Impact of the MHRA Safety Update on Vitamin B 12 Testing and Coding in Metformin Users: A Retrospective Primary Care Analysis

Impact of the MHRA Safety Update on Vitamin B 12 Testing and Coding in Metformin Users: A Retrospective Primary Care Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of the MHRA Safety Update on Vitamin B 12 Testing and Coding in Metformin Users: A Retrospective Primary Care Analysis Ian Parsonage, David Wainwright, Julian Barratt This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7306714/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Dec, 2025 Read the published version in BMC Primary Care → Version 1 posted 14 You are reading this latest preprint version Abstract Background: Metformin is the most commonly prescribed first-line oral treatment for type 2 diabetes mellitus (T2DM) in the UK. Long-term therapy has been linked to vitamin B 12 deficiency, a concern recognised for decades but not consistently addressed. In June 2022, the UK Medicines and Healthcare products Regulatory Agency (MHRA) classified low vitamin B 12 levels as a common adverse effect of metformin and advised clinicians to consider periodic testing in at-risk patients. Translating such regulatory advice into routine practice can be challenging, and the extent to which the MHRA guidance has influenced testing and diagnostic coding for vitamin B 12 deficiency in primary care remains unclear. This study evaluated trends in vitamin B 12 testing and deficiency coding in metformin-treated patients compared with the general population before and after the 2022 MHRA Drug Safety Update. Methods: A retrospective quantitative analysis was conducted using Read code data from 148,000 electronic medical records across three Primary Care Networks (PCNs) in the Southwest of England. Vitamin B 12 testing and deficiency coding rates were compared in patients prescribed metformin and the general population across two periods: pre-guidance (2017–2021) and post-guidance (2022–2024). Welch’s t-tests were used to determine statistical significance, with p < 0.05 considered significant. Results: Among patients prescribed metformin, vitamin B 12 testing rates rose from 34.5% (SD = 1.8) pre-guidance to 38.2% (SD = 0.4) post-guidance (p = 0.008). In the general population, testing rates also increased from 12.2–14.7% (p = 0.009). However, coding for vitamin B 12 deficiency remained unchanged at 0.25% in the metformin group and decreased slightly from 0.072–0.060% in the general population, with no statistically significant difference (p = 0.997 and p = 0.348 respectively). Conclusions: This study demonstrated that the release of the MHRA Drug Safety Update was associated with a modest (4% increase overall) but statistically significant increase in vitamin B 12 testing in patients prescribed metformin. However, diagnostic coding practices did not change, suggesting limited translation of safety alerts into structured documentation. Further research is warranted to explore barriers to implementation and evaluate interventions aimed at improving monitoring and coding compliance in primary care. Vitamin B12 Metformin Deficiency Knowledge Screening Healthcare professional Clinician Awareness Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Background Global prevalence of type 2 diabetes mellitus (T2DM) is projected to increase to 7079 individuals per 100,000 by 2030, reflecting a continued rise across all regions of the world 1 . There are concerning trends of rising prevalence in lower-income countries 1 . According to the position statement from both the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA), metformin is the first-choice oral therapy for every patient with T2DM 2 . Even when patients are commenced on insulin, metformin therapy should be continued if tolerated 3 . Metformin belongs to a group of oral hypoglycemic drugs called biguanides 4 . Metformin remains the primary oral therapy recommended in the UK for adults with T2DM who have normal kidney function, with widespread prescribing across the NHS 5 , with approximately 24.1 million items dispensed in the UK 6 . Metformin has been shown to improve macrovascular outcomes and reduce the absolute risk of death and all-cause mortality 7 . An underexposed side effect of metformin is that it increases the risk of a cobalamin (Vitamin B 12 ) deficiency by diminishing the cobalamin uptake in the terminal ileum 8 . The ileal cobalamin absorption is a calcium-dependent process, and a currently postulated hypothesis is that metformin competes with calcium for the mucosal cell membrane in the terminal ileum, causing cobalamin malabsorption 4 , 9 . Vitamin B 12 is a water-soluble vitamin that plays a very fundamental role in DNA synthesis, optimal haemopoiesis and neurological function. The clinical picture of vitamin B 12 deficiency, hence, is predominantly of features of haematological and neurocognitive dysfunction 10 . The prevalence of vitamin B 12 deficiency was 6% in adults younger than 60 years and 20% in adults older than 60 years 11 . The prevalence was higher in those with T2D, up to 30% 12 . Vitamin B 12 deficiency can be especially detrimental in people with T2D as the vitamin B12-related neuropathy can be misinterpreted as diabetic peripheral neuropathy, delaying diagnosis and timely treatment of vitamin B 12 deficiency 13 . A relationship between long-term metformin use and vitamin B 12 deficiency has been long discussed, and many clinicians will have come across this in clinical practice; however, until now, we have been without any official guidance on management 14 . Despite this relationship being known about since 1971, it was only in 2017 that the ADA recommended considering periodic vitamin B 12 testing in metformin-treated patients 15 . No clear guidelines have been published regarding screening, diagnosing, and managing these deficiencies 16 . In June 2022, following a European review, the MHRA issued updated advice indicating that this adverse effect is more common than earlier estimates had suggested 17 . Consequently, the prescribing information for all medicines containing metformin was revised to reflect this risk. The MHRA now classifies vitamin B 12 deficiency as a common adverse effect of high-dose or long-term metformin, with prevalence estimates of up to 10% 17 . The updated product information includes new published advice to healthcare professionals to test vitamin B 12 levels in those presenting with anaemia or neuropathy and that periodic vitamin B 12 monitoring should be considered in patients with risk factors (see Fig. 1 ) for vitamin B 12 deficiency 17 . Awareness of monitoring for adverse effects from medication has been shown to be poor. An example of this is a study 18 exploring the monitoring of long-term adverse side effects for nitrofurantoin (e.g. pulmonary toxicity such as Interstitial Lung Disease, hepatotoxicity such as Chronic Hepatitis and peripheral neuropathy). That study concluded that many clinicians were unaware of the potential for significant complications from long term nitrofurantoin use 18 . Indeed, an Oxford survey of 443 GPs found most GPs had poor understanding of the absolute benefits and harms of common treatments, only about 10.9% of answers were correct within a narrow margin, and nearly 65% of GPs admitted low confidence in their knowledge 19 . In addition, currently, there are no current studies based on clinicians in the UK exploring the awareness of side effects of Metformin. Furthermore, in the UK it’s estimated that adverse drug events are one of the most common sources of avoidable harm in primary care. A study commissioned in England calculated that about 237 million medication errors occur annually, with nearly 38% of these originating in primary care settings 20 . While not all errors cause harm, a significant number do, a UK based research study found around 6.5% of unplanned hospital admissions are attributable to adverse drug reactions 21 , many of which could be preventable with better prescribing knowledge and monitoring. There continues to be a recognised gap between research evidence and the incorporation of such findings into routine clinical practice and policy-making 22 . The National Institute for Health and Care research (NIHR) argues, the process is often challenging, variable and slow when implementing new research into practice 23 . Evidence linking metformin to vitamin B 12 deficiency has long been circulated in specialist diabetes and academic literature. An MHRA safety communication was issued to raise clinician awareness of this adverse effect. Therefore, the aim of this study is to explore the overall incidence of coding vitamin B 12 deficiency in primary care settings and if there was any impact on vitamin B 12 monitoring in metformin-treated patients in a primary care setting, following the change in MHRA guidance 17 . Method Study design In this quantitative study design, Read code data of vitamin B 12 blood tests and the Read code of vitamin B 12 deficiency/ low serum vitamin B 12 will be retrospective analysed, utilising the GPs electronic medical notes. The authors local geographical PCNs were chosen. As all of the data required via the inclusion criteria are aggregated from the medical register no sampling technique is required. Study setting The study will utilise a geographical area containing 3 Primary Care Networks (PCNs). It was chosen as it provided a sample size that was realistic for the resources for the study and utilised the same computer system for the electronic notes meaning only one audit algorithm needed to be designed (helping with the reliability of the data). Study participants and sampling The study participants included all the GP surgeries that were part of the 3 PCNs. The 3 PCNs represented a patient population size of approx.148,000 which included a mixture of different