The aim of this review
The aim of this review was to assess the effects of acetyl-L-carnitine (ALC) on diabetic peripheral neuropathy (DPN) in people with diabetes. We were particularly interested in whether ALC could relieve pain, and also aimed to identify any harmful effects.
We are uncertain whether ALC reduces pain in DPN, as the evidence is sparse and of very low certainty. Adverse events may be no more common than with placebo, but the evidence here is also very uncertain.
What was studied in the review?
Diabetes is a condition where the amount of sugar in the blood is abnormally high. Damage to nerve fibres as a result of diabetes is called DPN. DPN is a frequent and severe complication of diabetes, affecting about 50% of people with long-term diabetes. Overall, 16% to 24% of people with diabetes experience chronic pain due to nerve damage. The feet, legs, and hands are primarily affected by DPN.
There is a need for therapies to restore nerve function and relieve the symptoms of DPN. The Cochrane review authors searched for evidence from randomised trials on the effects of ALC in DPN. Evidence from randomised trials is usually more reliable than other study designs.
The main results of the review
The review authors found four relevant trials, which involved 906 adults with diabetes. Three studies compared ALC with a placebo (an inactive, dummy compound), and one compared ALC with methylcobalamin (a form of vitamin B12).
The certainty of the evidence from the studies ranged from low to very low, which means that we cannot be confident in the findings. The key reasons for this were that results were not always completely or clearly reported, the studies had serious limitations, and the results lacked precision.
In people with nerve damage due to diabetes, it is uncertain whether ALC reduces pain after 12 months of therapy, compared to placebo. The trials provided little or no information on the effects of ALC on functional impairment, sensory testing, and symptoms. Even when trials provided data, the quality of evidence was too low to draw reliable conclusions. The study that compared ALC with methylcobalamin did not assess pain. Functional impairment and symptoms may improve to a similar extent with ALC and methylcobalamin.
Harmful side effects may be no more frequent with ALC than with placebo. The evidence on adverse events from the trial comparing ALC with methylcobalamin was very uncertain.
Two of the four studies were funded by a manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer.
We are very uncertain whether ALC causes a reduction in pain after 6 to 12 months' treatment in people with DPN, when compared with placebo, as the evidence is sparse and of low certainty. Data on functional and sensory impairment and symptoms are lacking, or of very low certainty. The evidence on adverse events is too uncertain to make any judgements on safety.
Diabetic peripheral neuropathy (DPN) is a common and severe complication that affects 50% of people with diabetes. Painful DPN is reported to occur in 16% to 24% of people with diabetes. A complete and comprehensive management strategy for the prevention and treatment of DPN, whether painful or not, has not yet been defined.
Research into treatment for DPN has been characterised by a series of failed clinical trials, with few noteworthy advances. Strategies that support peripheral nerve regeneration and restore neurological function in people with painful or painless DPN are needed. The amino acid acetyl-L-carnitine (ALC) plays a role in the transfer of long-chain fatty acids into mitochondria for β-oxidation. ALC supplementation also induces neuroprotective and neurotrophic effects in the peripheral nervous system. Therefore, ALC supplementation targets several mechanisms relevant to potential nerve repair and regeneration, and could have clinical therapeutic potential. There is a need for a systematic review of the evidence from clinical trials.
To assess the effects of ALC for the treatment of DPN.
On 2 July 2018, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We checked references, searched citations, and contacted study authors to identify additional studies.
We included randomised controlled trials (RCTs) and quasi-RCTs of ALC compared with placebo, other therapy, or no intervention in the treatment of DPN. Participants could be of any sex and age, and have type 1 or type 2 diabetes mellitus, of any severity, with painful or painless DPN. We accepted any definition of minimum criteria for DPN, in accordance with the Toronto Consensus. We imposed no language restriction.
Pain was the primary outcome, measured as the proportion of participants with at least 30% (moderate) or 50% (substantial) decrease in pain over baseline, or as the score on a visual analogue scale (VAS) or Likert scale for pain.
We followed standard Cochrane methods.
We included four studies with 907 participants, which were reported in three publications. Three trials studied ALC versus placebo (675 participants); in one trial the dose of ALC was 2000 mg/day, and in the other two trials, it was 1500 mg/day or 3000 mg/day. The fourth trial studied ALC 1500 mg/day versus methylcobalamin 1.5 mg/day (232 participants). The risk of bias was high in both trials of different ALC doses and low in the other two trials.
No included trial measured the proportion of participants with at least moderate (30%) or substantial (50%) pain relief. ALC reduced pain more than placebo, measured on a 0- to 100-mm VAS (MD -9.16, 95% CI -16.76 to -1.57; three studies; 540 participants; P = 0.02; I² = 56%; random-effects; very low-certainty evidence; a higher score indicating more pain). At doses of 1500 mg/day or less, the VAS score after ALC treatment was little different from placebo (MD -0.05, 95% CI -10.00 to 9.89; two studies; 159 participants; P = 0.99; I² = 0%), but at doses greater than 1500 mg/day, ALC reduced pain more than placebo (MD -14.93, 95% CI -19.16 to -10.70; three studies; 381 participants; P < 0.00001; I² = 0%). This subgroup analysis should be viewed with caution as the evidence was even less certain than the overall analysis, which was already of very low certainty.
Two placebo-controlled studies reported that vibration perception improved after 12 months. We graded this evidence as very low certainty, due to inconsistency and a high risk of bias, as the trial authors did not provide any numerical data. The placebo-controlled studies did not measure functional impairment and disability scores. No study used validated symptom scales. One study performed sensory testing, but the evidence was very uncertain.
The fourth included study compared ALC with methylcobalamin, but did not report effects on pain. There was a reduction from baseline to 24 weeks in functional impairment and disability, based on the change in mean Neuropathy Disability Score (NDS; scale from zero to 10), but there was no important difference between the ALC group (mean score 1.66 ± 1.90) and the methylcobalamin group (mean score 1.35 ± 1.65) groups (P = 0.23; low-certainty evidence).
One placebo-controlled study reported that six of 147 participants in the ALC > 1500 mg/day group (4.1%) and two of 147 participants in the placebo group (1.4%) discontinued treatment because of adverse events (headache, facial paraesthesia, and gastrointestinal disorders) (P = 0.17). The other two placebo-controlled studies reported no dropouts due to adverse events, and more pain, paraesthesia, and hyperaesthesias in the placebo group than the 3000 mg/day ALC group, but provided no numerical data. The overall certainty of adverse event evidence for the comparison of ALC versus placebo was low.
The study comparing ALC with methylcobalamin reported that 34/117 participants (29.1%) experienced adverse events in the ALC group versus 33/115 (28.7%) in the methylcobalamin group (P = 0.95). Nine participants discontinued treatment due to adverse events (ALC: 4 participants, methylcobalamin: 5 participants), which were most commonly gastrointestinal symptoms. The certainty of the adverse event evidence for ALC versus methylcobalamin was low.
Two studies were funded by the manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer.