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[STUDENT SELECTED COMPONENT 1

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How Effective is α-Lipoic Acid in Treating Diabetic
Neuropathy?
Introduction
My grandmother is an 80 year old Malaysian Chinese woman. She was
diagnosed with Type 2 Diabetes 4 years ago when she was admitted to the
hospital due to an asthma attack.
2 years later, she began feel numbness in her feet. When inquired, she
added that her feet felt cold and she has trouble walking sometimes,
describing it as ‘walking on cotton wool’. Sometime later, she complained
of burning and crawling pains in her feet. These are signs of diabetic
neuropathy.
One of her friends who is having the same problem recommended her to
take α-lipoic supplements. However, she is sceptical of the supplements
because no such treatment option exists in Malaysia, and it is fairly new in
the market. This study will help determine the effectiveness and safety of
α-lipoic acid in treating diabetic neuropathy.

What is Diabetic Neuropathy?
Diabetic Neuropathy is one of the complications that could arise due to
diabetes. It involves the presence of signs and symptoms of peripheral
nerve dysfunction after all other possible causes are excluded. It affects
around 50% of Type 1 and Type 2 diabetic patients, the most common
being the ‘diabetic foot’.
The pathophysiology and causes for diabetic neuropathy are still unclear,
but a few solid hypotheses exists, one of them being the vascular
hypothesis. According to said hypothesis, the main cause of diabetic
neuropathy is the occlusion of the vasa nervorum or small arteries that
supply the peripheral nerves. [1] However, the existence of symmetrical
neuropathy suggests a metabolic cause. Increased production of fructose
and sorbitol in Schwann cells due to hyperglycaemia may disrupt the
structure and function of said cell. [2]
There are many varieties of diabetic neuropathy, such as symmetrical
mainly sensory polyneuropathy, acute painful neuropathy,
mononeuropathy and mononeuritis multiplex, diabetic amyotrophy, and
autonomic neuropathy. Among all of these, symmetrical mainly sensory
polyneuropathy and acute painful neuropathy are the more common types
of diabetic neuropathy. These are the ones that will be assessed in the
studies below.
The signs and symptoms may include tingling, numbness (that can
become permanent), burning sensations especially in the evening, and
pain in the affected parts.

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How Effective is α-Lipoic Acid in Treating Diabetic Neuropathy? |
SSC

ALA is being marketed as an antioxidant in the form of supplementary pills and is being used as a treatment for diabetic neuropathy only in Germany. double-blind placebo-controlled trial on 328 type-2 diabetic patients with symptomatic peripheral neuropathy in Germany. Currently. There was also significant improvement on the response rates after 19 days (defined as an improvement of at least 30% in the TSS) in patients that took ALA compared to PLAC. The inclusion of rate of adverse events to show that ALA had no significant adverse effects was commendable. adequate sample size of roughly 300 subjects. The Hamburg Pain Adjective List (HPAL) and the Neuropathy Symptom and Disability Scores (NSDS) were assessed at the baseline on the 19 th day. I will be looking at a number of clinical trials done on ALA which are related to treating diabetic neuropathy. SYDNEY and ORPRIL trials. The Total Symptom Score in the feet of patients who took ALA were reduced significantly compared to the patients who took PLAC. The main focus of these studies is to determine the effect of ALA on diabetic neuropathy. It also does not cause significant adverse reactions. 3 of them were performed to this date. 600 or 100 mg ALA) or placebo (PLAC) are randomly assigned to the patients. The ALADIN study had a large. if not. Other well-known and commonly cited studies also include the NATHAN. ALA 600mg recorded the highest response rate and also the lowest rate of adverse events. Intravenous infusion of α-lipoic acid (ALA) of 3 doses (1200. It was also randomised. The most well-known clinical trials performed on this topic are the ALADIN (Alpha-Lipoic Acid in Diabetic Neuropathy) studies. Rate of adverse events was also taken into account. Literature Review The aim of this SSC study is to find out the effectiveness of ALA in treating diabetic neuropathy. It is an essential cofactor in many enzyme complexes that are involved in aerobic metabolism. More researches are ongoing to further prove ALA’s effectiveness in treating diabetic neuropathy as well as other conditions that are caused by metabolic disturbances.[STUDENT SELECTED COMPONENT 1] What is α-Lipoic Acid (ALA)? ALA or otherwise known as Thioctic Acid (TA) is an organosulfur compound derived from octanoic acid. Baseline scores of neuropathic symptoms were taken throughout the study. 2 How Effective is α-Lipoic Acid in Treating Diabetic Neuropathy? | SSC . This study shows that intravenous treatment of 600 mg of ALA is capable of reducing symptoms of diabetic neuropathy significantly in a span of 3 weeks. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant α-lipoic acid: A 3-week multicentre randomized controlled trial (ALADIN Study) [3] Ziegler et al. conducted a 3-week multicentre. double-blinded and placebo controlled which further increases its reliability. randomised.

