OBJECTIVES—We aimed to determine whether ranirestat, an aldose reductase inhibitor, maintains the improved nerve function observed in patients with diabetic sensorimotor polyneuropathy (DSP) after completing a 12-week nerve biopsy study.

RESEARCH DESIGN AND METHODS—Patients with mild to moderate DSP, as determined by the presence of sural nerve responses, were enrolled in a double-blind, placebo-controlled biopsy trial and randomized to placebo or 5 or 20 mg/day ranirestat for 12 weeks. Patients completing this biopsy study were offered a 48-week extension at the same ranirestat dose or at 5 mg/day ranirestat if they were originally treated with placebo. Electrophysiological tests, the Toronto Clinical Neuropathy Score, and vibration perception thresholds (VPTs) were performed at entry and at 12 (end of the biopsy study) and 60 (end of the 48-week extension) weeks.

RESULTS—Peroneal motor nerve conduction velocity (NCV) improved in the 20-mg/day group following 60 weeks of treatment. Sural and median sensory NCV improved after both 12 and 60 weeks of treatment with 20 mg/day. VPT improved after 60 weeks of treatment with 20 mg/day. Ranirestat was well tolerated with no difference in adverse events between the 5- and 20-mg/day groups.

CONCLUSIONS—Twenty milligrams ranirestat per day improves NCV and VPT following 60 weeks of administration. The improved sensory nerve function observed after 12 weeks of therapy was maintained at 60 weeks, and improved motor nerve function was observed at 60 weeks.

In spite of advances in the management of diabetes, diabetic sensorimotor polyneuropathy (DSP) continues to be a frequent and potentially serious complication, leading to foot ulceration and amputation (1). A fundamental pathophysiological mechanism in DSP is aberrant activity of the polyol pathway, in which hyperglycemia increases aldose reductase enzyme activity (2). This activation then results in an increased conversion of glucose to sorbitol, leading to accumulation of sorbitol and fructose in nerves. If the aldose reductase enzyme system could be pharmacologically inhibited by an aldose reductase inhibitor (ARI) with decreases in nerve sorbitol and fructose, nerve damage might be prevented and possibly reversed.

Ranirestat (AS-3201), a novel ARI developed by Dainippon Pharmaceutical (Osaka, Japan) demonstrated potent inhibition of the polyol pathway after 12 weeks of treatment (3). In this phase 2 trial, patients were randomized to one of three groups: placebo or 5 or 20 mg/day ranirestat in a double-blind fashion for 12 weeks. The placebo-treated patients had a mean nerve sorbitol concentration of 3.14 × 10−2 nmol/mg wet nerve, similar to other reports from studies (4). This was reduced by 65.2% in those patients who received 5 mg/day ranirestat and by 83.5% in those who received 20 mg/day ranirestat. Concomitant with inhibition of the polyol pathway, patients had improved sensory nerve conduction velocities (NCVs), particularly those receiving the higher dose. On completion of the 12-week sural nerve biopsy study, patients were offered a 48-week extension phase and treated with either 5 or 20 mg/day ranirestat. We aimed to determine whether the improved nerve function observed in the biopsy study was maintained after 60 weeks of treatment with ranirestat.

The extension study was a multicenter, double-blind, randomized, efficacy study in which patients previously randomized to placebo in the original 12-week phase 2 biopsy study received 5 mg/day ranirestat. Those previously randomized to either 5 or 20 mg/day ranirestat continued their same dose. The double blind was maintained for all patients, investigators, technicians, and research staff. The efficacy procedures including nerve conduction studies (NCS), vibration perception threshold (VPT), and the Toronto Clinical Neuropathy Score (TCNS) were performed as previously described at entry into the 12-week biopsy study, at the end of the biopsy study, which was entry into the 48-week extension for each patient, and at the end of the extension, i.e., 60 weeks of treatment (3). Those patients who switched from placebo to 5 mg daily were not included in the efficacy analyses due to the different duration of treatment with ranirestat. The TCNS evaluates the signs and symptoms of DSP (5). The maximum TCNS has a value of 19 points by which the severity of DSP is categorized, i.e., 0–5: no neuropathy, 6–8: mild neuropathy, 9–11: moderate neuropathy, and ≥12: severe neuropathy.

