THE EFFICACY OF ALDOSE REDUCTASE INHIBITORS IN THE MANAGEMENT OF DIABETIC COMPLICATIONS - COMPARISON WITH INTENSIVE INSULIN-TREATMENT AND PANCREATIC TRANSPLANTATION

Recently, aldose reductase inhibitors (ARIs) have been registered in s everal countries for the improvement of glycaemic control. However, th eir efficacy is still controversial. ARIs inhibit the enhanced flux of glucose through the polyol pathway. As such, they can never be more e ffective than normoglycaemia, and so their potential benefits and limi tations should be considered relative to the effects of prolonged eugl ycaemia. The clinical effects of ARIs can be put into perspective by a ssessing the effects of improved glycaemic control attained in randomi sed trials of intensive insulin treatment [such as the Diabetes Contro l and Complications Trial (DCCT)] and after pancreatic transplantation . Although direct comparison of these 3 interventions is hampered by d ifferences in patient populations, duration and methods of follow-up a nd in the potency of ARIs, the effects of these 3 metabolic interventi ons and their course in time appear remarkably similar. For neuropathy , all 3 interventions induce an increase in average motor nerveconduct ion velocity of approximately 1 m/sec during the first months of treat ment. At the same time, improvement of painful symptoms may occur. The se 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 regenera tion and some sensory recuperation. Experience with ARIs in nephropath y is still limited, but similar improvements in glomerular filtration rate and, less consistently, in urinary albumin excretion were found d uring short term normoglycaemia produced by all 3 forms of treatment. Comparison of a small number of studies, however, shows differences be tween 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 not ed with ARIs. New microaneurysm formation was slightly reduced in a si ngle long term study with the ARI sorbinil, but the preventive effects on the overall levels of retinopathy seemed less strong than in normo glycaemia trials of similar duration. However, the pharmacodynamic eff ects 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 prolong ed intensive insulin therapy and pancreatic transplantation have demon strated that very strict metabolic control must be maintained continuo usly for many years before a significant reduction of complications ca n be demonstrated. In practice, this will often be impossible, especia lly 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 c omplications (particularly neuropathy) and who remain hyperglycaemic d espite all efforts to achieve good glycaemic control. A large, lengthy prospective trial, with a size and design similar to the DCCT, will b e necessary to finally assess the possibilities and limitations of ARI s in preventing, arresting or reversing the complications of diabetes mellitus.