[STUDENT SELECTED COMPONENT 1] This study was supported by ASTA Medica AG. making the sample size far too small. making the study more reliable. 2 sources of bias can be identified in this study. Treatment of Diabetic Polyneuropathy with the Antioxidant Thioctic Acid (α-Lipoic Acid): A Two Year Multicenter Randomized Double-blind Placebo-controlled Trial (ALADIN II) [4] Reljanovic et al. Therefore it can be argued that this introduced a potential source of bias. Unlike the ALADIN 1 study. 3 different treatments were given to the patients randomly: 2x600 mg of Thioctic Acid (TA 1200). MNCV and MNDL) which are used by medical professionals. Similar to ALADIN 1. placebo-controlled trial on 299 patients that were recruited from 32 outpatient centres in Germany. 600 mg of TA plus placebo (PLA) (TA 600) or placebo and placebo (PLA). significant changes were observed between the TA and PLA groups for SNCV. randomized. However no significant differences were observed between the groups for NDS and tibial MNDL. ALADIN 2 is also randomized. Severity or improvement of diabetic neuropathy was assessed by the Neuropathy Disability Score (NDS) and the electrophysiological attributes of the sural and tibial nerve. After 24 months. ALADIN also extended the study duration to 2 years. The TSS questionnaire was given to the patients themselves to answer. SNAP. showing TA’s long term effects on diabetic neuropathy. the ALADIN 2 study replaced questionnaires with measuring tools (SNCV. which may not be as reliable as an assessment made by a medical professional. All of the study subjects were Germans ranging from 50 to 70 years old. doubleblinded. The number of patients dropped from 299 to 65 because the independent reviewers excluded patients with highly variable data. SNAP and MNCV whereby TA groups showed improvement and PLA groups showed deterioration. reproducibility may be compromised if applied to other countries. ALADIN 2’s limitations lie in the sample size. These Type 1 and Type 2 diabetic patients all have symptomatic polyneuropathy. 3 How Effective is α-Lipoic Acid in Treating Diabetic Neuropathy? | SSC . Delayed nerve conduction velocity is the earliest functional change in a diabetic nerve and can serve as a useful measuring tool for severity of early-stage diabetic neuropathy. double-blinded and placebo-controlled. Since all of the study subjects were German. a reliable study method used for clinical trials. which is a pharmaceutical company. so the same results may not be able to be reproduced in Malaysia for elderly patients. conducted a two-year multicentre. This study shows that α-lipoic acid (TA) has a positive effect on some aspects of nerve conduction. Sensory nerve conduction velocity (SNCV) and sensory nerve action potential (SNAP) are measured for the sural nerve while motor nerve conduction velocity (MNCV) and motor nerve distal latency (MNDL) are measured for the tibial nerve. being the exclusion of a large amount of study subjects and that this study was supported by a pharmaceutical company: ASTA Medica AG.

