Alpha-Lipoic Acid for the Prevention and Treatment of Diabetic Neuropathy
July 2000; Volume 3; 73-77
By Robert J. Nardino, MD
Can the krebs cycle be used to practice medicine? the search for agents that can impact the incidence of complications irrespective of blood glucose level continues. Alpha-lipoic acid (ALA), also known as thioctic acid, is a cofactor of the pyruvate dehydrogenase enzyme complex in the energy-producing Krebs cycle. Studied most thoroughly in Germany, ALA is used there to prevent and treat diabetic neuropathy.
Disease Course
In the Diabetes Control and Complications Trial, intensive hypoglycemic therapy resulted in a 64% relative reduction in the incidence of clinical diabetic neuropathy.1 Although tight glycemic control is the standard for prevention of this complication, it is difficult to achieve in many patients. Diabetic neuropathy manifests as sensory loss of the distal extremities, painful neuropathy, or autonomic neuropathy with gastroparesis, orthostasis, and neurogenic bladder. Distal neuropathy often leads to foot ulcers, which result in increased morbidity (for example, amputation) and are associated with increased mortality. Amitriptyline is the standard for treatment of painful neuropathy symptoms. Gabapentin has been shown to be similar in efficacy to amitriptyline.2 Aldose-reductase inhibitors, despite extensive research, have been disappointing in the treatment of diabetic neuropathy.
Biochemistry
In the mitochondria, blood glucose is converted to pyruvate during glycolysis. ALA is manufactured in the mitochondria and is a cofactor in the pyruvate dehydrogenase complex, which converts pyruvate into acetyl-CoA. The reduced form of ALA is the active form, and it acts as a hydrogen donor for other enzymes in the complex. Two lipoic acid groups also are attached to a lysine residue of dihydrolipoyl transacetylase, the core enzyme of the pyruvate dehydrogenase complex.
Pharmacology
ALA is both water- and lipid-soluble. The only available study on the pharmacokinetics of ALA was conducted on 12 healthy volunteers and compared 200 mg or 600 mg oral doses with a 200 mg intravenous dose.3 There was no difference in the plasma clearance (half-life) between the two oral doses.
Pathogenesis
Recent research has defined the role of oxidative stress, resulting from increased free radical activity, in the pathogenesis of diabetic neuropathy. This has been demonstrated in diabetic rats, in which oxidative stress led to delayed nerve conduction velocities.4 It appears that neural hypoxia from an impaired microvascular supply is the insult that contributes to nerve damage; in addition, in rats with experimental diabetic neuropathy, nerve glucose uptake is reduced. A variety of antioxidants can prevent this reduced blood flow in experimental models.
Mechanism of Action
ALA acts as an antioxidant and increases cellular glutathione levels. It may also improve glucose utilization.
In diabetic patients with poor glycemic control and albuminuria, administration of ALA reduced biochemical markers of oxidative stress (plasma lipid hydroperoxides).5 In 10 patients with diabetes and neuropathy, ALA therapy led to improvement in the microcirculatory response and to (desired) cooling of the extremity.6 In animal models, parenteral ALA resulted in enhanced glucose transport and utilization.7,8
Early studies with low-dose ALA supplementation in humans resulted in increased levels of pyruvate and lactate, suggesting that the pyruvate dehydrogenase enzyme complex was being inhibited. However, this was subsequently overcome by the use of higher doses. ALA treatment resulted in an improved response to glucose loading in a small sample of lean and obese diabetic patients.9,10 However, the effect on fasting blood sugar was very small.
Relevant Animal Studies
The reduction in nerve glucose uptake in experimental diabetic neuropathy can be reversed in a dose-dependent fashion with ALA administration, and this reduction is accompanied by improved neural function.11 ALA supplementation also prevented reperfusion injury of peripheral nerves in an animal model.12
Clinical Studies
Ziegler et al reviewed the studies of ALA and diabetic neuropathy.13 Fifteen clinical trials have been completed with a variety of patient populations, treatment protocols, and outcome measures. Studies using less than 600 mg/d ALA showed no clinical or physiologic benefit. Studies using more than 600 mg/d ALA did show some evidence of reduced symptoms and improved nerve function as based on neuroelectrophysiology. However, most of the studies have been small, and the benefits modest.
