Ryan Bradley, ND, MPH
Bill Walter, ND
Whether patient, family member, or health-care provider, we all know caring for diabetes requires more than 'just' keeping blood sugar balanced (which is challenging enough). There are also the associated conditions - e.g., high cholesterol, high blood pressure, neuropathy, etc., requiring time and attention to prevent severe complications which can greatly impair quality of life and rapidly limit functionality. In this month’s 'Complementary Corner' we’re going to shine a spotlight on a natural product with great potential in the care for diabetes called 'alpha-lipoic acid' (or ALA for short). ALA is a sulfur-containing compound present in human cells, where it is required for energy production within the mitochondria. In addition to its critical role in energy production, ALA is known to have antioxidant and anti-inflammatory properties - both of which are useful in managing diabetes and its complications. Research on ALA includes large clinical trials supporting its role in treating neuropathy, but research suggests it may help improve insulin sensitivity, lower blood sugar and cholesterol, improve blood vessel tone, and decrease inflammation and oxidative stress.
Use in diabetes: Neuropathy
In diabetes, 'neuropathy' typically refers to nerve damage accumulated over years or decades as a result of increased oxidative stress and reductions in blood flow. When occurring in the extremities (typically the legs and feet), neuropathy can lead to pain, tingling, and numbness. This loss of sensation can in turn lead to unnoticed injuries, which is why people with diabetes should have their feet checked by healthcare providers at each visit. In addition to the extremities, however, neuropathy can also develop in the nerves of the internal organs - leading to problems with the heart or digestive system. Because of its antioxidant properties1 and its ability to improve blood-vessel circulation to the nerves,2 ALA has received significant attention as a possible treatment for diabetic peripheral neuropathy, and it has been used in Germany for decades as a treatment for this painful and dangerous complication.
Dr. Dan Ziegler’s team at the German Diabetes Clinic has conducted a number of clinical trials in patients with type 2 diabetes trying to determine optimal doses of ALA for diabetic neuropathy. The Alpha-Lipoic Acid in Diabetic Neuropathy (ALADIN) Study found significant benefit in using intravenous ALA (IV-ALA) for a period of 3 weeks, with an effective dose of 600 or 1200mg daily.3 A 2004 meta-analysis conducted by Ziegler found several other studies supporting the use of 600mg IV-ALA for three weeks.4
...oral doses of 600, 1200, or 1800mg of ALA for five weeks led to significant improvement in neuropathy symptoms...
Unfortunately, intravenous therapy is costly and requires close clinical supervision, factors which led to research administering ALA by mouthwith mixed results. A small Romanian study of 26 patients found symptomatic improvement with oral ALA (600mg daily) after three months.5 Ziegler replicated these findings in the 2006 SYDNEY-2 trial, finding that oral doses of 600, 1200, or 1800mg of ALA for five weeks led to significant improvement in neuropathy symptoms, with the best safety profile at 600mg.6 Notably, side effects were observed and included nausea, vomiting, and vertigo, which increased in a dose-dependent manner between 1200 and 1800mg per day.
In contrast, ALADIN-III (Ziegler, again), monitored 509 patients after three weeks of IV-ALA followed by oral ALA at 600mg three times daily for six months, but found no clinically significant improvement in symptom scores after 6 months of oral treatment, when compared to placebo.7 ALADIN-III started with three weeks of IV-ALA as a lead-in - it’s possible this more direct method of administering ALA is what led to the disappointing findings in using oral ALA in this study.
From a clinical perspective, diabetic neuropathy is challenging to treat, and often requires expensive drugs with notable side effects
From a clinical perspective, diabetic neuropathy is challenging to treat, and often requires expensive drugs with notable side effects (typically antidepressant and antiepileptic drugs used for pain management). Yet in 2006 a review of SYDNEY-2 found ALA may be as effective as many commonly used pharmaceuticals, without the expense and other complexities of managing typical prescription medications.8 An updated meta-analysis in 2012 continued to support using IV-ALA and some benefit in using 600mg of oral ALA for diabetic peripheral neuropathy.9
Using ALA for “autonomic” (cardiac or digestive) neuropathies is less well-studied. Ziegler’s team found benefit in using ALA for cardiac neuropathy. Using a measure of cardiac health called heart-rate variability (HRV), they found 800mg of oral ALA for four months led to improvement, when compared to placebo.3 A Bulgarian team led by Tankova found similar benefit to cardiac and digestive-system neuropathy after a three-week IV course followed by 600mg daily for 50 days, though these were patients with type 1 diabetes.10 Interestingly, nerve pain and inflammation not associated with diabetes (but that often gets confused with neuropathy in people with diabetes) such as carpal tunnel syndrome11 and sciatica12 may also respond to ALA.
Improving Insulin Sensitivity, Lowering Glucose and Lipids
While most of the research on ALA in diabetes has focused on its effects on neuropathy, several clinical trials have now found ALA may increase insulin sensitivity and help reduce blood sugar and lipids, largely through improving measures of oxidative stress and inflammation.
