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Long-Term Clinical Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy

The 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial

¹ Chubu Rosai Hospital, Nagoya, Japan
² Institute for Adult Diseases Asahi Life Foundation, Tokyo, Japan
³ Department of Medicine, Metabolism, and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
⁴ Saiseikai Shibuya Satellite Clinic, Tokyo, Japan
⁵ Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
⁶ Research Institute of Lifestyle-Related Diseases, Osaka, Japan
⁷ Tohoku Rosai Hospital, Sendai, Japan
⁸ Hamamatsu Institute of Clinical Pharmacology and Therapeutics, Hamamatsu, Japan
⁹ Faculty of Engineering, Tokyo University of Science, Tokyo, Japan
¹⁰ Shiga University of Medical Science, Otsu, Japan

Address correspondence and reprint requests to Nigishi Hotta, MD, PhD, Chubu Rosai Hospital, 1-10-6 Komei, Minato-ku, Nagoya 455-8530, Japan. E-mail: hotta{at}chubuh.rofuku.go.jp

OBJECTIVE—We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy.

RESEARCH DESIGN AND METHODS—Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) 40 m/s, and HbA_1c 9% were enrolled in this open-label, multicenter study and randomized to 150 mg/day epalrestat or a control group. After excluding the withdrawals, 289 (epalrestat group) and 305 (control group) patients were included in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception threshold [VPT]), cardiovascular autonomic nerve function, and subjective symptoms.

RESULTS—Over the 3-year period, epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s (P < 0.001). Although a benefit with epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, and cramping improved significantly with epalrestat versus the control group. The effects of epalrestat on median MNCV were most evident in subjects with better glycemic control and with no or mild microangiopathies.

CONCLUSIONS—Long-term treatment with epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited microangiopathy.

Abbreviations: ADCT, Aldose Reductase Inhibitor-Diabetes Complications Trial • ARI, aldose reductase inhibitor • MFWL, minimum F-wave latency • MNCV, motor nerve conduction velocity • VPT, vibration perception threshold

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