Diabetic neuropathy is associated with elevated aldose reductase activity. Any agent that inhibits this enzyme might, therefore, provide an effective treatment for this common complication of diabetes.OBJECTIVE
To assess the efficacy and safety of the aldose reductase inhibitor, epalrestat, for the treatment of diabetic neuropathy.DESIGN AND INTERVENTION
The Aldose Reductase Inhibitor-Diabetes Complications Trial (ADCT) was a 3-year, multi-center, open-label, randomized, controlled trial. Inclusion criteria included age ≥20 years, at least two indications of neurological dysfunction (which included median motor nerve conduction velocity [MNCV] ≥40 m/s), no foot ulceration, and glycated hemoglobin (HbA1c) levels ≤9%. Patients with arteriosclerosis obliterans, renal disease, liver disease, or neurological dysfunction caused by disease other than diabetes were excluded, as were those already receiving medication for diabetic neuropathy or agents that might affect the symptoms of diabetic neuropathy. Oral epalrestat (50 mg) was administered three times daily before meals, and both the epalrestat and control groups continued their usual diabetic treatment. Study visits were every 6 months. The median MNCV was measured in the patient's nondominant arm, the minimum F-wave latency (MFWL) was measured with electromyography, and the vibration perception threshold (VPT) was measured with a 128 Hz tuning fork. Other parameters assessed included Achilles tendon reflexes, retinopathy, microalbuminuria, adverse events, and subjective symptom changes.OUTCOME MEASURES
The primary outcome measure was the change from baseline to study end in median MNCV. Secondary outcome measures included the change from baseline to study end in MFWL and VPT.RESULTS
The epalrestat and control groups comprised 289 and 305 patients, respectively. The primary efficacy analysis included 181 patients from the epalrestat group and 215 from the control group. Treatment with epalrestat resulted in a marked improvement in MFWL and no deterioration in median MNCV or VPT. In the control group, however, MFWL, median MNCV, and VPT deteriorated over the study period. The difference between the groups in median MNCV at study end was 1.6 m/s (P<0.001). Although there was no deterioration of cardiovascular autonomic nerve function in the epalrestat group, the difference between the groups did not reach significance. A similar result was observed for resting heart rate and Achilles tendon reflexes. At baseline, subjective symptoms of diabetic neuropathy were similar in both groups. At study end, however, the epalrestat group had a greater improvement in subjective symptoms than the control group did. Retinopathy and microalbuminuria were also more likely to improve in the epalrestat group than the control group. The beneficial effects of epalrestat were most apparent in patients with good glycemic control (HbA1c<7%). Adverse events were only assessed in the epalrestat group and included liver function abnormalities and gastrointestinal symptoms. Overall, 8.8% of patients reported adverse events.CONCLUSION
Epalrestat improved the symptoms of diabetic neuropathy and was well tolerated.