Ranirestat for the management of diabetic sensorimotor polyneuropathy

Abstract

Objective: Aldose 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 methods: A 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).

Results: At 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 <or= 0.05) and at weeks 24 and 36 and in peroneal motor NCV at weeks 36 and 52 (P <or= 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.

Conclusions: Treatment 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.

Trial registration: ClinicalTrials.gov NCT00101426.

Figure 1

Changes from baseline in the summed sensory NCV. Summed sensory NCV includes bilateral sural and proximal median sensory nerves. Data shown are LSM ± SEM change from baseline for last observation carried forward. Adjusted P values: placebo vs. 10 mg (P = 0.962), 20 mg (P = 0.246), and 40 mg (P = 0.369) at week 52.

Figure 2

Changes from baseline in the summed motor NCV. The summed motor NCV includes the median, peroneal, and tibial nerves. Data shown are LSM ± SEM change from baseline for last observation carried forward. Adjusted P values: placebo vs. 10 mg (P = 0.247), 20 mg (P = 0.028), and 40 mg (P = 0.002) at week 12; placebo vs. 10 mg (P = 0.296), 20 mg (P = 0.152), and 40 mg (P = 0.036) at week 24; placebo vs. 10 mg (P = 0.188), 20 mg (P = 0.029), and 40 mg (P = 0.013) at week 36; placebo vs. 10 mg (P = 0.913), 20 mg (P = 0.123), and 40 mg (P = 0.162) at week 52.

Figure 3

Changes from baseline in peroneal motor NCV. *P < 0.05; **P < 0.01. Data shown are LSM ± SEM change from baseline for last observation carried forward. Adjusted P values: placebo versus ranirestat all doses at week 36 (P ≤ 0.035); placebo vs. 10 mg (P = 0.014), 20 mg (P = 0.015), and 40 mg (P = 0.108) at week 52.