[PHNUTR-L] Lipoic acid: the neglected antioxidant?

[Kathrynne Holden, MS, RD]

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                                  NUTRITION RESEARCH REVIEW


Study 1: Alpha-lipoic acid and diabetic wounds
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An Italian trial looked at the effect of giving alpha-lipoic acid (ALA) 
to diabetics being treated with hyperbaric oxygen for chronic wounds.

Subjects and method: RCT on 20 non-smoking, older patients (mean age 75 
yrs) with diabetes and a chronic wound (30+ days old) undergoing 
hyperbaric oxygen therapy. Patients were given either placebo or ALA 
(300 mg twice/day) for 30 days.

Results: Compared with placebo, ALA induced a significant rise in plasma 
a-tocopherol concentration and inhibited the rise in interleukin-6 
levels, as well as the oxidative DNA damage and lipid peroxidation seen 
when placebo was given along with the hyperbaric oxygen (all p<0.05). 
Wound healing was significantly improved in the ALA group compared with 
placebo at both 20 and 80 days.

Reference: Biochem Biophys Res Commun. 2005 Jul 29;333(2):404-10.


Studies 2/3: Open trials for diabetic nerves
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Two non-blinded trials (in Korea and Romania) tested ALA for the 
treatment of diabetic neuropathy.

Subjects and methods: In the Korean study,  31 diabetics with 
polyneuropathy completed an 8 week course of ALA 600 mg/day.  In the 
Romanian study,  75 diabetics with autonomic neuropathy were randomised 
to receive either ALA (600mg/day, IV for the first 10 days) or act as 
controls.
Results: Study 2: Total symptom score was significantly reduced at 4 and 
more so at 8 weeks, as were individual symptom scores for pain, burning 
sensation, paraesthesia, and numbness (all p<0.05).

Study 3: There was a significant improvement in several aspects of 
autonomic function, including Valsalva manoeuvre, deep-breathing test, 
postural BP change (lying-to standing) and overall cardiovascular 
autonomic neuropathy score - see Graph in Acrobat version.

Refs: Study 2: J Diabetes Complications. 2004 Mar-Apr;18(2):79-85.
and:
Study 3: Rom J Intern Med. 2004;42(2):457-64.

COMMENTS
Alpha-lipoic acid (ALA) can be synthesised by most organisms, and 
dietary sources include spinach, broccoli, beef and Brewer’s yeast. It 
is a powerful antioxidant in both aqueous and lipid environments and 
can, for example, cross readily into the brain. It regenerates other 
antioxidants, (e.g. glutathione, vitamins C and E). It has a direct role 
in mitochondrial energy production as a co-factor for several 
dehydrogenase enzymes involved in carbohydrate metabolism (ref.1-3).

ALA has long been of interest as a potential therapeutic agent in 
diabetes, including both the microvascular and neuropathic pathologies. 
This stems from ALA’s metabolic role and also because diabetes results 
in chronic oxidant stress (ref.4). A number of studies (including a RCT) 
found that ALA improved insulin sensitivity to a degree comparable, in 
the short term, with oral hypoglycaemics (ref.4, 5). And there is the 
intriguing possibility that insulin resistance is itself caused, at 
least in part, by oxidant stress (ref.6, 7).

The use of ALA to treat diabetic neuropathy has received some attention, 
particularly since conventional treatment has little to offer (ref.8). A 
meta-analysis of 4 trials of ALA involving 1,258 patients found a 
benefit of 16-25% (compared with placebo) in signs and symptoms of 
neuropathy (e.g. ankle reflexes, pain, burning, numbness, pin-prick and 
touch-pressure sensation) after 3 weeks treatment (ref.9). This is 
supported by new studies 2 and 3, and results of another open trial 
(from the authors of Study 3) of ALA for diabetic neuropathy of the 
cranial nerves (ref.10).

Renal complications of diabetes have also been treated with ALA with 
some success, so far only in animals, and this might apply to some other 
forms of kidney damage as well. Animal and in vitro studies suggest a 
potential for counteracting renal and other manifestations of toxicity, 
e.g. from heavy metals and anti-cancer drugs (ref.11-14).

Another possible application is the slowing down of aging and 
neurodegeneration through ALA’s action on mitochondria (ref.1). Although 
there is some tentative in vitro evidence of such a mitochondrial 
effect, there is only very little evidence of an impact on dementia 
(ref.15-17).

If we were looking for clinical uses of such a powerful antioxidant, 
there are many candidates. Burning mouth syndrome is an unusual one for 
which three trials of ALA (two open, and all with the same principal 
author) had positive results (ref.18). Cancer cachexia, 
ischaemia-reperfusion injury, liver disease, hypertension and other 
cardiovascular risk factors, photoaging of skin, obesity, glaucoma and 
cataracts are all conditions for which ALA has been tried, in most cases 
in small open trials and/or animal studies, but for which human RCT 
evidence is not yet convincing (ref.2, 3, 19-23).

These various studies have however suggested ALA to be a safe supplement 
at reasonable doses, even in renal failure (ref.18, 24, 25). Although 
more RCTs are clearly needed, we believe that current evidence is strong 
enough to warrant consideration of ALA as part of any antioxidant 
supplementation `cocktail’, and particularly for diabetics, for whom it 
can be trialled to treat neuropathy and possibly also in renal failure 
and to enhance glucose control. For the other disorders listed above, 
its potential currently remains mainly speculative but interesting.

References:
1. Altern Med Rev. 2005 Dec;10(4):268-93.
2. J Nutr. 2003 Nov;133(11):3327-30.
3. Altern Med Rev. 1998 Aug;3(4):308-10.
4. Diabetes Technol Ther. 2000 Autumn;2(3):401-13.
5. Free Radic Biol Med. 1999 Aug;27(3-4):309-14.
6. Free Radic Biol Med. 2006 Jan 1;40(1):3-12.
7. Treat Endocrinol. 2003;2(6):389-400.
8. J Investig Med. 2004 Jan;52(1):33-44.
9. Diabet Med. 2004 Feb;21(2):114-21.
10. Int J Clin Pract. 2005 Jun;59(6):645-50.
11. J Am Soc Nephrol. 2001 Jan;12(1):124-33.
12. Kidney Blood Press Res. 2003;26(5-6):303-14.
13. Curr Med Chem. 2004 May;11(9):1135-46.
14. Altern Med Rev. 2002 Dec;7(6):456-71.
15. Clin Nutr. 2005 Oct;24(5):794-800.
16. Cochrane Database Syst Rev. 2004;(1):CD004244.
17. Diabetes Res Clin Pract. 2001 Jun;52(3):175-83.
18. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD002779.
19. Expert Opin Investig Drugs. 2004 Dec;13(12):1641-3.
20. Cancer Epidemiol Biomarkers Prev. 2004 Oct;13(10):1651-9.
21. Clin Exp Hypertens. 2004 Oct-Nov;26(7-8):593-601.
22. Br J Dermatol. 2003 Oct;149(4):841-9.
23. Free Radic Biol Med. 1998 Apr;24(6):1023-39.
24. J Clin Pharmacol. 2005 Mar;45(3):313-28.
25. Treat Endocrinol. 2004;3(3):173-89.

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Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
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