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Tolrestat for Mild Diabetic Neuropathy: A 52-Week, Randomized, Placebo-Controlled Trial

Dario Giugliano, MD; Raffaele Marfella, MD; Antonio Quatraro, MD; Nicoletta De Rosa, MD; Teresa Salvatore, MD; Domenico Cozzolino, MD; Antonio Ceriello, MD; and Roberto Torella, MD
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From the University of Naples, Naples, Italy. Requests for Reprints: Dario Giugliano, MD, Via Emilia 1, 80021 Afragola (NA), Italia. Grant Support: In part by a grant from Ministero Pubblica Istruzione.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1993;118(1):7-11. doi:10.7326/0003-4819-118-1-199301010-00002
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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.


Grahic Jump Location
Figure 1.
Individual values of the four cardiovascular reflex tests.Top.Bottom.

In the basal state (Basal) and after 12 months of treatment with the aldose-reductase inhibitor tolrestat. Patients are non–insulin-dependent diabetics; means (SD) of the basal and post-treatment values are represented by a larger filled circle. Individual values of the four cardiovascular reflex tests in 20 non–insulin-dependent diabetic patients assigned to the placebo treatment. The units of measurement for deep breathing are for expiration/inspiration ratio; for lying-to-standing, 30/15 ratio; and for Valsalva, longest/shortest R-R ratio.

Grahic Jump Location




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