Ranirestat Improves Electrophysiologic but not Clinical Measures of Diabetic Polyneuropathy: A Meta-Analysis

Ranirestat, an aldose reductase inhibitor evaluated in several randomised controlled trials (RCTs) in diabetic peripheral neuropathy (DPN). However, to date, no meta-analysis has evaluated the efficacy and safety of ranirestat in DPN. We undertook this meta-analysis to address this knowledge gap. Detailed search of electronic databases for RCTs published till December 2021 was done at Cochrane register, Medline, PubMed, Embase, clinicaltrials.gov, ctri.nic.in, global health and Google Scholar using the Boolean search strategy: ((ranirestat) OR (aldose reductase inhibitor)) AND ((diabetes) OR (“diabetes mellitus”)). The primary outcome was to evaluate changes in nerve conduction velocities (NCV) of different nerves. The secondary outcomes were to evaluate alterations in amplitudes, F-wave latencies of nerves, modified Toronto Clinical Neuropathy Score (mTCNS) and adverse events. Data from 5 studies involving 1461 patients with DPN was analysed to establish the impact of ranirestat (20-40 mg/day) as compared to placebo on different electrophysiologic outcomes over a median follow-up of 52 weeks. Patients receiving ranirestat had significantly greater improvement in proximal median sensory NCV [MD 0.77 m/s (95%CI: 0.50–1.05); P < 0.01; I(2) = 26%], distal median sensory NCV [MD 0.91 m/s (95%CI: 0.87–0.95); P < 0.01; I(2) = 0%], median motor NCV [MD 0.63 m/s (95%CI: 0.60–0.66); P < 0.01; I(2) = 0%], tibial motor NCV [MD 0.46 m/s (95%CI: 0.43–0.49); P < 0.01; I(2) = 0%] and peroneal motor NCV [MD 0.80 m/s (95%CI: 0.66–0.93); P < 0.01; I(2) = 0%]. mTCNS was not significantly different among groups. Treatment-emergent adverse events [risk ratio (RR) 0.85 (95%CI: 0.63–1.14); P = 0.28; I(2) = 0%] and severe adverse events [RR 1.35 (95%CI: 0.86–2.11); P = 0.20; I(2) = 0%] were comparable across study groups. In people with established DPN with long-standing diabetes, ranirestat is safe and effective in improving electrophysiologic but not clinical DPN.