Neuropathy is a common and well-known complication of chronic hyperglycemia due to diabetes mellitus. Distal symmetric polyneuropathy, a form frequently affecting patients with diabetes, characteristically begins in the toes and traverses proximally in symmetric fashion.
Symptoms of this late complication include loss of sensation, vibration sense, temperature sensation and muscle weakness. Often, these patients will describe hot, burning, tingling or throbbing pain that accompanies these symptoms. Those with distal symmetric polyneuropathy also have nighttime pain, which imposes a substantially detrimental effect on their quality of life.1 Researchers have also found increasing age, obesity and peripheral arterial disease to be risk factors for the eventual development of neuropathy.2
There are several strategies for alleviating neuropathic pain. Current mainstays include providing symptomatic treatment with anticonvulsants, such as pregabalin (Lyrica, Pfizer) and gabapentin (Neurontin, Pfizer), or tricyclic antidepressants. However, these medications merely relieve the symptoms and do not alter the actual pathogenetic mechanism of the disease. Furthermore, these medications are associated with adverse effects and contraindications that limit the utility of these drugs.3 Medications that modify disease progression by addressing the underlying cause of symptoms would be useful in providing long-term care for our patients, ideally without side effects.
Oxidative stress and free radical generation are deeply implicated in the development of late diabetic complications. Host antioxidant defenses act to reduce reactive oxygen species that oxidative phosphorylation in the mitochondria normally produce. Excessive glucose metabolism increases production of these free radicals and persistently high blood glucose causes the body to take up glucose through other pathways that increase free radical formation.
These processes are known to facilitate increased production of acetylated glycation end products (AGEs), protein kinase C and nitric oxide intermediates, which research has linked with microvascular and macrovascular complications involved with nerve degeneration.4 The harmful effects of AGEs occur through intracellular damage and interaction with their receptor for advanced glycation endproducts (RAGE). This leads to expression of nuclear factor kappa B (NF-KB) and consequent production of cytokines and procoagulant factors.5 In fact, authors have specifically shown that AGEs alter structural proteins of peripheral nerve tissue, namely by glycosylation of myelin protein in Schwann cells and modification of its basement membrane proteins.6
Given the influence of chronic hyperglycemia on complications of diabetes, controlling blood sugar levels in patients though lifestyle modification and dietary restriction is essential. However, this principle can be difficult for many patients to attain. Lowering blood sugar may not significantly improve the symptoms of clinical neuropathy in all patients with diabetes and one also needs to consider the occurrence of hypoglycemic episodes with enhanced glucose control for patient safety.7
A Closer Look At The Research On Alpha-Lipoic Acid
When approved therapeutic options fail to alleviate the pain associated with peripheral neuropathy, doctors should consider the use of antioxidants as a supplement. Alpha-lipoic acid is one such endogenously produced molecule that researchers have shown to be a scavenger of certain free radicals and a recycler of other antioxidants.8 The antioxidant properties of this inexpensive over-the-counter medication make it a potential candidate for correcting the underlying pathogenesis of diabetic complications.
Various researchers have studied the clinical use of alpha-lipoic acid for diabetic complications and it has been associated with limited side effects. A meta-analysis conducted in Germany including 1,258 patients analyzed multiple clinical trials that investigated the use of alpha-lipoic acid for distal symmetric polyneuropathy.9 Using intravenous infusion of 600 mg per day for three weeks, Ziegler and colleagues demonstrated improvements in pain and paresthesia as per the Total Symptom Score and improved pinprick sensation, touch pressure sensation and ankle reflexes as per Neuropathy Impairment Scores.10 The authors then evaluated the efficacy and dose-response effects of oral alpha-lipoic acid by using dosages of 600 mg, 1,200 mg and 1,800 mg among three groups for five weeks. They noted a decrease in scores for stabbing and burning pain in all treatment groups, and concluded that the improvement of symptoms was not dose-dependent. Recorded adverse effects, the most common of which was nausea, were dose-dependent.
Ziegler and colleagues expanded upon these short-term findings by orally administering alpha-lipoic acid 600 mg once daily to patients with type 1 and type 2 diabetes with distal symmetric polyneuropathy.11 The authors extended the study timeline to four years, making it the longest randomized study of distal symmetric polyneuropathy to date. They found an improvement in certain neuropathic measurements, such as the pinprick test and muscular strength. However, their primary outcome composite score, which mainly included neurophysiologic nerve conduction studies, did not show significant improvement. The authors attributed this to the disease condition being unexpectedly static in the placebo group over the treatment period.
