Diabetic Neuropathy - Treatment

Alpha Lipoic Acid - updated: 15 March 2008

Lipoic acid (LA) and its reduced form dihydrolipoic acid (DHLA, are present in all prokaryotic and eukaryotic cells. Lipoic acid was once considered a vitamin, but now it is commonly accepted that it can be synthesized de novo in human cells. LA has long been known as a coenzyme of multienzymatic complexes catalyzing the decarboxylation of alpha-ketoacids, but the present investigations are focused on its antioxidative properties. Both LA and DHLA have proved to be potent free radicals scavengers and metal chelators. They are also responsible for the regeneration of active forms of other cellular antioxidants, including vitamins C and E. Moreover, lipoic acid is involved in the regulation of carbohydrate and lipid metabolism. LA is easily absorbed from the gastrointestinal tract, is able to cross the blood-brain barrier, and does not exhibit any serious side effects. All these features make lipoic acid a very promising drug. Nowadays, this compound is used in the treatment of diabetic neuropathy, fungi, and metal poisoning, as well as in liver disorders. The application of lipoic acid in treating other diseases, including hypertension and autoimmunological disorders, needs careful evaluation.

Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial

Diabetes Care. 2006 Nov;29(11):2365-70.

Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R.

OBJECTIVE: The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients' global assessment of efficacy. RESULTS: Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (>/=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients' global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. CONCLUSIONS: Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.

Publication Types:

• multicenter, randomized, double-blind, placebo-controlled trial

The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial

Diabetes Care. 2003 Mar;26(3):770-6

Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O'Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D; SYDNEY Trial Study Group.

OBJECTIVE: Because alpha-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(+) K(+) ATPase activity in experimental diabetes and in humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms. RESEARCH DESIGN AND METHODS: Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n = 60) or placebo (n = 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Secondary end points were sum scores of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction, quantitative sensation tests (QSTs), and an autonomic test. RESULTS: At randomization, the groups were not significantly different by the criteria of metabolic control or neuropathic end points. After 14 treatments, the TSS of the ALA group had improved from baseline by an average of 5.7 points and the placebo group by an average of 1.8 points (P < 0.001). Statistically significant improvement from baseline of the ALA, as compared with the placebo group, was also found for each item of the TSS (lancinating and burning pain, asleep numbness and prickling), NIS, one attribute of nerve conduction, and global assessment of efficacy. CONCLUSIONS: Intravenous racemic ALA, a potent antioxidant, rapidly and to a significant and meaningful degree, improved such positive neuropathic sensory symptoms as pain and several other neuropathic end points. This improvement of symptoms was attributed to improved nerve pathophysiology, not to increased nerve fiber degeneration. Because of its safety profile and its effect on positive neuropathic sensory symptoms and other neuropathic end points, this drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy.

Publication Types:

• Review

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

Exp Clin Endocrinol Diabetes. 1999;107(7):421-30

Ziegler D, Reljanovic M, Mehnert H, Gries FA.

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.

Publication Types:

• Review

Thioctic acid for patients with symptomatic diabetic polyneuropathy: a critical review

Treat Endocrinol. 2004;3(3):173-89

Ziegler D.

Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. A growing body of evidence suggests that oxidative stress resulting from enhanced free-radical formation and/or defects in antioxidant defense is implicated in the pathogenesis of diabetic neuropathy. Markers of oxidative stress such as superoxide anion and peroxynitrite production are increased in diabetic patients in relation to the severity of polyneuropathy. In experimental diabetic neuropathy, oxygen free-radical activity in the sciatic nerve is increased, and treatment with thioctic acid, a potent lipophilic antioxidant, results in prevention or improvement of the diabetes-induced neurovascular and metabolic abnormalities in various organ systems. Pharmacodynamic studies have shown that thioctic acid favorably influences the vascular abnormalities of diabetic polyneuropathy such as impaired microcirculation, increased indices of oxidative stress, and increased levels of markers for vascular dysfunction, such as thrombomodulin, albuminuria, and nuclear factor-kappaB. Thus far, seven controlled randomized clinical trials of thioctic acid in patients with diabetic neuropathy have been completed (Alpha-Lipoic Acid in Diabetic Neuropathy [ALADIN I-III], Deutsche Kardiale Autonome Neuropathie [DEKAN], Oral Pilot [ORPIL], Symptomatic Diabetic Neuropathy [SYDNEY], Neurological Assessment of Thioctic Acid in Neuropathy [NATHAN] II) using different study designs, durations of treatment, doses, sample sizes, and patient populations. Recently, a comprehensive analysis was undertaken of trials with comparable designs that met specific eligibility criteria for a meta-analysis to obtain a more precise estimate of the efficacy and safety of thioctic acid (600mg intravenously for 3 weeks) in diabetic patients with symptomatic polyneuropathy. This meta-analysis included the largest sample of diabetic patients (n = 1258) ever to have been treated with a single drug or class of drugs to reduce neuropathic symptoms, and confirmed the favorable effects of thioctic acid based on the highest level of evidence (Class Ia: evidence from meta-analyses of randomized, controlled trials). The following conclusions can be drawn from these trials: (i) short-term treatment for 3 weeks using intravenous thioctic acid 600 mg/day reduces the chief symptoms of diabetic polyneuropathy to a clinically meaningful degree; (ii) this effect on neuropathic symptoms is accompanied by an improvement of neuropathic deficits, suggesting potential for the drug to favorably influence underlying neuropathy; (iii) oral treatment for 4-7 months tends to reduce neuropathic deficits and improve cardiac autonomic neuropathy; and (iv) clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of the drug. Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I) is being conducted in North America and Europe to investigate effects on progression of diabetic polyneuropathy, using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment.