The study inclusion criteria for the biopsy study have been previously described (3). Only patients completing the 12-week biopsy study were offered the 48-week extension study. The central core laboratory (University of Toronto) continued to review all NCS, VPT, and TCNS results for each patient to ensure the consistency of study procedures and high quality data (6). The extension study was approved by the institutional review boards at each of the six participating centers. All study patients provided separate written informed consent for the extension study.

Study end points

Baseline values for NCS, VPT, and TCNS were taken from the entry values into the 12-week biopsy study, as were the plasma ranirestat levels. The efficacy end points were changes in NCS, VPT, and the TCNS at the end of the extension, which is a full 60 weeks of treatment compared with entry into the biopsy study, and also changes compared with entry into the extension. Plasma ranirestat levels were measured at weeks 14, 16, 20, 24, and 36 from entry into the biopsy study.

Adverse events were carefully documented during the study. Clinical laboratory tests were periodically performed with an electrocardiogram at entry into the extension then at weeks 36 and 60. Neurological and physical examinations were performed at entry and at the end of the extension study.

Analytic procedures

Electrophysiologic measurements.

The same standardized procedures were used in the extension study as described for the 12-week biopsy study (3). The only difference was that unilateral sural nerve testing was done at week 60 from entry into the biopsy study as a sural nerve had been biopsied and no response would be expected.

Biochemical measurements

Plasma ranirestat levels were measured as previously described (3).

VPT

VPT was measured at the first toe by the method of limits using a neurothesiometer (Horwell Scientific, London, U.K.).

Statistical analyses

The results are based on the modified intent-to-treat patient population, i.e., those patients with at least one postdose efficacy assessment (NCS and/or TCNS). Baseline refers to predose data for patients treated with 5 and 20 mg/day ranirestat from entry into the biopsy study (week 0). Demographic and baseline characteristics were analyzed for homogeneity using the Wilcoxon’s rank-sum test for continuous variables or the χ2 test for categorical variables. TCNS severity scores were analyzed using the Cochran-Mantel-Haenszel test, controlling for center effect. Within-group comparisons between the baseline value and postdose value were assessed using the paired t test. Intergroup comparisons for the 5 and 20 mg/day groups were assessed using an ANCOVA model, including baseline values and site as covariates. Predefined medically meaningful covariates were not included in the model if they were found to be homogeneous at baseline. Statistical tests were declared statistically significant if the calculated P value was <0.050, except for baseline homogeneity, which were declared statistically significant if the P value was <0.100. Since this was an extension study, the number of patients per group was determined from the biopsy study, which was powered to show changes in sural nerve polyol levels, not for changes in NCS or the TCNS.

Demographics

Ninety-two of 94 eligible patients entered the double-blind extension phase: 34 were given placebo to 5 mg/day ranirestat, 31 were given 5 mg/day ranirestat, and 27 were given 20 mg/day ranirestat; 82.6% of patients completed the extension study (30 at placebo to 5 mg/day, 31 at 5 mg/day, and 25 at 20 mg/day). The demographic information has previously been described for entry into the biopsy study, where the three groups were shown to be comparable (3). The demographic information is presented in Table 1 for those who continued into the extension study. The treatment groups remain comparable. Most of the patients had type 2 diabetes for ∼14 years and DSP for ∼5 years at study entry. Glycemic control as indicated by the mean HbA1c was similar.

Baseline data for the NCS, TCNS, and VPT are presented in Table 2 for those who continued into the extension study. All groups had similar nerve function at entry with mild to moderate DSP based on the NCS and TCNS results. The 20-mg/day group had more severe DSP based on differences in bilateral sural, proximal median sensory, and median motor NCV that reached statistical significance (P < 0.100) for the baseline homogeneity ANCOVA testing. These observed values for the corresponding parameter at baseline (week 0) were adjusted for as a covariate in the corresponding change from baseline ANCOVA.

Electrophysiology

The changes in NCV at 12 and 60 weeks are shown in Fig. 1. The previous 12-week biopsy study showed that peroneal motor NCV deteriorated in the placebo group by −0.4 m/s. Peroneal motor NCV did not significantly change in the other groups at the end of week 12. For those continuing in the extension study, peroneal motor NCV improved in the 5-mg/day group by 1.2 m/s (P = 0.04) from weeks 0 to 60 and by 1.0 m/s (P = 0.05) in those receiving 20 mg/day during this same period. In the 20-mg/day group, the NCV improved by 1.2 m/s (P = 0.007) during the extension period from weeks 12 to 60 (data not shown). In other words, the improvement in peroneal motor NCV with ranirestat treatment was not observed until treatment extended beyond 12 weeks.

