Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials.

Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycaemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. In the past two decades several medical treatments that exert their effects despite hyperglycaemia have been derived from the experimental pathogenetic concepts of diabetic neuropathy. Such compounds have been designed to improve or slow the progression of the neuropathic process and are being evaluated in clinical trials, but with the exception of alpha-lipoic acid (thioctic acid) which is available in Germany, none of these drugs is currently available in clinical practice. Here we review the current evidence from the clinical trials that assessed the therapeutic efficacy and safety of thioctic acid in diabetic polyneuropathy. Thus far, 15 clinical trials have been completed using different study designs, durations of treatment, doses, sample sizes, and patient populations. Within this variety of clinical trials, those with beneficial effects of thioctic acid on either neuropathic symptoms and deficits due to polyneuropathy or reduced heart rate variability resulting from cardiac autonomic neuropathy used doses of at least 600 mg per day. The following conclusions can be drawn from the recent controlled clinical trials. 1.) Short-term treatment for 3 weeks using 600 mg of thioctic acid i.v. per day appears to reduce the chief symptoms of diabetic polyneuropathy. A 3-week pilot study of 1800 mg per day given orally indicates that the therapeutic effect may be independent of the route of administration, but this needs to be confirmed in a larger sample size. 2.) The effect on symptoms is accompanied by an improvement of neuropathic deficits. 3.) Oral treatment for 4-7 months tends to reduce neuropathic deficits and improves cardiac autonomic neuropathy. 4.) Preliminary data over 2 years indicate possible long-term improvement in motor and sensory nerve conduction in the lower limbs. 5.) Clinical and postmarketing surveillance studies have revealed a highly favourable safety profile of the drug. Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I Study) is being conducted in North America and Europe aimed at slowing the progression of diabetic polyneuropathy using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment.

Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy.

Short-term trials with the antioxidant thioctic acid (TA) appear to improve neuropathic symptoms in diabetic patients, but the long-term response remains to be established. Therefore, Type 1 and Type 2 diabetic patients with symptomatic polyneuropathy were randomly assigned to three treatment regimens: (1) 2 x 600(mg of TA (TA 1200), (2) 600)mg of TA plus placebo (PLA) (TA 600) or (3) placebo and placebo (PLA). A trometamol salt solution of TA of 1200 or 600 mg or PLA was intravenously administered once daily for five consecutive days before enrolling the patients in the oral treatment phase. The study was prospective, PLA-controlled, randomized, double-blind and conducted for two years. Severity of diabetic neuropathy was assessed by the Neuropathy Disability Score (NDS) and electrophysiological attributes of the sural (sensory nerve conduction velocity (SNCV), sensory nerve action potential (SNAP)) and the tibial (motor nerve conduction velocity (MNCV), motor nerve distal latency (MNDL)) nerve. Statistical analysis was performed after independent reviewers excluded all patients with highly variable data allowing a final analysis of 65 patients (TA 1200: n = 18, TA 600: n = 27; PLA: n = 20). At baseline no significant differences were noted between the groups regarding the demographic variables and peripheral nerve function parameters for these 65 patients. Statistically significant changes after 24 months between TA and PLA were observed (mean +/- SD) for sural SNCV: +3.8 +/- 4.2 m/s in TA 1200, +3.0+/-3.0m/s in TA 600, -0.1+/-4.8m/s in PLA (p < 0.05 for TA 1200 and TA 600 vs. PLA); sural SNAP: +0.6+/-2.5 microV in TA 1200, +0.3+/-1.4 microV in TA 600, -0.7 +/- 1.5 microV in PLA (p = 0.076 for TA 1200 vs. PLA and p < 0.05 for TA 600 vs. PLA), and in tibial MNCV: +/- 1.2 +/- 3.8 m/s in TA 1200, -0.3 +/- 5.2 m/s in TA 600, 1.5 +/- 2.9 m/s in PLA (p < 0.05 for TA 1200 vs. PLA). No significant differences between the groups after 24 months were noted regarding the tibial MNDL and the NDS. We conclude that in a subgroup of patients after exclusion of patients with excessive test variability throughout the trial, TA appeared to have a beneficial effect on several attributes of nerve conduction.

[The diabetic foot. The Croatian model--national consensus (clinical recommendations for diagnosis, prevention and therapy)]. / Dijabeticko stopalo. Hrvatski model--nacionalno usuglaseno misljenje (klinicke preporuke za dijagnostiku, prevenciju i lijecenje).

Diabetic foot occurs due to the loss of protective sense and circulation disorder and a marked proneness to infections. Mechanical stress of bone growths frequently leads to ulcerations. The prevention and timely treatment of diabetic foot requires the participation of both patients and all health care levels. This consensus is given for the purpose of procedure standardization. Education is the basis of prevention and should be carried out with every patient suffering from diabetes mellitus and those with a sensory defect in particular. Appropriate footwear significantly contributes to prevention and treatment of ulcers. As regards the treatment, the necessity of surgical approach with a long term and often manifold antibiotic therapy should be pointed out. Infections are usually mixed. The deeper the ulceration, the more likely the infection with anaerobes and Gram-negative bacteria occurs in addition to Gram-positive ones which are normally present in surface lesions. Strict metabolic control is a precondition for successful treatment. In conclusion, diabetic foot is a major health problem which requires multidisciplinary approach with permanent patient education as its essential part, and a specific cooperation of all levels and different health care specialties.

Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy.

AIMS: To evaluate the efficacy and safety of short-term oral treatment with the antioxidant thioctic acid (TA) on neuropathic symptoms and deficits in patients with Type 2 diabetes mellitus with symptomatic polyneuropathy. METHODS: Patients were randomly assigned to oral treatment with 600 mg of TA t.i.d. (n = 12) or placebo (n = 12) for 3 weeks. Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) in the feet were scored at weekly intervals and summarized as a Total Symptom Score (TSS). The Hamburg Pain Adjective List (HPAL) and the Neuropathy Disability Score (NDS) were assessed at baseline and day 19. RESULTS: At baseline the TSS, HPAL, and NDS were not significantly different between the groups. The TSS in the foot decreased from baseline to day 19 by -3.75 +/- 1.88 points (-47%) in the TA group and by -1.94 +/- 1.50 points (-24%) in the placebo group (P= 0.021 for TA vs. placebo). The total HPAL score decreased from baseline to day 19 by -2.20 +/- 1.65 points (-60%) in the TA group and by -0.96 +/- 1.32 points (-29%) in the placebo group (P = 0.072 for TA vs. placebo). The NDS decreased by -0.27 +/- 0.47 points in the TA group, whereas it slightly increased by +0.18 +/- 0.4 points in the placebo group (P = 0.025 for TA vs. placebo). No differences between the groups were noted regarding the rates of adverse events. CONCLUSIONS: These preliminary findings indicate that oral treatment with 600 mg of TA t.i.d. for 3 weeks may improve symptoms and deficits resulting from polyneuropathy in Type 2 diabetic patients, without causing significant adverse reactions.