Publication Types:

• Review

Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis

Diabet Med. 2004 Feb;21(2):114-21

Ziegler D, Nowak H, Kempler P, Vargha P, Low PA.

AIMS: To determine the efficacy and safety of 600 mg of alpha-lipoic acid given intravenously over 3 weeks in diabetic patients with symptomatic polyneuropathy. METHODS: We searched the database of VIATRIS GmbH, Frankfurt, Germany, for clinical trials of alpha-lipoic acid according to the following prerequisites: randomized, double-masked, placebo-controlled, parallel-group trial using alpha-lipoic acid infusions of 600 mg i.v. per day for 3 weeks, except for weekends, in diabetic patients with positive sensory symptoms of polyneuropathy which were scored by the Total Symptom Score (TSS) in the feet on a daily basis. Four trials (ALADIN I, ALADIN III, SYDNEY, NATHAN II) comprised n=1258 patients (alpha-lipoic acid n=716; placebo n=542) met these eligibility criteria and were included in a meta-analysis based on the intention-to-treat principle. Primary analysis involved a comparison of the differences in TSS from baseline to the end of i.v. Treatment between the groups treated with alpha-lipoic acid or placebo. Secondary analyses included daily changes in TSS, responder rates (> or =50% improvement in TSS), individual TSS components, Neuropathy Impairment Score (NIS), NIS of the lower limbs (NIS-LL), individual NIS-LL components, and the rates of adverse events. RESULTS: After 3 weeks the relative difference in favour of alpha-lipoic acid vs. placebo was 24.1% (13.5, 33.4) (geometric mean with 95% confidence interval) for TSS and 16.0% (5.7, 25.2) for NIS-LL. The responder rates were 52.7% in patients treated with alpha-lipoic acid and 36.9% in those on placebo (P<0.05). On a daily basis there was a continuous increase in the magnitude of TSS improvement in favour of alpha-lipoic acid vs. placebo which was noted first after 8 days of treatment. Among the individual components of the TSS, pain, burning, and numbness decreased in favour of alpha-lipoic acid compared with placebo, while among the NIS-LL components pin-prick and touch-pressure sensation as well as ankle reflexes were improved in favour of alpha-lipoic acid after 3 weeks. The rates of adverse events did not differ between the groups. CONCLUSIONS: The results of this meta-analysis provide evidence that treatment with alpha-lipoic acid (600 mg/day i.v.) over 3 weeks is safe and significantly improves both positive neuropathic symptoms and neuropathic deficits to a clinically meaningful degree in diabetic patients with symptomatic polyneuropathy.

Publication Types:

• Review

The effect of alpha-lipoic acid on symptoms and skin blood flow in diabetic neuropathy

Diabet Med. 2007 Sep;24(9):1034-8. Epub 2007 May

Jin HY, Joung SJ, Park JH, Baek HS, Park TS.

AIMS: Multiple pathogenic pathways are involved in diabetic neuropathy and diverse treatments have been tried without success. The aim of this study was to assess the effect of alpha-lipoic acid on skin blood flow in patients with diabetic neuropathy. METHODS: We measured skin blood flow in 13 control subjects and 19 patients with diabetic neuropathy using the laser Doppler blood flow technique. Skin blood flow and the extent of skin blood flow changes were compared before and after diabetic patients received 600 mg/day alpha-lipoic acid intravenously for 14 days. RESULTS: Although no significant differences in absolute values of skin blood flow or in the extent of changes were noted, symptoms were reduced after alpha-lipoic acid treatment. CONCLUSIONS: This study suggests that alpha-lipoic acid, a potent antioxidant, improves symptoms of diabetic neuropathy. Larger studies are needed to determine whether improvements in skin blood flow also occur in patients with diabetic neuropathy.