socio-economic backgrounds and both a rural and urban population. As all data required via the inclusion criteria (Fig. 2) will be aggregated from the medical register no sampling technique will be required. Participants’ recruitment There was no transfer of any personal information, which means patient’s notes were not accessed individually, the aggregated data was extracted anonymously from medical records using Read code data. Informed consent to collect the data was gained from the Clinical Director (CD) of each participating organisation. As no personal identifiable information was collected and no electronic medical notes were individually accessed, individual consent of patients was not deemed necessary. This was agreed both by the University of Bath Ethics board and the Health Regulatory Authority. Once agreed the PCN CD discussed it with each surgery individually and written consent was gained from each surgery as they are legally the data controller for their medical records. Data collection The study analysed Read code data from the medical register and specifically looked at vitamin B 12 level testing in adult patients who had more than 1 year of metformin use, 5 years prior to the guidance publication (June 2022) and who filled at least two consecutive prescriptions of metformin to establish compliance. The same data was collected for the general population (excluding the patients on metformin) to act as a comparison group. The same data was collected, but for the time period after June 2022 (when the MHRA alert was released) with again data being collected for patients on metformin and the general population. The data collection tool was also run for the Read codes related to low vitamin B 12 serum levels and vitamin B 12 deficiency for patients on metformin and the general population across both time periods, to explore if this is coded in the medical notes (as this puts the patients in the high-risk category as per the MHRA guidelines). The primary outcome was to explore if the incidence of vitamin B 12 testing increased in the patient population on metformin before and after the guidance was issued. The secondary outcome was to explore if the incidence of vitamin B 12 deficiency diagnosed in patients on metformin changed after the MHRA guidance was released Data analysis Summary statistics were initially used to describe the data collected. To explore the differences in the percentage of patients coded for vitamin B 12 deficiency and the percentage of patients who had received a blood test for vitamin B 12 before and after 2022, an independent samples Welch’s t-tests was performed for each group. Welch’s t-test was chosen due to the small sample sizes and potential violation of equal variance assumptions between the time periods. A two-tailed significance level of p < 0.05 was considered indicative of statistical significance. Formal testing for skewness was not undertaken due to the small number of annual data points available, particularly in the post-guidance period (n = 2), which limits meaningful interpretation of distribution shape. Given the nature of the aggregated percentage data and the use of Welch’s t-test, a method robust to non-normality and unequal variances, this was considered acceptable within the context of the analysis Results Blood tests Analysis of Read code data across three PCNs revealed an increase in vitamin B 12 testing among patients prescribed metformin following the publication of the MHRA Drug Safety Update 17 . During the 2017–2021 period, an average of 4,229 patients on metformin were recorded annually, with approximately 1,453 individuals (34.5%) receiving a vitamin B12 blood test each year. In the period 2022–2024, although the average number of metformin users remained similar at 4,188 per year, the number of patients undergoing vitamin B12 testing increased to around 1,599 annually (38.2%). A similar trend was observed in the general population not taking metformin, where the average number of individuals tested each year rose from 4,733 (12.2% of the eligible population) before the MHRA Drug Safety Update 17 to 5,326 (14.7%) after its release. This is highlighted in Fig. 3 , which shows a Box plot graph demonstrating the annual proportion of metformin-prescribed patients receiving vitamin B 12 testing as a percentage. In the period 2017–2021, the mean testing rate was 34.5% and indicating moderate variability and a few low-end outliers. Post-guidance (2022–2024), the mean rose to 38.2%, with a tighter whisker spanning 37.9–42%. The median shifted upward, and consistency improved, with fewer low-end outliers. Nonetheless, there are fewer data points in the second group which may skew the results. These results are further supported in Fig. 4 , which shows an Independent T test comparing the % of vitamin B 12 blood tests undertaken in patients taking metformin pre and post issue of the MHRA guidance. In patients prescribed metformin, the proportion undergoing vitamin B 12 testing showed a statistically significant increase following the MHRA Drug Safety Update 17 . Between 2017 and 2021, an average of 34.5% (SD = 1.8) of patients on metformin received a vitamin B 12 test, compared to 38.2% (SD = 0.4) between 2022 and 2024. Welch’s t-test indicated this increase was statistically significant ( t (4.66) = -4.38, p = 0.008), with a large effect size (Cohen’s d = -2.47, 95% CI: -4.40 to -0.44), suggesting a meaningful change in clinical testing behaviour over time. Whilst Fig. 5 , illustrates a boxplot graph comparing the periods of testing for the percentage of patients receiving vitamin B 12 blood tests for patients in the general population (excluding patients on metformin). The pre-guidance mean was 12.8%, which rose to 14.6%. The box plots reveal a modest upward shift and consistent spread with some overlapping distribution compared to the metformin group. Figure 6 further showed that a similar pattern was observed in the general population (excluding metformin users), where the percentage of individuals tested increased from 12.2% (SD = 1.3) in 2017–2021 to 14.7% (SD = 0.4) in 2022–2024. This difference was also statistically significant ( t (5.05) = -4.10, p = 0.009), with a large effect size (Cohen’s d = -2.35, 95% CI: -4.24 to -0.37). The significant increase suggests a broader trend in testing practices following the regulatory alert. Coding The Read code entries revealed that the rate of coding for vitamin B 12 deficiency among patients prescribed metformin remained low and unchanged following the MHRA Drug Safety Update 17 . In the years 2017–2021, an average of 4,229 patients were prescribed metformin annually, with approximately 11 patients per year (0.250%) receiving a formal Read code indicating vitamin B 12 deficiency. This figure remained consistent in the 2022–2024 period, with a comparable average of 4,188 patients on metformin and again just 11 patients annually (0.250%) being coded for deficiency. In the general population (excluding metformin users), coding rates were even lower: on average, 28 patients per year (0.072%) were coded for deficiency before the MHRA guidance 17 , compared with 26 patients annually (0.060%) after the update. This further illustrated in the box plot graph in Fig. 7 display coding rates for B 12 deficiency in patients taking metformin. Pre-guidance, the mean coding incidence was 0.25%, reflecting sparse detection. Post-guidance, the mean doubled to 0.21%, with whiskers reaching up to 0.34%, and a few high-end outliers. Figure 8 demonstrates an independent T test result comparing the % of patients with a new read code for vitamin B 12 deficiency across two periods: 2017–2021 and 2022–2024 (post MHRA alert 17 ). Amongst the patients prescribed metformin, the mean percentage of patients with a Read code indicating B 12 deficiency remained relatively unchanged (0.250%, SD = 0.047 in 2017–2021 vs. 0.250%, SD = 0.084 in 2022–2024). This difference was not statistically significant (Welch’s t (2.75) = -0.004, p = 0.997), and the effect size was negligible (Cohen’s d = -0.004, 95% CI: -1.44 to 1.43), indicating no meaningful change in coding rates following the 2022 MHRA Drug Safety Update 17 . As shown in Fig. 9 , illustrates the coding rates among the general population patients (excluding patients taking metformin), which remained low and stable, with means of 0.6% pre- versus 0.58% post-guidance. The whiskers and outliers were minimal. As shown in Fig. 10 , the general population (excluding metformin users), the percentage of patients coded as B 12 deficient decreased slightly from 0.072% (SD = 0.024) in 2017–2021 to 0.060% (SD = 0.005) in 2022–2024. This change was also not statistically significant (Welch’s t (4.56) = 1.05, p = 0.348), and the effect size was small to moderate (Cohen’s d = 0.59, 95% CI: -0.90 to 2.03), suggesting only minimal variation in coding practices over time. Discussion The results of this study demonstrated above suggest a statistically significant increase in vitamin B 12 blood testing in patients on metformin following the MHRA safety alert in 2022 17 in the geographical area involved in this study. Whilst the proportion of tested patients rose from 34.5–38.2%, this improvement, though statistically valid (p = 0.008), represents only a modest shift in clinical behaviour. Despite the observed improvement in testing rates, the overall proportion of metformin users tested remains below 40%, indicating that routine B 12 monitoring is not yet embedded in standard clinical practice. This is consistent with findings from other similar studies 24 which found that only 31% of patients on metformin, over four years had ever received a vitamin B 12 blood test. Additionally, the concurrent increase in testing within the general population (from 12.2–14.7%, p = 0.009) suggests that the rise may reflect a broader trend towards more routine