The median motor NCV deteriorated in the placebo group in the 12-week biopsy study by 0.39 m/s. The NCV for the 5-mg/day group deteriorated by 1.1 m/s (P = 0.10) from entry to week 60, with an insignificant change of −0.1 m/s (P = 0.9) in the 20-mg/day group to week 60.

The right sural NCV slightly deteriorated in the placebo group in the 12-week biopsy study. The 5-mg/day group improved by 0.7 m/s (P = 0.42) at week 60. The 20-mg/day group showed an improvement of 1.3 m/s (P = 0.07) after 60 weeks of treatment. The left sural nerve was biopsied at the end of the previous 12-week biopsy study in most patients, so NCS results were not available.

The proximal median sensory NCV was unchanged in the placebo group in the 12-week biopsy study and showed some improvement for the 5-mg/day group at week 60, by 0.5 m/s (P = 0.31). The 20-mg/day group improved in the 12-week biopsy study and then improved further by 3.4 m/s (P = 0.01) at week 60. There was a trend of difference (P = 0.05) between the 5- and 20-mg/day groups following 60 weeks of treatment, indicating that 20 mg/day had a greater treatment effect. The lack of improvement in the distal median sensory NCV is likely due to mechanical factors at the carpal tunnel in patients with diabetes (7).

VPT

VPT did not change significantly in the placebo or 5-mg/day groups in the 12-week biopsy study or in the extension study at 60 weeks. VPT tended to improve in both toes in those treated with 20 mg/day ranirestat, but there was some asymmetry in the changes. The left side decreased by 1.9 volts (P = 0.09) compared with 0.8 volts (P = 0.50) for the right side.

TCNS

Mean changes in the symptom, sensory test, reflex, and total scores from entry are shown in Fig. 2 by treatment group. A decrease in score indicates fewer clinical features of DSP. The symptom score (0–6) decreased by –1.0 for the 5-mg/day treatment group (P < 0.001) and by –0.6 for the 20-mg/day group (P = 0.01) from weeks 0 to 60. The sensory test score (0–5) decreased by −0.2 for the 5-mg/day treatment group (P = 0.08) and −0.4 for the 20-mg/day group (P = 0.08). The combined symptom and sensory scores (0–11) decreased by −1.2 for the 5-mg/day group (P < 0.001) and by –1.0 for the 20-mg/day group (P = 0.009) from weeks 0 to 60.

In the placebo to 5-mg/day group, the number of patients with severe neuropathy increased from five at entry into the biopsy study to eight at week 12 while receiving placebo. From weeks 12 to 60, the number with no neuropathy increased from one to three. For the 5-mg/day group, from weeks 0 to 60, the number with no neuropathy increased from one to five; those with severe neuropathy dropped from nine to seven. For the 20-mg/day group, from weeks 0 to 60, the number with no neuropathy increased from two to four, and those with severe neuropathy decreased from eight to six. This improvement is even more encouraging because the 20-mg/day group had more abnormal nerve function as shown by NCS at week 0 compared with the 5-mg/day group.

Pharmacokinetics

Plasma ranirestat levels are proportional to dose with no evidence of drug accumulation (data not shown).

Safety

Ranirestat was well tolerated for up to 60 weeks of administration. The prevalence of treatment-emergent adverse events was similar between the 5- and 20-mg groups. No clinically significant changes were observed for the other safety parameters.

The results of the extension study demonstrate that effective inhibition of the polyol pathway by the ARI, ranirestat, is maintained with long-term treatment. The unexpected improvements in nerve function and clinical features of DSP after 12 weeks of treatment with 20 mg/day rantirestat were not lost but became even more evident after 60 weeks of therapy, as shown by the current findings, although the extension study was not powered to show changes in NCS or the TCNS.

