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Abstract
Introduction Diabetic neuropathy (DN) is common in patients diagnosed with diabetes mellitus. This often causes peripheral nerve damage. For many years vitamin B12 and alpha-lipoic acid (ALA) have been regarded as components that can be used in reducing markers of inflammation and oxidative stress. In this study, we will explore the effectiveness of vitamin B12 and ALA as a possible treatment for diabetic mellitus/neuropathy, emphasising markers of inflammation, lipid profile, and glucose metabolism.
Methods and analysis We will conduct a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P). The search strategies and information sources for the literature will be PubMed, Google Scholar, Web of Science and Science direct. The literature search will include studies published from inception until 30 June 2022. All included studies will be evaluated for quality and risk of bias according to the Cochrane guidelines. To investigate the stability of the results, we will conduct a sensitivity analysis of the outcomes. All data analysis will be performed using Review Manager V.5. 4.
Ethical and dissemination This systematic review and meta-analysis will not require ethical approval from an institution committee as it does not have direct participants. We will obtain all our data from previous studies. The findings will be disseminated through publications in peer-reviewed journals and presented at local and international seminars and conferences.
- diabetic neuropathy
- general diabetes
- lipid disorders
- diabetes & endocrinology
- nutrition & dietetics
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Introduction
Diabetic neuropathy (DN) is a heterogeneous type of nerve damage associated with diabetes mellitus (DM), the condition most often damages nerves in the legs and feet.1 It presents both clinically and subclinically affecting the peripheral nervous system due to an increase in glucose concentration which interferes with nerve signalling.1 2
Following the discovery of insulin as a treatment for DM, the prevalence of DN has since increased significantly due to patients with DM having a longer life expectancy.2 It has been estimated that at least 50% of patients with DM will develop DN in their life, with approximately 20% experiencing neuropathic-related pains.1 2 Nerves are susceptible to changes in glucose concentrations, and insulin treatment makes it impossible for neurons to continue regulating glucose uptake.3 4
For many years, vitamin B12 and alpha-lipoic acid (ALA) have been regarded as components that reduce pain and oxidative stress. Vitamin B12 is essential in the metabolism of essential fatty acids involved in the maintenance of nerve myelin and direct scavenging of reactive oxygen species (ROS). However, patients with DN on metformin treatment have been shown to have low vitamin B12; this is because metformin on its own impairs vitamin B12 absorption. When vitamin B12 deficiency is prolonged, it leads to nerve degeneration, causing irreversible nerve damage.5 Previous researchers have explored the benefits of vitamin B12 and have discovered that it stimulates nerve regeneration by promoting axon growth of neural cells after peripheral nerve damage.6
On the other hand, the naturally occurring ALA, an organosulfur compound derived from octanoic acid,7 is required to generate energy in the mitochondria by various enzymes. Most importantly, ALA is a potent antioxidant agent that can neutralise ROS and nerve blood flow, resulting in improved distal nerve conductions1. Additionally, ALA acts as a scavenger for free radicals intracellularly and extracellularly to repair oxidative damage.8 9 Furthermore, ALA has been shown to increase the uptake of glucose to control glucose metabolism.7–9 Moreover, another study showed an improvement in glucose level and insulin sensitivity following the use of ALA treatment in patients with type 2 diabetes mellitus.10 In metabolic syndromes, a previous meta-analysis demonstrated that treatment of ALA improves the marker of inflammation.11 However, it is still unclear how these compounds impact the markers of inflammation and related glucose parameters in patients with diabetes/DN. A previous meta-analysis assessing the effect of ALA on lipid profiles revealed a significant decrease in lipid profiles; however, this was conducted in patients with various conditions, including diabetes, schizophrenia, obesity, renal disease and hyperthyroidism.12 Therefore, this systematic review and meta-analysis aim to explore the effectiveness of vitamin B12 and ALA as either monotherapy or dual treatment for DM/neuropathy with major emphasis on markers of inflammation, lipid profile, and glucose metabolism.
Methodology
This protocol for a systematic review and meta-analysis is aimed at evaluating the beneficial impact of vitamin B12 and ALA in DM with a major focus on markers of inflammation, lipid profile and glucose metabolism. The review will follow the Preferred Reporting Items for Systematic reviews and Meta-Analysis protocol (PRISMA-P;13 online supplemental file 1).