blood test ordering in primary care, rather than a targeted response to the MHRA Drug Safety Update 17 . This is consistent with UK-wide data showing rising diagnostic testing volumes across all major analytes over the last decade, with what appears to be vitamin B 12 as being no exception 25 , 26 . Nonetheless, this study has only found a modest statistically significant increase in B 12 testing after the MHRA Drug Safety Update 17 , which supports the impression that regulatory safety updates can exert some influence on practice, albeit modest. This is further supported in literature in which prior studies have reported similar effects following national guidance changes 27 , 28 . Though, research has shown that successful translation of guidance into routine practice is often dependent on accompanying education, audit, or system-level prompts 29 . In this study, there is no indication that practices had access to clinical decision support or embedded alerts encouraging B 12 testing in high-risk patients. Interestingly, the increase in testing was not mirrored by a corresponding rise in diagnosis of vitamin B 12 deficiency. The findings suggest that either vitamin B 12 deficiency remains under-identified in this group, or that testing is being undertaken without clear action on the results. This is not unique to B 12 deficiency. Other studies have shown similar under-coding in primary care, often linked to lack of time, diagnostic uncertainty, or reliance on free-text entries rather than structured Read codes 30 . The findings of this study are consistent with other respective studies. Other authors 24 , 31 noted a low coding rate, though this study reports a considerably lower rate than the other studies. The coding rates reported in the other studies were between 0.5%-2.6%. Additionally, one of these studies reported a coding rate of 2.6% whilst the actual number of patients with vitamin B 12 deficiency found in the study was 8.4% 24 . Based on the data above, there is a risk that subtle, or early-stage deficiency is not being recognised at all. The low rate of vitamin B 12 deficiency coding raises concerns about missed or subclinical cases. Comparable studies suggest that early B 12 deficiency, particularly in patients with borderline results, is frequently overlooked unless symptoms are overt 31 . This is especially problematic in patients with T2DM, where B 12 related neuropathy may be mistakenly attributed to diabetic neuropathy, delaying appropriate intervention 13 . The study’s findings reflect known challenges in translating policy into practice. The PARIHS framework (Promoting Action on Research Implementation in Health Services) emphasises the interplay between evidence, context, and facilitation in successful implementation 32 . In this case, the strength of the evidence linking metformin with B 12 deficiency is well established, but its implementation appears constrained by potential contextual factors such as competing clinical priorities, lack of system prompts, and possible limited training. It has been argued that research consistently shows that passive dissemination of guidelines, such as publication of alerts, has minimal effect unless accompanied by active implementation strategies 29 , 33 . Nonetheless, the findings should be interpreted considering several limitations. The post MHRA guidance 17 time frame includes only two full years (2022–2024), limiting the power to detect longer-term behavioural trends or seasonal variations. Additionally, there is not enough data points post guidance to accurately analyse if the joint upward trend in blood tests undertaken, was statistically significant between the metformin and general population group. Furthermore, while the inclusion of a comparison group (the general population) strengthens the internal validity, the study cannot definitively attribute causality to the MHRA alert 17 without accounting for other contemporaneous factors, such as changes in local policies. Conclusion This study demonstrates a modest but statistically significant increase in vitamin B 12 testing among patients prescribed metformin following the MHRA Drug Safety Update 17 . However, the majority of patients remained untested, and no corresponding improvement in Read coding was observed. These findings suggest that while safety alerts may influence testing behaviours to some extent, but it remains limited. The lack of change in coding practices highlights an important gap in clinical that may affect patient safety, data quality, and care continuity. Exploring the reasons for this gap and tools to aid clinicians to improve on coding is essential for good patient care. Potential future research should explore the mechanisms underlying low uptake of vitamin B 12 monitoring, possibly through surveys about clinicians’ awareness or qualitative interviews with clinicians exploring facilitators and barriers in implementing this guidance. This could inform future intervention studies examining whether audit-feedback cycles, embedded Clinical system alerts, or template modifications in GP software could improve testing and coding compliance. Declarations Ethics approval and consent to participate This project is part of a wider thesis as part of a Post Doctoral award. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki (2013). Ethical approval was granted by the University of Bath Research Ethics Committee (reference 1759-7102) and the Health Research Authority (IRAS ID 336490), with the University of Bath acting as study sponsor. All methods were performed in accordance with relevant institutional and national research guidelines and regulations. The study utilised anonymised, aggregated data extracted from electronic medical records; no identifiable personal data were collected, and individual patient consent was therefore not required. Informed consent to collect the data was gained from the Clinical Director of each participating organisation. As no personal identifiable information was collected and no electronic medical notes were individually accessed, individual consent was not necessary. This was agreed both by the University of Bath Ethics board and the Health Regulatory Authority. Consent for publication Not applicable Availability of data and materials Data is provided within the manuscript or supplementary information files. Competing interests There are no conflicts of interest to declare. All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. Funding This is being undertaken as part of a self-funded Post Doctoral course and is subject to any external funding. Authors' contributions IP developed the original idea for the research question as part of a wider research project. The lead author performed the literature search and initial manuscript drafting. IP led the design of the study/ methodology and collected the data. IP wrote the first draft of the manuscript. DW and JB provided inputs to the methods, study design and critically revised the manuscript. DW and JB provided input on the data analysis. Co-authors contributed to refining the research questions, methodology, and interpretation. The guarantor role includes oversight of all aspects of study conduct. The guarantor accepts responsibility for the integrity of the work and the decision to publish. Authorship criteria were met by all listed contributors, with no omissions. 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Additional Declarations No competing interests reported. Supplementary Files SupplementationData.xlsx Cite Share Download PDF Status: Published Journal Publication published 05 Dec, 2025 Read the published version in BMC Primary Care → Version 1 posted Editorial decision: Revision requested 09 Oct, 2025 Reviews received at journal 05 Oct, 2025 Reviews received at journal 03 Oct, 2025 Reviews received at journal 26 Sep, 2025 Reviewers agreed at journal 24 Sep, 2025 Reviews received at journal 24 Sep, 2025 Reviewers agreed at journal 23 Sep, 2025 Reviewers agreed at journal 22 Sep, 2025 Reviewers agreed at journal 21 Sep, 2025 Reviewers invited by journal 12 Sep, 2025 Editor assigned by journal 10 Sep, 2025 Editor invited by journal 14 Aug, 2025 Submission checks completed at journal 14 Aug, 2025 First submitted to journal 14 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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2022-2024\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7306714/v1/99e0a2f86d5aa7b23244817a.jpg"},{"id":91937657,"identity":"d06c316d-d3ae-435e-b580-9907f9174e2c","added_by":"auto","created_at":"2025-09-23 03:00:51","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":61276,"visible":true,"origin":"","legend":"\u003cp\u003eBox plot graph of annual vitamin B\u003csub\u003e12\u003c/sub\u003e blood tests undertook as a percentage of the general population excluding patients on metformin.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7306714/v1/c85c6c44299bfe2ae1f99ea5.jpg"},{"id":91932853,"identity":"0848d383-cce7-42fe-9b5b-2f21742cf062","added_by":"auto","created_at":"2025-09-23 02:36:52","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":133004,"visible":true,"origin":"","legend":"\u003cp\u003eWelch’s T test result comparing % of vitamin B\u003csub\u003e12\u003c/sub\u003e blood tests of patients from the general population from 2017-2021 against 2022-2024\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7306714/v1/16466999ae9b3969d7672a18.jpg"},{"id":91936729,"identity":"8df2e8db-6c72-433f-9f97-bc9a27de331f","added_by":"auto","created_at":"2025-09-23 02:52:51","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":50805,"visible":true,"origin":"","legend":"\u003cp\u003eBox plot of annual vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency coding recorded as a percentage of the population of patients taking metformin.