The magnitude of NCV improvement after ranirestat therapy for 60 weeks is an indicator of the strong efficacy of this ARI in polyol pathway inhibition. In population studies, Arezzo (8) reported that motor NCV decreased by ∼0.5 m/s per year in patients with diabetes. Greene et al. (9) reported a decline in peroneal motor NCV and median and sural sensory NCV of >0.25 m/s in the placebo-treated patients in a zenarestat study. Brown et al. (10) reported more detail on these same patients, indicating a decline of median forearm sensory NCV of −0.05 m/s (n = 360), of peroneal motor NCV of −0.2 m/s (n = 359), and of sural CV of −0.65 m/s (n = 359) in 12 months. Other authors (11,12) have reported deterioration in NCV in patients with DSP. In this slowly progressive chronic disorder, ARI therapy would be expected to slow or halt the progression of NCV deterioration. Thus, the small deteriorations in motor and sensory NCV found in the placebo patients after 12 weeks are as expected, and greater decline would be predicted after 60 weeks. However, the improved NCV of 1 m/s for lower-limb motor and sensory nerves and of >3 m/s in the forearm median sensory nerve following 60 weeks of treatment with 20 mg/day ranirestat are completely unexpected and indicate the strong efficacy of ranirestat. The lack of change for median distal sensory NCV is likely due to mechanical factors at the carpal tunnel in patients with diabetes (6,7).

The magnitude of change in NCV is greater at 60 weeks than at 12 weeks. Also, improved VPT were first evident at 60 weeks, although the changes in VPT were not statistically significant. These findings suggest that ARIs have sustained and increasing effects on nerve function and clinical sensory activity that can be observed after 12 months of therapy.

Finally, the improvement in the TCNS scores and the shift in DSP severity on a simple clinical grading scale after 60 weeks of therapy confirm the clinical relevance of the improvements in NCS and VPT testing (5). Together with improved nerve function and sensation, more patients were classified as having no neuropathy and fewer as having severe DSP at 60 weeks.

The improvement in nerve function, VPT, and DSP severity observed with 20 mg/day ranirestat in this study as well as the 83.5% inhibition of nerve sorbitol levels found in the biopsy study suggest that 20 mg/day ranirestat would be clinically effective for the management of DSP. The findings in the current study are in keeping with a previous study of zenarestat, another ARI, that showed that dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by a signficiant improvement in NCV (9). In particular, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter sural nerve myelinated fibers. Given the lack of a placebo group and statistical power in the current study, the results need to be confirmed in a placebo-controlled trial of comparable duration, i.e., 12 months. Nonetheless, the current findings support the polyol pathway as being a major pathophysiological mechanism underlying DSP (2).

Ranirestat Study Group members

Andre Belanger, Centre de Recherche Clinique de Laval, Laval, Canada; V.B., University Health Network, Toronto, Canada; Denis Brunet, Enfant-Jesus du Centre Hospitalier Affilie Universitaire de Quebec, Quebec, Canada; Ian Grant, New Halifax Infirmary, Halifax, Canada; Aaron Vinik, Diabetes Research Institute, Norfolk, VA; and Sherwyn Schwartz, Diabetes and Glandular Disease, San Antonio, TX.

Figure 1—

Changes in NCV during the biopsy and extension studies for placebo (week 12), 5 mg/day ranirestat (weeks 12 and 60), and 20 mg/day ranirestat (weeks 12 and 60). Proximal median sensory NCV improved in the 20-mg group by ∼1.8 m/s at week 12 and 3.4 m/s at week 60. Peroneal motor NCV improved by ∼1 m/s at week 60 for both the 5- and 20-mg groups. The improvement in sural NCV at week 12 was maintained at week 60. P value; paired t test within-group comparison from entry into the biopsy study to week 60. †P < 0.100; *P < 0.050;**P < 0.010 vs. baseline.

Figure 1—

Changes in NCV during the biopsy and extension studies for placebo (week 12), 5 mg/day ranirestat (weeks 12 and 60), and 20 mg/day ranirestat (weeks 12 and 60). Proximal median sensory NCV improved in the 20-mg group by ∼1.8 m/s at week 12 and 3.4 m/s at week 60. Peroneal motor NCV improved by ∼1 m/s at week 60 for both the 5- and 20-mg groups. The improvement in sural NCV at week 12 was maintained at week 60. P value; paired t test within-group comparison from entry into the biopsy study to week 60. †P < 0.100; *P < 0.050;**P < 0.010 vs. baseline.

Close modal
Figure 2—

TCNS improves in patients treated with ranirestat. A decrease in score indicates fewer symptoms and signs of DSP. P values; paired t test within-group comparison from entry to end of the biopsy study then to the end of the extension. *P < 0.050; **P < 0.010; ***P < 0.001 vs. baseline.