Supplemental material
Patient and public involvement
No patient involved.
Aim
The study’s main aim is to explore the effectiveness of vitamin B12 and ALA as a possible treatment for DM/DN with major emphasis on markers of inflammation, lipid profile, and glucose metabolism.
Questions
Does ALA increase the uptake of glucose for better glycaemic control?
Do vitamin B12 and ALA improve markers of inflammation?
What is the impact of vitamin B12/ALA on lipid profile among patients with diabetes?
Participants/population
We will consider studies conducted in patients with diabetes/DN on either vitamin B12 or ALA as supplements.
Intervention
We will consider studies conducted on patients living with DM/DN on Vitamin B12 and ALA supplementations. If vitamin B12 and ALA are used in the same trial, and there is a comparator/control, such studies will be analysed as dual treatment versus placebo/control. However, if one treatment is used in a trial, it will be subgrouped as monotherapy versus placebo/control.
Design
Randomised controlled trials.
Comparator
The comparator will be divided into two:
Patients with DM/DN on placebo.
Healthy participants not on any treatment (control).
Outcomes
Improved markers of inflammation such as tumour necrosis factor-alpha, interleukin-6 and C reactive protein.
Improved glucose parameters, fasting blood glucose and insulin.
Improved lipid profile, total cholesterol, triglyceride, low-density lipoprotein, andhigh-density lipoprotein.
Eligibility criteria
Inclusion
All studies will be reviewed for inclusions, and where there may be uncertainty, the studies in the review will be required to meet the following criteria.
The randomised controlled trials focus on the effects of vitamin B12 and ALA in DM/DN.
Strengths and limitations of this study
This proposed review will comprehensively assess published randomised controlled trials on the primary research question, focusing on glycaemic control, inflammation and lipid profile in patients with diabetes on either monotherapy or dual treatment of vitamin B12 and alpha-lipoic acid.
A comprehensive search for literature will be conducted on the database to source out and retrieve studies relevant to our research question.
This will be the primary systematic review and meta-analysis conducted to evaluate the single or dual supplementation of these treatments in diabetes mellitus.
The anticipated limitation includes heterogeneity that may arise due to different dosages, forms of diabetes, dual or monotherapy and also the duration of intervention.
However, subgroup and sensitivity analysis will be performed to source the exact cause of heterogeneity.
The studies that use human subjects with diabetes/DN.
The studies published in English.
Exclusion
Animal studies and studies that are non-English will be excluded from this review. This is partially because translating studies from other languages end up losing the exact results obtained from such studies. Reviews will not be considered. Cohorts, case–control, case studies and experimental studies will all be excluded. Those studies that use other drugs will be deemed irrelevant to the current study.
Search strategy and information sources
PubMed, Google Scholar, Scopus, Web of Science and Science direct databases will be searched to identify suitable sources for this review. Two independent investigators (PKL and KM) will conduct the literature search. MesH terms and text words will be used, including ‘vitamin B12’ and synonyms, ‘alpha-lipoic acid’, ‘diabetes mellitus’, and ‘diabetic neuropathy’. The search will be divided into two to source out studies on vitamin B12 and ALA in diabetes. The search will seek studies published in English from inception until 30 June 2022 (online supplemental file 2). Furthermore, studies that meet the inclusion criteria will be screened, and data will be extracted and presented in a tabular format.
Supplemental material
Study selection
The screening of studies will be conducted by two independent investigators (PKL and KM) to avoid inconsistency in terms of eligibility of studies. First, studies will be screened by the titles, abstracts, keywords and synonyms, followed by identifying the full-text articles, if available. In case of discrepancies between two investigators (PKL and KM), the resolution will be reached through discussion and reviewing the study in question. Mendeley desktop reference manager (V.1.19.4) will be used to save extracted data, saving relevant and excluded studies. Furthermore, reference lists of included studies will be screened to identify other relevant studies. Studies meeting the inclusion criteria will then be subjected to data collection, critical appraisal, risk, and quality evaluation.
