Key messages
• We found that alpha-lipoic acid treatment compared with placebo (dummy treatment) probably has little or no effect on the symptoms of nerve damage and may have little or no effect on impairment after six months of treatment.
• There is probably little or no difference between alpha-lipoic acid and placebo in the occurrence of unwanted effects that cause people to stop using treatment.
• We found no studies to help us answer whether alpha-lipoic acid treatment can improve quality of life or complications of nerve damage (ulceration, amputation, or both) in people with diabetes.
What is diabetic peripheral neuropathy?
People with diabetes have too much sugar in their blood because their pancreas cannot make any insulin (type 1 diabetes) or cannot make enough insulin (type 2 diabetes). Diabetes is one of the most common non-communicable diseases (diseases not spread by infection), and it is becoming more common every year. People with both type 1 and type 2 diabetes develop complications.
High blood sugar can decrease blood flow in the blood vessels that supply the nerves, resulting in nerve damage (diabetic peripheral neuropathy). The main symptom of this condition is pain. Other symptoms include tingling, a burning sensation, numbness, shooting or sharp aches, and even extreme sensitivity to clothes touching the skin. These symptoms are caused by direct nerve damage, which is different from typical pain caused by injury or tissue damage. For this reason, usual painkiller medicines do not alleviate pain caused by peripheral neuropathy. People with this condition can also experience weakness, loss of reflexes, or loss of sensation (together known as impairment), which can disrupt normal functions such as walking.
How is diabetic peripheral neuropathy treated?
Medicines used to treat depression or epilepsy may improve symptoms of diabetic peripheral neuropathy. Some studies have suggested that alpha-lipoic acid (an antioxidant made naturally in the body) may help because of its presumed anti-inflammatory effects.
What did we want to find out?
We wanted to find out if alpha-lipoic acid was better than no treatment or placebo (dummy treatment) for improving symptoms of diabetic peripheral neuropathy, impairment, quality of life, and complications of diabetic peripheral neuropathy (ulceration, amputation, or both) in people with type 1 or type 2 diabetes. We also wanted to know if alpha-lipoic acid had any unwanted effects.
What did we do?
We searched for studies that investigated alpha-lipoic acid treatment compared to no treatment or placebo for at least six months. We analysed and summarised the results of the trials and rated our confidence in the findings.
What did we find?
We found three studies that analysed 816 adults with type 1 and type 2 diabetes. The participants received either alpha-lipoic acid or placebo. The dose of alpha-lipoic acid ranged from 600 mg/day to 1800 mg/day.
Alpha-lipoic acid compared to placebo probably has little or no effect on symptoms of diabetic peripheral neuropathy and may have little or no effect on impairment after six months of treatment. There is probably little or no difference between alpha-lipoic acid and placebo in terms of unwanted effects that cause people to stop treatment.
No studies measured the effect of alpha-lipoic acid treatment on quality of life or complications of peripheral neuropathy.
Until alpha-lipoic acid is proven effective, there is no rationale for comparing it with active treatments.
What are the limitations of the evidence?
We are moderately confident in the evidence on symptoms and unwanted effects because in all three studies, the investigators lost contact with many participants before the end of treatment (loss to follow-up). We have little confidence in the evidence on impairment, because of loss to follow-up and because the result was very imprecise.
How up-to-date is this evidence?
The evidence is current to 11 September 2022.
Our analysis suggests that ALA probably has little or no effect on neuropathy symptoms or adverse events at six months, and may have little or no effect on impairment at six months. All the studies were at high risk of attrition bias. Therefore, future RCTs should ensure complete follow-up and transparent reporting of any participants missing from the analyses.
Diabetic peripheral neuropathy (DPN) is a frequent complication in people living with type 1 or type 2 diabetes. There is currently no effective treatment for DPN. Although alpha-lipoic acid (ALA, also known as thioctic acid) is widely used, there is no consensus about its benefits and harms.
To assess the effects of alpha-lipoic acid as a disease-modifying agent in people with diabetic peripheral neuropathy.
On 11 September 2022, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and two clinical trials registers. We also searched the reference lists of the included studies and relevant review articles for additional references not identified by the electronic searches.
We included randomised clinical trials (RCTs) that compared ALA with placebo in adults (aged 18 years or older) and that applied the study interventions for at least six months. There were no language restrictions.
We used standard methods expected by Cochrane. The primary outcome was change in neuropathy symptoms expressed as changes in the Total Symptom Score (TSS) at six months after randomisation. Secondary outcomes were change in neuropathy symptoms at six to 12 months and at 12 to 24 months, change in impairment, change in any validated quality of life total score, complications of DPN, and adverse events. We assessed the certainty of the evidence using GRADE.
Our analysis incorporated three trials involving 816 participants. Two studies included people with type 1 or type 2 diabetes, while one study included only people with type 2 diabetes. The duration of treatment was between six months and 48 months. We judged all studies at high risk of overall bias due to attrition.
ALA compared with placebo probably has little or no effect on neuropathy symptoms measured by TSS (lower score is better) after six months (mean difference (MD) −0.16 points, 95% confidence interval (CI) −0.83 to 0.51; 1 study, 330 participants; moderate-certainty evidence). The CI of this effect estimate did not contain the minimal clinically important difference (MCID) of 0.97 points. ALA compared with placebo may have little or no effect on impairment measured by the Neuropathy Impairment Score-Lower Limbs (NIS-LL; lower score is better) after six months (MD −1.02 points, 95% CI −2.93 to 0.89; 1 study, 245 participants; low-certainty evidence). However, we cannot rule out a significant benefit, because the lower limit of the CI surpassed the MCID of 2 points. There is probably little or no difference between ALA and placebo in terms of adverse events leading to cessation of treatment within six months (risk ratio (RR) 1.48, 95% CI 0.50 to 4.35; 3 studies, 1090 participants; moderate-certainty evidence).
No studies reported quality of life or complications associated with DPN.