Adverse Events Induced by Metformin Treatment in Patients with Type 2 Diabetes Mellitus: Metaanalysis

Metformin is used as a first-line treatment in patients with type 2 diabetes mellitus and have a significant...


Introduction
Type 2 diabetes mellitus [T2DM] is a metabolic condition characterised by hyperglycaemia resultingfrom insulin resistant or impaired insulin function [1]. T2DM have a high risk of developingcardiovascular disease [CVD] compared to individuals without diabetes [2,3]. The pharmacological therapies currently used in the prevention of secondary complications associatedwith T2DM include metformin; this class of drugs improve insulin sensitivity and reduce body weight [4]. Although this drug provides therapeutic benefits in T2DM patients and associated CVD, there areother concerns it poses to individuals using it, including decreasing serum vitamin B12 levels [5]. In aclinical setting, when it is not detected early or if there is an incorrect diagnosis, this deficiency remainsuntreated, resulting in severe deficiency.
Thus, peripheral neuropathy as a result of vitamin B12 deficiency may contribute to theaggravation of diabetic peripheral neuropathy [6,7]. The progression of neurologic damage due tovitamin B12 deficiency can be treated if diagnosed early with the administration of vitamin B12 [9]. However, if there is misdiagnosis, permanent neurological damage may not be reversed [7]. Additionally, these patients present with gastric abnormalities, including diarrhoea, nausea, and loss ofappetite, others may present with a sore and reddened tongue. These abnormalities may result in anunexpected reduction in body weight. Similarly, hepatomegaly and jaundice around the eyes and skinmay also be observed [10]. Although previous studies have reported vitamin B12 deficiency associated with metformin, there iscontradicting outcomes presented. Moreover, some studies show no association [11]; others areshowing positive association. Therefore, we aimed to conduct a first meta-analysis on the effect ofmetformin treatment on vitamin B12 level and associated events in patients living with type 2 diabetesmellitus. Furthermore, to assess the efficacy of this drug in ameliorating cardiovascular diseaseassociated with type 2 diabetes mellitus.

Material and Methods
Preferred Reporting Item for Systematic Reviews and Meta-Analysis [PRISMA] Guidelines [12] was used when preparing this meta-analysis [Appendix file 1].
The ethics approval was not needed as this study only assess data extracted from already published studies.

Research question
Does metformin treatment alleviate type 2 diabetes mellitus related adverse events?

Search Strategy and Information Source
PubMed-Medline electronic database was used to search for published literature using the MedicalSubject Headings [MeSH] terms ''metformin'', "vitamin B12 deficiency" and ''diabetes mellitus''without language restriction. The studies meeting eligibility criteria were subjected to critical evaluationand included in the final synthesis. The search was for studies published since inception until 07 March2020. The exact search strategy is attached in appendix 1.

Study Selection
The selection procedure was conducted by two authors

Assessment of Risk and Quality
The assessment of the quality of each included study was evaluated using a standard score by independent authors investigators. Cochrane tool was used to assess the risk of bias and quality of the studies. The disagreement between the two independent authors was resolved through discussion and reevaluation of study in question. subgroup analysis and sensitivity tests. The I2 = 0%, I2 = 50%, were no and substantial level of heterogeneity respectively. Considering high clinical heterogeneity, a random effects model was used for meta-analyses in case of substantial heterogeneity while the fixedeffect model was used for studies which showed no presence of heterogeneity. Subgroup analyses were performed according to different events, including CVD, anaemia, neuropathy, retinopathy, nephropathy, stroke, hypertension and vitamin B12 deficiency.

Data Synthesis and Analysis
Publication bias was visually assessed using the funnel plots [symmetrical shape demonstrating an absence of publication bias].
A probability values of less than 0.05 were considered significant statistically.

Overview of the Included Studies
All included studies were published in peer-review journals from 2003 to 2018, and their characteristicsare shown in Table   1. The included studies comprised of 25936 participants, 14720   Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

5-Apr
Information Sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

4
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. 4 Study Selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). 4

Data Collection process 10
Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

Data Items 11
List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 5

Risk of bias in individual studies 12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Summary Measures 13
State the principal summary measures (e.g., risk ratio, difference in means). 5

Synthesis of Results 14
Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. 5

Table 3S
Section/topic # Checklist item Reported on page #

Risk of bias across studies 15
Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). 5

Additional analyses 16
Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. 5

Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. 6 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. 6 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 9

Results of individual studies 20
For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

8-Jul
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

8-Jul
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 9 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).

Summary of evidence 24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

Limitations 25
Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). 11

Conclusions 26
Provide a general interpretation of the results in the context of other evidence, and implications for future research. 11

Funding 27
Describe sources of funding for the systematic review and other support (e.g., supply of data), role of funders for the systematic review.  (Figure 3).   (Figure 4).   Table 1).

Publication Bias
The risk of publication bias was assessed graphically by use of funnel plots, and amongst all adverseevents in the included studies, there was no evidence of publication bias trough graphical presentationsof funnel plots as indicated in (Figures 1S-3S).  [5,16,17]. Diabetic neuropathycan also manifest other symptoms, including impaired vibration and muscle sensation [8]. Thus,peripheral neuropathy induced by vitamin B12 deficiency due to metformin treatment may contribute tothe severe diabetic peripheral neuropathy [6,7]. The progression of neurological trauma associated withvitamin B12 deficiency is treatable if diagnosed early with the administration of vitamin B12 [9].However, if there is misdiagnosis, neurological damage may not be reversed [7].

Discussion
Diabetic patients frequently present with anaemia which is common blood disorders resulting intodevelopment and exacerbation into micro and macrovascular complications [26].

Conclusion
Based on the finding synthesised in this meta-analysis, we have shown that type 2 diabetes mellituspatients on metformin treatment have a high risk of developing vitamin B12 deficiency which furtherpredisposes them to neuropathy, and other related adverse events including anaemia, retinopathy, nephropathy, stroke and myocardial infarction, of importance, is its beneficial effects in reducingcardiovascular disease including hypertension.

Strength and Limitation
One of the limitations includes different study design amongst the included studies. With that been said,the study has its strength which ranges from good quality of studies been included. The

Ethical Considerations
Not required as this is review and analysis of studies that are already published.

Source of Funding
The study was partially funded by the National Research Foundation of South Africa [NRF, grantno:121496].

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships thatcould have appeared to influence the work reported in this manuscript.

Author Contribution
KM and MSM contributed equally from conceptualisation, screening, analysis, first draft to the finalapproval for publication of this manuscript.