Ranirestat for the Management of Diabetic Sensorimotor Polyneuropathy

Abstract

OBJECTIVEAldose reductase inhibitors (ARIs) are potential disease modifiers for diabetes complications. We aimed to determine whether ranirestat, an ARI, could slow or reverse the course of diabetic sensorimotor polyneuropathy (DSP).RESEARCH DESIGN AND METHODSA total of 549 patients with DSP were randomly assigned to treatment with placebo or 10, 20, or 40 mg/day ranirestat for 52 weeks in this multicenter, double-blind study. Efficacy was evaluated by nerve conduction studies, the modified Toronto Clinical Neuropathy Score (mTCNS), and quantitative sensory tests (QSTs).RESULTSAt week 52, the summed sensory (bilateral sural plus proximal median sensory) nerve conduction velocity (NCV) did not show significant changes from baseline (2.0 m/s for placebo compared with 3.2–3.8 m/s for ranirestat). Significant improvement in the summed motor (peroneal, tibial, and median) NCV was observed with 20 and 40 mg/day ranirestat treatment at week 12 (P ≤ 0.05) and at weeks 24 and 36 and in peroneal motor NCV at weeks 36 and 52 (P ≤ 0.05) for the 20 mg/day ranirestat group. The mTCNS and QST results did not differ among the groups during the study. Ranirestat was well tolerated with no pertinent differences in drug-related adverse events or in effects on clinical laboratory parameters, vital signs, or electrocardiograms among the four groups.CONCLUSIONSTreatment with ranirestat appears to have an effect on motor nerve function in mild to moderate DSP, but the results of this study failed to show a statistically significant difference in sensory nerve function relative to placebo.

Long-Acting C-Peptide and Neuropathy in Type 1 Diabetes: A 12-Month Clinical Trial

“…The natural progression of DPN would be expected to result in a slowing of SNCV i by ;0.6-0.7 m/s after 12 months (25,26). Nevertheless, several clinical trials in patients with diabetic neuropathy have reported increases in SNCV i in the placebo group of a similar or somewhat smaller magnitude (14,27,28) than that observed in the current study.…”

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…In patients with diabetes treated with ranirestat for 12 weeks, the drug dose dependently inhibited sorbitol and fructose levels in the sural nerve (Bril and Buchanan, 2004), and a 48-week extension of this study revealed an improvement in SNCV by Ն1 m/s relative to baseline and compared with placebo (Bril and Buchanan, 2006). Unfortunately, in phase 3 testing, 52 weeks of ranirestat treatment (20 and 40 mg/day) failed to improve summed SNCV, possibly related to an unexpected improvement in SNCV in the placebo group (Bril et al, 2009). However significant improvements in MNCV were observed and the drug was well tolerated, suggesting that a more refined trial design may demonstrate efficacy in the primary endpoint of summed SNCV (Bril et al, 2009).…”

“…Unfortunately, in phase 3 testing, 52 weeks of ranirestat treatment (20 and 40 mg/day) failed to improve summed SNCV, possibly related to an unexpected improvement in SNCV in the placebo group (Bril et al, 2009). However significant improvements in MNCV were observed and the drug was well tolerated, suggesting that a more refined trial design may demonstrate efficacy in the primary endpoint of summed SNCV (Bril et al, 2009).…”

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

“…However, it failed to show a statistically significant difference in sensory nerve function relative to placebo. Ranirestat was well tolerated with no pertinent differences in drug-related adverse events or in effects on clinical laboratory parameters, vital signs, or electrocardiograms among the four groups [99].…”

“…Ranirestat has been well studied by Bril and coworkers [98,99]. In a double-blind, placebocontrolled nerve biopsy trial study, 12-week-treatment with ranirestat at a dose of 5 or 20 mg/day improved nerve function in patients with diabetic sensorimotor polyneuropathy, and the improvement could be maintained.…”