carry the burden of complications. The effects of ARIs and of normoglycaemia appear to be similar. This justifies the use of ARIs in patients who are threatened by diabetic complications (particularly neuropathy) and who remain hyperglycaemic despite all efforts to achieve good glycaemic control. A large, lengthy prospective trial, with a size and design similar to the DCCT, will be necessary to finally assess the possibilities and limitations of ARIs in preventing, arresting or reversing the complications of diabetes mellitus.