placebo controlled trial ALADIN study. the differences were considered insignificant to a clinically meaningful degree. therefore the results may not be the same if the study is reproduced in other countries. adding a source of bias. The ALADIN 3 study had the largest sample size out of all the ALADIN studies consisting of 509 patients. like ALADIN 1 and 2. with more improvements shown in the ALA groups. all of the study subjects are German. conducted another multicentre. 509 Type 2 Diabetic outpatients with symptomatic peripheral neuropathy were recruited for this trial. Treating it on the other hand is an entirely different matter. Similar to the ALADIN 1 study. doubleblinding and placebo controlling. followed by placebo (PLAC) three times a day orally for 6 months (A-P). Similar to ALADIN 1. 600 mg ALA once daily intravenously for 3 weeks. Despite the results showing the limited effectiveness of ALA. the study’s reliability is maintained through randomizing. double-blinded. which are arguably less reliable than an assessment made by medical professionals. 181 Type 1 and Type 2 Diabetic patients with symptomatic Distal 4 How Effective is α-Lipoic Acid in Treating Diabetic Neuropathy? | SSC . ALADIN 3 used questionnaires that are answered by the patients themselves. compensating for dropouts and extreme observations as well as providing a better picture for analysis. followed by 600 mg ALA three times a day orally for 6 months (A-A).[STUDENT SELECTED COMPONENT 1] Treatment of Symptomatic Diabetic Polyneuropathy With the Antioxidant α-Lipoic Acid: A 7-month multicenter randomized controlled trial (ALADIN III Study) [5] Ziegler et al. Oral Treatment With α-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy: The SYDNEY 2 trial [6] Ziegler et al. They were randomly assigned to sequential treatment with 600 mg α-lipoic acid (ALA) once daily intravenously for 3 weeks. randomized. the treatment nonetheless is still associated with a positive effect on neuropathic deficits rather than symptoms. Therefore it shows that ALA is capable of slowing the progression of diabetic neuropathy. differences in changes were noted between the ALA and PLAC groups. randomized. ALADIN 3 was supported by a pharmaceutical company named ASTA Medica AG. However. placebo-controlled trial Symptomatic Diabetic Neuropathy (SYDNEY) 2 study. Also. followed by placebo three times a day orally for 6 months (P-P). conducted a third multicentre. double-blinded. The study design not only allowed comparisons between ALA and PLA but also between intravenous and oral ALA. Using neuropathic deficits rather than neuropathic symptoms as primary criteria for ALA efficacy may be better since the difference in changes of symptoms were insignificant. As mentioned in the ALADIN 1 and 2 studies. and placebo once daily intravenously for 3 weeks. Lastly. ALADIN 3 also accounted for the rate of adverse events to prove the safety of ALA. The Total Symptom Score (TSS) for neuropathic symptoms and the Neuropathy Impairment Score (NIS) were used as measuring tools. After both 3 weeks and 7 months. Rate of adverse events was also taken into account and the data analysis performed was based on the intention to treat.

The sample size of the study was 181. thus decreasing the results’ reliability. Efficacy and Safety of Antioxidant Treatment With α-Lipoic Acid over 4 Years in Diabetic Polyneuropathy: The NATHAN 1 trial [7] In 2011. Measuring tools used were the Neuropathy Impairment Score (NIS). The SYDNEY 2 study design is randomized. This study shows 3 important points. a pharmaceutical company which introduces a source of bias. with ALA 600 having the highest response rate (which is defined by more than or equal to 50% reduction in TSS) of 62%. 1800 mg (ALA 1800) of α-lipoic acid (ALA) or placebo (PLA) for 5 weeks. Adverse event rates were also taken into account. All ALA groups recorded a significant decrease in TSS scores compared to the PLA group. Using patient questionnaires may produce less accurate results than using assessments done by medical professionals. Ziegler et al. ALA dose is linked with the increase of adverse effects like nausea. 460 diabetic patients with mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN) were recruited from 36 medical centres in the US. Daily oral dose of 600 mg ALA provides the best risk-to-benefit ratio. NSC score and patient’s global assessment of efficacy. Dosedependent adverse effects of nausea. After a 1-week placebo run-in period. individual symptoms of TSS. No significant difference was seen in changes from baseline to 5 How Effective is α-Lipoic Acid in Treating Diabetic Neuropathy? | SSC .[STUDENT SELECTED COMPONENT 1] Symmetric Polyneuropathy (DSP) were recruited from 2 centres in Israel and 3 centres in Russia. A total of 5 different outcome measurements were used cover the broad scope of diabetic neuropathy. 1200 mg (ALA 1200). They were randomly assigned 600 mg of once-daily oral α-lipoic acid (ALA) or placebo (PLA) for 4 years. double-blinded and placebocontrolled. Study subjects are comprised of patients of 2 different nationalities. therefore increasing the reproducibility of this study. The results of this study can only be reproduced in Russia and Israel. Finally. Primary outcome measure was a composite score of NIS. allowing multiple outcomes to be achieved at the same time. Rate of serious adverse events were noted. vomiting and vertigo showed an increase in the safety analysis. Drug safety was also assessed by observing for the presence of adverse effects. Neuropathy Impairment Score (NIS) and patient’s global assessment of efficacy. which is not an adequate sample size for a study of this magnitude. Outcome measuring tools include the Total Symptom Score (TSS). Daily ALA oral treatment for 5 weeks resulted in DSP patients having reduced neuropathic symptoms and deficits. The SYDNEY 2 study was funded by MEDA Pharma. vomiting and vertigo. conducted another multicenter randomized doubleblinded parallel-group trial for the Neurological Assessment of Thioctic Acid in Diabetic Neuropathy (NATHAN) study. making the research reliable as said design is the most suitable for clinical trials. NIS-LL and 7 neurophysiologic tests. NIS for lower limbs (NIS-LL) and 7 neurophysiologic tests including nerve conduction and quantitative sensory tests (QSTs). Neuropathy Symptoms and Change (NSC) score. Significant improvements were also observed in stabbing and burning pain (individual symptom). Canada and Europe. the patients were assigned once-daily oral doses of 600 mg (ALA 600).

