Effect of 4-Year Antioxidant Treatment with α-Lipoic Acid in Diabetic Polyneuropathy: The NATHAN 1 Trial.

Ziegler, Dan; Low, Phillip A.; Boulton, Andrew J.; Vinik, Aaron I.; Freeman, Roy; Samigullin, Rustem; Tritschler, Hans; Munzel, Ullrich; Maus, Joachim; Schuette, Klemens; Dyck, Peter J.

The aim of this study was to evaluate the efficacy and safety of α-lipoic acid over 4 years in diabetic patients with mild to moderate distal symmetric polyneuropathy (DSP). In this multicenter, randomized, double-masked, parallel-group clinical trial 460 diabetic patients with stage I or stage 2a DSP were randomly assigned to oral treatment with α-lipoic acid 600 mg qd (ALA; n=233) or placebo (n=227) for 4 years following a 6-week placebo run-in phase. Primary outcome measure was a composite score including the Neuropathy Impairment Score of the lower limbs and 7 nerve function tests (NIS[LL]+7 tests). Secondary outcome measures included the Total Symptom Score (TSS) Neuropathy Symptoms and Change (NSC), NIS, NIS[LL], individual NIS components, motor and sensory nerve conduction attributes, and quantitative sensory testing (QST). Data analysis was based on the intention to treat. The demographic variables and the outcome measures at baseline were comparable between the groups as were the HbA1c levels during follow-up. The NIS[LL]+7 tests composite score decreased after 4 years vs baseline by 0.45±0.37 (mean±SEM) in the ALA group and increased by 0.34±0.35 points in the placebo group (p=0.105). The NIS and NIS[LL] improved by 0.68±0.44 and 0.34±0.30 points on ALA and worsened by 0.61±0.46 and 0.43±0.31 points on placebo, respectively (p=0.028 and p=0.051). The NIS[LL] muscular weakness subscore improved by 0.21±0.11 on ALA and deteriorated by 0.17±0.15 on placebo (p=0.045). The NSC score for weakness severity improved by 0.05±0.03 points on ALA and worsened by 0.04±0.03 points on placebo (p=0.008). No significant differences between both groups after 4 years were noted for the nerve conduction parameters and QST. The rates of adverse events were comparable between the groups during the study. Serious adverse events and deaths occurred in 88 (38.1%) and 3 (1.3%) patients in the ALA group and 63 (28.0%) and 6 (2.7%) partients in the placebo group, respectively. In conclusion, 4-year treatment with α-lipoic acid in mild to moderate DSP is well tolerated and improves some neuropathic deficits and symptoms, but not nerve conduction. Future long-term trials should not anticipate significant progression of DSP in diabetic patients.

ANTIOXIDANTS; LIPOIC acid; POLYNEUROPATHIES; DRUG efficacy; PEOPLE with diabetes

Diabetes, 2007, Vol 56, pA2

0012-1797

Academic Journal