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Effect of an Aldose Reductase Inhibiting Agent on Limited Joint Mobility in IDDM

Painless and nondisabling limitation of joint mobility (LJM), primarily affecting the hands, has been found in —50% of postadolescent patients with >5 yr duration of diabetes, with age being a more important determinant than duration of diabetes, as is also seen with other complications (1). Several studies have indicated an approximately fourfold risk of microvascular complications in those with LJM as opposed to those without (1-3). Thus, any intervention that would reduce LJM could, theoretically, improve the long-term prognosis for the more serious complications of insulindependent diabetes mellitus (IDDM). Such a possibility was suggested by the report of improvement in LJM with the use of an aldose reductase inhibitor, sorbinil, in three patients who had substantial functional impairment but who did not have the syndrome described in young patients (4). Nonetheless, other connective tissue proliferation syndromes seen in diabetes might have a similar biochemical basis to LJM. Were this to be true, the milder changes of young patients with LJM should respond most rapidly and dramatically to an intervention that interrupts the process. This study was undertaken as a double-blind placebo-controlled trial of the aldose reductase inhibitor, ponalrestat (5), in 13 white patients (11 men, 2 women), age 18-25 yr, with diabetes duration of 6-23 yr. A 1 mo singleblinded placebo-treated baseline period was followed by 6 mo of double-blinded treatment (ponalrestat n = 7, placebo n = 6) and a 1 mo single-blinded placebo washout period. Periodic safety and efficacy evaluations included a complete hematologic profile, chemical profile, urinalysis, and physical examination. Glucose control was assessed by determination of glycosylated hemoglobin (GHb) concentrations. LJM was staged 1-4 according to established criteria (1) and patients were randomly assigned within each of two groups stratified by stage of LJM to receive either ponalrestat (500 mg once daily) or a matching placebo. Patients were instructed to return unused tablets at the next study visit for determination of compliance, which was very high.