\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7306714/v1/73a98079268bd2682781ae7f.jpg"},{"id":91931227,"identity":"d7e08934-8a2b-43c8-8376-43833e7f8c5f","added_by":"auto","created_at":"2025-09-23 02:28:52","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":136092,"visible":true,"origin":"","legend":"\u003cp\u003eWelch’s T test result comparing % of vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency coding of patients on metformin from 2017-2021 against 2022-2024.\u003c/p\u003e","description":"","filename":"8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7306714/v1/85c79fd506493860bb082531.jpg"},{"id":91935377,"identity":"250acbd0-50c8-4756-9ae4-c62b08da9255","added_by":"auto","created_at":"2025-09-23 02:44:51","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":51624,"visible":true,"origin":"","legend":"\u003cp\u003eBox plot of annual vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency coding recorded as a percentage of the general population excluding patients taking metformin.\u003c/p\u003e","description":"","filename":"9.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7306714/v1/83acc2e75ba4bf97e8f28caa.jpg"},{"id":91931221,"identity":"1d0cfb05-1151-433d-b90a-acbc16d75866","added_by":"auto","created_at":"2025-09-23 02:28:52","extension":"jpg","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":119415,"visible":true,"origin":"","legend":"\u003cp\u003eWelch’s T test result comparing % of vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency coding of patients in the general population from 2017-2021 against 2022-2024.\u003c/p\u003e","description":"","filename":"10.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7306714/v1/ea4c2d985ee71538bbd5588f.jpg"},{"id":97724457,"identity":"405fca2a-3ad3-4932-bbac-821e141bd1aa","added_by":"auto","created_at":"2025-12-08 16:12:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1638898,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7306714/v1/b06b738a-de68-4bca-adcf-2a72c106bdc0.pdf"},{"id":91931203,"identity":"2b4e41d2-7a8f-426c-9828-872652d3057d","added_by":"auto","created_at":"2025-09-23 02:28:51","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":13032,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementationData.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7306714/v1/887924174be6b034d9032b75.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of the MHRA Safety Update on Vitamin B 12 Testing and Coding in Metformin Users: A Retrospective Primary Care Analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eGlobal prevalence of type 2 diabetes mellitus (T2DM) is projected to increase to 7079 individuals per 100,000 by 2030, reflecting a continued rise across all regions of the world\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. There are concerning trends of rising prevalence in lower-income countries\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. According to the position statement from both the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA), metformin is the first-choice oral therapy for every patient with T2DM\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Even when patients are commenced on insulin, metformin therapy should be continued if tolerated\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eMetformin belongs to a group of oral hypoglycemic drugs called biguanides\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Metformin remains the primary oral therapy recommended in the UK for adults with T2DM who have normal kidney function, with widespread prescribing across the NHS\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, with approximately 24.1\u0026nbsp;million items dispensed in the UK\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Metformin has been shown to improve macrovascular outcomes and reduce the absolute risk of death and all-cause mortality\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAn underexposed side effect of metformin is that it increases the risk of a cobalamin (Vitamin B\u003csub\u003e12\u003c/sub\u003e) deficiency by diminishing the cobalamin uptake in the terminal ileum\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The ileal cobalamin absorption is a calcium-dependent process, and a currently postulated hypothesis is that metformin competes with calcium for the mucosal cell membrane in the terminal ileum, causing cobalamin malabsorption \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eVitamin B\u003csub\u003e12\u003c/sub\u003e is a water-soluble vitamin that plays a very fundamental role in DNA synthesis, optimal haemopoiesis and neurological function. The clinical picture of vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency, hence, is predominantly of features of haematological and neurocognitive dysfunction\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe prevalence of vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency was 6% in adults younger than 60 years and 20% in adults older than 60 years\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The prevalence was higher in those with T2D, up to 30%\u003csup\u003e12\u003c/sup\u003e. Vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency can be especially detrimental in people with T2D as the vitamin B12-related neuropathy can be misinterpreted as diabetic peripheral neuropathy, delaying diagnosis and timely treatment of vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eA relationship between long-term metformin use and vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency has been long discussed, and many clinicians will have come across this in clinical practice; however, until now, we have been without any official guidance on management\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Despite this relationship being known about since 1971, it was only in 2017 that the ADA recommended considering periodic vitamin B\u003csub\u003e12\u003c/sub\u003e testing in metformin-treated patients\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. No clear guidelines have been published regarding screening, diagnosing, and managing these deficiencies\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn June 2022, following a European review, the MHRA issued updated advice indicating that this adverse effect is more common than earlier estimates had suggested\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Consequently, the prescribing information for all medicines containing metformin was revised to reflect this risk. The MHRA now classifies vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency as a common adverse effect of high-dose or long-term metformin, with prevalence estimates of up to 10%\u003csup\u003e17\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe updated product information includes new published advice to healthcare professionals to test vitamin B\u003csub\u003e12\u003c/sub\u003e levels in those presenting with anaemia or neuropathy and that periodic vitamin B\u003csub\u003e12\u003c/sub\u003e monitoring should be considered in patients with risk factors (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) for vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAwareness of monitoring for adverse effects from medication has been shown to be poor. An example of this is a study\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e exploring the monitoring of long-term adverse side effects for nitrofurantoin (e.g. pulmonary toxicity such as Interstitial Lung Disease, hepatotoxicity such as Chronic Hepatitis and peripheral neuropathy). That study concluded that many clinicians were unaware of the potential for significant complications from long term nitrofurantoin use\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Indeed, an Oxford survey of 443 GPs found most GPs had poor understanding of the absolute benefits and harms of common treatments, only about 10.9% of answers were correct within a narrow margin, and nearly 65% of GPs admitted low confidence in their knowledge\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. In addition, currently, there are no current studies based on clinicians in the UK exploring the awareness of side effects of Metformin.\u003c/p\u003e\u003cp\u003eFurthermore, in the UK it\u0026rsquo;s estimated that adverse drug events are one of the most common sources of avoidable harm in primary care. A study commissioned in England calculated that about 237\u0026nbsp;million medication errors occur annually, with nearly 38% of these originating in primary care settings\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. While not all errors cause harm, a significant number do, a UK based research study found around 6.5% of unplanned hospital admissions are attributable to adverse drug reactions\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, many of which could be preventable with better prescribing knowledge and monitoring.\u003c/p\u003e\u003cp\u003eThere continues to be a recognised gap between research evidence and the incorporation of such findings into routine clinical practice and policy-making\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. The National Institute for Health and Care research (NIHR) argues, the process is often challenging, variable and slow when implementing new research into practice\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eEvidence linking metformin to vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency has long been circulated in specialist diabetes and academic literature. An MHRA safety communication was issued to raise clinician awareness of this adverse effect. Therefore, the aim of this study is to explore the overall incidence of coding vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency in primary care settings and if there was any impact on vitamin B\u003csub\u003e12\u003c/sub\u003e monitoring in metformin-treated patients in a primary care setting, following the change in MHRA guidance\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design\u003c/h2\u003e\u003cp\u003eIn this quantitative study design, Read code data of vitamin B\u003csub\u003e12\u003c/sub\u003e blood tests and the Read code of vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency/ low serum vitamin B\u003csub\u003e12\u003c/sub\u003e will be retrospective analysed, utilising the GPs electronic medical notes. The authors local geographical PCNs were chosen. As all of the data required via the inclusion criteria are aggregated from the medical register no sampling technique is required.