Vibration detection threshold was improved in patients enrolled in the 28-week study.
Reviewed by Nigishi Hotta, MD

The aldose reductase inhibitor (ARI) was tested in 22 type 2 diabetic patients, aged ≥20 years, with polyneuropathy and stable blood glucose control (mean HbA1c 7.2%).

Patients had not used another ARI ≤3 months before baseline. For 28 weeks, patients took 1mg of fidarestat, an investigational drug, daily before breakfast. Lead investigator Nigishi Hotta, MD, and colleagues were able to confirm results from previous studies that suggest that fidarestat (SNK-860, Sanwa Kagaku Kenkyusho, Nagoya, Japan) is an effective treatment for diabetic peripheral neuropathy.

Previously, Dr. Hotta studied the effects of fidarestat in 279 type 1 and type 2 diabetic patients with neuropathy during a double-blind placebo controlled study.² Patients in the previous study were treated with the same dose of the ARI as in the current study, however the duration of the trial was 52 weeks.

Investigators concluded that fidarestat altered the progression of diabetic neuropathy and positively affected subjective symptoms.

POTENT, PROMISING ARI

In an unrelated study,³ investigators wrote that fidarestat is a “potent and promising ARI, possibly useful for both preventing and treating diabetic neuropathy.” In that investigation, 58 type 2 diabetic patients took 1mg fidarestat daily for 4 weeks and experienced a normalization of elevated sorbitol content levels of erythrocytes.    

Investigators of the current study, published in Clinical Drug Investigation, measured upper and lower extremity VDT and studied the severity of diabetic polyneuropathy symptoms with a C64 quantitative tuning fork (Takano Manufacturing Co, Nagoya, Japan) at baseline, 12 and 28 weeks. The upper extremity threshold test point was the third finger, and the lower extremity test point was the first toe. Both were done on the left extremities and were evaluated using the paired t-test.

Evaluation of VDT, which investigators concluded had a negative correlation to upper and lower limb numbness, cold and hot flushes, difficulty walking and hypoaesthesia, was performed in 19 patients (Table 1). Lower extremity threshold at baseline was 3.6 ±0.4 and 4.8 ±0.5 after therapy (P=.0001). In the upper extremity, thresholds were 4.9 ±0.4 and 6.3 ±0.4, respectively (P=.0017) (Table 2).

VDT EVALUATION

Patients with decreased VDT experienced numbness in their extremities that became worse as the threshold decreased, investigators noted. VDT of ≤2 denoted hypoaesthesia.

“These results suggest that development of hypoaesthesia indicates considerable neuropathic progress,” they wrote. “It is known that in diabetic polyneuropathy the sensory nervous system is disturbed, and vibration [detection] is reduced in the early stages of the disease process.” 

Subjective symptoms were checked with the Friedman test once every four weeks: Paraesthesia, (numbness, rigidity, heaviness) spontaneous pain and hypoaesthesia (tactile sense, algaesthesia) were rated on a scale of 0 to 4, where 0 referred to no severity and 4 referred to severe.

SUBJECTIVE SYMPTOMS IMPROVED

Results indicted that fidarestat significantly improved the subjective symptoms in the lower extremity including numbness, cold and hot flushes (P<.0001), spontaneous pain (P=.0002) and pain that caused difficulty walking (P=.0015). Improvements in upper extremity were not statistically significant, the investigators wrote.

Diabetic polyneuropathy is usually present during early stages of diabetes. Polyol pathway acceleration, oxidative stress, accelerated glycation and abnormal protein kinase C metabolism may be the cause of the diabetes complication. Early treatment with fidarestat may prevent further complications from the dysfunction, investigators wrote. These may include myocardial infarction or sudden death.

Nigishi Hotta, MD, is from the Third Department of Internal Medicine, Nagoya University School of Medicine, Japan. He can be reached at hotta@chubuh.rofuku.go.jp.

1. Hotta N, Yasuda K, Sumita Y, et al. Effects of a Novel Aldose Reductase Inhibitor, Fidarestat (SNK-860), on Vibration Perception Threshold and Subjective Symptoms in Patients with Diabetic Polyneuropathy. Clin Drug Invest. 2004;24:671-680.
2. Hotta N, Toyota T, Matsuoka K, et al. Clinical Efficacy of Fidarestat, a Novel Aldose Reductase Inhibitor, for Diabetic Peripheral Neuropathy. Diabetes Care. 2001;24:1776-1782.
3. Asano T, Saito Y, Kawakami M, et. al. Fidarestat (SNK-860), a potent aldose reductase inhibitor, normalizes the elevated sorbitol accumulation in erythrocytes of diabetic patients. J Diabetes Complications. 2002;16:133-138.