Clinical Drug Investigation

, Volume 15, Issue 2, pp 111–121 | Cite as

Effect of Aldose Reductase Inhibition on Heart Rate Variability in Patients with Severe or Moderate Diabetic Autonomic Neuropathy

  • Triantaffilos P. Didangelos
  • Vasilios G. Athyros
  • Dimitrios T. Karamitsos
  • Athanasios A. Papageorgiou
  • Georgios I. Kourtoglou
  • Athanasios G. Kontopoulos
Clinical Pharmacodynamic


Patients with diabetic autonomic neuropathy (DAN) have an increased cardiovascular mortality rate compared with diabetic patients without DAN. Heart rate variability (HRV) time and frequency domain indices are strong predictors of malignant arrhythmias and sudden cardiac death. This prospective, randomised, double-blind, placebo-controlled study analysed the long-term effect of an aldose reductase inhibitor, tolrestat, on HRV time and frequency domain variables in 45 patients with diabetes mellitus (DM) and DAN. Patients were randomised into tolrestat (n = 22) and placebo (n = 23) groups. Tolrestat (200 mg/day) or placebo were administered, respectively, for a period of 12 months. HRV was assessed at months 0, 3, 6, 9 and 12. The HRV level of the 45 patients was compared with that of 20 patients with DM, with analogous glycaemic control, without DAN and 20 healthy controls, of similar age and gender. At the twelfth month, tolrestat, compared with placebo, had a beneficial effect on HRV indices related to vagal tone. Compared with baseline, HRV time and frequency domain indices showed no significant improvement. Moreover, at the twelfth month of tolrestat administration, HRV indices remained less than that of patients with DM but without DAN, and healthy controls. The 12 patients of the 22 with moderate DAN benefited more than the 10 patients of the 22 with severe DAN. At the twelfth month no patient showed deterioration in HRV indices with tolrestat as was seen with placebo. Our data suggest that tolrestat slows down the progression of DAN compared with placebo. This effect of an aldose reductase inhibitor may contribute to a reduction in risk for malignant ventricular arrhythmias. The early detection of DAN is imperative for successful intervention.


Adis International Limited Heart Rate Variability Drug Invest High Frequency Power Aldose Reductase Inhibitor 
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Copyright information

© Adis International Limited 1998

Authors and Affiliations

  • Triantaffilos P. Didangelos
    • 1
  • Vasilios G. Athyros
    • 2
  • Dimitrios T. Karamitsos
    • 1
  • Athanasios A. Papageorgiou
    • 3
  • Georgios I. Kourtoglou
    • 1
  • Athanasios G. Kontopoulos
    • 2
  1. 1.Division of DiabetologyAristotelian University, Hippocration HospitalThessalonikiGreece
  2. 2.Division of CardiologyAristotelian University, Hippocration HospitalThessalonikiGreece
  3. 3.2nd Propedeutic Department of Internal MedicineAristotelian University, Hippocration HospitalThessalonikiGreece

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