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy setting\u003c/h3\u003e\n\u003cp\u003eThe study will utilise a geographical area containing 3 Primary Care Networks (PCNs). It was chosen as it provided a sample size that was realistic for the resources for the study and utilised the same computer system for the electronic notes meaning only one audit algorithm needed to be designed (helping with the reliability of the data).\u003c/p\u003e\n\u003ch3\u003eStudy participants and sampling\u003c/h3\u003e\n\u003cp\u003eThe study participants included all the GP surgeries that were part of the 3 PCNs. The 3 PCNs represented a patient population size of approx.148,000 which included a mixture of different socio-economic backgrounds and both a rural and urban population. As all data required via the inclusion criteria (Fig.\u0026nbsp;2) will be aggregated from the medical register no sampling technique will be required.\u003c/p\u003e\u003ch2\u003eParticipants\u0026rsquo; recruitment\u003c/h2\u003e\u003ch\u003eThere was no transfer of any personal information, which means patient\u0026rsquo;s notes were not accessed individually, the aggregated data was extracted anonymously from medical records using Read code data.\u003c/p\u003e\u003cp\u003eInformed consent to collect the data was gained from the Clinical Director (CD) of each participating organisation. As no personal identifiable information was collected and no electronic medical notes were individually accessed, individual consent of patients was not deemed necessary. This was agreed both by the University of Bath Ethics board and the Health Regulatory Authority. Once agreed the PCN CD discussed it with each surgery individually and written consent was gained from each surgery as they are legally the data controller for their medical records.\u003c/p\u003e\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eThe study analysed Read code data from the medical register and specifically looked at vitamin B\u003csub\u003e12\u003c/sub\u003e level testing in adult patients who had more than 1 year of metformin use, 5 years prior to the guidance publication (June 2022) and who filled at least two consecutive prescriptions of metformin to establish compliance. The same data was collected for the general population (excluding the patients on metformin) to act as a comparison group. The same data was collected, but for the time period after June 2022 (when the MHRA alert was released) with again data being collected for patients on metformin and the general population.\u003c/p\u003e\u003cp\u003eThe data collection tool was also run for the Read codes related to low vitamin B\u003csub\u003e12\u003c/sub\u003e serum levels and vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency for patients on metformin and the general population across both time periods, to explore if this is coded in the medical notes (as this puts the patients in the high-risk category as per the MHRA guidelines).\u003c/p\u003e\u003cp\u003eThe primary outcome was to explore if the incidence of vitamin B\u003csub\u003e12\u003c/sub\u003e testing increased in the patient population on metformin before and after the guidance was issued. The secondary outcome was to explore if the incidence of vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency diagnosed in patients on metformin changed after the MHRA guidance was released\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eData analysis\u003c/h2\u003e\u003cp\u003eSummary statistics were initially used to describe the data collected. To explore the differences in the percentage of patients coded for vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency and the percentage of patients who had received a blood test for vitamin B\u003csub\u003e12\u003c/sub\u003e before and after 2022, an independent samples Welch\u0026rsquo;s t-tests was performed for each group. Welch\u0026rsquo;s t-test was chosen due to the small sample sizes and potential violation of equal variance assumptions between the time periods. A two-tailed significance level of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered indicative of statistical significance.\u003c/p\u003e\u003cp\u003eFormal testing for skewness was not undertaken due to the small number of annual data points available, particularly in the post-guidance period (n\u0026thinsp;=\u0026thinsp;2), which limits meaningful interpretation of distribution shape. Given the nature of the aggregated percentage data and the use of Welch\u0026rsquo;s t-test, a method robust to non-normality and unequal variances, this was considered acceptable within the context of the analysis\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eBlood tests\u003c/h2\u003e\u003cp\u003eAnalysis of Read code data across three PCNs revealed an increase in vitamin B\u003csub\u003e12\u003c/sub\u003e testing among patients prescribed metformin following the publication of the MHRA Drug Safety Update\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. During the 2017\u0026ndash;2021 period, an average of 4,229 patients on metformin were recorded annually, with approximately 1,453 individuals (34.5%) receiving a vitamin B12 blood test each year. In the period 2022\u0026ndash;2024, although the average number of metformin users remained similar at 4,188 per year, the number of patients undergoing vitamin B12 testing increased to around 1,599 annually (38.2%). A similar trend was observed in the general population not taking metformin, where the average number of individuals tested each year rose from 4,733 (12.2% of the eligible population) before the MHRA Drug Safety Update\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e to 5,326 (14.7%) after its release.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThis is highlighted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e, which shows a Box plot graph demonstrating the annual proportion of metformin-prescribed patients receiving vitamin B\u003csub\u003e12\u003c/sub\u003e testing as a percentage. In the period 2017\u0026ndash;2021, the mean testing rate was 34.5% and indicating moderate variability and a few low-end outliers. Post-guidance (2022\u0026ndash;2024), the mean rose to 38.2%, with a tighter whisker spanning 37.9\u0026ndash;42%. The median shifted upward, and consistency improved, with fewer low-end outliers. Nonetheless, there are fewer data points in the second group which may skew the results.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThese results are further supported in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e, which shows an Independent T test comparing the % of vitamin B\u003csub\u003e12\u003c/sub\u003e blood tests undertaken in patients taking metformin pre and post issue of the MHRA guidance. In patients prescribed metformin, the proportion undergoing vitamin B\u003csub\u003e12\u003c/sub\u003e testing showed a statistically significant increase following the MHRA Drug Safety Update\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Between 2017 and 2021, an average of 34.5% (SD\u0026thinsp;=\u0026thinsp;1.8) of patients on metformin received a vitamin B\u003csub\u003e12\u003c/sub\u003e test, compared to 38.2% (SD\u0026thinsp;=\u0026thinsp;0.4) between 2022 and 2024. Welch\u0026rsquo;s t-test indicated this increase was statistically significant (\u003cem\u003et\u003c/em\u003e(4.66) = -4.38, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008), with a large effect size (Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e = -2.47, 95% CI: -4.40 to -0.44), suggesting a meaningful change in clinical testing behaviour over time.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWhilst Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e, illustrates a boxplot graph comparing the periods of testing for the percentage of patients receiving vitamin B\u003csub\u003e12\u003c/sub\u003e blood tests for patients in the general population (excluding patients on metformin). The pre-guidance mean was 12.8%, which rose to 14.6%. The box plots reveal a modest upward shift and consistent spread with some overlapping distribution compared to the metformin group.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e further showed that a similar pattern was observed in the general population (excluding metformin users), where the percentage of individuals tested increased from 12.2% (SD\u0026thinsp;=\u0026thinsp;1.3) in 2017\u0026ndash;2021 to 14.7% (SD\u0026thinsp;=\u0026thinsp;0.4) in 2022\u0026ndash;2024. This difference was also statistically significant (\u003cem\u003et\u003c/em\u003e (5.05) = -4.10, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009), with a large effect size (Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e = -2.35, 95% CI: -4.24 to -0.37). The significant increase suggests a broader trend in testing practices following the regulatory alert.