Natural Progression of Diabetic Peripheral Neuropathy in the Zenarestat Study Population

Abstract

OBJECTIVE -The aim of this study was to report the baseline and natural progression of diabetic peripheral neuropathy over 12 months in a large mild-to-moderate neuropathy population.RESEARCH DESIGN AND METHODS -Patients from a multicentered trial of zenarestat, an aldose reductase inhibitor, had serial measures of neurologic function, including nerve conduction studies (NCSs), quantitative sensory testing (QST), and clinical neuropathy rating scores at baseline and at 12 months. Baseline population descriptors and changes in neurologic function in placebo-treated patients were analyzed. CONCLUSIONS -The neurologic decline over 12 months is evident when measured by NCS and cool thermal QST. Other measures (vibration QST, neuropathy rating scores, monofilament examination) are insensitive to changes over 12 months in a mild-to-moderate affected population of this size. RESULTS Diabetes Care 27:1153-1159, 2004D iabetic peripheral neuropathy (DPN) is a debilitating condition affecting as many as one-half of all patients with diabetes during the course of their disease (1). The progressive, irreversible course of the disease ultimately leads to an increased incidence of ulceration and limb amputations (2).Currently, therapy is limited to intensive glycemic control and symptomatic treatments. It is critical to identify the appropriate study population within the broad continuum of the disease when evaluating potential therapies. For example, pancreatic islet transplantation work suggests that severe neuropathy is not amenable to therapy (3,4). Defining a mildto-moderate, perhaps more responsive, DPN population may be helpful in identifying new therapeutic modalities (5).Objective, yet clinically meaningful, data characterizing the natural progression of mild-to-moderate DPN are also lacking. One issue is the uncertain rate of disease progression (6,7). Another is lack of agreement regarding the clinical relevance of the available scientifically rigorous measures of DPN. The San Antonio neuropathy consensus called for study designs requiring multiple, often expensive electrophysiologic, sensory, and clinical tools to document disease progression and response to therapy (8,9). Only a fraction of these tools translate directly to patient outcomes. None are widely used in clinical practice or are accessible to primary care practitioners.Increased nerve sorbitol and fructose associated with hyperglycemia remain a hypothesized causal mechanism of DPN. Inhibition of aldose reductase, the enzyme responsible for converting glucose to sorbitol, demonstrates reduced nerve degeneration and improved nerve conduction in animal models and humans (10). Previous aldose reductase inhibitors (ARIs) have been plagued with problems, including occasional marginal efficacy, lack of tissue permeability, and a variety of toxicities lacking a common causal mechanism.Zenarestat, a highly potent ARI, was evaluated in a large phase 3 trial of mild distal symmetrical DPN, using guidelines provided by the consensus panels (8,9,11). This study was ...

Electrophysiological Patterns of Diabetic Polyneuropathy: Experience from a Tertiary Care Hospital of Bangladesh

“…Similar to our patients, reduction of amplitudes was shown to be more marked in lower limb nerves. In general, nerve conduction declined in all nerves tested, with the decline in sural sensory conduction velocity achieving statistical significance 10 . Sensory nerve action potential amplitude is reduced by up to 60% in the legs 11 .…”

Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy

“…Moreover, HbA 1c levels at baseline were less than 7.0% in 50% of our subjects, whereas patients with good glycemic control were excluded in the zenarestat study. Furthermore, the other factors may have greater effects, because a clinical study (Brown et al, 2004) has demonstrated that the changes of nerve function test results during 12 months were independent of baseline HbA 1c stratification in a large diabetic peripheral neuropathy population. It has been speculated that the ability to improve or preserve nerve function may be limited by disease severity ).…”

Long-Term Effects of Ranirestat (AS-3201) on Peripheral Nerve Function in Patients With Diabetic Sensorimotor Polyneuropathy

“…Greene et al (9) reported a decline in peroneal motor NCV and median and sural sensory NCV of Ͼ0.25 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 Ϫ0.05 m/s (n ϭ 360), of peroneal motor NCV of Ϫ0.2 m/s (n ϭ 359), and of sural CV of Ϫ0.65 m/s (n ϭ 359) in 12 months. Other authors (11,12) have reported deterioration in NCV in patients with DSP.…”