Figure 2—

TCNS improves in patients treated with ranirestat. A decrease in score indicates fewer symptoms and signs of DSP. P values; paired t test within-group comparison from entry to end of the biopsy study then to the end of the extension. *P < 0.050; **P < 0.010; ***P < 0.001 vs. baseline.

Close modal
Table 1—

Demographic profile for patients in the extension

Ranirestat
P value (5 vs. 20 mg)*
Placebo/5 mg5 mg20 mg
n 30 31 25  
Type of diabetes     
    Type 1 2 (6.7) 3 (9.7) 3 (12.0) 0.780 
    Type 2 28 (93.3) 28 (90.3) 22 (88.0) — 
Characteristic     
    Age at onset of diabetes (years) 44.1 ± 10.3 47.2 ± 12.7 45.6 ± 15.4 0.980 
    Duration of diabetes (years) 16.1 ± 10.5 14.4 ± 9.0 13.7 ± 12.0 0.504 
    Age at onset of DSP (years) 55.0 ± 7.6 56.5 ± 7.3 54.6 ± 8.2 0.373 
    Duration of DSP (years) 5.2 ± 3.0 5.0 ± 3.4 4.8 ± 4.4 0.464 
    Fasting glucose (mg · day−1 · l−1) 152.1 ± 35.5 173.5 ± 51.4 129.8 ± 52.6 0.241 
    HbA1c (%) 8. 04 ± 1.26 8.18 ± 1.20 8.25 ± 1.30 0.915 
Ranirestat
P value (5 vs. 20 mg)*
Placebo/5 mg5 mg20 mg
n 30 31 25  
Type of diabetes     
    Type 1 2 (6.7) 3 (9.7) 3 (12.0) 0.780 
    Type 2 28 (93.3) 28 (90.3) 22 (88.0) — 
Characteristic     
    Age at onset of diabetes (years) 44.1 ± 10.3 47.2 ± 12.7 45.6 ± 15.4 0.980 
    Duration of diabetes (years) 16.1 ± 10.5 14.4 ± 9.0 13.7 ± 12.0 0.504 
    Age at onset of DSP (years) 55.0 ± 7.6 56.5 ± 7.3 54.6 ± 8.2 0.373 
    Duration of DSP (years) 5.2 ± 3.0 5.0 ± 3.4 4.8 ± 4.4 0.464 
    Fasting glucose (mg · day−1 · l−1) 152.1 ± 35.5 173.5 ± 51.4 129.8 ± 52.6 0.241 
    HbA1c (%) 8. 04 ± 1.26 8.18 ± 1.20 8.25 ± 1.30 0.915 

Data are means ± SD or n (%).

*

P values; χ2 test for type of diabetes and Wilcoxon rank-sum test for the other parameters between 5 and 20 mg ranirestat. The placebo/5-mg group consists of those patients who received placebo during the biopsy study then 5 mg/day ranirestat in the extension. Data are shown for the modified intent-to-treat patients; i.e., those with at least one postdose efficacy assessment.

Data at the entry to the extension study.

Predose data at week 0.