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCoding\u003c/h3\u003e\n\u003cp\u003eThe Read code entries revealed that the rate of coding for vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency among patients prescribed metformin remained low and unchanged following the MHRA Drug Safety Update\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In the years 2017\u0026ndash;2021, an average of 4,229 patients were prescribed metformin annually, with approximately 11 patients per year (0.250%) receiving a formal Read code indicating vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency. This figure remained consistent in the 2022\u0026ndash;2024 period, with a comparable average of 4,188 patients on metformin and again just 11 patients annually (0.250%) being coded for deficiency. In the general population (excluding metformin users), coding rates were even lower: on average, 28 patients per year (0.072%) were coded for deficiency before the MHRA guidance\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, compared with 26 patients annually (0.060%) after the update.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThis further illustrated in the box plot graph in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e display coding rates for B\u003csub\u003e12\u003c/sub\u003e deficiency in patients taking metformin. Pre-guidance, the mean coding incidence was 0.25%, reflecting sparse detection. Post-guidance, the mean doubled to 0.21%, with whiskers reaching up to 0.34%, and a few high-end outliers.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e8\u003c/span\u003e demonstrates an independent T test result comparing the % of patients with a new read code for vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency across two periods: 2017\u0026ndash;2021 and 2022\u0026ndash;2024 (post MHRA alert\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e). Amongst the patients prescribed metformin, the mean percentage of patients with a Read code indicating B\u003csub\u003e12\u003c/sub\u003e deficiency remained relatively unchanged (0.250%, SD\u0026thinsp;=\u0026thinsp;0.047 in 2017\u0026ndash;2021 vs. 0.250%, SD\u0026thinsp;=\u0026thinsp;0.084 in 2022\u0026ndash;2024). This difference was not statistically significant (Welch\u0026rsquo;s \u003cem\u003et\u003c/em\u003e (2.75) = -0.004, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.997), and the effect size was negligible (Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e = -0.004, 95% CI: -1.44 to 1.43), indicating no meaningful change in coding rates following the 2022 MHRA Drug Safety Update\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e9\u003c/span\u003e, illustrates the coding rates among the general population patients (excluding patients taking metformin), which remained low and stable, with means of 0.6% pre- versus 0.58% post-guidance. The whiskers and outliers were minimal.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e10\u003c/span\u003e, the general population (excluding metformin users), the percentage of patients coded as B\u003csub\u003e12\u003c/sub\u003e deficient decreased slightly from 0.072% (SD\u0026thinsp;=\u0026thinsp;0.024) in 2017\u0026ndash;2021 to 0.060% (SD\u0026thinsp;=\u0026thinsp;0.005) in 2022\u0026ndash;2024. This change was also not statistically significant (Welch\u0026rsquo;s \u003cem\u003et\u003c/em\u003e (4.56)\u0026thinsp;=\u0026thinsp;1.05, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.348), and the effect size was small to moderate (Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.59, 95% CI: -0.90 to 2.03), suggesting only minimal variation in coding practices over time.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results of this study demonstrated above suggest a statistically significant increase in vitamin B\u003csub\u003e12\u003c/sub\u003e blood testing in patients on metformin following the MHRA safety alert in 2022\u003csup\u003e17\u003c/sup\u003e in the geographical area involved in this study. Whilst the proportion of tested patients rose from 34.5\u0026ndash;38.2%, this improvement, though statistically valid (p\u0026thinsp;=\u0026thinsp;0.008), represents only a modest shift in clinical behaviour. Despite the observed improvement in testing rates, the overall proportion of metformin users tested remains below 40%, indicating that routine B\u003csub\u003e12\u003c/sub\u003e monitoring is not yet embedded in standard clinical practice. This is consistent with findings from other similar studies\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e which found that only 31% of patients on metformin, over four years had ever received a vitamin B\u003csub\u003e12\u003c/sub\u003e blood test.\u003c/p\u003e\u003cp\u003eAdditionally, the concurrent increase in testing within the general population (from 12.2\u0026ndash;14.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009) suggests that the rise may reflect a broader trend towards more routine blood test ordering in primary care, rather than a targeted response to the MHRA Drug Safety Update\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. This is consistent with UK-wide data showing rising diagnostic testing volumes across all major analytes over the last decade, with what appears to be vitamin B\u003csub\u003e12\u003c/sub\u003e as being no exception\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eNonetheless, this study has only found a modest statistically significant increase in B\u003csub\u003e12\u003c/sub\u003e testing after the MHRA Drug Safety Update\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, which supports the impression that regulatory safety updates can exert some influence on practice, albeit modest. This is further supported in literature in which prior studies have reported similar effects following national guidance changes\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Though, research has shown that successful translation of guidance into routine practice is often dependent on accompanying education, audit, or system-level prompts\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. In this study, there is no indication that practices had access to clinical decision support or embedded alerts encouraging B\u003csub\u003e12\u003c/sub\u003e testing in high-risk patients.\u003c/p\u003e\u003cp\u003eInterestingly, the increase in testing was not mirrored by a corresponding rise in diagnosis of vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency. The findings suggest that either vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency remains under-identified in this group, or that testing is being undertaken without clear action on the results. This is not unique to B\u003csub\u003e12\u003c/sub\u003e deficiency. Other studies have shown similar under-coding in primary care, often linked to lack of time, diagnostic uncertainty, or reliance on free-text entries rather than structured Read codes\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe findings of this study are consistent with other respective studies. Other authors\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e noted a low coding rate, though this study reports a considerably lower rate than the other studies. The coding rates reported in the other studies were between 0.5%-2.6%. Additionally, one of these studies reported a coding rate of 2.6% whilst the actual number of patients with vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency found in the study was 8.4%\u003csup\u003e24\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eBased on the data above, there is a risk that subtle, or early-stage deficiency is not being recognised at all. The low rate of vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency coding raises concerns about missed or subclinical cases. Comparable studies suggest that early B\u003csub\u003e12\u003c/sub\u003e deficiency, particularly in patients with borderline results, is frequently overlooked unless symptoms are overt\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. This is especially problematic in patients with T2DM, where B\u003csub\u003e12\u003c/sub\u003e related neuropathy may be mistakenly attributed to diabetic neuropathy, delaying appropriate intervention\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe study\u0026rsquo;s findings reflect known challenges in translating policy into practice. The PARIHS framework (Promoting Action on Research Implementation in Health Services) emphasises the interplay between evidence, context, and facilitation in successful implementation\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. In this case, the strength of the evidence linking metformin with B\u003csub\u003e12\u003c/sub\u003e deficiency is well established, but its implementation appears constrained by potential contextual factors such as competing clinical priorities, lack of system prompts, and possible limited training. It has been argued that research consistently shows that passive dissemination of guidelines, such as publication of alerts, has minimal effect unless accompanied by active implementation strategies\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eNonetheless, the findings should be interpreted considering several limitations. The post MHRA guidance\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e time frame includes only two full years (2022\u0026ndash;2024), limiting the power to detect longer-term behavioural trends or seasonal variations. Additionally, there is not enough data points post guidance to accurately analyse if the joint upward trend in blood tests undertaken, was statistically significant between the metformin and general population group. Furthermore, while the inclusion of a comparison group (the general population) strengthens the internal validity, the study cannot definitively attribute causality to the MHRA alert\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e without accounting for other contemporaneous factors, such as changes in local policies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrates a modest but statistically significant increase in vitamin B\u003csub\u003e12\u003c/sub\u003e testing among patients prescribed metformin following the MHRA Drug Safety Update\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. However, the majority of patients remained untested, and no corresponding improvement in Read coding was observed. These findings suggest that while safety alerts may influence testing behaviours to some extent, but it remains limited.