Alpha-lipoic acid in the treatment of autonomic diabetic neuropathy (controlled, randomized, open-label study).

Rom J Intern Med. 2004;42(2):457-64

Tankova T, Koev D, Dakovska L.

AIM: to evaluate the effect of alpha-lipoic acid in autonomic diabetic neuropathy in a controlled, randomized, open-label study. MATERIAL AND METHODS: 46 patients with type 1 diabetes and different forms of autonomic neuropathy, of mean age 38.1 +/- 12.5 years and mean duration of diabetes 16.8 +/- 8.9 years were treated with alpha-lipoic acid for 10 days 600mg daily iv, thereafter one film tablet of 600mg daily for 50 days. 29 type 1 diabetic patients with autonomic diabetic neuropathy, of mean age 40.2 +/- 9.3 years and mean duration of diabetes 15.4 +/- 7.9 years served as a control group. We have followed-up patients' complaints, Ewing's tests, laboratory parameters of oxidative stress. RESULTS: There was a significant improvement after treatment in the score for severity of cardiovascular autonomic neuropathy--from 6.43 +/- 0.9 to 4.24 +/- 1.8 (p<0.001), while in the control group it worsened from 6.18 +/- 1.3 to 6.52 +/- 0.9 (p>0.1). We found improvement in the Valsalva manoeuvre after treatment - from 1.05 +/- 0.04 to 1.13 +/- 0.08 (p<0.001); in the deep-breathing test -from 3.4 +/- 2.8 to 10.4 +/- 5.7 (p<0.001); and in the lying-to-standing test--from 0.99 +/- 0.01 to 1.01 +/- 0.02 (p>0.1), while in the control group there was no improvement. There was a beneficial effect of treatment on the change of systolic blood pressure at the lying-to-standing test--from 22.7 +/- 11.5 to 9.8 +/- 7.9 (p<0.001), while in the control group the change was 20.5 +/- 11.1 mmHg and 19.7 +/- 12.9 mmHg (p>0.1), respectively. We found improvement in diabetic enteropathy in six patients; in the complaints of dizziness, instability upon standing in six patients; in neuropathic edema of the lower extremities in four patients and in erectile dysfunction in four patients after treatment, while in the control group no change was reported in the symptoms and signs of autonomic neuropathy by the end of the follow-up period. There were changes in the laboratory parameters of oxidative stress after therapy--total serum antioxidant capacity increased from 20.42 +/- 1.8 to 22.96 +/- 2.3 microgH2O2/ml/min (p<0.05), serum SOD activity - from 269.8 +/- 31.1 to 319.8 +/- 29.IU/l (p=0.02) and erythrocyte SOD--from 0.89 +/- 0.10 to 1.11 +/- 0.09 U/gHb (p=0.04). CONCLUSION: Our results demonstrate that alpha-lipoic acid (Thiogamma) appears to be an effective drug in the treatment of the different forms of autonomic diabetic neuropathy.

Publication Types:

• controlled, randomized, open-label study

Peripheral neuropathy: pathogenic mechanisms and alternative therapies

Altern Med Rev. 2006 Dec;11(4):294-329

Head KA.

Peripheral neuropathy (PN), associated with diabetes, neurotoxic chemotherapy, human immunodeficiency virus (HIV)/antiretroviral drugs, alcoholism, nutrient deficiencies, heavy metal toxicity, and other etiologies, results in significant morbidity. Conventional pain medications primarily mask symptoms and have significant side effects and addiction profiles. However, a widening body of research indicates alternative medicine may offer significant benefit to this patient population. Alpha-lipoic acid, acetyl-L-carnitine, benfotiamine, methylcobalamin, and topical capsaicin are among the most well-researched alternative options for the treatment of PN. Other potential nutrient or botanical therapies include vitamin E, glutathione, folate, pyridoxine, biotin, myo-inositol, omega-3 and -6 fatty acids, L-arginine, L-glutamine, taurine, N-acetylcysteine, zinc, magnesium, chromium, and St. John's wort. In the realm of physical medicine, acupuncture, magnetic therapy, and yoga have been found to provide benefit. New cutting-edge conventional therapies, including dual-action peptides, may also hold promise.

Publication Types:

• Review

Botanicals and dietary supplements in diabetic peripheral neuropathy.