Table 2—

Baseline NCS, VPT, and TCNS results for patients in the extension study*

Ranirestat
P value (5 vs. 20 mg)
Placebo/5 mg5 mg20 mg
n 30 31 25  
NCV (m/s)     
    Sural, right 42.2 ± 4.5 41.8 ± 5.3 39.3 ± 4.9 0.053 
    Sural, left 41.6 ± 4.0 41.8 ± 5.9 39.2 ± 3.9 0.050 
    Median sensory, elbow 55.0 ± 5.5 55.4 ± 4.8 53.5 ± 4.1 0.090 
    Median sensory, wrist 45.6 ± 10.1 48.9 ± 7.2 48.7 ± 5.2 0.852 
    Median motor 49.6 ± 3.6 52.3 ± 3.5 50.4 ± 4.2 0.091† 
    Peroneal motor 39.1 ± 3.5 40.6 ± 3.4 38.8 ± 4.8 0.307 
VPT (volts)     
    Right 21.7 ± 9.0 21.6 ± 8.5 21.2 ± 6.8 0.993 
    Left 21.6 ± 8.4 21.1 ± 9.1 21.2 ± 6.9 0.773 
TCNS (n = 19) 10.2 ± 3.6 10.1 ± 3.0 9.4 ± 4.0 0.249 
Ranirestat
P value (5 vs. 20 mg)
Placebo/5 mg5 mg20 mg
n 30 31 25  
NCV (m/s)     
    Sural, right 42.2 ± 4.5 41.8 ± 5.3 39.3 ± 4.9 0.053 
    Sural, left 41.6 ± 4.0 41.8 ± 5.9 39.2 ± 3.9 0.050 
    Median sensory, elbow 55.0 ± 5.5 55.4 ± 4.8 53.5 ± 4.1 0.090 
    Median sensory, wrist 45.6 ± 10.1 48.9 ± 7.2 48.7 ± 5.2 0.852 
    Median motor 49.6 ± 3.6 52.3 ± 3.5 50.4 ± 4.2 0.091† 
    Peroneal motor 39.1 ± 3.5 40.6 ± 3.4 38.8 ± 4.8 0.307 
VPT (volts)     
    Right 21.7 ± 9.0 21.6 ± 8.5 21.2 ± 6.8 0.993 
    Left 21.6 ± 8.4 21.1 ± 9.1 21.2 ± 6.9 0.773 
TCNS (n = 19) 10.2 ± 3.6 10.1 ± 3.0 9.4 ± 4.0 0.249 

Data are means ± SD.

*

Predose data (week 0) are shown for the 5- and 20-mg ranirestat group, and data at the entry to the extension study (week 12) are shown for placebo/5-mg group.

P value <0.05. P values; Wilcoxon rank-sum test between 5 and 20 mg ranirestat. The 20-mg group appears to have slightly more severe DSP based on the above parameters, but none of the differences achieved statistical significance.

We thank Dainippon Pharmaceuticals, Osaka, Japan, for grant support.

We also thank David Liang for assistance with table and figure preparation and MyLan Ngo for assistance in core laboratory management.

1.
Oates PJ: Polyol pathway and diabetic peripheral neuropathy.
Int Rev Neurobiol
50
:
325
–392,
2002
2.
Gabbay KH, O’Sullivan JB: The sorbitol pathway: enzyme localization and content in normal and diabetic nerve and cord.
Diabetes
17
:
239
–243,
1968
3.
Bril V, Buchanan RA, the AS-3201 Study Group: Aldose reductase inhibition by AS-3201 in sural nerve from patients with diabetic sensorimotor polyneuropathy.
Diabetes Care
27
:
2369
–2375,
2004
4.
Bril V, Ono Y, Buchanan RA: Sural nerve sorbitol in patients with diabetic sensorimotor polyneuropathy.
Diabetes Care
27
:
1160
–1163,
2004
5.
Bril V, Perkins BA: Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy.
Diabetes Care
25
:
2048
–2052,
2002
6.
Bril V, Ellison R, Ngo M, Bergstrom B, Raynard D, Gin H: Electrophysiological monitoring in clinical trials: Roche Neuropathy Study Group.
Muscle Nerve
21
:
1368
–1373,
1998
7.
Perkins BA, Olaleye D, Bril V: Carpal tunnel syndrome in patients with diabetic polyneuropathy.
Diabetes Care
25
:
565
–569,
2002
8.
Arezzo JC: The use of electrophysiology for the assessment of diabetic neuropathy.
Neurosci Res Commun
21
:
13
–23,
1997
9.
Greene DA, Arezzo JC, Brown MB, the Zenarestat Study Group: Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy: Zenarestat Study Group.
Neurology
53
:
580
–591,
1999
10.
Brown MJ, Bird SJ, Watling S, Kaleta H, Hayes L, Eckert S, Foyt HL: Natural progression of diabetic peripheral neuropathy in the zenarestat study population.
Diabetes Care
27
:
1153
–1159,
2004
11.
Laudadio C, Sima AAF: Progression rates of diabetic neuropathy in placebo patients in an 18-month clinical trial: Ponalrestat Study Group.
J Diabetes Complications
12
:
121
–127,
1998
12.
Diabetes Control and Complications Trial Research Group: Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial.
Ann Neurol
38
:
869
–880,
1995

*A list of the members of the Renirestat Study Group can be found in the appendix.

V.B. is on an advisory panel for, has received honoraria/consulting fees from, and has received grant/research support from Dainippon Pharmaceuticals.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.