Measuring methods include Total Symptoms Score (TSS) where neuropathic symptoms are scored weekly. Rate of adverse events were noted and analysed. However. Several of the tests were conducted by medical professionals.d 600 mg ALA treatment for 3 weeks may improve symptoms and deficits of polyneuropathy in Type 2 Diabetic patients. the effects were minor and the chance of them happening was low. whereas the PLA group recorded a slight increase. The only limitation this study had is that it is funded by a pharmaceutical company called MEDA Pharma. There was no difference in rate of adverse events between the 2 groups. The ALA group recorded a 47% improvement for TSS and a 60% improvement for HPAL. This study shows that a 4 year ALA treatment for DSPN patients showed meaningful clinical improvement and prevention of neuropathic impairment progression. Although adverse effects were recorded for ALA. NIS-LL and NIS-LL muscular weakness subscore was significantly better in the ALA group. QST and nerve conduction did not worsen with PLA.d oral treatment of 600 mg of ALA or placebo (PLA) for 3 weeks. Taking rate of adverse events into account eliminates a potential source of bias. A number (specific number not mentioned) of patients were randomly assigned to t. NDS was slightly decreased in the ALA group. double-blinded and placebo-controlled.i. conducted an ORPIL (Oral Pilot Study) study in 1999 after the first ALADIN trial to determine the efficacy and safety of short-term oral treatment with ALA on neuropathic symptoms and deficits in Type 2 Diabetic patients with symptomatic polyneuropathy. making the results more accurate than results based on patient-answered questionnaires. This study showed that t. The randomized. The ORPIL trial was randomized. The rate of adverse events was 10% higher in the ALA group compared to the PLA group. Multiple measuring methods were used to cover the broad scope of diabetic neuropathy’s symptoms and impairments. Having many outcome measures allowed the researchers to determine the effectiveness or efficacy of ALA. The sample size of 460 subjects across 3 different nationalities increases the reproducibility of the study in said countries.i. More patients showed clinically meaningful improvement and fewer patients showed progression in NIS and NIS-LL. placebo-controlled study design suits this clinical trial well. which introduces a source of bias. Effects of 3-week oral treatment with the antioxidant thioctic acid (α-lipoic acid) in symptomatic diabetic polyneuropathy: The ORPIL study [8] Ruhnaut et al. The treatment also does not cause significant adverse effects. the change in NIS.[STUDENT SELECTED COMPONENT 1] primary end point between ALA and PLA groups. The Hamburg Pain Adjective List (HPAL) and the Neuropathy Disability Score (NDS). 6 How Effective is α-Lipoic Acid in Treating Diabetic Neuropathy? | SSC . like a pharmaceutical company hiding the side effects of a drug that it sells to increase sales. making the results reliable. double-blinded. HPAL and NDS were assessed at day 1 and 19. The strengths in this NATHAN 1 study far outweigh its limitations. increasing the reliability of the results.