\u003c/p\u003e\u003cp\u003eThe lack of change in coding practices highlights an important gap in clinical that may affect patient safety, data quality, and care continuity. Exploring the reasons for this gap and tools to aid clinicians to improve on coding is essential for good patient care.\u003c/p\u003e\u003cp\u003ePotential future research should explore the mechanisms underlying low uptake of vitamin B\u003csub\u003e12\u003c/sub\u003e monitoring, possibly through surveys about clinicians\u0026rsquo; awareness or qualitative interviews with clinicians exploring facilitators and barriers in implementing this guidance. This could inform future intervention studies examining whether audit-feedback cycles, embedded Clinical system alerts, or template modifications in GP software could improve testing and coding compliance.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project is part of a wider thesis as part of a Post Doctoral award.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the ethical principles of the Declaration of Helsinki (2013). Ethical approval was granted by the University of Bath Research Ethics Committee (reference 1759-7102) and the Health Research Authority (IRAS ID 336490), with the University of Bath acting as study sponsor. All methods were performed in accordance with relevant institutional and national research guidelines and regulations. The study utilised anonymised, aggregated data extracted from electronic medical records; no identifiable personal data were collected, and individual patient consent was therefore not required.\u003c/p\u003e\n\u003cp\u003eInformed consent to collect the data was gained from the Clinical Director of each participating organisation. As no personal identifiable information was collected and no electronic medical notes were individually accessed, individual consent was not necessary. This was agreed both by the University of Bath Ethics board and the Health Regulatory Authority.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no conflicts of interest to declare. All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is being undertaken as part of a self-funded Post Doctoral course and is subject to any external funding.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIP developed the original idea for the research question as part of a wider research project. The lead author performed the literature search and initial manuscript drafting. IP led the design of the study/ methodology and collected the data. IP wrote the first draft of the manuscript. DW and JB provided inputs to the methods, study design and critically revised the manuscript. DW and JB provided input on the data analysis. Co-authors contributed to refining the research questions, methodology, and interpretation. \u0026nbsp;The guarantor role includes oversight of all aspects of study conduct.\u003c/p\u003e\n\u003cp\u003eThe guarantor accepts responsibility for the integrity of the work and the decision to publish. Authorship criteria were met by all listed contributors, with no omissions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKhan, M.A.B., Hashim, M.J., King, J.K., Govender, R.D., Mustafa, H. and Al Kaabi, J., 2019. Epidemiology of Type 2 Diabetes \u0026ndash; Global Burden of Disease and Forecasted Trends. Journal of Epidemiology and Global Health [Online], 10(1), p.107. Available from: https://doi.org/10.2991/jegh.k.191028.001.\u003c/li\u003e\n\u003cli\u003eDavies, M.J., Aroda, V.R., Collins, B.S., Gabbay, R.A., Green, J., Maruthur, N.M., Rosas, S.E., Del Prato, S., Mathieu, C., Mingrone, G., Rossing, P., Tankova, T., Tsapas, A. and Buse, J.B., 2022. Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care [Online], 45(11), pp.2753\u0026ndash;2786. Available from: https://doi.org/10.2337/dci22-0034.\u003c/li\u003e\n\u003cli\u003eInzucchi, S.E., Bergenstal, R.M., Buse, J.B., Diamant, M., Ferrannini, E., Nauck, M., Peters, A.L., Tsapas, A., Wender, R. and Matthews, D.R., 2012. Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach. Diabetes Care [Online], 35(6), pp.1364\u0026ndash;1379. Available from: https://doi.org/10.2337/dc12-0413.\u003c/li\u003e\n\u003cli\u003eAl Zoubi, M.S., Al Kreasha, R., Aqel, S., Saeed, A., Al-Qudimat, A.R. and Al-Zoubi, R.M., 2024. Vitamin B12 deficiency in diabetic patients treated with metformin: A narrative review. Irish Journal of Medical Science (1971 -) [Online], 193(4), pp.1827\u0026ndash;1835. Available from: https://doi.org/10.1007/s11845-024-03634-4.\u003c/li\u003e\n\u003cli\u003eNational Institute for Health and Care Excellence (NICE) (2022) Type 2 diabetes in adults: management (NG28). Available at: https://www.nice.org.uk/guidance/ng28 [Accessed 25 June 2025].\u003c/li\u003e\n\u003cli\u003eStatista (2024) Number of metformin prescriptions in England 2010\u0026ndash;2023. Available at: https://www.statista.com/statistics/number-of-prescriptions-metformin-uk/ [Accessed 25 June 2025].\u003c/li\u003e\n\u003cli\u003eUK Prospective Diabetes Study Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. The Lancet, 352(9131), pp.854\u0026ndash;865.\u003c/li\u003e\n\u003cli\u003eBiemans, E., Hart, H.E., Rutten, G.E.H.M., Cuellar Renteria, V.G., Kooijman-Buiting, A.M.J. and Beulens, J.W.J., 2014. Cobalamin status and its relation with depression, cognition and neuropathy in patients with type 2 diabetes mellitus using metformin. Acta Diabetologica [Online], 52(2), pp.383\u0026ndash;393. Available from: https://doi.org/10.1007/s00592-014-0661-4.\u003c/li\u003e\n\u003cli\u003eBauman, W.A., Shaw, S., Jayatilleke, E., Spungen, A.M. and Herbert, V., 2000. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care [Online], 23(9), pp.1227\u0026ndash;1231. Available from: https://doi.org/10.2337/diacare.23.9.1227.\u003c/li\u003e\n\u003cli\u003eKibirige, D., Mugenyi, L., Kaddu, M., Opio, C., Lalitha, R., Mutebi, E. and Sajatovic, M., 2015. Vitamin B12 deficiency among adult diabetic patients in Uganda: relation to glycaemic control and haemoglobin concentration. Journal of Diabetes \u0026amp;amp; Metabolic Disorders [Online], 15(1). Available from: https://doi.org/10.1186/s40200-016-0250-x.\u003c/li\u003e\n\u003cli\u003eHunt, A., Harrington, D. and Robinson, S., 2014. Vitamin B12 deficiency. BMJ [Online], 349(sep04 1), pp.g5226\u0026ndash;g5226. Available from: https://doi.org/10.1136/bmj.g5226.\u003c/li\u003e\n\u003cli\u003eNervo M, Lubini A, Raimundo FV, Faulhaber GA, Leite C, Fischer LM, Furlanetto TW. Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil. Rev Assoc Med Bras (1992). 2011 Jan-Feb;57(1):46-9.\u003c/li\u003e\n\u003cli\u003eAlvarez, M., Sierra, O.R., Saavedra, G. and Moreno, S., 2019. Vitamin B12 deficiency and diabetic neuropathy in patients taking metformin: a cross-sectional study. Endocrine Connections [Online], 8(10), pp.1324\u0026ndash;1329. Available from: https://doi.org/10.1530/ec-19-0382.\u003c/li\u003e\n\u003cli\u003eDavies, J. (2022) Metformin and vitamin B12: long overdue guidance. Journal of Diabetes Nursing, 26(5), pp.1\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eCarracher, A.M., Marathe, P.H. and Close, K.L., 2018. International Diabetes Federation 2017. Journal of Diabetes [Online], 10(5), pp.353\u0026ndash;356. Available from: https://doi.org/10.1111/1753-0407.12644.\u003c/li\u003e\n\u003cli\u003eInfante, M., Leoni, M., Caprio, M. and Fabbri, A., 2021. Long-term metformin therapy and vitamin B12 deficiency: an association to bear in mind. World Journal of Diabetes [Online], 12(7), pp.916\u0026ndash;931. Available from: https://doi.org/10.4239/wjd.v12.i7.916.\u003c/li\u003e\n\u003cli\u003eMedicines and Healthcare products Regulatory Agency (MHRA) (2022) Metformin and vitamin B12 deficiency: Drug safety update. Available at: https://www.gov.uk/drug-safety-update/metformin-risk-of-vitamin-b12-deficiency [Accessed 25 June 2025].\u003c/li\u003e\n\u003cli\u003eSpeirs, T.P., Tuffin, N., Mundy-Baird, F., Sakota, H., Mulholland, S., Westlake, M., Lyon, M., Medford, A.R., Sharp, C., Darby, M., Albur, M., Keeley, F., Burden, H., Kenward, C., Jonas, E., Barratt, S. and Adamali, H.I., 2021. Long-term nitrofurantoin: an analysis of complication awareness, monitoring, and pulmonary injury cases. BJGP Open [Online], 5(6), p.BJGPO.2021.0083. Available from: https://doi.org/10.3399/bjgpo.2021.0083.\u003c/li\u003e\n\u003cli\u003eTreadwell, J.S., Wong, G., Milburn-Curtis, C., Feakins, B. and Greenhalgh, T., 2020. GPs\u0026rsquo; understanding of the benefits and harms of treatments for long-term conditions: an online survey. BJGP Open [Online], 4(1), p.bjgpopen20X101016. Available from: https://doi.org/10.3399/bjgpopen20x101016.\u003c/li\u003e\n\u003cli\u003eElliott, R.A., Camacho, E., Jankovic, D., Sculpher, M.J. and Faria, R., 2020. Economic analysis of the prevalence and clinical and economic burden of medication error in England. BMJ Quality \u0026amp;amp; Safety [Online], 30(2), pp.96\u0026ndash;105. Available from: https://doi.org/10.1136/bmjqs-2019-010206.\u003c/li\u003e\n\u003cli\u003eOsanlou, R., Walker, L., Hughes, D.A., Burnside, G. and Pirmohamed, M., 2022. Adverse drug reactions, multimorbidity and polypharmacy: a prospective analysis of 1 month of medical admissions. BMJ Open [Online], 12(7), p.e055551. Available from: https://doi.org/10.1136/bmjopen-2021-055551.\u003c/li\u003e\n\u003cli\u003eZullig, Fan, C., Jia, L., Fang, F., Zhang, Y., Faramand, A., Chong, W. and Hai, Y., 2020. Adjunctive Intermittent Pneumatic Compression in Hospitalized Patients Receiving Pharmacologic Prophylaxis for Venous Thromboprophylaxis: A Systematic Review and Meta‐Analysis. Journal of Nursing Scholarship [Online], 52(4), pp.397\u0026ndash;405. Available from: .