Data extraction and management
Reference manager (Mendeley desktop V.1.19.4) will be used to store retrieved studies from databases. Review Manager software V.5.4 will be sued to analyse all data and creation of forest and funnel plots. Based on the characteristics of the study, we will prepare an excel form for data collection before data extraction. Outcomes and effect measures for eligible studies will be extracted and filled in the data extraction form by two independent investigators (PKL and KM). Any disagreement can be resolved by discussing it between the two investigators (PKL and KM) or seeking a third investigators opinion. The primary data to be extracted are as follows: the first authors and year of publication of the study, the country where the study was carried out, source of funding, interventions in the experimental group (monotherapy or dual therapy), interventions in the control group, time of treatment, number of participants in each group, age and sex of participants, outcomes and effect measures. To seek clarity about the study, corresponding authors will be contacted.
Risk of bias assessment
All relevant studies will be evaluated following the Cochrane guidelines.14 15 Two investigators (PLK and KM) will independently evaluate the methodological design by assessing these seven bias items, random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective reporting. Individual items will be categorised as ‘Low risk,’ ‘High risk’ or ‘Unclear risk’. The disagreement between the two investigators (PLK and KM) in terms of bias risk will be resolved through further discussion and re-evaluation of such an item and the study in question.
Sensitivity analysis
To assess the stability of the results, we will conduct a sensitivity analysis for the outcomes16 with the use of RevMan V.5.4. We will exclude one study included in the analysis, then re-analyse the pooled estimates and compare effect size with the size of the initial effect.
Publication bias
Suppose studies greater than 10 are included in the meta-analysis. In that case, the symmetry of the funnel plot will be evaluated to examine publication bias,17 and the results will be interpreted with care.
Strength of the quality of evidence
In this planned, systematic review and meta-analysis, the study’s evidence quality will be investigated following the Grading of Recommendations Assessment, Development and Evaluation (GRADE).18 19 This is classified into four levels: high, medium, low and very low. We will use the GRADE profiler 3.2 for analysis.20
Subgroup analysis
If the obtained results are heterogeneous, we will perform a subgroup analysis to find the source of heterogeneity,21 22 which can arise from study design, race, age, sex, different intervention forms, drug dosage, forms of diabetes, monotherapy or dual therapy and duration of treatment.
Statistical analysis
We will use the Review Manager software V.5.4 (The Nordic Cochrane Center, The Cochrane Collaboration, 2014, Copenhagen, Denmark) to analyse all data. The mean difference (MD) or standardised MD (SMD) and 95% CI will be estimated for continuous data. If the same scale is used to measure an outcome in different studies, MD will be used. Similarly, we will use SMD if different scales are used to measure the same outcome. If an outcome measure contains less than two trials, we will summarise the results descriptively. Meta-analysis will be carried out if at least two or more studies report the same outcome. However, in case of an insufficient number of studies to perform a meta-analysis, a qualitative synthesis will be performed.23 The statistical level of heterogeneity among included studies will be assessed using the Cochran Q test (x2) and the I 2 statistical tests. We will classify the heterogeneity using the predefined rules.22 An I 2 of 0%–25% will be classified as low heterogeneity, I 2 of 25%–50% represents moderate heterogeneity24 and an I 2 of 75%–100% represents high heterogeneity. We will use the fixed-effects model when the p value from an χ2 test is more than 0.10 or I2 ≤50%. A subgroup analysis will be conducted to identify possible sources for statistical heterogeneity, considering prespecified factors. A descriptive summary of individual studies will be made when a meta-analysis is not possible.
Discussion
DN has no existing medical cure, and prevention will be crucial. With tight glucose control, we can see a decrease in the progression of nerve damage. However, this warrants for effective medical intervention. This systematic review and meta-analysis focus on vitamin B12 and ALA as monotherapy or dual treatments in DM/DN. These components have shown properties that decrease oxidative stress and increase nerve myelination. A previous meta-analysis assessing the effect of ALA on lipid profiles revealed a significant decrease in lipid profiles; however, this was conducted in patients with various conditions, including diabetes, schizophrenia, obesity, renal disease and hyperthyroidism.12 So, there is a need for evaluation of the effects of both ALA and vitamin B12 on lipid profile, glycaemia and inflammation in DM.
Ethics statements
Patient consent for publication
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Collaborators Not applicable.
Contributors KM and PKL conceptualised, designed and initiated the protocol. PLK and KM drafted the original manuscript. KM revised and edited the final version of the protocol. All authors approved the final version of the manuscript submitted for publication. Authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.