...several clinical trials have now found ALA may increase insulin sensitivity and help reduce blood sugar and lipids...
Perhaps the most detailed study of glycemic effects used 600mg IV-ALA daily for two weeks in 22 patients, finding this therapy led to improvements in fasting and average glucose, insulin sensitivity, plus beneficial effects on LDL, HDL, and total cholesterol (the study was too short to measure changes in hemoglobin A1c).13 While intravenous therapy is an impractical therapy for several reasons, the study is important to consider because the team also tracked important measures of inflammation and oxidative stress (e.g., measures including tumor necrosis factor (TNF), interleukin-6 (Il-6), 8-isoprostandin, and malondialdehyde (MDA)) which are typically elevated in diabetes, and perpetuate inflammation and oxidative stress. ALA significantly reduced each of these markers. In addition, the researchers found a statistical correlation between insulin sensitivity and each individual marker of inflammation and oxidative stress - lending credence to the idea that by reducing oxidative stress and inflammation, ALA can then increase insulin sensitivity and improve blood sugar and lipid control.
Studies of ALA administered orally have found similar beneficial results for hyperglycemia. Seventy-four patients were divided into four groups (placebo, and 600mg ALA once, twice, or thrice daily) for a 4-week trial to examine its effects on insulin sensitivity, using a measurement called the Metabolic Clearance of Glucose (MCR). ALA treatment led to significant improvement in MCR, though there was no significant difference between doses.14 Another trial found improvements in insulin resistance and fasting glucose after 300mg of oral ALA daily for eight weeks.15 Fructosamine - an infrequently used, shorter-term measure of blood sugar control - was found to decrease by about 10% after 12 weeks of treatment with a controlled-release ALA formula.16 An additional small trial of 600mg/day of oral ALA was found to increase insulin sensitivity in people with type 2 diabetes.17 Less exciting is a Brazilian study of 102 people with DM-II, which only measured non-significant trends toward improvements in lipids and insulin sensitivity after four months of oral ALA (600mg).18
Despite the equivocal finding from Brazil, the preponderance of studies found benefit for insulin sensitivity and glycemic control (and lipids, to a lesser extent). Although these preliminary findings are very promising, studies of longer duration, i.e., several years, are required to learn exactly how ALA compares with mainstream prescription drugs for blood sugar control.
Alpha-Lipoic Acid: Other uses
Two trials have found IV-ALA may be a useful therapy to prevent or treat endothelial dysfunction...
Modest weight loss (2.1% of body weight) was measured in a trial of 360 obese individuals with a mixture of diabetes, high blood pressure, and high cholesterol after 20 weeks of oral ALA, though only by using relatively high doses - 1800mg daily (1200mg was tested, but didn’t show significant results). To put these results into perspective: consider that with a loss of 2.1% of body weight, an individual weighing 220 pounds (100kg) might expect to lose 4.6 pounds (2.1kg) after 20 weeks on a high dose of this supplement (provided they could tolerate the side effects that many other studies have found at dosages this high, i.e., nausea, vomiting, and vertigo. The expense of treatment with ALA at a dose this high for an extended period of time would also be substantial (about $2.40/day or $72.00/month - which is enough to hire a personal trainer once a month to help optimize a physical activity regimen).
Endothelial dysfunction - a diminished response of the lining of blood vessels - is one of the early stages of cardiovascular disease, and may be triggered by high levels of blood sugar leading to oxidative stress. Two trials have found IV-ALA may be a useful therapy to prevent or treat endothelial dysfunction, though these studies were of short duration (two or three weeks) and the long-term clinical implications remain unclear.19,20
Using Alpha-Lipoic Acid Safely
The research using oral alpha-lipoic acid have found it useful for diabetic neuropathy, as well as possibly having some beneficial effects on blood sugar and lipids.
Many of the studies mentioned above used alpha-lipoic acid intravenously, which may be impractical to access unless in a hospital (or in a state which allows for intravenous therapies to be performed by naturopathic doctors or integrative medical providers or nurse practitioners). The research using oral alpha-lipoic acid have found it useful for diabetic neuropathy, as well as possibly having some beneficial effects on blood sugar and lipids. Because of its glucose-lowering effects, it should be used cautiously by anybody on other anti-diabetic medications as it may reduce blood sugar too rapidly and contribute to hypoglycemic reactions.
Interestingly, there are two mirror-image structures of ALA, 'R-LA' and 'S-LA'. R-LA is present naturally while S-LA is only created synthetically. Most of the ALA on the market is a mixture of 'R' and 'S', although recently natural product companies have been heavily marketing the 'R' form; however, at this point in time the vast majority of the available clinical research has been performed on the 'R/S' mixture and therefore the 'R-only' form may not be worth the additional cost.