The major clinical studies have been conducted in Germany by Ziegler’s group. In the ALA in Diabetic Neuropathy trial (ALADIN), 328 patients with type 2 diabetes mellitus and symptomatic neuropathy were randomized to treatment with 1,200 mg, 600 mg, or 100 mg parenteral ALA or placebo.14 At three weeks, the 600 mg and 1,200 mg groups showed improvement over placebo in symptoms.
ALADIN II added an oral treatment phase.15 Sixty-five type 1 and 2 diabetics with symptomatic polyneuropathy were randomized to 600 mg or 1,200 mg intravenous ALA or placebo, for five days, followed by oral ALA for two years. Endpoints were Neuropathy Disability Score (no change), and nerve conduction velocities (significant improvement).
ALADIN III, the largest study to date, was a multicenter, randomized, double-blind, placebo-controlled trial.16 In this trial, 509 patients with type 2 diabetes and evidence of symptomatic symmetric distal neuropathy were randomly assigned to 600 mg ALA given intravenously for three weeks or placebo, followed by 600 mg given orally tid for six months or placebo.
There were two outcome measures: Total Symptom Score and Neuropathy Impairment Score. The Total Symptom Score was based on the presence of pain, burning, and numbness in the feet. The Total Symptom Score decreased after three weeks with ALA therapy, but was no different than placebo when the study concluded after seven months. The Neuropathy Impairment Score was based on motor function, stretch reflexes, and sensation (vibration, proprioception, pinprick, and touch-pressure). This score was improved in the ALA group at both three weeks and seven months. A major limitation was that 25% of the patients dropped out of the trial.
All of the preceding studies included parenteral therapy. Only one small three-week study used only oral therapy.17
In the Deutsche Kardiale Autonome Neuropathie study (DEKAN), 73 patients with cardiac autonomic neuropathy as measured by heart rate variability were treated with 800 mg/d ALA or placebo.18 There was a small increase in heart rate variability but no change in symptoms. Again, a large number of patients dropped out of the trial (17 of 73), limiting the ability to detect a clinically meaningful difference.
Lack of effectiveness, intercurrent disease, and noncompliance were reasons cited for the high dropout rates in these studies. The effects of ALA occurred without lowering of the blood sugar.
Adverse Effects
In both the ALADIN and DEKAN studies, no significant adverse effects were reported. In the ALADIN study, adverse events were equivalent in the treatment and placebo groups. Others have reported skin rash. Because of improved insulin sensitivity, there is a theoretical risk of hypoglycemia, but the clinical importance of this side effect is unknown. ALA may interfere with thiamine utilization. There are no data available concerning the use of ALA in pregnancy or lactation, and its use in these settings should be avoided.
Drug Interactions
No drug interactions with ALA have been described. The glucose-lowering effect of ALA in clinical trials was modest, and adjustment of insulin or oral hypoglycemic drugs should be based on the results of home glucose monitoring.
Other Effects
The first clinical use of ALA in humans was to treat a variety of liver diseases, including ethanol-induced damage, mushroom poisoning, and carbon tetrachloride toxicity. ALA was found to be effective at inhibiting replication of HIV-1 in cultured T lymphocytes.19 It also is being investigated as a means to mitigate the toxic effect of certain chemotherapeutic agents.
ALA is used by some diabetic patients to lower blood glucose levels. It is approved as a drug in Germany for the treatment of diabetic neuropathy, and the recommendation is parenteral treatment for three weeks followed by oral therapy, as in the ALADIN III trial.
Formulation
ALA can be found in foods that contain mitochondria in large amounts. The best dietary source is probably red meat, the ingestion of which many patients are now limiting. Investigations are underway to determine the amount contained in plant foods.
Most supplements contain doses in the 50-100 mg range, but some contain higher doses to more easily approach the doses used in clinical trials. (See Table 1 for price comparison of ALA supplements.)
| Table 1-Price comparisons of alpha-lipoic acid | ||
| Manufacturer | Formulation | Price/Quantity |
| Carlson Laboratories | 300 mg | $22.50/30 tablets |
| Source Naturals, Inc. | 200 mg | $27.60/60 tablets |
| Solgar Co. | 200 mg | $26.50/50 vegicaps |
| Twinlab, Inc. | 100 mg | $21.95/60 capsules |
| Country Life | 100 mg | $18.95/50 capsules |
| The Vitamin Shoppe | 100 mg | $31.95/120 tablets |
| Natrol, Inc. | 100 mg | $29.95/100 capsules |
| Kal | 100 mg | $27.58/60 tablets |
| Source: Online mail-order firms | ||
Conclusion
ALA has demonstrated antioxidant properties, and increasing evidence implicates oxidative stress in the etiology of diabetic neuropathy. Randomized clinical trials, conducted primarily in Germany, have demonstrated some improvement in nerve function, and to a lesser extent, symptoms in diabetic patients with peripheral neuropathy.
