TOLRESTAT FOR MILD DIABETIC NEUROPATHY - A 52-WEEK, RANDOMIZED, PLACEBO-CONTROLLED TRIAL

Objective: To evaluate the effectiveness and safety of tolrestat, an aldose-reductase inhibitor, in patients with mild diabetic autonomic and peripheral neuropathy. Design: Randomized, placebo-controlled, double-blind 52-week trial. Setting: University hospital clinic. Patients: Forty-five diabetic patients with asymptomatic autonomic neuropathy identified by at least one pathologic cardiovascular reflex test result. Interventions: All patients were given placebo during a 4-week run-in period (single-blind). Twenty patients were randomly assigned to continue to receive placebo, and 25 were assigned to treatment with tolrestat (200 mg/d given in the morning). Measurements and Results: At 12 months, improvements in nerve functions occurred in patients receiving tolrestat. Compared with baseline values, postural hypotension decreased by a value of 5.9 mm Hg (95% CI, 1.6 to 8.7); deep-breathing, maximum/minimum heart rate (expiration/inspiration ratio) increased by a value of 0.026 (CI, 0.015 to 0.036); and lying-to-standing heart rate ratio (30:15 ratio) increased by a value of 0.032 (CI, 0.027 to 0.052). In the placebo group, all test results except postural hypotension deteriorated. Vibration perception threshold at the malleolus and great toe of the dominant leg improved in the tolrestat group (- 1.4; CI, - 3.69 to - 1.09) but tended to worsen in the placebo group during the study period. No important side effects were detected in either group. Conclusions: The progression of mild diabetic autonomic and peripheral neuropathy may be halted or even reversed by pharmacologic intervention with the aldose-reductase inhibitor tolrestat.