\u003c/li\u003e\n\u003cli\u003eNational Institute for Health and Care Research (NIHR) (2022) Implementation and impact: translating research into practice. Available at: https://www.nihr.ac.uk/impact [Accessed 25 June 2025].\u003c/li\u003e\n\u003cli\u003eQureshi, S., Ainsworth, A. and Winocour, P., 2011. Metformin therapy and assessment for vitamin B12 deficiency: is it necessary? Practical Diabetes [Online], 28(7), pp.302\u0026ndash;304. Available from: https://doi.org/10.1002/pdi.1619.\u003c/li\u003e\n\u003cli\u003eJones, T., Patel, R., Elwenspoek, M.M.C., Watson, J.C., Mann, E., Alsop, K. and Whiting, P.F., 2022. Variation in laboratory testing for patients with long-term conditions: a longitudinal cohort study in UK primary care. BJGP Open [Online], 7(1), p.BJGPO.2022.0139. Available from: https://doi.org/10.3399/bjgpo.2022.0139.\u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Sullivan, J.W., Stevens, S., Hobbs, F.D.R., Salisbury, C., Little, P., Goldacre, B., Bankhead, C., Aronson, J.K., Perera, R. and Heneghan, C., 2018. Temporal trends in use of tests in UK primary care, 2000-15: retrospective analysis of 250 million tests. BMJ [Online], p.k4666. Available from: https://doi.org/10.1136/bmj.k4666.\u003c/li\u003e\n\u003cli\u003eDusetzina SB, Higashi AS, Dorsey ER, Conti R, Huskamp HA, Zhu S, Garfield CF, Alexander GC. Impact of FDA drug risk communications on health care utilization and health behaviors: a systematic review. Med Care. 2012 Jun;50(6):466-78. doi: 10.1097/MLR.0b013e318245a160.\u003c/li\u003e\n\u003cli\u003eMorrow, R.L., Mintzes, B., Souverein, P.C., De Bruin, M.L., Roughead, E.E., Lexchin, J., Kemp-Casey, A., Puil, L., Sketris, I., Mangin, D., Hallgreen, C.E., Pearson, S.-A., Lopert, R., Bero, L., Ofori-Asenso, R., Gnjidic, D., Sarpatwari, A., Perry, L.T. and Dormuth, C.R., 2022. Influence of drug safety advisories on drug utilisation: an international interrupted time series and meta-analysis. BMJ Quality \u0026amp;amp; Safety [Online], 31(3), pp.179\u0026ndash;190. Available from: https://doi.org/10.1136/bmjqs-2021-013910.\u003c/li\u003e\n\u003cli\u003eGreenhalgh T, Robert G, Macfarlane F, Bate P, Kyriakidou O. Diffusion of innovations in service organizations: systematic review and recommendations. Milbank Q. 2004;82(4):581-629. doi: 10.1111/j.0887-378X.2004.00325.x.\u003c/li\u003e\n\u003cli\u003eTulloch, J.S., Beadsworth, M.B., Vivancos, R., Radford, A.D., Warner, J.C. and Christley, R.M., 2020. GP coding behaviour for non-specific clinical presentations: a pilot study. BJGP Open [Online], 4(3), p.bjgpopen20X101050. Available from: https://doi.org/10.3399/bjgpopen20x101050.\u003c/li\u003e\n\u003cli\u003eAlshammari, A., Iqbal, R. and Baksh, I., 2019. Vitamin B12 deficiency and the knowledge and practice of physicians regarding screening for vitamin B12 deficiency among type 2 diabetic patients on metformin in selected hospitals in Riyadh, Saudi Arabia. Journal of Family Medicine and Primary Care [Online], 8(7), p.2306. Available from: https://doi.org/10.4103/jfmpc.jfmpc_416_19.\u003c/li\u003e\n\u003cli\u003eKitson, A.L., Rycroft-Malone, J., Harvey, G., McCormack, B., Seers, K. and Titchen, A., 2008. Evaluating the successful implementation of evidence into practice using the PARiHS framework: theoretical and practical challenges. Implementation Science [Online], 3(1). Available from: https://doi.org/10.1186/1748-5908-3-1.\u003c/li\u003e\n\u003cli\u003eGrol, R. and Grimshaw, J., 2003. From best evidence to best practice: effective implementation of change in patients\u0026rsquo; care. The Lancet [Online], 362(9391), pp.1225\u0026ndash;1230. Available from: https://doi.org/10.1016/s0140-6736(03)14546-1.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-primary-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"famp","sideBox":"Learn more about [BMC Primary Care](https://bmcprimcare.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12875","title":"BMC Primary Care","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Vitamin B12, Metformin, Deficiency, Knowledge, Screening, Healthcare professional, Clinician, Awareness","lastPublishedDoi":"10.21203/rs.3.rs-7306714/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7306714/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e\u003cp\u003eMetformin is the most commonly prescribed first-line oral treatment for type 2 diabetes mellitus (T2DM) in the UK. Long-term therapy has been linked to vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency, a concern recognised for decades but not consistently addressed. In June 2022, the UK Medicines and Healthcare products Regulatory Agency (MHRA) classified low vitamin B\u003csub\u003e12\u003c/sub\u003e levels as a common adverse effect of metformin and advised clinicians to consider periodic testing in at-risk patients. Translating such regulatory advice into routine practice can be challenging, and the extent to which the MHRA guidance has influenced testing and diagnostic coding for vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency in primary care remains unclear. This study evaluated trends in vitamin B\u003csub\u003e12\u003c/sub\u003e testing and deficiency coding in metformin-treated patients compared with the general population before and after the 2022 MHRA Drug Safety Update.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eA retrospective quantitative analysis was conducted using Read code data from 148,000 electronic medical records across three Primary Care Networks (PCNs) in the Southwest of England. Vitamin B\u003csub\u003e12\u003c/sub\u003e testing and deficiency coding rates were compared in patients prescribed metformin and the general population across two periods: pre-guidance (2017\u0026ndash;2021) and post-guidance (2022\u0026ndash;2024). Welch\u0026rsquo;s t-tests were used to determine statistical significance, with \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered significant.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003eAmong patients prescribed metformin, vitamin B\u003csub\u003e12\u003c/sub\u003e testing rates rose from 34.5% (SD\u0026thinsp;=\u0026thinsp;1.8) pre-guidance to 38.2% (SD\u0026thinsp;=\u0026thinsp;0.4) post-guidance (p\u0026thinsp;=\u0026thinsp;0.008). In the general population, testing rates also increased from 12.2\u0026ndash;14.7% (p\u0026thinsp;=\u0026thinsp;0.009). However, coding for vitamin B\u003csub\u003e12\u003c/sub\u003e deficiency remained unchanged at 0.25% in the metformin group and decreased slightly from 0.072\u0026ndash;0.060% in the general population, with no statistically significant difference (p\u0026thinsp;=\u0026thinsp;0.997 and p\u0026thinsp;=\u0026thinsp;0.348 respectively).\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e\u003cp\u003eThis study demonstrated that the release of the MHRA Drug Safety Update was associated with a modest (4% increase overall) but statistically significant increase in vitamin B\u003csub\u003e12\u003c/sub\u003e testing in patients prescribed metformin. However, diagnostic coding practices did not change, suggesting limited translation of safety alerts into structured documentation. Further research is warranted to explore barriers to implementation and evaluate interventions aimed at improving monitoring and coding compliance in primary care.\u003c/p\u003e","manuscriptTitle":"Impact of the MHRA Safety Update on Vitamin B 12 Testing and Coding in Metformin Users: A Retrospective Primary Care Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 02:28:47","doi":"10.21203/rs.3.rs-7306714/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-09T15:52:05+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-05T06:43:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-03T16:36:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-26T15:11:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"129092375728420155259318124363895274903","date":"2025-09-24T10:51:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-24T07:45:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"276784331490367989005338304249580862869","date":"2025-09-23T15:00:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"239457183712275829301150233473353859183","date":"2025-09-22T12:54:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"274942447091441266107256990077546123669","date":"2025-09-21T14:23:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-12T11:33:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-10T04:19:55+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-14T16:40:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-14T09:23:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Primary Care","date":"2025-08-14T09:19:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-primary-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"famp","sideBox":"Learn more about [BMC Primary Care](https://bmcprimcare.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12875","title":"BMC Primary Care","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9f138bc3-ab49-4e11-a91c-c121dd293589","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T16:08:16+00:00","versionOfRecord":{"articleIdentity":"rs-7306714","link":"https://doi.org/10.1186/s12875-025-03116-1","journal":{"identity":"bmc-primary-care","isVorOnly":false,"title":"BMC Primary Care"},"publishedOn":"2025-12-05 15:58:28","publishedOnDateReadable":"December 5th, 2025"},"versionCreatedAt":"2025-09-23 02:28:47","video":"","vorDoi":"10.1186/s12875-025-03116-1","vorDoiUrl":"https://doi.org/10.1186/s12875-025-03116-1","workflowStages":[]},"version":"v1","identity":"rs-7306714","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7306714","identity":"rs-7306714","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}