it is only logical to find out whether ALA is effective in treating diabetic neuropathy of said age group. Lastly. ALA is capable of reducing symptoms and impairments of diabetic neuropathy. relieving pain due to neuropathy and improving some aspects of nerve conduction. there is a potential source of bias as this research is funded by ASTA Medica AG. However. I cannot say with 100% confidence that ALA is effective for the elderly Malaysian Chinese. and thus in turn affecting what his or her patient believes. type 2 diabetic patients aged from 60 to 80 years old with symptomatic diabetic neuropathy will be recruited from multiple medical centres in Malaysia. Therefore. a pharmaceutical company. placebo-controlled study as it best suits clinical trials like this. Research Question Although the results in the studies above put ALA in a positive light. it has not been proven to be effective for Malaysians of certain age groups.i.”[10] The reason behind double blinding is that a doctor's belief in the value of a treatment can affect his or her behaviour. Conclusion After going through papers on α-lipoic acid (ALA) clinical trials. multicenter.[STUDENT SELECTED COMPONENT 1] No comment can be made on the sample size as it was not mentioned in the report. According to a report by Jadad et al. the adverse effects mentioned are minor and the patients who have them do not differ much in number when compared to the placebo groups. be it an oral supplement or intravenous treatment. I propose the research question: How effective is α-lipoic acid in treating symptomatic diabetic neuropathy in elderly Malaysian Chinese? The type of study will be a 2-month. it can be concluded that ALA is beneficial to patients with diabetic neuropathy. randomized. doubleblinded. it would be better if assessments made by medical professionals using medical instruments like measuring nerve conductivity were used. In order to answer this question. I conclude that ALA is an effective form of treatment for diabetic neuropathy. These benefits may improve the quality of life of a diabetic patient with neuropathy. In my grandmother’s case. 3 out of the 6 studies mentioned above reported increased adverse effects in ALA patient groups. Outcome measures will include the Total Symptom Score (TSS) 7 How Effective is α-Lipoic Acid in Treating Diabetic Neuropathy? | SSC . It may have a place in treating diabetic neuropathy in the future. Lastly. Since diabetes and diabetic neuropathy is more prevalent in older age groups. A multicenter study allows for a larger sample size as patients are recruited from multiple medical centres in the country. While using patient-answered questionnaires like the TSS provides a valid assessment of neuropathy sensory systems [9]. placebos are used so that a certain treatment that is being studied has a control group to compare against.d 600 mg oral ALA and placebo (PLA) for 12 months. blinding is necessary in randomized clinical trials as “blind assessments produced significantly lower and more consistent scores than open assessments. They will be assigned at random to 2 different treatment regimens: t. Around 500 Malaysian Chinese.

Neuropathy Impairment Score (NIS).[STUDENT SELECTED COMPONENT 1] that will be assessed weekly. Results will be compared between the ALA group and the PLA group. the accuracy of the results will be affected. Main text 2945 Research Question 371 Total Word Count 8 3316 How Effective is α-Lipoic Acid in Treating Diabetic Neuropathy? | SSC . If possible. the patients should avoid taking any supplements or medications that may improve their condition. if a patient takes medications related to their condition. neurophysiologic tests such as tests on nerve conductivity and Quantitative Sensory Tests (QSTs) will be assessed after 2 months. As unethical as it sounds. Neuropathy Disability Score (NDS). On the other hand.

Diabetes Care. Assessing the Quality of Reports of Randomized Clinical Trials: Is Blinding Necessary?. Ziegler. et al..[STUDENT SELECTED COMPONENT 1] References 1.. Effects of 3-week oral treatment with the antioxidant thiotic acid (α-lipoic acid) in symptomatic diabetic polyneuropathy. 1999. 1425-1433. Treatment of Symptomatic Diabetic Polyneuropathy With the Antioxidant α-Lipoic Acid. 9 How Effective is α-Lipoic Acid in Treating Diabetic Neuropathy? | SSC . Stuttgart. 5. A. 1040-1043. et al...Jadad. Controlled Clinical Trials. Bastyr. pp. s. Issue 22. Diabetes Care. pp. Ziegler. M. Ruhnau. Germany: Georg Thieme Verlag. Clinical Therapeutics. 2365-2370. pp.. et al. D. Reljanovic. A. D. 1995. 7. F. P. Diabetic Medicine. pp. Ziegler. Textbook of Diabetic Neuropathy. Issue 34. Issue 16. D. 2011. pp. A.. Free Rad. pp. Issue 29. Price. et al. 2009. 2003. Daibetes Care. Ziegler. K.l. Issue 17.. 1-12. Cameron. & Bril.. Treatment of Diabetic Polyneuropathy with the Antioxidant Thioctic Acid (α-Lipoic Acid): A Two Year Multicenter Randomized Double-blind Placebo-controlled Trial (ALADIN II). Low. & Clark. J. N. 7th ed. 2005.:Elsevier Limited.. 3. et al.. V. E. D. 10. D. Kumar. 2. Development and Validity Testing of the Neuropathy Total Symptom Score-6: Questionnaire for the Study of Sensory Symptoms of Diabetic Peripheral Neuropathy... R. 6. 2006. P. 171-179. 2054-2060. M.. Oral Treatment With α-Lipoic Acid Improves Symptomatic Diabetic Improves Symptomatic Diabetic. Res. 1278-1294. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant α-lipoic acid. pp. 9. 4. Kumar & Clark's Clinical Medicine. 1999. 1999. Efficacy and Safety of Antioxidant Treatment With α-Lipoic Acid Over 4 Years in Diabetic Polyneuropathy. 1996. & Ziegler. Issue 38. Volume 31.et al. Diabetologia. pp. 27(8). 8. Gries. et al. 1296-1301.. E. K. L.-J.