Despite this shortcoming, the authors found that administration of alpha-lipoic acid ameliorated many of the clinical symptoms of distal symmetric polyneuropathy, suggesting an improvement in microvascular blood flow to nerves mediated by the antioxidant effects of the drug.11 This series of work demonstrated promising results in supporting the use of once daily 600 mg of alpha-lipoic acid orally in alleviating symptoms associated with peripheral neuropathy in patients with both type 1 and 2 diabetes with no serious adverse events.
Authors have specifically investigated the influence of blood glucose on the efficacy of alpha-lipoic acid. While the aforementioned studies excluded patients with HbA1c > 10%, recent studies have aimed to reveal the effects of alpha-lipoic acid on those with and without good glycemic control. Ibrahimpasic administered 600 mg IV of alpha-lipoic acid for three weeks and followed this with 600 mg oral for four months.12 The patients had concomitant treatment with insulin and oral anti-diabetes drugs. In regard to the 20 patients with type 2 diabetes in the study, there were two groups: those with HbA1c <7% (group one) and those with HbA1c >7% (group two). Both groups reported improvements in their subjective opinion of their condition.
However, Ibrahimpasic found that group one had significant improvement in paresthesia, night leg pain and gait disturbance, suggesting that alpha-lipoic acid treats symptoms of distal symmetric polyneuropathy more effectively when clinicians pair this with better glucose control of the patient with diabetes.12
What You Should Know About The Specific Effects Of Alpha-Lipoic Acid
Numerous studies have gauged the effect of alpha-lipoic acid on other major factors associated with diabetes, including insulin sensitivity and obesity.13,14 Lee and colleagues showed the influence of antioxidants on insulin sensitivity by demonstrating increased glucose uptake in skeletal muscles treated with alpha-lipoic acid.15 In addition, they found that triglyceride content was lower in soleus muscles.
Recent work using high-fat fed obese Zucker rats with a genetic and dietary predilection for obesity and dyslipidemia demonstrated that alpha-lipoic acid provides protection against triglyceride accumulation in the liver.16 A Chinese study involving obese patients with impaired glucose tolerance, putting them at high risk for type 2 diabetes, revealed improved insulin sensitivity and plasma lipid profile with only a two-week regimen of 600 mg alpha-lipoic acid daily.17
Further, an Italian study observed significant decreases in weight, body mass index, blood pressure and abdominal circumference in both pre-obese and obese patients treated with 800 mg alpha-lipoic acid daily for four months.18 Although it is difficult to attain normoglycemia in patients with developed diabetes, an Indian study demonstrated the ability of a variety of antioxidants to decrease HbA1c levels in people with type 2 diabetes after 90 days of administration.19 Patients who received alpha-lipoic acid showed a significant decrease in mean HbA1c from 11.49 to 9.96 percent.
Alpha-lipoic acid has also shown protective effects on the kidneys as demonstrated by a decrease in microalbuminuria in type 2 patients with diabetes after treatment with 600 mg daily alpha-lipoic acid for six months.20 Morcos and colleagues also looked at the beneficial effect of alpha-lipoic acid on endothelial cells in patients with type 1 and 2 diabetes, using an increase in unbound plasma thrombomodulin as a marker of endothelial cell damage. Patients treated with daily dosing of 600 mg alpha-lipoic acid had a significant decrease in plasma thrombomodulin after 18 months.21 It is also noteworthy that patients with renal impairment taking alpha-lipoic acid do not require dose adjustment.22
The observed side effects of alpha-lipoic acid have been minimal although Ziegler and coworkers noted nausea, vomiting and vertigo from oral administration.9 Of these side effects, nausea was most common, affecting 13 percent of the group receiving the oral 600 mg daily dosage of alpha-lipoic acid with vertigo affecting 4 percent and vomiting affecting 2 percent of the same group. Recent studies have also reported rare incidents of insulin autoimmune syndrome, characterized by hypoglycemia and high serum insulin levels in genetically predisposed Caucasian and Japanese patients taking alpha-lipoic acid.23
The antioxidant properties of alpha-lipoic acid have long been known and the potential benefit of the modality in a wide array of diabetic complications is clear. Despite the positive results researchers have observed with alpha-lipoic acid’s effect on the symptoms of diabetic peripheral neuropathy, robust evidence showcasing its ability to reverse progression of complications is not yet available. More long-term studies may help gauge the efficacy of the drug, possibly as a supplement to anti-diabetes medication.