The side effects reported from the use of ALA are chiefly gastrointestinal, but may include itching and headache. Side effects are rare at doses of 600mg daily, but increase steadily at 1200mg and 1800mg. So far, no significant drug interactions have been reported with ALA, which supports a generally safe profile when used in standard doses.21
As with any new medication - natural or pharmaceutical - working with a licensed healthcare practitioner experienced with natural products (i.e., not a health food store clerk) is the safest way to add ALA to a complex regimen of diabetes medications. At the very least, ALA should be added to existing treatments slowly at a low dose to ensure tolerance. Finally, despite the promise that ALA and other natural products might have for diabetes and its various complications, the tried and true approach to balancing blood sugar and cholesterol doesn’t come in a bottle - it comes from a sustainable approach to diet, physical activity, and stress management!
In health- Ryan Bradley, ND, MPH and Bill Walter, ND
Ryan Bradley, ND, MPH is a naturopathic doctor, clinical researcher and epidemiologist in San Diego, CA. He is Assistant Director of Research at the National College of Natural Medicine in Portland, OR. In addition to his research, he is a practicing clinician specializing in natural and integrative approaches to treating type 2 diabetes, chronic kidney disease and heart disease at Pacific Pearl La Jolla.
1. Gianturco V, Bellomo A, D'Ottavio E, et al. Impact of therapy with alpha-lipoic acid (ALA) on the oxidative stress in the controlled NIDDM: a possible preventive way against the organ dysfunction? Arch Gerontol Geriatr. 2009;49 Suppl 1:129-133.
2. Haak E, Usadel KH, Kusterer K, et al. Effects of alpha-lipoic acid on microcirculation in patients with peripheral diabetic neuropathy. Exp Clin Endocrinol Diabetes.2000;108(3):168-174.
3. Ziegler D, Gries FA. Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes. Sep 1997;46 Suppl 2:S62-66.
4.Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. Feb 2004;21(2):114-121.
5. Negrisanu G, Rosu M, Bolte B, Lefter D, Dabelea D. Effects of 3-month treatment with the antioxidant alpha-lipoic acid in diabetic peripheral neuropathy. Rom J Intern Med. Jul-Sep 1999;37(3):297-306.
6. Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. Nov 2006;29(11):2365-2370.
7.Ziegler D, Hanefeld M, Ruhnau KJ, 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. Aug 1999;22(8):1296-1301.
8. Tang J, Wingerchuk DM, Crum BA, Rubin DI, Demaerschalk BM. Alpha-lipoic acid may improve symptomatic diabetic polyneuropathy.
9. Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N, Bilo HJ. Alpha lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials.
Int J Endocrinol.
10. Tankova T, Koev D, Dakovska L. Alpha-lipoic acid in the treatment of autonomic diabetic neuropathy (controlled, randomized, open-label study).
Rom J Intern Med.
11. Di Geronimo G, Caccese AF, Caruso L, Soldati A, Passaretti U. Treatment of carpal tunnel syndrome with alpha-lipoic acid.
Eur Rev Med Pharmacol Sci.
12. Memeo A, Loiero M. Thioctic acid and acetyl-L-carnitine in the treatment of sciatic pain caused by a herniated disc: a randomized, double-blind, comparative study.
Clin Drug Investig.
13. Zhang Y, Han P, Wu N, et al. Amelioration of lipid abnormalities by alpha-lipoic acid through antioxidative and anti-inflammatory effects.
Obesity (Silver Spring).
14. Jacob S, Ruus P, Hermann R, et al. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial.
Free Radic Biol Med.
15. Ansar H, Mazloom Z, Kazemi F, Hejazi N. Effect of alpha-lipoic acid on blood glucose, insulin resistance and glutathione peroxidase of type 2 diabetic patients.
Saudi Med J.
16. Evans JL, Heymann CJ, Goldfine ID, Gavin LA. Pharmacokinetics, tolerability, and fructosamine-lowering effect of a novel, controlled-release formulation of alpha-lipoic acid.
17. Kamenova P. Improvement of insulin sensitivity in patients with type 2 diabetes mellitus after oral administration of alpha-lipoic acid. Hormones (Athens). Oct-Dec 2006;5(4):251-258.
18. de Oliveira AM, Rondo PH, Luzia LA, D'Abronzo FH, Illison VK. The effects of lipoic acid and alpha-tocopherol supplementation on the lipid profile and insulin sensitivity of patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Diabetes Res Clin Pract. May 2011;92(2):253-260.
19. Heinisch BB, Francesconi M, Mittermayer F, et al. Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial. Eur J Clin Invest. Feb 2010;40(2):148-154.
20. Xiang GD, Sun HL, Zhao LS, Hou J, Yue L, Xu L. The antioxidant alpha-lipoic acid improves endothelial dysfunction induced by acute hyperglycaemia during OGTT in impaired glucose tolerance. Clin Endocrinol (Oxf). May 2008;68(5):716-723.
21. Gleiter CH, Schreeb KH, Freudenthaler S, et al. Lack of interaction between thioctic acid, glibenclamide and acarbose. Br J Clin Pharmacol. Dec 1999;48(6):819-825.