J Am Board Fam Pract. 2003 Jan-Feb;16(1):47-57

Halat KM, Dennehy CE.

BACKGROUND: Many persons use botanicals and dietary supplements for chronic conditions that do not respond to traditional Western medications. Tricyclic antidepressants, a common treatment option for diabetic neuropathy, can have many side effects and are a poor choice in certain populations (eg, the elderly). As such, patients might turn to botanicals and dietary supplements, not realizing that these products are not well regulated. METHODS: This article reviews botanicals and dietary supplements that have been involved in randomized controlled trials (RCTs) for diabetic neuropathy. We searched MEDLINE for English-language literature dating from 1966 to April 2001 using the following subject headings: (1) diabetes and botanical, herb, and supplement, (2) neuropathy and botanical, herb, and supplement, and (3) diabetic neuropathy and botanical, herb, and supplement. RESULTS: Our search found agents that might improve symptoms of neuropathy (eg, evening primrose oil, alpha-lipoic acid, capsaicin) without affecting glucose control. Botanicals and dietary supplements involved in only one RCT or associated with little clinical benefit were reviewed in brief. CONCLUSIONS: Evening primrose oil, alpha-lipoic acid, and capsaicin have received the greatest attention for their use in diabetic neuropathy, but further studies are needed to confirm their efficacy. Patients using these products need to be informed of potential drug interactions and side effects.

Publication Types:

• Review

Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy

Diabetes. 1997 Sep;46 Suppl 2:S62-6

Ziegler D, Gries FA.

Antioxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes, providing a rationale for a potential therapeutic value in diabetic patients. The effects of the antioxidant alpha-lipoic acid (thioctic acid) were studied in two multicenter, randomized, double-blind placebo-controlled trials. In the Alpha-Lipoic Acid in Diabetic Neuropathy Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. The total symptom score (TSS) (pain, burning, paresthesia, and numbness) in the feet decreased significantly from baseline to day 19 in ALA 1,200 and ALA 600 vs. PLAC. Each of the four individual symptom scores was significantly lower in ALA 600 than in PLAC after 19 days (all P < 0.05). The total scale of the Hamburg Pain Adjective List (HPAL) was significantly reduced in ALA 1,200 and ALA 600 compared with PLAC after 19 days (both P < 0.05). In the Deutsche Kardiale Autonome Neuropathie Studie, patients with NIDDM and cardiac autonomic neuropathy diagnosed by reduced heart rate variability were randomly assigned to treatment with a daily oral dose of 800 mg alpha-lipoic acid (ALA) (n = 39) or placebo (n = 34) for 4 months. Two out of four parameters of heart rate variability at rest were significantly improved in ALA compared with placebo. A trend toward a favorable effect of ALA was noted for the remaining two indexes. In both studies, no significant adverse events were observed. In conclusion, intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is safe and effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in NIDDM.

Publication Types:

• Review

Influence of food intake on the bioavailability of thioctic acid enantiomers

Eur J Clin Pharmacol (1996) 50 : 513–514

C. H. Gleiter · B. S. Schug · R. Hermann · M. Elze H. H. Blume · U. Gundert-Remy

The plasma concentration time curves are shown in Fig. 1. The values of AUC0–t (last) and Cmax of the R(+)-TA are higher than those for S([)-TA (Table 1). Administration of racemic TA after food ingestion reduced the AUC0–t (last) and Cmax values of both enan-tiomers (Table 1). The geometric means for the ratio AUC0–t (last) fed/ fasted were 76.5% (90% CI 64.1, 91.2) for R(+)-TA and 83.3% (90% CI 69.9, 99.3) for S([)-TA. The geometric means for the ratio of Cmax were 65.4% (90% CI 46.7, 91.5; P < 0.05) for R(+)-TA and 70.9% (90% CI 50.4, 99.6; P < 0.05) for S([)-TA. The mean di¤erence of tmax was 1.5 h (90% CI 0.9, 2.1; P < 0.05) for both enantiomers. As shown previously (Gleiter et al. 1995), in the pre-sent study the bioavailability of S([)-TA was lower than that of R(+)-TA. Food may signiŢcantly decrease TA bioavailability. Data on metabolites or excretion balance are not available in order to further elucidate reduction. It has been shown that the bioavailability of both enantiomers of TA is reduced in fasted diabetic patients with delayed gastric emptying (Gleiter et al. 1995). As therapy with TA is a typical long-term treat-ment, it appears particularly important that the extent of absorption remains unaltered. In order to achieve maximal absorption, it is recommended to ingest the drug while the stomach is empty.

Publication Types:

• Review

Publication Types:

• Review