Lifestyle modification is another critical factor that patients cannot ignore. Many foods such as broccoli and spinach contain small amounts of alpha-lipoic acid and other antioxidants that patients can easily add to a daily diet. We advise regular monitoring for patients taking 600 mg oral alpha-lipoic acid daily and one should responsibly document their condition. Observe patients for side effects, including episodes of hypoglycemia. Patients should maintain vigilant blood sugar control. With these cautions in mind, alpha-lipoic acid can be a very useful and safe option in the management of diabetic peripheral neuropathy.
Mr. Ragothaman is a third-year student at the Western University of Health Sciences College of Podiatric Medicine.
Dr. Shofler is an Assistant Professor at the Western University of Health Sciences College of Podiatric Medicine.
- Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract. 2000;47(2):123-8.
- Ziegler D, Rathmann W, Dickhaus T, et al. Neuropathic Pain in Diabetes, Prediabetes and Normal Glucose Tolerance: The MONICA/KORA Augsburg Surveys S2 and S3. Pain Medicine. Pain Med. 2009 Mar;10(2):393-400.
- Ziegler D. Painful diabetic neuropathy: treatment and future aspects. Diabetes Metab Res Rev. 2008;24 (Suppl 1):S52-7.
- Johansen JS, Harris AK, Rychly DJ, Ergul A. Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Cardiovasc Diabetol. 2005;4(1):5.
- Mohamed AK, Bierhaus A, Schiekofer S, et al. The role of oxidative stress and NF-kappaB activation in late diabetic complications. Biofactors. 1999;10(2-3):157-67.
- Wada R, Yagihashi S. Role of advanced glycation end products and their receptors in development of diabetic neuropathy. Ann NY Acad Sci. 2005;1043:598e604.
- Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012, Issue 6. Art. No.: CD007543.
- Packer L, Witt E, and Tritschler HJ. Alpha-Lipoic Acid as a Biological Antioxidant. Free Radical Biology Medicine. 1995;19(2):227-250.
- Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365-70.
- Ziegler D, Nowak H, Kempler P, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004 Feb;21(2):114-21.
- Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34(9):2054-60.
- Ibrahimpasic K. Alpha lipoic acid and glycaemic control in diabetic neuropathies at type 2 diabetes treatment. Med Arch. 2013;67(1):7-9.
- Gavin TP, Ernst JM, Caudill SE, et al. Insulin sensitivity is related to glycemic control in type 2 diabetes and diabetes remission after Roux-en Y gastric bypass. Surgery. 2014;155(6):1036-43.
- Chaturvedi N. The burden of diabetes andits complications: trends and implications forintervention. Diabetes Res Clin Pract. 2007;76 Suppl 1:S3-12.
- Lee WJ, Song KH, Koh EH, et al. Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem Biophys Res Commun. 2005;332(3):885-91.
- Carrier B, Wen S, Zigouras S, et al. Alpha-lipoic acid reduces LDL-particle number and PCSK9 concentrations in high-fat fed obese Zucker rats. PLoS One. 2014;9(3):e90863.
- 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). 2011 Aug;19(8):1647-53.
- Carbonelli MG, Di Renzo L, Bigioni M, et al. Alpha-lipoic acid supplementation: a tool for obesity therapy? Curr Pharm Des. 2010;16(7):840-6.
- Udupa A, Nahar P, Shah S, et al. A comparative study of effects of omega-3 fatty acids, alpha lipoic acid and vitamin E in type 2 diabetes mellitus. Ann Med Health Sci Res. 2013;3(3):442-6.
- Bao XH, Xu J, Chen Y, et al. Alleviation of podocyte injury: the possible pathway implicated in anti-inflammation of alpha-lipoic acid in type 2 diabetics. Aging Clin Exp Res. 2014; 26(5):483-9.
- Morcos M, Borcea V, Isermann B, et al. Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study. Diabetes Res Clin Pract. 2001;52(3):175-83.
- Teichert J, Tuemmers T, Achenbach H, et al. Pharmacokinetics of alpha-lipoic acid in subjects with severe kidney damage and end-stage renal disease. J Clin Pharmacol. 2005;45(3):313-28.
- Gullo D, Evans JL, Sortino G, et al. Insulin autoimmune syndrome (Hirata Disease) in European Caucasians taking alpha-lipoic acid. Clin Endocrinol (Oxf). 2013; 81(2):204-9.
For further reading, see the DPM Blog “Exploring The Potential Of Alpha Lipoic Acid For Diabetic Neuropathy” by Allen Jacobs, DPM at http://tinyurl.com/9whjlyo .