However, these studies have suffered from high dropout rates, and there are no studies specifically addressing neuropathy prevention in patients who have not yet developed it. Preventive effects are inferred by slowing the progression of established neuropathy. In addition, it is not clear whether oral dosing alone will be effective, as the largest studies have been performed primarily with parenteral therapy, though one study demonstrated no significant difference in plasma half-life between oral and intravenous doses.3
A large multicenter trial in North America and Europe investigating oral ALA and its effect on slowing the progression of diabetic neuropathy has been initiated. Another area of investigation is the combination of ALA and gamma-linoleic acid. The ultimate test of efficacy would be a decrease in neuropathy-related morbidity, such as infection, amputation, and mortality.
Recommendation
Patients with type 1 or 2 diabetes with symptomatic peripheral neuropathy may benefit from ALA therapy. The current best evidence supports intravenous therapy for three weeks followed by oral doses; however, intravenous therapy is not available in the United States. It is unclear whether oral therapy alone leads to the same benefit. Patients deciding to try this treatment should take 600 mg/d. Because ALA may lower blood sugar levels, blood glucose monitoring should be done more frequently after initiating ALA therapy. Further research is necessary to determine if patients without neuropathy should use ALA to prevent its development.
Dr. Nardino is Program Director of the Internal Medicine Residency at the Hospital of Saint Raphael in New Haven, CT, and Assistant Clinical Professor of Medicine, Yale University School of Medicine.
References
1. The effect of intensive diabetes therapy on the development and progression of neuropathy. The Diabetes Control and Complications Trial Research Group. Ann Intern Med 1995;122:561-568.
2. Morello CM, et al. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med 1999;159:1931-1937.
3. Teichert J, et al. Investigations on the pharmacokinetics of alpha-lipoic acid in healthy volunteers. Int J Clin Pharmacol Ther 1998;36:625-628.
4. Cameron NE, et al. Effects of alpha-lipoic acid on neurovascular function in diabetic rats: Interaction with essential fatty acids. Diabetologia 1998;41:390-399.
5. Borcea V, et al. Alpha-lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria. Free Radic Biol Med 1999;26:1495-1500.
6. Haak ES, et al. The effect of alpha-lipoic acid on the neurovascular reflex arc in patients with diabetic neuropathy assessed by capillary microscopy. Microvasc Res 1999;58:28-34.
7. Jacob S, et al. The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. Diabetes 1996;45:1024-1029.
8. Estrada DE, et al. Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: Participation of elements of the insulin signaling pathway. Diabetes 1996;45:1798-1804.
9. Konrad T, et al. Alpha-lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care 1999;22:280-287.
10. Jacob S, et al. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittelforschung 1995;45:872-874.
11. Kishi Y, et al. Alpha-lipoic acid: Effect on glucose uptake, sorbitol pathway, and energy metabolism in experimental diabetic neuropathy. Diabetes 1999;48:2045-2051.
12. Mitsui Y, et al. Alpha-lipoic acid provides neuroprotection from ischemia-reperfusion injury of peripheral nerve. J Neurol Sci 1999;163:11-16.
13. Ziegler D, et al. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: Current evidence from clinical trials. Exp Clin Endocrinol Diabetes 1999;107:421-430.
14. Ziegler D, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995;38:1425-1433.
15. Reljanovic M., et al. 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. Free Radic Res 1999;31:171-179.
16. Ziegler D, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: A 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care 1999;22:1296-1301.
17. Ruhnau KJ, et al. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med 1999;16:1040-1043.
18. Ziegler D, et al. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Diabetes Care 1997;20:369-373.
19. Baur A, et al. Alpha-lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication. Klin Wochenschr 1991;69:722-724.
July 2000; Volume 3; 73-77
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