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A new aldose reductase inhibitor may be a potential treatment for
diabetic sensorimotor polyneuropathy.
Reviewed by Vera Bril, MD
The investigators said that despite advances in the management of diabetes, DSP continues to be a frequent complication leading to foot ulceration and amputation. “A fundamental pathophysiologic mechanism in DSP is aberrant activity of the polyol pathway in which hyperglycemia increases aldose reductase enzyme activity,” Dr. Bril said. The activation leads to an increased conversion of glucose to sorbitol and fructose. Studies have indicated that increased sorbitol in the nerves of animals is associated with damage.2,3 The investigators of this current study hypothesized that if the aldose reductase enzyme system could be inhibited pharmacologically, the consequences could be prevented or possibly reversed.
POTENT NERVE INHIBITION
The novel aldose reductase inhibitor (ARI) used in this study was developed by Dainippon Pharmaceuticals, and demonstrates selective, reversible and potent inhibition of the aldose reductase enzyme system. “We aimed to determine whether AS-3201 inhibits sorbitol and fructose accumulation in sural nerve from patients with DSP,” Dr. Bril wrote. “Furthermore, we aimed to explore the functional changes in DSP that might predict future clinical benefit for patients treated with an ARI for a sufficient length of time.”
Patients in the multicenter, double-blind, randomized, placebo-controlled efficacy study were assigned to one of three treatment groups: AS-3201 5 mg/day, AS-3201 20 mg/day or placebo for 12 weeks. Upon patient entry, a medical history, physical and neurological examinations, nerve conduction studies, vibration detection threshold tests and the Toronto Clinical Neuropathy Score were performed. Patients also had clinical laboratory tests.
SUFFICIENT NERVE FIBERS
The 101 patients enrolled had type 1 or type 2 diabetes for at least 6 months, were 18 to 70 years old, had stable glycemic control for at least 3 months prior to entry and HbA1c ≥7% but ≤11%. DSP was determined by modified San Antonio Criteria, according to Dr. Bril.
“The requirement for sural nerve potential amplitude responses of at least 1 µV ensured the presence of sufficient nerve fibers to allow demonstration of sorbitol accumulaton in peripheral nerves, if not inhibited by AS-3201.
The investigators determined a study endpoint of sorbitol inhibition in the sural nerve. Secondary endpoints were nerve fructose inhibition, penetration of AS-3201 into the sural nerve, sorbitol and fructose concentrations in erythrocytes, AS-3201 concentration in plasma, and the compound’s safety.
Dr. Bril and colleagues reported that there were no significant clinical, electrophysiological or laboratory baseline differences between the groups. The nerve sorbitol concentration of 3.14 x 10-2 nmol/mg wet nerve in patients in the placebo group was inhibited by 65% and 84% in patients assigned AS-3201 at 5 mg/day and 20 mg/day, respectively (P<.001). The levels of fructose were similarly inhibited, they reported, and sensory nerve conduction velocities (NCV) improved by ≥1 m/s (P<.05).
PROMISING OUTCOMES AND CHANGES
Biochemical outcomes as well as functional and clinical changes in this study were promising, Dr. Bril wrote. “The improved sensory NCV observed in the group who received 20 mg/day for 3 months combined with an 83.5% inhibition of the nerve sorbitol levels indicates that 20 mg/day is more likely to be an effective dose,” she wrote. “The correlation observed between the inhibition rate of 83.5% and improvement in sensory NCV supports the polyol pathway as a possible pathogenic mechanism for DSP.”
She added that the results were unexpected after just 3 months, as previous authors suggested at least 1 year of treatment was required to detect any changes. While the role of the pathway is well established, this study provides proof of concept for a specific ARI agent and warrants additional study, the authors concluded.
Vera Bril, MD, is from the department of medicine at the University of Toronto. She can be reached at vera.bril@utoronto.ca.
1. Bril V, Buchanan RA. Aldose reductase inhibition by AS-3201 in sural nerve from patients with diabetic sensorimotor polyneuropathy. Diabetes Care. 2004;27:2369-2375.
2. Oates PJ. Polyol pathway and diabetic peripheral neuropathy. Int Rev Neurobiol. 2002;50:325-392.
3. Gabbay KH, O’Sullivan JB. The sorbitol pathway: enzyme location and content in normal and diabetic nerve and cord. Diabetes. 1968;17:239-243.